Abstract: CONTEXT: Expectations play a central role in the mechanism of the placebo effect. In Parkinson disease (PD), the placebo effect is associated with release of endogenous dopamine in both nigrostriatal and mesoaccumbens projections, yet the factors that control this dopamine release are undetermined. OBJECTIVE: To determine how the strength of expectation of clinical improvement influences the degree of striatal dopamine release in response to placebo in patients with moderate PD. DESIGN: Randomized, repeated-measures study with perceived expectation as the independent between-subjects variable. SETTING: University of British Columbia Hospital, Vancouver, British Columbia, Canada. Patients Thirty-five patients with mild to moderate PD undergoing levodopa treatment. Intervention Verbal manipulation was used to modulate the expectations of patients, who were told that they had a particular probability (25%, 50%, 75%, or 100%) of receiving active medication when they in fact received placebo. MAIN OUTCOME MEASURES: The dopaminergic response to placebo was measured using [11C]raclopride positron emission tomography. The clinical response was also measured (Unified Parkinson Disease Rating Scale) and subjective responses were ascertained using patient self-report. RESULTS: Significant dopamine release occurred when the declared probability of receiving active medication was 75%, but not at other probabilities. Placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication. Whereas response to prior medication was the major determinant of placebo-induced dopamine release in the motor striatum, expectation of clinical improvement was additionally required to drive dopamine release in the ventral striatum. CONCLUSIONS: The strength of belief of improvement can directly modulate dopamine release in patients with PD. Our findings demonstrate the importance of uncertainty and/or salience over and above a patient's prior treatment response in regulating the placebo effect and have important implications for the interpretation and design of clinical trials.
Abstract: OBJECTIVES: To determine the impact of age-related decline in dopamine transporter (DAT) expression on motor function in the elderly. METHODS: About 33 normal individuals of a wide age range were scanned with PET employing d-threo-[(11)C]-methylphenidate (MP, a marker of DAT) and [(11)C]-dihydrotetrabenazine (DTBZ, that binds to the vesicular monoamine transporter Type 2). Motor function was assessed using the Purdue Pegboard Test (PPB). We analyzed the relationship between [(11)C]-MP and motor performance. RESULTS: Age ranged from 27- to 77-year old (mean +/- SD, 54.75 +/- 14.14). There was no age-related decline in binding potentials (BP) for [(11)C]-DTBZ. In contrast, [(11)C]-MP BP was inversely related to age in all striatal regions analyzed (caudate: reduction of 11.2% per decade, P < 0.0001, r = -0.86; putamen: reduction of 10.5% per decade, P < 0.0001, r = -0.80). A differential effect of [(11)C]-MP on PPB could be observed according to age group. There was a positive relation between the PPB and [(11)C]-MP in young individuals (coefficient = 13.56), whereas in individuals greater than 57 years this relationship was negative (coefficient = -19.53, P = 0.031). CONCLUSIONS: Our findings confirm prior observations of age-related DAT decline and suggest that this phenomenon is independent of changes in VMAT2. After the fifth decade of life, this reduction in DAT binding is associated with a motor performance comparable to mid-adult life. These findings imply that biochemical processes associated with healthy aging may offset the naturaldecline in motor function observed in the elderly.
Abstract: BACKGROUND: Brain serotonin(2) (5-hydroxytryptamine(2); 5-HT(2)) receptors were considered potential targets for therapeutic efficacy of electroconvulsive therapy (ECT), but pre-clinical studies showed that electroconvulsive shock up-regulates 5-HT(2) receptors in contrast to antidepressant medications, which down-regulate brain 5-HT(2) receptors. Positron emission tomography (PET) studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT(2) receptors, but the effects of ECT on these receptors in individuals with depression are unknown. AIMS: To determine if a course of ECT alters brain 5-HT(2) receptors in individuals with depression and whether such changes correlate with improvement in symptoms. METHOD: Fifteen people with major depression, refractory to antidepressant therapy and referred for a course of ECT, had an [18F]setoperone scan during baseline drug-free washout period and another after a course of ECT. We assessed changes in brain 5-HT(2) receptors with ECT and their relationship to therapeutic outcome. RESULTS: Widespread reduction in brain 5-HT(2) receptors was observed in all cortical areas with changes slightly more prominent in the right hemisphere. There was a trend for correlation between reduction in brain 5-HT(2) receptors in right parahippocampal gyrus, right lingual gyrus and right medial frontal gyrus, and improvement in depressive symptoms. CONCLUSIONS: Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT(2) receptors in individuals with depression. The ability of ECT to further down-regulate brain 5-HT(2) receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression.
Abstract: BACKGROUND: Pain is a prominent nonmotor symptom in Parkinson's disease (PD) but has not been well studied. OBJECTIVE: The aim of this study is to assess thermal experience and emotional content, as well as side-to-side sensory differences in PD "off" and "on" dopaminergic therapy following thermal cutaneous stimulation. DESIGN: Cross-sectional design. SETTING: University teaching hospital. METHODS: Twelve PD subjects experiencing motor fluctuations but no pain symptoms and 13 healthy controls participated in the study. Heat pain and emotional content were assessed using a thermode and visual analog scales in medication on and off states in PD and without medication in healthy controls. RESULTS: There were no side to side differences in heat pain intensity or between PD medication on state and PD medication off state. Unexpectedly, PD subjects reported a higher degree of unpleasantness in response to heat pain while on medication compared with the off state. CONCLUSIONS: These results suggest that the perception of heat pain is mediated, at least in part, by nondopaminergic systems in PD, while dopamine might modulate the affective component of pain.
Abstract: Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein (SNCA) and tau (MAPT) in 44 patients from 19 affected families. Using this limited number of available LRRK2 mutation carriers, we provide evidence that mutations in the kinase domain of Lrrk2 significantly decrease AAO compared to mutations in the ROC (Ras/GTPase of complex proteins) domain. Furthermore, polymorphic variations in MAPT show a significant association with AAO in individuals with LRRK2 mutations. Our results await replication in future studies with a larger number of LRRK2 mutation carriers, but indicate an association of mutation-affected protein domain and mutation-extrinsic genetic factors with AAO and suggest that these factors could contribute to explain the phenotypic heterogeneity observed in LRRK2-linked PD.
Abstract: OBJECTIVE: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. METHODS: Thirty-six patients with PD with motor fluctuations were assessed with PET using [(11)C]-d-threo-methylphenidate (MP) and [(11)C]-(+/-) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. RESULTS: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 +/- 0.36, dyskinesia 1.39 +/- 0.28; mean +/- SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 +/- 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 +/- 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. CONCLUSIONS: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias.
Abstract: The objective of this study is to assess dyskinesias in 34 Parkinson's disease patients randomized to receive bilateral fetal nigral transplantation with 4 donors per side (12), 1 donor per side (11), or placebo (11). Videotape recordings were performed at the baseline, 3, 6, 12, 18, and 24 month visits during the "practically defined off" (12 hours after last evening dopaminergic therapy) and "best on" (best response following morning dopaminergic therapy) states. Videotapes were analyzed in random order by a blinded investigator. Dyskinesias during "best on" (on-medication dyskinesia) were observed in all, but 1 patient at baseline, and in all patients at each subsequent visit. There were no differences between groups. No patient had dyskinesia at baseline in "practically-defined off" ("off-medication" dyskinesia). Following transplantation, off-medication dyskinesia was observed in 13 of 23 patients, but not in any patient in the placebo group (P = 0.019). There was no difference in dyskinesia score between patients in the 1 and 4 donor groups. On-medication dyskinesias were typically generalized and choreiform, whereas off-medication dyskinesias were usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off-medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias.
Abstract: BACKGROUND: Since the causative gene linked to PARK8 parkinsonism was identified as LRRK2, LRRK2 gene mutations have been found to occur in about 4% of patients with hereditary Parkinson disease (PD); this percentage is even higher in certain populations. Moreover, no clear clinical differences between PARK8-linked parkinsonism and sporadic PD have been identified. Neuropathologic findings have been diverse in PARK8 parkinsonism, but few of the clinicopathologic examinations have been performed in the same family tree. We aimed to describe PET and neuropathologic findings in members of the same family tree with PARK8 parkinsonism. METHODS: We conducted PET of 2 subjects and neuropathologically examined 8 subjects in the same family from the Sagamihara district, the original source of PARK8-linked parkinsonism (I2020T mutation). RESULTS: The results of the PET scans were virtually identical to those seen in sporadic PD. The neuropathologic study results showed pure nigral degeneration with no Lewy bodies in 6 cases. One case, however, showed the presence of Lewy bodies and was similar neuropathologically to conventional PD with Lewy bodies. Another case had multiple system atrophy pathology. CONCLUSIONS: Our study of PARK8-linked parkinsonism affecting several members of the same pedigree shows that the same gene mutation can induce diverse neuropathologies, even if the clinical picture and PET findings are virtually identical.
Abstract: A recent study has concluded that the use of (123)I-2 beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)nortropane single-photon emission computed tomography ((123)I-FP-CIT SPECT) is cost-effective or cost-saving in patients in whom the diagnosis of Parkinson disease versus essential tremor is uncertain. This conclusion is based on numerous assumptions, not all of which are likely to be universally applicable. The economic advantages associated with the use of (123)I-FP-CIT SPECT will vary depending on the prevalence of Parkinson disease in the group of patients with uncertain diagnosis, the cost of usual clinical evaluation including other diagnostic tests, and the consequences of either delaying or inappropriately instituting dopaminergic therapy. The cost-effectiveness of radionuclide scanning is likely to increase in the future if a therapy is developed with a convincing impact on disease progression, the early institution of which confers a better outcome.
Abstract: OBJECTIVE: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome. METHODS: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes. RESULTS: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP. INTERPRETATION: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons.
Abstract: Positron emission tomography has been widely exploited to study the progression of Parkinson's disease (PD) and the associated motor impairment. It is however now increasingly appreciated that much of the disability of PD arises from non-motor complications, including cognitive and behavioural problems, sleep disturbances, pain and autonomic dysfunction. Recent studies in which these problems were investigated are reviewed in this paper. Although interesting findings are emerging, much work remains to be done. This will depend upon the ability to investigate non dopaminergic mechanisms as well as extra-striatal release of dopamine and the capacity to assess the impact of behaviourally relevant stimuli on neurotransmitter release and on networks of brain activation. Functional imaging studies, including PET, SPECT and functional MRI may provide valuable insights into the pathophysiology of disorders such as Parkinson's disease (PD), where structural changes are limited. Until recently, the major focus of such studies has been either on patterns of cerebral blood flow or glucose metabolism at rest or following a variety of activation paradigms, or on studies of the dopamine (DA) system. This article will review non-motor aspects of PD. While there is an enormous volume of imaging literature on the motor aspects of PD or motoric complications, that will not be addressed here.
Abstract: Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.
Abstract: It has been suggested that dopamine derived from exogenous levodopa may not follow vesicular dynamics in Parkinson's disease (PD). Using a novel PET method based on the sensitivity of [(11)C]-dihydrotetrabenazine (DTBZ) binding to changes in vesicular dopamine levels, we show here that striatal [(11)C]-DTBZ binding decreases after levodopa administration in advanced PD, likely reflecting an increase in vesicular dopamine levels. Endogenous dopamine and exogenously derived dopamine seem to follow the same vesicular dynamics.
Abstract: Parkinson's disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinson's disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinson's disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.
Abstract: Studies showed that the dopamine (DA) transporter (DAT) modulates changes in levodopa-derived synaptic dopamine levels (Delta(DA)) in Parkinson's disease (PD). Here we evaluate the relationship between DAT and Delta(DA) in the 6-hydroxydopamine model of Parkinson's disease to investigate these mechanisms as a function of dopaminergic denervation and in relation to other denervation-induced regulatory changes. 27 rats with a unilateral 6-hydroxydopamine lesion (denervation approximately 20-97%) were imaged with (11)C-dihydrotetrabenazine (VMAT2 marker), (11)C-methylphenidate (DAT marker) and (11)C-raclopride (D2-type receptor marker). For denervation <75%Delta(DA) was significantly correlated with a combination of relatively preserved terminal density and lower DAT. For denervation <90%, Delta(DA) was significantly negatively correlated with DAT with a weaker dependence on VMAT2. For the entire data set, no dependence on pre-synaptic markers was observed; Delta(DA) was significantly positively correlated with (11)C-raclopride binding-derived estimates of DA loss. These findings parallel observations in humans, and show that (i) regulatory changes attempt to normalize synaptic DA levels (ii) a lesion-induced functional dependence of Delta(DA) on DAT occurs up to approximately 90% denervation (iii) for denervation < 75% relative lower DAT levels may relate to effective compensation; for higher denervation, lower DAT levels likely contribute to oscillations in synaptic DA associated with dyskinesias.
Abstract: OBJECTIVE: To determine the sensitivity of positron emission tomography with 11C-labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinson's disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD. METHODS: Untreated patients with early PD (n = 27) and age-matched control subjects (n = 33) underwent DTBZ/positron emission tomography scanning to measure binding to the presynaptic type 2 vesicular monoamine transporter site in dopaminergic neurons in basal ganglia regions. Clinical symptoms were rated with the Unified Parkinson's Disease Rating Scale. RESULTS: Mean striatal DTBZ binding values in the patient group were decreased as compared with control subjects (p < 0.001) in all regions examined. The difference between patients and control subjects was most marked in the midputamen, where only one patient had DTBZ binding within 3 standard deviations of the control mean. Bradykinesia and rigidity scores correlated with DTBZ binding in the contralateral midputamen region, particularly for the clinically least affected limbs. Tremor scores showed no significant correlation. INTERPRETATION: Reduced striatal binding of DTBZ is associated with early PD. Tremor appears to be only partially related to presynaptic dopaminergic function and may have a mechanism differing from that of symptoms such as bradykinesia. The method appears to be most sensitive in mildly affected individuals with a possible "floor" effect that may limit the degree of additional change occurring once more severe clinical symptoms are evident.
Abstract: OBJECTIVE: Little is known about the progression of dopaminergic dysfunction in LRRK2-associated Parkinson disease (PD). We sought to characterize the neurochemical progression with multitracer PET in asymptomatic members of parkinsonian kindred (family D, Western Nebraska) carrying LRRK2 (R1441C) mutation. METHOD: Thirteen family D subjects underwent PET scans of presynaptic dopaminergic integrity and five subjects were rescanned 2 to 3 years later. RESULTS: In subjects 8, 9 (mutation carriers), and 13 (genealogically at risk subject), there was a decline in PET markers over the course of the study that was significantly greater than the expected rate of decline in healthy controls. Reduced dopamine transporter binding was the earliest indication of subclinical dopaminergic dysfunction and progression to clinical disease was generally associated with the emergence of abnormal fluorodopa uptake. CONCLUSION: PET study of presymptomatic members of our LRRK2 kindred revealed dopaminergic dysfunction that progressed over time. This represents an ideal group to study the natural history of early disease and the potential effects of neuroprotective interventions.
Abstract: BACKGROUND: There is an urgent need for therapies that slow or reverse the progression of Parkinson's disease (PD). Neurotrophic factors can improve the function of degenerating neurons and protect against further neurodegeneration, and gene transfer might be a means to deliver effectively these factors to the brain. The aim of this study was to assess the safety, tolerability, and potential efficacy of gene delivery of the neurotrophic factor neurturin. METHODS: In this phase I, open-label clinical trial, 12 patients aged 35-75 years with a diagnosis of PD for at least 5 years in accordance with the UK Brain Bank Criteria received bilateral, stereotactic, intraputaminal injections of adeno-associated virus serotype 2-neurturin (CERE-120). The first six patients received doses of 1.3x10(11) vector genomes (vg)/patient, and the next six patients received 5.4x10(11) vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850. FINDINGS: The procedure was well tolerated. Extensive safety monitoring in all patients revealed no clinically significant adverse events at 1 year. Several secondary measures of motor function showed improvement at 1 year; for example, a mean improvement in the off-medication motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) of 14 points (SD 8; p=0.000121 [36% mean increase; p=0.000123]) and a mean increase of 2.3 h (2; 25% group mean increase; p=0.0250) in on time without troublesome dyskinesia were seen. Improvements in several secondary measures were not significant, including the timed walking test in the off condition (p=0.053), the Purdue pegboard test of hand dexterity (p=0.318), the reduction in off time (p=0.105), and the activities of daily living subscore (part II) of the UPDRS (p=0.080). (18)F-levodopa-uptake PET did not change after treatment with either dose of CERE-120. INTERPRETATION: The initial data support the safety, tolerability, and potential efficacy of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available. FUNDING: Ceregene; Michael J Fox Foundation for Parkinson's Research.
Abstract: OBJECTIVE: Functional imaging techniques represent useful tools to assess in vivo the neurochemical alterations and functional connectivity in Parkinson disease (PD). Here, the authors review the various approaches and potential application of these imaging techniques to the study of PD. METHOD: Radiotracer imaging using dopaminergic markers facilitates assessment of pre- and postsynaptic nigrostriatal integrity, while imaging with other appropriate radiotracers explores nondopaminergic neurotransmitter function, local metabolism, blood flow, and mechanisms potentially related to disease progression and pathogenesis. Activation studies using functional MRI detect blood oxygen level dependent signal, as an indirect marker of neuronal activity. RESULT: Functional imaging techniques have been applied to infer the potential role of inflammation and other factors in etiopathogenesis as well as to study compensatory and regulatory mechanisms in early PD and subclinical disease in genetic forms of PD. Imaging studies also help to understand the neurobiological basis of motor and nonmotor complications. Recent reports suggest a role for striatal dopaminergic transmission in modulating neurobehavioral processes including the placebo effect in PD. Although functional imaging has been employed to monitor disease progression, the discordance between clinical outcome and imaging measures after therapeutic interventions precludes their use as surrogate end points in clinical trials. Beyond these limitations and potential challenges, imaging techniques continue to find wide application in the study of PD. CONCLUSION: Functional imaging can provide meaningful insights into mechanisms underlying various aspects of motor and nonmotor dysfunction in Parkinson disease and the role of striatal dopaminergic transmission in behavioral processes beyond motor control. These modalities hold promise to study the preclinical phase and to elucidate further the benefits and complications of surgical interventions and the utility of neuroprotective strategies.
Abstract: Neuroimaging studies have provided a major contribution to our understanding of the mechanisms of the placebo effect in neurological and psychiatric disorders. Expectation of symptom improvement has long been believed to play a critical role in the placebo effect, and is associated with increased endogenous striatal dopamine release in Parkinson's disease and increased endogenous opioid transmission in placebo analgesia. Evidence from positron emission tomography and functional magnetic resonance imaging studies suggests that expectations of symptom improvement are driven by frontal cortical areas, particularly the dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortices. The ventral striatum is involved in the expectation of rewarding stimuli and, together with the prefrontal cortex, has also been shown to play an important role in the placebo-induced expectation of therapeutic benefit. Understanding the mechanisms of the placebo effect has important implications for treatment of several medical conditions, including depression, pain, and Parkinson's disease.
Abstract: A 48-year-old man presented with a progressive gait disorder. He had longstanding ataxia, oculomotor apraxia, motor delay, and cognitive impairment, diagnosed as cerebral palsy. Physical examination revealed ataxia, oculomotor apraxia, extrapyramidal signs, and a wide-based, shuffling gait. Magnetic resonance imaging showed vermian aplasia, consistent with Joubert syndrome. Positron emission tomography scan revealed normal fluorodopa uptake, but elevated raclopride binding, compatible with dopamine deficiency. This case demonstrates that a patient with Joubert syndrome may survive into adulthood and present as a chronic neurologic disorder with subacute extrapyramidal signs.
Abstract: Recent studies suggest that, for many adult-onset neurological diseases, persons born at a certain time of year are at higher risk of the disease. Small-scale studies have suggested that persons born in the spring may be at higher risk of developing Parkinson's disease (PD) late in life. There have also been suggestions that there are clusters of PD birth dates in the years of major influenza pandemics. To determine whether there is any seasonal variation in the birth dates of PD patients, we examined birth dates of 8,168 PD patients collected from subspecialty movement disorder clinics across Canada. Patterns of seasonality of birth were examined and compared with the general Canadian population. In addition, we compared counts of patients born in the years of major influenza pandemics with the number born in the surrounding years. We found no evidence of systematic seasonal variation in PD incidence by birth date, or of clustering of birth dates during influenza pandemic years in PD patients.
Abstract: OBJECTIVE: To investigate the role of the dopamine transporter (DAT) in the regulation of synaptic dopamine (DA) levels in Parkinson's disease and its role in the preservation of DA in presynaptic terminals. METHODS: Ten Parkinson's disease patients (age, 62.9 +/- 9.5 years; Unified Parkinson's Disease Rating Scale motor score in "off" state, 28.5 +/- 8.2) underwent positron emission tomography with (11)C-methylphenidate (MP, a DAT marker), (11)C-dihydrotetrabenazine (a vesicular monoamine transporter 2 marker), and (18)F-fluorodopa, leading to the determination of the MP and (11)C-dihydrotetrabenazine binding potentials (BPs) and the effective distribution volume for (18)F-fluorodopa, the inverse of DA turnover. Seven patients also underwent positron emission tomography with (11)C-raclopride before and 1 hour after levodopa administration to estimate levodopa-induced changes in synaptic DA concentration. RESULTS: We found a significant positive correlation between effective distribution volume and BP(MP) (r = 0.93; p < 0.001) and a significant negative correlation between changes in synaptic DA concentration and BP(MP) (r = -0.93; p = 0.04), independent of disease severity and duration. INTERPRETATION: These data show that in Parkinson's disease, greater DAT levels are directly associated with lower DA turnover and lower changes in synaptic DA concentration. This implies that an important functional role of DAT is to maintain relatively constant synaptic DA levels and to preserve DA in nerve terminals. A decrease in DAT, although potentially serving as a compensatory mechanism in early disease, may ultimately result in increased DA turnover and higher oscillations in synaptic DA concentration, thereby possibly predisposing toward the occurrence of motor complications as disease progresses.
Abstract: Functional imaging can be used to detect preclinical evidence of dopamine deficiency in people deemed to be at increased risk of Parkinson's disease (PD) based on genetic or environmental risk, or because they have clinical features such as REM sleep behaviour disorder that may be a harbinger of PD. Positron emission tomography (PET) using [11C]dihydrotetrabenazine to label the vesicular monoamine transporter type 2 (VMAT2), a variety of 11C- or 18F-labeled ligands for the membrane dopamine transporter (DAT), or 6-[18F]fluoro-L-dopa (FD), which assesses uptake and decarboxylation of levodopa as well as vesicular storage of radiolabeled dopamine, can all be used, and all provide comparable, but somewhat different information. DAT binding using either PET or SPECT appears to be the most sensitive marker of dopamine denervation, while FD uptake is subject to compensatory upregulation and its reduction may more closely herald the onset of clinical disease. Alterations in glucose metabolism and in dopamine release also occur in the asymptomatic hemisphere of subjects with unilateral PD. An interesting potential application of PET is the determination of non-dopaminergic abnormalities that correlate with the presence of clinically apparent pre-motor symptoms of PD.
Abstract: Paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by attacks of dystonia or chorea lasting minutes to hours. Recently, mutations in the myofibrillogenesis regulator 1 gene (MR-1) have been identified in 10 unrelated PNKD kindreds. The authors describe a Canadian PNKD family who does not have mutations in the MR-1 gene and links to a separate locus at 2q31. This indicates that there are at least two different genes responsible for PNKD.
Abstract: In this study, we assessed the changes of endogenous dopamine (DA) levels in response to methylphenidate in 5 patients with idiopathic Parkinson's disease (PD) and 6 healthy controls. Three-dimensional positron emission tomography was performed with the D2 receptor antagonist [11C]raclopride (RAC) at baseline and 1 hour following the administration of oral methylphenidate (0.8 mg/kg) to assess changes in dopamine levels indirectly. Oral methylphenidate produced no significant change in extracellular DA levels in the putamen, as estimated by comparing changes in RAC binding at baseline and 1 hour following its administration in PD subjects and healthy controls. However, there were small changes in RAC binding of opposite direction in caudate and ventral striatal regions compared between the two groups. Although there was no consistent improvement in motor function in the PD group, some patients did experience a subjective high in response to methylphenidate (MP). Failure of oral MP to alter extracellular DA levels in putamen could result from degeneration of presynaptic dopaminergic terminals, with consequent severe reductions in the levels of endogenous DA and dopamine transporter in PD subjects. Our data provide in vivo neurochemical support for the lack of clinical efficacy following MP in PD patients and are also in keeping with reduced DA release following amphetamine in PD subjects.
Abstract: OBJECTIVE: Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). METHODS: Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake. RESULTS: At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). INTERPRETATION: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.
Abstract: To determine whether the degree to which a patient with Parkinson's disease expects therapeutic benefit from subthalamic nucleus-deep brain stimulation (STN-DBS) influences the magnitude of his or her improved motor response, 10 patients with idiopathic Parkinson's and bilateral STN-DBS were tested after a 12-hour period off medication and stimulation. Four consecutive UPDRS III scores were performed in the following conditions: (a) stimulation OFF, patient aware; (b) stimulation OFF, patient blind; (c) stimulation ON, patient aware; and (d) stimulation ON, patient blind. Statistical significance (P = 0.0001) was observed when comparing main effect ON versus OFF (mean ON: 32.55; mean OFF: 49.15). When the stimulation was OFF, patients aware of this condition had higher UPDRS motor scores than when they were blinded (mean: 50.7 vs. 47.6). With the stimulation ON, UPDRS motor scores were lower when the patients were aware of the stimulation compared with when they were blinded (mean: 30.6 vs. 34.5). The interaction between these levels was significant (P = 0.049). This variation was important for bradykinesia and was not significant for tremor and rigidity. The authors conclude that the information about the condition of the stimulation enhanced the final clinical effect in opposite directions. The results presented support the role of expectation and placebo effects in STN-DBS in Parkinson's disease patients.
Abstract: OBJECTIVE: To report genealogic, clinical, imaging, neuropathologic, and genetic data from a Canadian kindred with dystonia and brain calcinosis originally described in 1985. METHODS: The authors performed clinical examinations and CT and PET studies of the head and analyzed blood samples. One autopsy was performed. RESULTS: The family tree was expanded to 166 individuals. No individuals were newly affected with dystonia, but postural tremor developed in two. The mean age at symptom onset was 19 years. Eight individuals had dystonia: three focal, one segmental, one multifocal, and three generalized. Seven displayed additional signs: chorea, intellectual decline, postural tremor, and dysarthria. CT studies were performed on five affected and 10 at-risk family members. All affected individuals and eight at-risk individuals had brain calcinosis. PET scans in two individuals showed reduced D(1)- and D(2)-receptor binding and reduced uptake of 6-[(18)F]fluoro-l-dopa. Autopsy of one affected individual showed extensive depositions of calcium in the basal ganglia, thalamus, cerebral white matter, and cerebellum. No specific immunohistochemistry abnormalities were seen. Genome search data showed no evidence of linkage to the previously described loci IBGC1, DYT1, and DYT12. CONCLUSIONS: The phenotype of this family consists of dystonia-plus syndrome. Brain calcium deposits vary in severity and distribution, suggesting that calcifications alone are not entirely responsible for the observed clinical signs. Further studies are needed to elucidate the etiology of this heterogeneous group of disorders.
Abstract: The placebo effect can be encountered in a great variety of medical conditions, but is particularly prominent in pain, depression and Parkinson's disease. It has been shown that placebo responses play a part in the effect of any type of treatment for Parkinson's disease, including drug therapy, deep brain stimulation and dopamine tissue transplantation. Recent studies have demonstrated that the placebo effect in Parkinson's disease is related to the release of substantial amounts of endogenous dopamine in both the dorsal and ventral striatum. As the ventral striatum is involved in reward processing, these observations suggest that the placebo effect may be linked to reward mechanisms. In keeping with this placebo-reward model, most recent experiments have shown activation of the reward circuitry in association with placebo responses in other disorders. In addition, as dopamine is the major neurotransmitter in the reward circuitry, the model predicts that the release of dopamine in the ventral striatum could be involved in mediating placebo responses not only in Parkinson's but also in other medical conditions.
Abstract: Structural imaging studies often reveal relatively limited findings in Parkinsonian disorders, as the most profound changes are neurochemical and hence better revealed by functional studies such as PET or SPECT. However, newer magnetic resonance techniques such as spectroscopy, diffusion weighted imaging, diffusion tensor imaging and magnetization transfer have shown promise in differentiating between idiopathic Parkinson's and the atypical parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy. We review here recent advances in functional imaging as well as in structural studies of basal ganglia disorders. Functional studies may give insights into mechanisms underlying disease pathogenesis, as well as neurochemical alterations.
Abstract: Over the past two decades, positron emission tomography (PET) has provided valuable insights into the mechanisms of nigrostriatal degeneration in Parkinson's disease (PD). Furthermore, it allows the in vivo assessment of disease progression and the evaluation of treatment interventions. In this review, we shall discuss some of the issues and concerns that arise with the use of PET as a surrogate marker of disease progression in Parkinson's disease.
Abstract: Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
Abstract: Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.
Abstract: Huntington's disease (HD) is a progressive disorder with no known cure. We report two-year postoperative positron emission tomography (PET) data from 7 HD patients who underwent intrastriatal fetal transplantation. Patients showed widespread reductions in glucose uptake with no significant change over 2 years. Dopamine receptor binding was significantly reduced in HD striatum. D1 binding did not change significantly following transplantation, but there was a significant loss of D2 binding. These findings may reflect loss of graft viability and/or disease progression. There was no significant relationship between changes in PET and clinical function. In summary, there was no benefit from transplantation.
Abstract: There are numerous concerns related to treatment choices involving early dopaminergic therapy in Parkinson's disease. These include the effect on the underlying progression of the neurodegenerative process as well as the development of motor complications such as fluctuations and dyskinesias. A number of recent basic and clinical studies have provided new insights but have also added confusion and controversy. This report summarizes presentations and discussion dealing with these issues from a one-day symposium involving Canadian Movement Disorders neurologists.
Abstract: Since the original 1995 report of a parkinsonian kindred, four individuals have been affected (mean age at onset, 65 years). All four had cardinal signs of Parkinson disease (PD) and good response to levodopa. Four autopsies showed neuronal loss and gliosis in the substantia nigra. Lewy bodies (LB) limited to brainstem nuclei were detected in one case, diffuse LB in the second, neurofibrillary tangles (NFT) without LB in the third, and neither NFT nor LB in the fourth. Genetic studies suggested linkage to the PARK8 locus on chromosome 12.
Abstract: Recent evidence indicates that the placebo effect in Parkinson's disease is mediated by the release of dopamine in the dorsal striatum. Interestingly, there is also placebo-induced dopamine release in the ventral striatum, which establishes a connection between the placebo effect and reward mechanisms. Specifically, we propose that placebo responses are related to the activation of the reward circuitry. Here, the clinical benefit induced by placebos represents the reward. The magnitude of the placebo effect likely depends on the a priori probability of clinical benefit. This notion has profound implications in the design of clinical trials and placebo investigations.
Abstract: Levodopa-treated Parkinson's disease is often complicated by the occurrence of motor fluctuations, which can be predictable ('wearing-off') or unpredictable ('on-off'). In contrast, untreated dopa-responsive dystonia (DRD) is usually characterized by predictable diurnal fluctuation. The pathogenesis of motor fluctuations in treated Parkinson's disease and diurnal fluctuation in untreated DRD is poorly understood. We have developed a mathematical model indicating that all these fluctuations in motor function can be explained by presynaptic mechanisms. The model is predicated upon the release of dopamine being subject to probabilistic variations in the quantity of dopamine released by exocytosis of vesicles. Specifically, we propose that the concentration of intravesicular dopamine undergoes dynamic changes according to a log-normal distribution that is associated with different probabilities of release failure. Changes in two parameters, (i) the proportion of vesicles that undergo exocytosis per unit of time and (ii) the proportion of dopamine subject to re-uptake from the synapse, allowed us to model different curves of levodopa response, for the same degree of nigrostriatal damage in Parkinson's disease. The model predicts the following periods of levodopa clinical benefit: 4 h for stable responders, 3 h for wearing-off fluctuators, and 1.5 h for on-off fluctuators. The model also predicts that diurnal fluctuation in untreated DRD should occur some 8 h after getting up in the morning. All these results fit well with clinical observations. Additionally, we calculated the probability of obtaining a second ON period after a single dose of levodopa in Parkinson's disease (the 'yo-yoing' phenomenon). The model shows that the yo-yoing phenomenon depends on how fast the curve crosses the threshold that separates ON and OFF states, which explains why this phenomenon is virtually exclusive to patients with on-off fluctuations. The model supports the idea that presynaptic mechanisms play a key role in both short-duration and long-duration responses encountered in Parkinson's disease. Dyskinesias may also be explained by the same mechanisms.
Abstract: A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson's disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the ventral striatum of patients with Parkinson's disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson's disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson's disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively.
Abstract: Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism.
Abstract: BACKGROUND: Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death. HYPOTHESIS: If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder. OBJECTIVE: To investigate the regional selectivity of dopamine terminal loss during the progression of PD. PARTICIPANTS: We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ). RESULTS: Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P<.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P<.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen. CONCLUSION: To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.
Abstract: BACKGROUND: The spatial and temporal pattern of excessive disease occurrence, termed clustering, may provide clues about the underlying etiology. OBJECTIVE: To report the occurrence of 3 clusters of Parkinson disease (PD) in Canada. DESIGN AND PATIENTS: We determined the population groups containing the clusters, geographical limits, and duration of exposure to the specific environments. We tested whether there was an excessive presence of Parkinson disease by calculating the probability of the observed cases occurring under the null hypothesis that the disease developed independently and at random in cluster subjects. Results of genetic testing for mutations in the alpha-synuclein, parkin, tau genes, and spinocerebellar ataxia genes (SCA2 and SCA3) were negative. RESULTS: The probabilities of random occurrence (P values) in the 3 clusters were P = 7.9 x 10 (-7)for cluster 1, P = 2.6 x 10 (-7)for cluster 2, and P = 1.5 x 10 (-7)for cluster 3. CONCLUSIONS: Our findings indicate an important role for environmental causation in Parkinson disease. A possible role exists for environmental factors such as viral infection and toxins in the light of current evidence.
Abstract: We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
Abstract: Familial idiopathic basal ganglia calcification (IBGC, Fahr disease) is an inherited neurologic condition characterized by basal ganglia and extra-basal ganglia brain calcifications, parkinsonism, and neuropsychiatric symptoms. The authors examined six families for linkage to the previously identified genetic locus (IBGC1) located on chromosome 14q. The authors found evidence against linkage to IBGC1 in five of the six families supporting previous preliminary studies demonstrating genetic heterogeneity in familial IBGC.
Abstract: Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [11C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [11C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.79, P < 0.001; for the putamen, r = 0.88, P < 0.0001). Patients with peak-dose dyskinesias had larger 1-h increases in synaptic dopamine levels than stable responders, but there were no between-group differences in [11C]raclopride binding 4 h post-levodopa. The corresponding (time x group) interaction term in the repeated measures analysis of covariance was significant, even after adjusting for between-group differences in duration of Parkinson's disease symptoms (for the caudate nucleus, P = 0.030; for the putamen, P = 0.021). Our results indicate that, at the synaptic level, an identical dose of levodopa induces increasingly larger 1-h changes in dopamine levels as Parkinson's disease progresses. Large levodopa-induced increases in synaptic dopamine concentration can lead to dramatic changes in receptor occupancy, which may be responsible for the emergence of peak-dose dyskinesias in Parkinson's disease.
Abstract: We report on two patients who developed a new postural and action tremor after chronic stimulation of the contralateral thalamus (VPM nucleus) during treatment of a complex regional facial pain syndrome. The tremor was only present during deep brain stimulation (DBS) and was suppressed with adjustment of the stimulation parameters. Tremor was seen only with low frequency stimulation (50 Hz or lower) and disappeared with higher stimulation frequencies. In addition to being an unusual side effect of thalamic DBS, we believe that this phenomenon affords insight into one possible mechanism underlying essential tremor (ET). A central oscillatory mechanism involving the olivocerebellar complex and the thalamus, which is a part of the cerebro-cerebello-cerebral circuit, is thought to play an important role in the genesis of ET. Induction of a tremor resembling ET in our patients indicates an active role for low frequency stimulation. A plausible explanation for this is that low frequency stimulation in the thalamic area enhances the output of the tremor-producing network. This leads credence to the concept of central oscillations in a "tremor circuit," of which the thalamus is a part, as being important in ET.
Abstract: Parkinson disease is characterized by the loss of dopaminergic neurons, thus decreasing the system's ability to produce and store dopamine (DA). Such ability is often investigated using 18F-fluorodopa (FD) positron emission tomography. A commonly used model to investigate the DA synthesis and storage rate is the modified Patlak graphical approach. This approach allows for both plasma and tissue input functions, yielding the respective uptake rate constants K(i) and K(occ). This method requires the presence of an irreversible compartment and the absence of any nontrapped tracer metabolite. In the case of K(occ), this last assumption is violated by the presence of the FD metabolite 3-O-methyl-[18F]fluoro-dopa (3OMFD), which makes the K(occ) evaluation susceptible to a downward bias. It was found that both K(i) and K(occ) are influenced by DA loss and thus are not pure measures of DA synthesis and storage. In the case of K(occ), the presence of 3OMFD exacerbates the effect of DA egress, thus introducing a disease-dependent bias in the K(occ) determination. These findings imply that K(i) and K(occ) provide different assessments of disease severity and that, as disease progresses, K(i) and especially K(occ) become more related to DA storage capacity and less to the DA synthesis rate.
Abstract: Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.
Abstract: There is growing recognition that Parkinson's disease (PD) is likely to arise from the combined effects of genetic predisposition as well as largely unidentified environmental factors. The relative contribution of each varies from one individual to another. Even in situations where more than one family member is affected, the predominant influence may be environmental. Although responsible for only a small minority of cases of PD, recently identified genetic mutations have provided tremendous insights into the basis for neurodegeneration and have led to growing recognition of the importance of abnormal protein handling in Parkinson's as well as other neurodegenerative disorders. Abnormal protein handling may increase susceptibility to oxidative stress; conversely, numerous other factors, including oxidative stress and impaired mitochondrial function can lead to impaired protein degradation. A limited number of environmental factors are known to be toxic to the substantia nigra; in contrast, some factors such as caffeine intake and cigarette smoking may protect against the development of PD, although the mechanisms are not established. We review the various genetic and environmental factors thought to be involved in PD, as well as the mechanisms that contribute to selective nigral cell death.
Abstract: Individuals with Parkinson's disease (PD) have difficulties rising from a chair; however, factors contributing to this inability have never been investigated. We compared lower extremity strength between individuals with PD and healthy controls and quantified the relationships between strength and the ability to rise from a chair. Ten men with mild PD and 10 sex- and age-matched controls performed maximal concentric, isokinetic knee and hip extensor torque on an isokinetic dynamometer to quantify muscle strength. Subjects also rose from a chair at their comfortable pace without the use of their arms and the duration of this task provided a measure of sit-to-stand (STS) ability. Subjects with PD were tested in an on- and off-medication state on different days. Mean hip and knee extensor torques were lower in subjects with PD, with greater deficits found at the hip. Greater hip strength was related to better STS ability in subjects with PD while greater knee strength was related to better STS ability in controls. These results show that individuals with mild PD generate smaller extremity forces compared to controls. Reduced strength, particularly at the hip, may be one factor that contributes to the difficulty of persons with PD to rise from a chair.
Abstract: Levodopa-induced dyskinesias are abnormal involuntary movements that develop as a side-effect of long-term treatment with levodopa for Parkinson's disease. The mechanisms underlying such effects are unclear but may include abnormal stimulation of dopamine D(3) receptors. Elevations in dopamine D(3) receptor mRNA and binding are seen in the denervated striatum of hemiparkinsonian rats treated chronically with levodopa, and these changes correlate well with behavioural sensitization in this model. Further investigation of dopamine D(3) receptor involvement in levodopa-induced dyskinesias is hampered by the lack of appropriately selective ligands for this receptor. Here, in vivo administration of an antisense oligonucleotide designed to reduce striatal dopamine D(3) receptor expression provides a level of specificity not available through traditional pharmacological approaches. Following chronic treatment with levodopa, hemiparkinsonian rats received intrastriatal infusion of oligonucleotide antisense to dopamine D(3) receptor mRNA for 5 days. Antisense treatment effectively and selectively reduced striatal dopamine D(3) receptor binding and blocked behavioural sensitization to the effects of repeated levodopa. These findings confirm the importance of the D3 receptor in the expression of behavioural sensitization to levodopa in animals with dopaminergic denervation and contribute to our limited understanding of the functional significance of this receptor. In that sensitization to the effects of repeated levodopa in this setting may be analogous to medication-induced dyskinesias in humans, our findings furthermore suggest that drugs which block D(3) function may be helpful in the treatment of dyskinesias, without necessarily exacerbating Parkinsonism.
Abstract: Tardive dyskinesia is a movement disorder that develops in 20-30% of patients treated with chronic neuroleptics. Whilst the pathogenesis of tardive dyskinesia remains unclear, altered expression of neuropeptides in the basal ganglia has been implicated in its emergence. The peptide neurotensin is expressed in both dopamine D1 receptor-bearing neurons of the direct striatonigral pathway and dopamine D2 receptor-bearing neurons of the indirect striatopallidal pathway. Increased levels of striatal neurotensin messenger RNA (mRNA) are reported following chronic neuroleptic therapy. Chronic treatment with the typical antipsychotic haloperidol elicits neurotensin immunoreactivity in a large number of striatopallidal and a modest number of striatonigral projection neurons, whilst treatment with the potent dopamine releaser, methamphetamine, induces intense neurotensin immunoreactivity in striatonigral projection neurons. In order to determine whether increased levels of striatal neurotensin mRNA in the direct striatonigral or the indirect striatopallidal pathway play a more influential role in the development of tardive dyskinesia, we explored the effects of a specific neurotensin antagonist in a rodent model (vacuous chewing movements [VCMs] induced by chronic neuroleptics). Three groups of animals received injections of fluphenazine decanoate (25 mg/kg) or its vehicle sesame oil every 3 weeks for at least 18 weeks. They were then surgically implanted with bilateral guide cannulae aimed at the striatum, the substantia nigra pars reticulata, or the globus pallidus respectively. After recovery, animals were infused with 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-imethoxyphenyl)pyrazol-3-yl)carbonylamino]tricyclo(3.3.1.1.(3.7))decan-2-carboxylic acid (SR48692; 0.25, 0.50, and 1.0 nmol/microl), or its vehicle (10% dimethyl sulfoxide [DMSO] in saline) and observed for 60 min. Intra-striatal, intra-nigral or intra-pallidal infusion of SR48692 attenuated neuroleptic-induced VCMs. These findings lend further support to a role for neurotensin in the development of VCMs but do not clarify which pathway plays a more important role. Thus, treatments that reduce or prevent the effects of increased neurotensin expression and release may be useful in the management of tardive dyskinesia.
Abstract: The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom duration <or=5 years) with onset before age 50 (n = 10) and with onset after age 50 (n = 10) were studied. The two groups were compared with respect to severity of nigrostriatal damage as evaluated by positron emission tomography (PET) scanning with 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ), and d-threo-[(11)C]methylphenidate ([(11)C]MP). We found no significant differences between younger- and older-onset PD patients with regard to any of the three presynaptic markers. For putamen, the P-values corresponding to the different PET measurements ranged from P = 0.34 ([(18)F]-dopa) to P = 0.79 ([(11)C]DTBZ). However, after adjusting for treatment and PD duration, regression analysis showed that [(18)F]-dopa uptake correlated positively with age of onset (r = 0.59; P = 0.010). No correlation was found between [(11)C]DTBZ and [(11)C]MP binding potentials and age of onset (P = 0.26 and P = 0.90, respectively). These data suggest that age-of-onset-dependent differences in clinical evolution are not likely to reflect early differences in nigrostriatal pathology in PD. Age-related differences in [(18)F]-dopa uptake may be related to changes in dopamine turnover.
Abstract: Thirty-four patients with advanced Parkinson's disease participated in a prospective 24-month double-blind, placebo-controlled trial of fetal nigral transplantation. Patients were randomized to receive bilateral transplantation with one or four donors per side or a placebo procedure. The primary end point was change between baseline and final visits in motor component of the Unified Parkinson's Disease Rating Scale in the practically defined off state. There was no significant overall treatment effect (p = 0.244). Patients in the placebo and one-donor groups deteriorated by 9.4 +/- 4.25 and 3.5 +/- 4.23 points, respectively, whereas those in the four-donor group improved by 0.72 +/- 4.05 points. Pairwise comparisons were not significant, although the four-donor versus placebo groups yielded a p value of 0.096. Stratification based on disease severity showed a treatment effect in milder patients (p = 0.006). Striatal fluorodopa uptake was significantly increased after transplantation in both groups and robust survival of dopamine neurons was observed at postmortem examination. Fifty-six percent of transplanted patients developed dyskinesia that persisted after overnight withdrawal of dopaminergic medication ("off"-medication dyskinesia). Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on these results.
Abstract: Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET.
Abstract: A major goal of research in Parkinson's disease (PD) has been the development of treatments to slow the progressive degeneration of the nigrostriatal dopaminergic system and to reduce the functional decline of patients. Because of the uncertainty in the ability of the clinical evaluation to reflect the status of the nigrostriatal dopaminergic system once dopaminergic therapy has commenced, investigators in PD have sought to develop alternative measures of disease. One approach, which has been extensively explored, is neuroimaging with radiotracers that interact with processes central to dopaminergic neurotransmission in the nigrostriatal dopaminergic axons-conversion of levodopa to dopamine through aromatic amino acid decarboxylase (AADC), [(18)F]fluorodopa PET, storage of dopamine in synaptic vesicles via the vesicular monoamine transporter 2 (VMAT2), (+)-[(11)C]dihydrotetrabenazine PET, and reuptake of dopamine into axons via the dopamine transporter (DAT), [(123)I]beta-CIT SPECT, and a number of other PET and SPECT ligands. During the 54(th) Annual Meeting of the American Academy of Neurology, a group of investigators active in the fields of biomakers, neuroimaging, and neuroprotection met to review the three techniques mentioned above. Prior to the meeting, the participants developed consensus on a set of 10 criteria for a neuroimaging technique to be considered adequate as a biomarker for progression of PD and levels at which the available data for each technique indicate that the criterion was met. The criteria and each of the three imaging techniques mentioned above were reviewed, and the results of that meeting are presented.
Abstract: Existing technologies permit the detection of changes in neurotransmitter and/or neuroreceptor expression. This may be useful for diagnosis, for monitoring disease progression, and for assessing the pathogenesis of complications associated with long-term treatment. Although the binding of [11C]raclopride to D2 receptors is subject to competition from endogenous dopamine, this can be exploited to estimate changes in synaptic levels of dopamine. Assessment of processes downstream to the receptor will require the development of new approaches.
Abstract: Levodopa effectively improves motor symptoms of Parkinson's disease. However, the beneficial effects of levodopa often erode over time with the emergence of response fluctuations. Although these response changes have been recognized from the early levodopa era, their mechanisms remain poorly understood. We investigated the role of dopamine (DA) terminal loss in the development of motor fluctuations by employing PET with [11C](+/-)dihydrotetrabenazine ([11C]DTBZ) as an in vivo marker for DA nerve terminals. Levodopa response was characterized by analysing the time-response curve to a single dose of levodopa with a finger-tapping test. PET scans were performed in 11 patients with asymmetric Parkinson's disease (age: 61.12 +/- 7.97 years; duration of Parkinson's disease: 10.55 +/- 4.53 years; mean +/- SD). Each patient performed finger-tapping tests for up to 5 h after taking a therapeutic dose of levodopa. Results showed significantly lower [11C]DTBZ binding potential (BP; Bmax/Kd) and baseline tapping rates on the more affected putamen and corresponding body side, respectively, than on the other (P = 0.003 for the former, P = 0.013 for the latter). Among the variables describing the time-response curve, the duration and early decay time were significantly shorter on the more affected side (P = 0.051 and P = 0.021, respectively). Latency to the onset and latency to 50% Emax (the magnitude of the levodopa response) were significantly longer on the more-affected side (P = 0.013 and P = 0.004, respectively). Emax was not significantly different between the two sides. The asymmetry (difference from the more affected to less affected side) of [11C]DTBZ BP in the putamen showed a highly significant correlation with the corresponding asymmetry of the estimated EC50 (levodopa concentration producing 50% of the maximal response; P = 0.022; r = -0.727), a marginally significant correlation with that of latency to the onset (P = 0.065; r = -0.583) and no significant correlation with that of the magnitude, duration or early decay time. This pattern of changes in levodopa response from the less affected to more affected side was similar to that from stable to fluctuating responders except for the latency to onset. These findings suggest a pathogenetic role for DA terminal loss in the development of motor fluctuations. However, the absence of a significant correlation between the early decay of levodopa response and DA terminal density suggests that DA terminal loss alone cannot account for the development of motor fluctuations. Therefore, our study suggests that both levodopa treatment and DA terminal loss contribute to the pathogenesis of motor fluctuations.
Abstract: Chronic neuroleptic treatment leads to the development of tardive dyskinesia in 20-30% of patients. While the pathogenesis of tardive dyskinesia remains elusive, altered opioid peptide function in striatal projection pathways of the basal ganglia has been implicated. Using a rodent model of vacuous chewing movements induced by chronic neuroleptic administration, we investigated regional involvement of opioid transmission in tardive dyskinesia. We examined the role of dynorphin in the direct striatonigral pathway by infusing nor-binaltorphimine, a selective kappa opioid receptor antagonist, into the substantia nigra pars reticulata. As well, infusions of naloxone (a non-specific opioid receptor antagonist), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP; a mu opioid receptor antagonist) or naltrindole (a delta opioid receptor antagonist) into the globus pallidus were used to establish the contribution of the striatopallidal pathway. Chronic fluphenazine treatment (25 mg/kg i.m. every 3 weeks for 18 weeks) resulted in a robust increase in vacuous chewing movements. Infusion of nor-binaltorphimine (5.0 nmol) into the substantia nigra pars reticulata significantly attenuated vacuous chewing movements. Infusion of naloxone (0.5 and 2.0 nmol) into the globus pallidus also significantly attenuated vacuous chewing. Infusion of naltrindole into the globus pallidus blocked vacuous chewing at all doses administered (0.5, 1.0, 2.0 nmol) while CTOP was only effective at the two higher doses. From these results we suggest that increases in dynorphin in the direct striatonigral pathway and enkephalin in the indirect striatopallidal pathway following chronic neuroleptic administration are both likely to contribute to tardive dyskinesia.
Abstract: An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.
Abstract: Somatostatin may play a role in several neuropsychiatric disorders, including Parkinson's disease. Although functional interactions between somatostatinergic and dopaminergic transmitter systems have been well documented, no study has been conducted in animals with experimental Parkinsonism to explore the effects of somatostatin on dopamine receptor-mediated behavior. In the present study, rats with unilateral 6-hydroxydopamine-induced destruction of the medial forebrain bundle were assessed following administration of the dopamine(1/2) receptor agonist apomorphine. Ipsilateral intrastriatal infusion of somatostatin produced a dose-related inhibition of apomorphine-induced rotations with maximal effect at a dose of 7.5 microg in 2 microl. This inhibitory effect of somatostatin was antagonized by the somatostatin antagonist cyclo-somatostatin (0.1 microg in 2 microl, intrastriatally). Neither somatostatin (up to 15 microg in 2 microl) nor cyclo-somatostatin on its own induced rotations; similarly, this dose of cyclo-somatostatin did not affect apomorphine-induced rotations. From these results we suggest that exogenous somatostatin, by directly acting on its specific receptors in the striatum, inhibits the effects of dopamine receptor activation in parkinsonian rats. We conclude that therapies based on modulation of somatostatin may be worth exploring in the management of Parkinson's disease and other disorders of the basal ganglia.
Abstract: BACKGROUND: Transplanted striatal cells have been demonstrated to survive, grow, establish afferent and efferent connections, and improve behavioral signs in animal models of Huntington's disease (HD). OBJECTIVE: To evaluate feasibility and safety and to provide preliminary information regarding the efficacy of bilateral human fetal striatal transplantation in HD. METHODS: Seven symptomatic patients with genetically confirmed HD underwent bilateral stereotactic transplantation of two to eight fetal striata per side in two staged procedures. Tissue was dissected from the lateral half of the lateral ventricular eminence of donors 8 to 9 weeks postconception. Subjects received cyclosporine for 6 months. RESULTS: Three subjects developed subdural hemorrhages (SDHs) and two required surgical drainage. One subject died 18 months after surgery from probable cardiac arrhythmia secondary to severe atherosclerotic cardiac disease. Autopsy demonstrated clearly demarcated grafts of typical developing striatal morphology, with host-derived dopaminergic fibers extending into the grafts and no evidence of immune rejection. Other adverse events were generally mild and transient. Mean Unified HD Rating Scale (UHDRS) motor scores were 32.9 plus minus 6.2 at baseline and 29.7 plus minus 7.5 12 months after surgery (p = 0.24). Post-hoc analysis, excluding one subject who experienced cognitive and motor deterioration after the development of symptomatic bilateral SDHs, found that UHDRS motor scores were 33.8 plus minus 6.2 at baseline and 27.5 plus minus 5.2 at 12 months (p = 0.03). CONCLUSIONS: Transplantation of human fetal striatal cells is feasible and survival of transplanted cells was demonstrated. Patients with moderately advanced HD are at risk for SDH after transplantation surgery.
Abstract: The biochemical bases of the placebo effect are still incompletely known. We show here that the placebo effect in Parkinson's disease is due, at least in part, to the release of dopamine in the striatum. We propose that the placebo effect might be related to reward mechanisms. The expectation of reward (i.e. clinical benefit) seems to be particularly relevant. According to this theory, brain dopamine release could be a common biochemical substrate for the placebo effect encountered in other medical conditions, such as pain and depression. Other neurotransmitters or neuropeptides, however, are also likely to be involved in mediating the placebo effect (e.g. opioids in pain disorders, serotonin in depression).
Abstract: PURPOSE OF REVIEW: We aim to review recent neuroimaging contributions to our understanding of the cause and pathogenesis of Parkinson's disease, as well as treatment-related complications of disease, with a focus on functional anatomy and neurochemistry. RECENT FINDINGS: Recent reports describe altered dopaminergic activity in extrastriatal regions, as well as changes in other monoaminergic systems, such as serotonin. Attempts to correlate altered dopaminergic function with personality traits have also been described in the last year. The role of different markers of presynaptic dopaminergic integrity in the assessment of disease progression is discussed, as is the role of biomarkers in detection of preclinical disease. Cerebral activation studies not only confirm altered function of cortico-striatal-thalamo-cortical loops in Parkinson's, but also emphasize the importance of networks involving the cerebellum. The ability to detect changes in synaptic availability of dopamine using positron emission tomography with [(11)C]raclopride is reviewed, including the application to detect altered levels of dopamine in response to pharmacological, mechanical and behavioral stimuli. Such studies have been used to identify altered patterns associated with the development of motor fluctuations, as well as a biochemical substrate underlying the placebo effect in Parkinson's. SUMMARY: Functional imaging studies can provide novel insights into the etiopathogenesis of Parkinson's disease, as well as the mechanisms that contribute to complications of long-term therapy. They also shed light on the mechanisms that may underly behavioral changes and benefit derived from surgical interventions.
Abstract: Recent evidence suggests that the placebo effect is mediated by the dopaminergic reward mechanisms in the human brain and that it is related to the expectation of clinical benefit. On the basis of this theory, we propose some criteria for the proper investigation of the placebo effect, and review the evidence for a placebo effect in Parkinson's disease, depression, pain, and other neurological disorders. We also discuss the evidence for the use of placebos in long-term substitution programmes for the treatment of drug addiction.
Abstract: There are few reports of positron emission tomography (PET) in juvenile parkinsonism (JP). We report on the results of (18)F-6-fluoro-L-dopa (FD) PET in a 14-year-old patient with JP of 5 years duration associated with atypical features. This is the youngest subject to be investigated to date. There was a severe asymmetric reduction in striatal FD uptake, with a rostrocaudal gradient in the putamen similar to that seen in adult-onset idiopathic parkinsonism. Extensive DNA analysis in this patient did not show mutations in the parkin gene.
Abstract: The authors describe an Alberta family with levodopa-responsive parkinsonism without cerebellar abnormalities. Genetic testing showed expanded repeats for SCA-2; other mutations for parkinsonism were excluded. The expanded allele shows interruption of the CAG repeat with CAA. PET in two affected members showed reduced fluorodopa uptake in striatum and normal raclopride binding. Families with autosomal dominant, levodopa-responsive parkinsonism should be tested for the SCA-2 mutation.
Abstract: BACKGROUND: We describe nine females with Rett Syndrome (RS), aged 14 to 26 years. All had had developmental delay before the end of their first year and had subsequently regressed to profound dementia with apraxia, ataxia, irregular respirations and often also seizures. METHODS: The Revised Gesell developmental assessment and Alpern-Boll Developmental Profile were used in modified form. Volumetric measurements of basal ganglia using MRI were compared with the findings in nine age-matched volunteer females. Positron emission scans with [18F]-6-fluorodopa and [11C]-raclopride were performed under light anesthesia with intravenous Propofol, and the findings were compared with those in healthy control girls. Bidirectional sequencing of the coding regions of the MECP2 gene was investigated in blood samples for mutational analyses. RESULTS: The RS females functioned at a mental age level ranging from about 4 to 15 months. The scores correlated with height, weight and head circumference. Magnetic resonance scans of basal ganglia showed a significant reduction in the size of the caudate heads and thalami in the Rett cases. Positron emission scans demonstrated that the mean uptake of fluorodopa in RS was reduced by 13.1% in caudate and by 12.5% in putamen as compared to the controls, while dopamine D2 receptor binding was increased significantly by 9.7% in caudate and 9.6% in putamen. Mutations in the coding regions of the MECP2 gene were present in all nine patients. No significant correlation between type and location of mutation and volumetric changes or isotope uptake was demonstrable. CONCLUSIONS: Our findings suggest a mild presynaptic deficit of nigrostriatal activity in Rett syndrome.
Abstract: The authors propose that the placebo effect is mediated by reward-related mechanisms. Recent evidence suggests that it is the expectation of reward (in this case, the expectation of clinical benefit) that triggers the placebo response. In Parkinson's disease, the placebo effect is mediated by the release of dopamine in the striatum. The authors argue that placebo-induced dopamine release in limbic structures, particularly in the nucleus accumbens, could also be a major biochemical substrate for the placebo effect encountered in other medical disorders. Other neuroactive substances involved in the reward circuitry (e.g., opioids) are also likely to contribute to the placebo response, and such contribution may be disorder specific (e.g., opioid release in placebo analgesia; serotonin regulation in response to placebo antidepressants). In addition, placebos may have a role in substitution programs for the treatment of drug addiction.
Abstract: Using the ability of [11C]raclopride to compete with dopamine for D(2)/D(3) receptors, we investigated by positron emission tomography the effect of placebo (saline) injection on dopamine release in the ventral striatum of patients with Parkinson's disease. We found evidence for placebo-induced dopamine release of similar magnitude to that reported in healthy volunteers after amphetamine administration. However, in contrast to the dorsal striatum, there were no differences in [11C]raclopride binding potential changes between patients who experienced the reward (those who reported placebo-induced clinical benefit) and those who did not. We conclude that the release of dopamine in the ventral striatum (nucleus accumbens) is related to the expectation of reward and not to the reward itself. These observations have potential implications for the treatment of drug addiction.
Abstract: OBJECTIVE: A previous study reported a higher than normal density of dopamine D(2) receptors in psychotic mania but not in nonpsychotic mania. The purpose of this study was to further examine D(2) receptor density in a larger sample of nonpsychotic manic patients by using positron emission tomography (PET) and [(11)C]raclopride. METHOD: Thirteen neuroleptic- and mood- stabilizer-naive patients with DSM-IV mania without psychotic features and 14 healthy comparison subjects underwent [(11)C]raclopride PET scans. Of the 13 patients, 10 were treated with divalproex sodium monotherapy. PET scans were repeated 2-6 weeks after commencement of divalproex sodium. D(2) receptor binding potential was calculated by using a ratio method with the cerebellum as the reference region. RESULTS: The [(11)C]raclopride D(2) binding potential was not significantly different in manic patients than in the comparison subjects in the striatum. Treatment with divalproex sodium had no significant effect on the [(11)C]raclopride D(2) binding potential in manic patients. There was no correlation between the D(2) binding potential and manic symptoms before or after treatment. CONCLUSIONS: These results suggest that D(2) receptor density is not altered in nonpsychotic mania and that divalproex sodium treatment does not affect D(2) receptor availability.
Abstract: We explored an objective method of measuring clinical severity of Parkinson's disease. Eighty-six patients with PD and 136 healthy subjects were studied. We serially carried out four types of finger tapping (FT) using a computerized drum machine: (i) repetitive one-finger tapping with an index-finger (F1K1); (ii) one-finger tapping on two keys separated by 20cm (F1K2); (iii) alternate tapping with index and middle fingers on two adjacent keys (F2K2); and (iv) F2K2 with contralateral activation (aF2K2). Analyses on FT included: (i) age and gender effects in healthy volunteers and Parkinson's disease; (ii) comparison between Parkinson patients and controls of similar age distribution; (iii) correlation with the Purdue Pegboard and Modified Columbia Scale in Disease; and (iv) in a subset of patients in whom PET scans were performed (n=30), correlation with 18F-DOPA uptake constant (Ki). In healthy subjects, there was a negative age effect on FT scores and a gender effect, with males scoring higher than females. All FT scores were significantly lower in the Parkinson patients, correlated with Purdue Peg Board, and inversely with the duration of illness, and with the Modified Columbia Scale. The 18F-DOPA Ki correlated significantly with aF2K2 (p=0.024), less so with PPB (p=0.038), but not with the Modified Columbia Scale. We conclude that alternating two-finger tapping with contralateral hand activation is a simple, objective test for measuring the severity of Parkinson's disease.
Abstract: We studied daytime sleepiness in 160 patients with Parkinson's disease and 40 normal subjects. We compared the prevalence of daytime sleepiness in patients who were taking levodopa alone, levodopa with bromocriptine, levodopa with ropinirole, and levodopa with pramipexole. We found that (1) all these anti-Parkinson drugs can cause daytime sleepiness; (2) 'dozing off' correlated highly with 'falling asleep without warning'; (3) after statistical adjustment for confounding variables there was no significant difference among the risks for any of these anti-Parkinson drugs causing daytime somnolence.
Abstract: Motor fluctuations are a major disabling complication in the treatment of Parkinson's disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively patients in the early stages of Parkinson's disease with a follow-up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed "wearing-off" fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [11C]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow-up. Thus, 1 hour post-levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent "wearing-off" phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa-related motor complications.
Abstract: Pallido-ponto-nigral degeneration (PPND) is a rapidly progressive disorder characterized by frontotemporal dementia with parkinsonism unresponsive to levodopa therapy. In this study, we have further characterized the regional abnormalities of cerebral function using PET with 6-[18F]fluoro-L-dopa (FD), [11C] raclopride (RAC), and 2-deoxy-2-fluoro-[18F]-D-glucose (FDG). FD and RAC scans were performed in 3 patients-2 new patients and a previously reported asymptomatic at-risk individual who became symptomatic 2years after the first FD scan. Cerebral glucose metabolism was studied by FDG in 2 other patients. In keeping with previous reports, there was a severe reduction of FD uptake, which affected both caudate and putamen to a similar degree in all 3 patients. RAC scans showed normal to elevated striatal D2-receptor binding in all patients. Cerebral glucose metabolism was globally reduced (>2 SD below control mean) in one patient, with maximal involvement of frontal regions, and to a lesser degree in the other patient. Our study showed severe presynaptic dopaminergic dysfunction with intact striatal D2 receptors in PPND patients, implying that the dopa unresponsiveness is probably a result of pathology downstream to the striatum. The pattern of presynaptic dysfunction contrasts with that seen in idiopathic parkinsonism, where the putamen is affected more than the caudate nucleus. The pattern of glucose hypometabolism correlates well with the presence of frontotemporal dementia.
Abstract: Positron emission tomography (PET) scan is considered to be the most useful tool with which to assess the integrity of nigrostriatal function in the living brain. Recently, different genetic defects have been associated with a variety of familial parkinsonian syndromes, the clinical phenotypes of which have varying degrees of similarities to idiopathic parkinsonism (IP), (sporadic Parkinson's disease). This review summarizes: (1) the PET scan findings (fluorodopa uptake and raclopride binding) in both familial parkinsonian syndromes and IP; and (2) the similarities and differences of the clinical and PET features between familial parkinsonian syndromes and IP. This analysis demonstrates that more similarities than differences exist in PET scan findings in the different familial parkinsonian syndromes with the exception of pallido-ponto-nigral degeneration (PPND), that is perhaps best considered as multisystem degeneration. As a result of this analysis, we believe that while different genetic defects may underlie different mechanisms of nigrostriatal degeneration, the final pattern of nigrostriatal dysfunction is essentially similar to that of IP. 'Parkinson's disease', therefore, may not represent a single disease entity, but rather the final manifestation of different pathogenetic mechanisms-mediated by genetic or environmental factors, or an interaction of genetic and environmental factors.
Abstract: The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.
Abstract: The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.
Abstract: The integrity of the dopaminergic system can be studied using positron emission tomography. The presynaptic tracers [11C]-methylphenidate and [11C]dihydrotetrabenazine (DTBZ) are used to investigate the dopamine transporter availability, the dopamine vesicular transporter integrity; the postsynaptic tracers [11C]-raclopride and [11C]-Schering 23990 (SCH) are used to probe the D2 and D1 receptors. These are reversible tracers, where the binding potential (BP) = Bmax/Kd often is used to quantify the amount of their specific binding to the sites of interest. The simplified tissue input methods to calculate BP are attractive, since they do not require a blood input function. The suitability and performance of two such methods were evaluated: the Logan graphical tissue method, and the Lammertsma reference tissue method (RTM). The BP estimates obtained with the two methods were nearly identical in most cases, with similar reliability and reproducibility indicating that all four tracers satisfy the assumptions required by each method. The correlations among the fitted parameters obtained from the RTM were estimated and were found not to introduce noticeable bias in the RTM BP and R1 estimates. R1 showed low intersubject and intrasubject variability. The k2 estimate showed good reliability for SCH with cerebellar input function and DTBZ with occipital input function.
Abstract: We used [18F]6-fluorodopa (FD) positron emission tomography (PET) to examine the severity of nigrostriatal dopaminergic dysfunction in 67 patients with Idiopathic Parkinsonism (IP), 52 with fluctuations and 15 with a stable response to levodopa. FD uptake (Ki) was reduced by 12% in the caudate (p = 0.08) and by 28% in the putamen (p = 0.0004) of patients with fluctuations compared to those with a stable response. However, there was considerable overlap of FD Ki values between the two groups. The fluctuators had a longer symptom duration (11.6 +/- 5.7 years) than the patients with a stable response to levodopa (4.3 +/- 2.4 years; p < 0.0001) and the age of onset of symptoms was earlier in the fluctuators (43.9 +/- 8.9 versus 54.1 +/- 10.4; p = 0.0004). Similar reductions in FD Ki in the fluctuators persisted following adjustment for these variables (7.5% in the caudate and 26% in the putamen; p = n.s. and 0.007, respectively). When smaller groups (n = 15 each) were matched for duration of symptoms, the reduction in caudate Ki in the fluctuators was only 1.9% (p = n.s.), but there was still a 24% reduction in putamen Ki (p = 0.05). These findings suggest that fluctuators and non-fluctuators may differ in the severity of their nigrostriatal damage and provide modest support for the hypothesis that fluctuations may in part reflect altered "buffering" capacity of dopaminergic nerve terminals. However, the considerable overlap between groups suggests that other factors such as altered postsynaptic mechanisms and/or increased turnover of dopamine may make a substantial contribution to the development of motor fluctuations.
Abstract: Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three-dimensional mode by using each tracer on 35 patients and 16 age-matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug-naive and drug-treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane DA transporter is down-regulated in the striatum of patients with PD.
Abstract: Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with levodopa in patients with Parkinson's disease. The pathophysiology underlying these dyskinesias remains unclear, although, it has been suggested that heightened activity of dopamine D(1) receptor-bearing striatonigral neurons may play a key role. Chronic pulsatile levodopa administration to hemiparkinsonian rats results in sensitization of rotational responses to apomorphine. This sensitization is thought to be analogous to levodopa-induced dyskinesias in humans. In these studies, we further clarify the role of the dopamine D(1A) receptor in this rodent model of levodopa-induced dyskinesias using an in vivo oligonucleotide antisense approach. Hemiparkinsonian rats received twice daily injections of levodopa for three weeks followed by intrastriatal infusion of dopamine D(1A) receptor antisense (7nmol/day, three days), a scrambled missense control sequence, or saline. Those animals treated with antisense displayed significantly fewer apomorphine-induced rotations than saline- or missense-treated controls.By reducing dopamine D(1A) receptor expression, we were able to attenuate sensitization of the response to apomorphine resulting from chronic pulsatile levodopa treatment. Thus, the dopamine D(1A) receptor appears to play a significant role in levodopa-induced dyskinesias and warrants further examination. These findings may have important implications for the development of selective treatment strategies designed to alleviate parkinsonian symptoms, while minimizing motor complications.
Abstract: Tardive dyskinesia develops as a common complication of long-term neuroleptic use. The emergence of such dyskinesias may reflect a shift in the balance of dopamine D(1) and D(2) receptor-mediated activity, with a relative increase in activity in the D(1) receptor-regulated direct striatonigral pathway. In rats, chronic treatment with the antipsychotic fluphenazine triggers a syndrome of vacuous chewing movements, which are attenuated by dopamine D(1) receptor antagonists. A similar syndrome can be seen in drug-naive animals following acute administration of selective dopamine D(1) receptor agonists. However, not all dopamine D(1) receptor agonists elicit these mouth movements. Thus, some investigators have suggested the existence of novel subtypes of the dopamine D(1) receptor. In these studies, we sought to clarify the role of the dopamine D(1A) receptor in vacuous chewing movements induced both by the selective dopamine D(1) receptor agonist SKF 38393, as well as by chronic neuroleptic administration, using in vivo oligonucleotide antisense to dopamine D(1A) receptor messenger RNA. Intrastriatal antisense treatment significantly and selectively attenuated striatal dopamine D(1) receptor binding, accompanied by reductions in SKF 38393- and chronic fluphenazine-induced vacuous chewing movements. These findings suggest that the dopamine D(1A) receptor plays an important role in the expression of vacuous chewing movements in a rodent model of tardive dyskinesia and may contribute to the pathogenesis of the human disorder. This may have important implications for the treatment of tardive dyskinesia in humans.
Abstract: The plasma membrane dopamine transporter is located on presynaptic nerve terminals and is responsible for the termination of dopaminergic neurotransmission via dopamine reuptake. The dopamine transporter may also contribute to the pathogenesis of Parkinson disease. Dopamine transporter expression correlates well with susceptibility to neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP)-induced parkinsonism. Recent studies have implicated the dopamine transporter in the uptake of both this neurotoxin and its metabolite, MPP(+), as well as another experimental neurotoxin, 6-hydroxydopamine. In these studies we examined the role of the dopamine transporter in the neurotoxicity of both MPP(+) and 6-hydroxydopamine in the rat brain using in vivo administration of phosphorothioate antisense oligonucleotides targeting dopamine transporter mRNA. Infusion of dopamine transporter antisense (1 nmol/day, 7 days) into the left substantia nigra pars compacta resulted in reduced (3)H-WIN 35-428 binding in the left striatum and significant levodopa and amphetamine-induced contralateral rotations. Unilateral pretreatment with dopamine transporter antisense prior to bilateral intrastriatal infusion of either MPP(+) or 6-hydroxydopamine resulted in asymmetrical striatal (3)H-WIN 35-428 binding and dopamine content as well as significant apomorphine-induced ipsilateral rotations, suggesting neuroprotection of nigrostriatal neurons on the antisense-treated side. Thus, the dopamine transporter appears to play a critical role in determining susceptibility to the experimental neurotoxins MPP(+) and 6-hydroxydopamine. In light of this, the dopamine transporter may prove useful, both as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention.
Abstract: The mechanism by which most people favor use of the right hand remains unknown. It has been proposed that asymmetries in the nigrostriatal dopamine system may be related to motor lateralization in humans. We explored this hypothesis in vivo by using [18F]fluorodopa positron emission tomography. Whereas the degree of right hand preference was found to correlate with left putamen dominance as assessed by asymmetry in fluorodopa uptake (K(i)), right caudate dominance was positively correlated with the level of performance during simultaneous bimanual movements in right-handed normal subjects. In addition, right-handed patients with Parkinson's disease with higher right than left caudate K(i) performed much better in bimanual movement tests than those in whom the K(i) value of the left caudate was higher than that of the right. These findings support the notion that the nigrostriatal dopaminergic system may play a role in motor lateralization, and suggest a functional model for bimanual movements. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon both the activation (through the dominant left putamen circuitry) of the left supplementary motor area (SMA), and the inhibition (through the right caudate circuitry) of motor programs stored in the right SMA.
Abstract: OBJECT: The goal of this study was to determine whether unilateral pallidotomy reduces parkinsonian pain. METHODS: Twenty-one patients suffering from Parkinson's disease (PD) were followed prospectively for 1 year after they had undergone a unilateral pallidotomy to assess the procedure's effect on pain related to PD. Pain unrelated to PD was not studied. Patients scored the level of their PD pain on an ordinal scale (0-10 points) preoperatively and 6 weeks and 1 year postoperatively. The results were analyzed using Wilcoxon's paired-ranks test (with Bonferroni correction) and showed a significant reduction in overall pain scores at 6 weeks (p < 0.001) and 1 year (p = 0.001) following pallidotomy. Various types of PD pain are described and their possible pathophysiological mechanisms are presented. CONCLUSIONS: Unilateral pallidotomy significantly reduces pain attributable to Parkinson's disease.
Abstract: The reproducibility of (+/-)-alpha-[11C] dihydrotetrabenazine (DTBZ) measures in PET was studied in 10 healthy human subjects, aged 22-76 y. METHODS: The scan-to-scan variation of several measures used in PET data analysis was determined, including the radioactivity ratio (target-to-reference), plasma-input Logan total distribution volume (DV), plasma-input Logan Bmax/Kd and tissue-input Logan Bmax/Kd values. RESULTS: The radioactivity ratios, plasma-input Bmax/Kd and tissue-input Bmax/Kd all have higher reliability than plasma-input total DV values. In addition, measures using the occipital cortex as the reference region have higher reliability than the same measures using the cerebellum as the reference region. CONCLUSION: Our results show that DTBZ is a reliable PET tracer that provides reproducible in vivo measurement of striatal vesicular monoamine transporter density. In the selection of reference regions for DTBZ PET data analysis, caution must be exercised in circumstances when DTBZ binding in the occipital cortex or the cerebellum may be altered.
Abstract: The diagnosis of Parkinson's disease is predominantly clinical, based on a combination of the cardinal features of tremor, bradykinesia and rigidity. The differential essentially lies between other conditions resulting in tremor, of which essential tremor is the commonest, and other akinetic-rigid syndromes. These include progressive supranuclear palsy, multiple system atrophy, toxins and other degenerative disorders, including diffuse Lewy body disease and corticobasal degeneration. The key clinical features of these disorders and a practical diagnostic approach are briefly reviewed in this article.
Abstract: Controversy over the etiology and pathogenesis of Parkinson's disease (PD) has continued for many years and while the details have changed, the uncertainty persists. Although heritability was most emphatically refuted a decade ago by many investigators, recent progress firmly indicates that genetic factors at least play a role, although probably to a variable degree from one individual to another. Evidence for a variety of other etiological factors is amassed from epidemiological studies, animal models, molecular and cellular biology. Genetic factors, infectious and immunological abnormalities, the effects of ageing, toxins (endogenous as well as exogenous) and other environmental factors may all contribute to the development of PD. Loss of nigral dopaminergic neurons may be mediated by varying combinations of oxidative free radical toxicity, impaired mitochondrial function, "weak excitotoxicity" and abnormal handling of cytoskeletal proteins, all of which may shift the balance regulating apoptotic cell death.
Abstract: OBJECTIVE: To assess the pattern of dopaminergic abnormalities in a Greek-American kindred (family H) with autosomal dominantly inherited, levodopa-responsive parkinsonism caused by a mutation of the gene encoding alpha-synuclein. BACKGROUND: Mutations of alpha-synuclein have been associated recently with dominantly inherited, levodopa-responsive parkinsonism. The pattern of dopamine deficiency and status of postsynaptic dopamine receptors in this condition have not been reported previously. The authors followed a large, six-generation family in whom the affected members carry the recently reported G209A mutation in the gene encoding alpha-synuclein. METHODS: The authors studied four affected and two clinically unaffected gene-negative members of family H using [18F]-6-fluoro-L-dopa (FD) and [11C]-raclopride (RAC) PET to assess presynaptic dopaminergic function and dopamine D2 receptors. The results were compared with normal subjects and patients with sporadic, idiopathic PD (IP). RESULTS: In affected individuals, FD uptake was reduced in both the caudate and the putamen, but the putamen was affected more severely than the caudate, as seen in IP. RAC binding was within the normal range, but the ratio of RAC binding in the putamen to that in the caudate was increased in affected members of family H. This pattern is similar to that seen in IP. CONCLUSIONS: PET of the nigrostriatal system in parkinsonism associated with a mutation in the ac-synuclein gene indicates that it results in a pattern of dopamine deficiency, with preserved D2 binding, indistinguishable from IP.
Abstract: We tested the hypothesis that asymptomatic carriers of dopa-responsive dystonia (DRD) have increased dopamine D2 receptors in the striatum that protect them from the clinical manifestations of dopaminergic deficiency. We examined striatal D2-receptor binding in (1) symptomatic subjects (treated and untreated) and (2) asymptomatic gene carriers. Using [11C]-raclopride PET, we found elevated striatal D2-receptor binding in both groups. In one of our drug-naive symptomatic subjects, 7 months of treatment with levodopa/carbidopa did not affect the receptor binding as measured on a second scan. We conclude that increased D2-receptor binding in DRD may be a homeostatic response to the dopaminergic deficit in subjects carrying the DRD gene, but is not the sole factor determining the clinical state of these individuals.
Abstract: Aging has long been implicated in the pathogenesis of Idiopathic Parkinsonism (IP). However, postmortem studies have demonstrated that the pathological changes in aging and IP affect the dopaminergic function in putamen and caudate nuclei differently. This has been considered by some authors as evidence against the role of aging in IP. We performed fluorodopa (FD) positron emission tomography (PET) in 36 patients with IP and 25 normal controls to test the hypothesis that the effect of aging on the striatal dopaminergic function in IP differs from the effect of aging in normal controls. We found that the FD uptake constant (Ki) in the caudate nucleus of patients with IP declines with both age (p = 0.002) and duration (p = 0.05) of symptoms. This effect was over and above that of normal aging (p = 0.007). We did not find a similar superimposed effect of age in the putamen. We conclude that the effect of aging on the dopaminergic function in the caudate nucleus in IP differs from that in normal aging. Whether this abnormal aging precedes and even predisposes to IP or is triggered by pathogenetic factors in IP is unclear.
Abstract: The reproducibility of [11C]SCH 23390 in PET was studied in 10 normal human subjects. METHODS: The scan-to-scan variation of several measures used in PET data analysis, including the radioactivity ratio, plasma-input Logan total distribution volume (DV), plasma-input Logan DV ratio (DVR) and tissue-input Logan Bmax/Kd values, was determined. RESULTS: There were significant correlations among the radioactivity ratio, plasma-input DVR and tissue-input Bmax/Kd. With the cerebellum as the reference region, these three measures also had high reliability (86%-95%), high between-subject s.d. (7.7%-11.3%) and small within-subject s.d. (2.3%-3.6%), indicating that they are comparable and useful measures for the assessment of dopamine D1 receptor binding. CONCLUSION: The radioactivity ratio and the tissue-input Bmax/Kd may be preferred methods for the evaluation of dopamine D1 receptor binding because these two methods do not require arterial blood sampling and metabolite analysis. Our results show that cerebellum is a reliable reference region for SCH 23390. When the Logan plasma-input function method is used in data analysis for SCH 23390, DVRs rather than total DV values should be used because of the poor reliability of the DV values and their lack of correlation with other measures. Carbon-11-SCH 23390 is thus a reliable and reproducible ligand for the study of dopamine D1 receptor binding by PET.
Abstract: Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.
Abstract: Positron emission tomography and single photon emission computed tomography have been used to measure receptor concentration and function through the use of a variety of radiotracers and data analysis techniques. Changes in presynaptic function and postsynaptic receptor concentration reflect both loss due to disease and compensatory responses.
Abstract: Fetal dopaminergic neurons grafted into the dopamine-depleted striatum have previously been shown to normalize neurochemical and behavioural abnormalities. However, the extent of graft-induced recovery of striatal compartments, which differ in their ontogeny, neurochemical properties and function, is still not clear. The striosome and matrix compartments of the striatum provide a segregated projection to somatostatin-containing GABAergic neurons of the rostral part of the entopeduncular nucleus and somatostatin-negative GABAergic neurons of the caudal part of the entopeduncular nucleus, respectively. In the present study, preprosomatostatin and glutamate decarboxylase messenger RNA levels in the rostral and caudal parts of the entopeduncular nucleus were determined six and 18 months postgrafting in rats with complete recovery of rotational behaviour following apomorphine challenge, and in rats with unilateral 6-hydroxydopamine lesions or sham lesions and no grafts. Sections were processed for in situ hybridization using 35S-labelled cRNA probes for glutamate decarboxylase (67,000 mol. wt isoform; GAD67) and preprosomatostatin. Autoradiographs showed a marked increase in preprosomatostatin messenger RNA within the ipsilateral entopeduncular nucleus in 6-hydroxydopamine-lesioned rats, and a substantially lower increase six months postgrafting. At 18 months postgrafting, the preprosomatostatin messenger RNA levels were symmetrical within the entopeduncular nucleus. Unilateral depletion of striatal dopamine resulted in a moderate increase in GAD67 messenger RNA levels within the ipsilateral entopeduncular nucleus, along with a substantial decrease in GAD67 levels within the contralateral nucleus. By six months postgrafting, the GAD67 levels had decreased considerably within the ipsilateral entopeduncular nucleus, while the messenger RNA levels had returned to normal within the contralateral nucleus. Interestingly, at 18 months postgrafting, the GAD67 levels remained decreased within the ipsilateral entopeduncular nucleus and were significantly lower than the normal value. The results indicate that fetal nigral grafts placed within the dopamine-depleted striatum can restore the neurochemical alterations seen in striatal target areas such as the entopeduncular nucleus. This may form the neurochemical basis of graft-induced behavioural recovery, as the normalization of neurotransmitter messenger RNA levels in the entopeduncular nucleus reflects the restoration of overall activity in both direct and indirect striatal output pathways. The results also indicate that the graft-derived dopaminergic innervation restores the output of both striosome and matrix compartments of the striatum. The present results also showed a progressive recovery leading to over-compensation of neurotransmitter messenger RNA levels following grafting, perhaps indicating the importance of feedback regulation of grafted dopaminergic neurons by the host.
Abstract: The effects of the neurotensin antagonist SR 48692 on the behavioural responses to the dopamine D1 receptor agonist SKF 38393 were investigated in the rat. SKF 38393 (5 mg/kg s.c.) elicited vacuous chewing movements (VCMs) and grooming, which were unaffected by SR 48692 (50 micrograms/kg i.p.). The dopamine D2 receptor antagonist raclopride (0.5 mg/kg s.c.) elicited a small increase in VCMs in animals treated with SR 48692 and attenuated grooming induced by SKF 38393. These effects were not otherwise modified by SR 48692. We conclude that VCMs induced by acute administration of a dopamine D1 receptor agonist are unlikely to be dependent upon enhanced release of neurotensin in the striatum or its projections. This is contrast to the vacuous chewing response which emerges following chronic administration of neuroleptics, which is attenuated by neurotensin receptor antagonist. Thus, inasmuch as chronic neuroleptic-induced VCMs in the rat may be analogous to tardive dyskinesia in humans, the responses induced by acute administration of a D1 agonist to the rat cannot be used as a model of this disorder. Furthermore, the behavioural effects of chronic neuroleptic administration reflect more than a simple shift in the balance of D1 versus D2 receptor stimulation.
Abstract: Treatment of Parkinson's disease with levodopa is associated with fluctuations in motor function and dyskinesias, which may in part depend upon the mode of levodopa treatment. In rats with unilateral 6-hydroxydopamine lesions, intermittent levodopa results in sensitization to apomorphine-induced rotation, associated with massive ipsilateral increases in nigral dynorphin. We assessed the effects of nigral infusion of the selective kappa opioid antagonist nor-binaltorphomine (nor-BNI) in this model. Nor-BNI reduced apomorphine-induced rotation in animals receiving intermittent levodopa to a level comparable with that seen in animals treated with continuous levodopa or with saline. These data suggest that behavioural sensitization arising from intermittent levodopa therapy in a rodent model of parkinsonism depends upon increased expression of dynorphin in the striatonigral pathway and provides further insight into the mechanisms underlying motor fluctuations which develop during the treatment of Parkinson's disease.
Abstract: The neuropeptide cholecystokinin (CCK) has been shown to interact with dopamine in various ways, including attenuation of dopamine D1 receptor-mediated vacuous chewing and grooming. While we have demonstrated a clear role for the CCK(A) receptor in the attenuation of dopamine D1 agonist-induced vacuous chewing, studies of grooming yielded anomalous results. We examined the effects of selective CCK receptor antagonists on the attenuation of SKF 38393-induced grooming by the CCKB agonist CCK-4. Administration of SKF 38393 (5 mg/kg s.c.) to male Sprague-Dawley rats resulted in a significant increase in grooming which was reduced to control levels by CCK-4 (20 mg/kg i.p.). Pretreatment with either the CCKA receptor antagonist devazepide or the CCK(B) receptor antagonist L-365,260 significantly attenuated this effect over a range of doses (20, 100, 500 microg/kg i.p.). The suppression of dopamine D1 agonist-induced grooming by CCK-4 does not appear to reflect a non-specific effect of anxiogenesis, as it was unaffected by the anxiolytic diazepam. The CCK receptor antagonists alone were without behavioural effect. Taken together with previous studies in models of anxiety and analgesia, our findings lend further support to the hypothesis that CCK-4 may act at a novel receptor subtype.
Abstract: An antisense oligonucleotide strategy was employed to specifically deplete postsynaptic striatal D2 receptors in order to determine the possible role of presynaptic D2 autoreceptors in mediating behavioral responses induced by low doses of apomorphine. A phosphorothioate-modified antisense oligonucleotide complementary to the first 19 bases of the coding region of D2 receptor mRNA, a scrambled sequence comprising the same bases, or saline was infused bilaterally into the striatum of adult rats, twice daily for 2 days via indwelling cannulae. After an interval of 8-12 h, rats were habituated and challenged with high (300 micrograms/kg; subcutaneous) or low (50 micrograms/kg; s.c.) doses of apomorphine or its vehicle (0.1% ascorbic acid). Yawning, vacuous chewing mouth movements, hypoexploration, and penile grooming induced by low-dose apomorphine were unaffected by antisense infusion into the striatum, whereas stereotypic sniffing following high-dose apomorphine was markedly suppressed. Intrastriatal infusion of antisense resulted in significantly diminished [3H]-raclopride binding, while binding of [3H]-SCH 23390 (D1 receptors) and [3H]-WIN 35428 (dopamine transporter) was unchanged. D2 mRNA levels determined by quantitative in situ hybridization were normal in the striatum and the substantia nigra. Our results confirm that stereotypic sniffing is mediated via postsynaptic D2 receptors in the striatum, and favor the notion that behavioral responses induced by low doses of apomorphine are mediated by presynaptic D2 autoreceptors.
Abstract: The effects of cholecystokinin (CCK) on behavioural responses to the dopamine D1 receptor agonist (+/- )SKF 38393 ((+/- )-2,3,4,5-tetrahydro-7,8- dihydroxy-1-phenyl-1H-3-benzazepine HCl) were studied in the rat. SKF 38393 (5 mg/kg s.c.) induced stereotyped grooming and vacuous chewing movements. Both responses were inhibited by CCK-8S (10-50 micrograms/kg i.p.), but the preferential CCKB receptor agonist CCK-4 (20-100 micrograms/kg i.p.) attenuated SKF 38393-induced grooming only. Suppression of SKF 38393-induced grooming and vacuous chewing movements by CCK-8S was blocked by the selective CCKA receptor antagonist MK-329 (also known as devazepide or L-364,718) (0.1, 0.3 mg/kg i.p.) but unaffected by the CCKB receptor antagonist L-365,260 (0.1, 0.3 mg/kg i.p.). We conclude that CCK can modify dopamine-mediated behavioural responses, possibly reflecting an action post-synaptic to dopamine terminals. The effect on dopamine D1 receptor agonist-induced vacuous chewing movements is probably mediated by CCKA receptors, while the effect on grooming may reflect an interaction with the CCKA receptor and/or a novel CCKB receptor subtype.
Abstract: The effects of acute challenge with ethanol were studied in a putative rodent model of tardive dyskinesia. Chronic administration of fluphenazine elicited vacuous chewing movements (VCMs) in the rat. Neuroleptic-induced VCMs were dose dependently suppressed by ethanol in a behaviorally specific fashion. Suppression by ethanol of neuroleptic-induced VCMs was reversed by pretreatment with the benzodiazepine inverse agonist Ro 15-4513 (2.5 mg/kg). These findings suggest that ethanol may acutely suppress neuroleptic-induced dyskinesias in humans via stimulation of GABAA receptors and are compatible with the previously reported clinical effects of alcohol consumption on the extrapyramidal system. Treatment strategies focussed on GABAergic stimulation deserve further investigation in the management of tardive dyskinesia.
Abstract: The effects of bilateral excitotoxic lesions of the subthalamic nucleus on vacuous chewing movements induced by chronic neuroleptic therapy were examined in the rat. Fluphenazine decanoate (25 mg/kg i.m.q 3 weeks x 24 weeks) induced vacuous chewing movements, as previously described. This response was suppressed to control levels in animals tested 1-3 weeks following bilateral infusion of quinolinic acid (100 nmol/1 microliter per side) into the subthalamic nucleus. Subthalamic nucleus lesions resulted in increased locomotion and sniffing in neuroleptic-naive animals, but these responses were suppressed by concomitant neuroleptic treatment. As vacuous chewing movements induced by chronic neuroleptics are considered to be analogous to tardive dyskinesia in humans, our findings lend further support to the importance of the subthalamic nucleus in the regulation of orofacial movements and suggest that tardive dyskinesia may, in part, be related to altered activity in this structure. This, in turn, suggests that current models of basal ganglia function are inadequate to account for certain pathological states and require re-examination.
Abstract: Recent advances in molecular biology have led not only to the identification of novel dopamine receptor subtypes, but also to the ability to selectively suppress the expression of these receptors. The approaches used to suppress receptor expression, as well as the problems in interpretation of the results are summarized. To date, these studies have confirmed the critical role for D2 receptors and the dopamine transporter in normal motor function, but the contributions of other receptor subtypes have not yet been adequately assessed.
Abstract: BACKGROUND: Etiologic hypotheses for Parkinson's disease have implicated environmental factors, genetic factors, or a combination of the two. METHODS: Data from a survey of elderly Canadians (n = 10,263) with regard to their history of Parkinson's disease and previous environmental exposures were analyzed. Exposure to various environmental factors was compared between 87 patients with Parkinson's disease and 2070 elderly controls without Parkinson's disease. RESULTS: Exposure to plastic resins (OR (odd ratio) = 8.79), epoxy resins (OR = 6.94), glues (OR = 4.26), paints (OR = 3.84), and petroleum (OR = 2.30) products was significantly (p < 0.05) associated with Parkinson's disease. CONCLUSION: These substances deserve further exploration with respect to the possible development of parkinsonism.
Abstract: The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the rat. When administered directly into the ventrolateral striatum of neuroleptic-naive animals, NT (2.5 micrograms/side) elicited vacuous chewing movements. This response was not seen following administration of NT into other striatal regions or the substantia nigra and was suppressed by the NT antagonist SR 48692 (100 micrograms/kg i.p.). Vacuous chewing movements were also seen following chronic administration of fluphenazine decanoate. These movements were likewise suppressed by SR 48692 (10-100 micrograms/kg i.p.), which failed to affect other behavioural responses and was without effect in neuroleptic-naive animals. Our data suggest that increased levels of endogenous NT within the ventrolateral striatum may play a critical role in the development of TD following chronic neuroleptic administration and that NT antagonists may be beneficial for the treatment of this disorder.
Abstract: Bilateral intranigral administration of the selective NK-1 tachykinin receptor agonist [AcArg6, Sar9, Met(O2)11]SP6-11 (0-1 nmol total bilateral dose) selectively induced grooming in rats. This response was blocked by concurrent intranigral administration of the NK-1 tachykinin receptor antagonist RP 67580 (2 nmol), but not by NK-2 (L-659,877) or NK-3 ([Trp7, beta-Ala8]NKA4-10) antagonists. Pretreatment with systemic opioid (naloxone 1.5 mg/kg) and D1 dopamine (SCH 23390 100 micrograms/kg) receptor antagonists also attenuated tachykinin-induced grooming, which was unaffected by D2 dopamine (sulpiride 30 mg/kg) or 5-HT2A+C (ritanserin 2 mg/kg) antagonists. Grooming induced by intranigral [AcArg6, Sar9, Met(O2)11]SP6-11 was also attenuated by bilateral 6-hydroxydopamine lesions of the substantia nigra. These findings indicate that grooming induced by intranigral tachykinins reflects activation of NK-1 receptors and is dependent upon endogenous dopamine and consequent selective stimulation of D1 dopamine receptors.
Abstract: The effects of lesioning mesostriatal dopamine projections or striatal neurons on tachykinin binding in the basal ganglia were assessed in the rat. 6-Hydroxydopamine lesions of the medial forebrain bundle destroyed striatal dopamine terminals as assessed by [3H]mazindol autoradiography, but did not significantly affect the binding of NK-1 ([3H][Sar9,Met(O2)11]substance P) or NK-3 ([3H]senktide) tachykinin ligands in the striatum. 6-Hydroxydopamine lesions significantly reduced NK-3 binding in the substantia nigra pars compacta, but not the ventral tegmental area. In contrast, striatal quinolinic acid lesions reduced both NK-1 and NK-3 binding in the striatum, but failed to affect NK-3 binding in the substantia nigra. These findings suggest that both NK-1 and NK-3 receptors within the striatum are predominantly post-synaptic with respect to dopamine neurons, whereas nigral NK-3 receptors are located on dopaminergic neurons.
Abstract: The effects of the opioid receptor antagonist naloxone on behavioural responses to the dopamine D1 receptor agonist SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride) were assessed in the rat. SKF 38393 (5 mg/kg s.c.) induced grooming and vacuous chewing mouth movements. SKF 38393-induced grooming was dose-dependently attenuated by naloxone (0.375-1.5 mg/kg s.c), while vacuous chewing movements were unaffected. These findings suggest that dopamine D1 receptor agonist-induced grooming is dependent upon opioid systems, while vacuous chewing movements are likely to be mediated via different pathways.
Abstract: The effects of both opiate agonists and the opiate antagonist naloxone were examined in a rodent model of tardive dyskinesia (TD). Chronic (approximately 20 weeks) administration of fluphenazine resulted in the emergence of vacuous chewing mouth movements (VCMs), a response which may be a useful model for this disorder. Fluphenazine-induced VCMs were not affected by a variety of selective opiate agonists administered intracerebroventricularly, but were potently suppressed by subcutaneous administration of the opiate antagonist naloxone. These findings suggest that increased opiate transmission may contribute to the pathogenesis of TD. Further investigation of the role of opiate antagonists in treating this disorder are warranted.
Abstract: We have previously demonstrated that intraperitoneal cholecystokinin (CCK-8S) suppresses the vacuous chewing mouth movements (VCM's) elicited by chronic neuroleptic administration in the rat, a possible model of tardive dyskinesia (TD) in humans. The studies described here were undertaken in order to better determine whether this effect is mediated centrally or peripherally. In the first set of experiments, CCK-8S (10, 30 or 50 ng, i.c.v.) was found to have no effect on VCM's elicited by 20 weeks treatment with fluphenazine decanoate (25 mg/kg, i.m., every 3 weeks). A second set of experiments was then performed to determine if the previously observed effects of intraperitoneal CCK-8S were vagally mediated. As previously described, CCK-8S (10, 30 or 60 micrograms/kg, i.p.) suppressed neuroleptic-induced VCM's in sham-operated animals without affecting the baseline VCM rate. Bilateral subdiaphragmatic vagotomy alone unexpectedly suppressed neuroleptic-induced VCM's to control levels and CCK-8S had no further effect. Vagotomy also prevented the suppressive effects of peripherally administered CCK-8S on rearing and grooming. We conclude that neuroleptic-induced VCM's may depend upon tonic activity in the vagus nerve and/or its central projections and that the effects of CCK-8S on this behavioural response are likely to be peripherally mediated.
Abstract: The effects of ageing on tachykinin-induced behaviours and tachykinin receptors were investigated in the rat. Infusion of the NK-3 tachykinin agonist senktide (0.25, 0.5 and 1 nmol) into the substantia nigra induced locomotion in young (4-6 months) animals but this response was attenuated in middle-aged (12 months) and old (27 months) animals. In contrast, senktide-induced wet dog shakes were not significantly affected by age. In the ventral tegmental area, senktide induced locomotion and wet dog shakes with bell-shaped dose-response curves which were unaffected by age. Senktide suppressed grooming but the effect reached significance in the older animals only. Quantitative receptor autoradiography revealed no effect of age on NK-1 tachykinin receptor density in the striatum while NK-3 receptor density declined in the ventrolateral striatum and to a nonsignificant degree in the substantia nigra but not in other striatal subregions or the ventral tegmental area. We conclude that ageing of the nervous system is not associated with widespread changes in tachykinin binding but differences in behavioural response to tachykinin agonists may reflect changes in other transmitter systems which respond to tachykinin input.
Abstract: We measured cortical glucose metabolism with positron emission tomography in 39 patients with Huntington's disease (HD) and in 34 controls. In the 23 patients with symptoms for less than 5 years, there was a 15% decrease in metabolism in frontal and inferior parietal cortex. In 16 patients with symptoms for more than 5 years, all cortical areas (except temporal) were significantly involved, with metabolic rates 25 to 30% below those of controls. These data indicate the presence of a diffuse abnormality of cortical function with early involvement of frontal lobes in HD, suggesting that the clinical manifestations may not be related solely to basal ganglia pathology, even in early disease.
Abstract: The major complications of therapy in PD are motor, autonomic and psychiatric. Motor complications may be associated with altered striatal bioavailability of levodopa, and may in part respond to changes in timing of drug administration, redistribution of dietary protein and the use of controlled-release preparations. Since long-term complications seem to be associated with higher cumulative doses of levodopa, the early use of adjunctive agents such as deprenyl and/or dopamine agonists is encouraged. Autonomic effects include impaired bladder and bowel function, impotence and postural hypotension. If conservative measures are ineffective, pharmacotherapy with domperidone, fludrocortisone, indomethacin or adrenergic agents may be required. Depression in PD is associated with decreased levels of noradrenaline and 5-HT and responds to tricyclic antidepressants. Drug-induced psychosis reflects stimulation of mesolimbic-cortical dopamine receptors. Alternatives include reduction of medication, the use of atypical neuroleptics (which may act at novel subtypes of the dopamine receptor) and electroconvulsive therapy.
Abstract: The effects of intracerebroventricular neurotensin and the neurotensin analogues neuromedin N and [D-Trp 11]neurotensin on the behavioural responses to chronic neuroleptic administration were investigated in the rat. Chronic (18 weeks) administration of a low dose (12.5 mg/kg, i.m., every 3 weeks) of fluphenazine decanoate alone failed to elicit the vacuous chewing mouth movements (VCMs) which have previously been reported following higher doses of this drug, but VCMs were seen in neuroleptic-treated animals following the additional administration of neurotensin. A higher dose of fluphenazine (25 mg/kg, i.m., every 3 weeks) greatly increased the VCM response, and this potentiation was suppressed to control levels by [D-Trp11]neurotensin, but unaffected by neuromedin N. These findings suggest that alterations in neurotensin may contribute to the deleterious extrapyramidal effects of long-term neuroleptic administration, and that [D-Trp11]neurotensin may attenuate these effects by blockade of neurotensin receptors within the central nervous system.
Abstract: The effects of selective NK-1, NK-2 and NK-3 tachykinin agonists in midbrain dopamine cell containing regions were investigated in the rat. The NK-3 agonist senktide induced locomotion, rearing and sniffing following infusion into the substantia nigra pars compacta, and to a lesser extent in the ventral tegmental area. These behavioural responses were not seen following infusion of the selective NK-1 agonist [Sar9,Met (O2)11]SP or the NK-2 agonist [N1e10]NKA4-10. In contrast, grooming was induced only by the NK-1 agonist administered into the substantia nigra. Yawning, chewing mouth movements and wet dog shakes were all seen following infusion of senktide into the ventral tegmental area. These findings suggest that (i) dopamine-mediated behavioural responses seen following tachykinin administration into the midbrain are dependent upon stimulation of NK-3 tachykinin receptors, (ii) tachykinin-induced grooming is mediated by stimulation of NK-1 receptors and (iii) some of the previously described 5-HT mediated behaviours seen following administration of NK-3 tachykinin agonists are probably generated by stimulation of 5-HT cell bodies in the ventral tegmental area.
Abstract: The effects of various manipulations of brain 5-HT mechanisms on the behavioural responses induced by the selective NK-3 tachykinin agonist senktide in rodents were assessed. Senktide elicited wet dog shakes in the rat which were attenuated by the 5-HT1C/2 antagonist mianserin and the selective 5-HT2 antagonist altanserin. Senktide-induced forepaw treading was stereospecifically attenuated by the 5-HT1A + B antagonist (-)-alprenolol. Senktide also elicited chewing mouth movements and yawning, which were unaffected by mianserin, altanserin, (+)- or (-)-alprenolol, or the selective 5-HT3 antagonist ICS 205-930, but attenuated by the muscarinic antagonist scopolamine. Penile grooming elicited by senktide was attenuated by mianserin, but was unaffected by the other antagonists. Senktide-induced wet dog shakes were enhanced by the 5-HT reuptake inhibitors citalopram and fluoxetine, suppressed by the monoamine oxidase (MAO)-B inhibitor pargyline, but unaffected by the MAO-A inhibitor clorgyline. Forepaw treading was potentiated by citalopram and clorgyline, but not significantly altered by fluoxetine or pargyline. Depletion of 5-HT by p-chlorophenylalanine (PCPA) in the rat attenuated senktide-induced wet dog shakes and forepaw treading. Neither PCPA nor 5,7-dihydroxytryptamine affected senktide-induced behaviours in the mouse, but the degree of brain 5-HT depletion caused by these treatments in mice was relatively small. These findings indicate that stimulation of NK-3 tachykinin receptors by senktide results in a complex behavioural syndrome which is mediated by multiple 5-HT receptors, and dependent upon intact stores of endogenous 5-HT. Independent stimulation of brain cholinergic mechanisms by senktide is also confirmed.
Abstract: The autoradiographic distribution of the selective NK-3 tachykinin agonist [3H]senktide was investigated in rat brain. [3H]Senktide bound with high affinity (KD less than 2.5 nM) and high specificity (greater than 75%) to cerebral cortex and numerous subcortical sites, including the substantia nigra pars compacta. In addition, moderately dense binding was seen in the median but not the dorsal raphe nucleus, and this was disrupted by 5,7-dihydroxytryptamine (5,7-DHT)-induced destruction of 5-HT neurons. 5,7-DHT lesions did not affect the binding of [3H]senktide to forebrain regions, suggesting that 5-HT terminals are devoid of NK-3 receptors.
Abstract: Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.
Abstract: Sensorimotor function and the behavioural responses to a range of doses of subcutaneous apomorphine were assessed in mature (6-8 months) and old (23-26 months) Sprague-Dawley rats of comparable weight. In addition, the locomotor activity response of 12-month-old and 24-month-old rats to continuous infusions (14 days by osmotic minipump) of a selective dopamine D2 agonist. (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 10 micrograms/h) was investigated. Measures of spontaneous locomotor activity and motor coordination revealed impairments in the aged animals. Low doses of apomorphine (10-50 micrograms/kg), which preferentially activate dopamine autoreceptors, induced yawning, chewing mouth movements and penile grooming. The frequency of yawning and duration of penile grooming were significantly decreased in the old animals. In contrast, 200 micrograms/kg of apomorphine induced stereotyped sniffing and licking or gnawing, and these responses were significantly increased in the aged animals. There was a 25% decrease in striatal dopamine levels in the aged animals in this experiment. PHNO increased the amplitude of the circadian rhythms in locomotor activity exhibited by mature rats, and daytime tolerance to the stimulant effects of PHNO was reversed by stress in these animals. Both of these effects were attenuated in the aged rats. These findings suggest that (1) the dopamine receptors mediating yawning and stereotypy have different anatomical locations (2) ageing is associated with decreased responsiveness to stimulation of dopamine autoreceptors, consequent upon the loss of dopaminergic nerve terminals, and (3) while the functional response to selective stimulation of postsynaptic D2 receptors decreases with age, the postsynaptic response to a mixed D1/D2 agonist increases.
Abstract: The selective NK-3 tachykinin receptor agonist senktide elicited yawning, chewing mouth movements and sexual arousal following subcutaneous administration (0.1-1.0 mg/kg) in the rat. These responses were not significantly affected by the dopamine antagonist haloperidol (0.03 mg/kg) or by 6-hydroxydopamine lesions of the nigrostriatal projection. In contrast, the behaviours were markedly attenuated by the peripheral and central muscarinic antagonist scopolamine (1 mg/kg), but not by the peripheral muscarinic antagonist N-methylscopolamine (1 mg/kg). These findings suggest that stimulation of NK-3 receptors produces yawning, chewing and sexual arousal by directly activating central cholinergic neurons.
Abstract: The behavioural effects of the selective NK-3 tachykinin receptor agonist senktide were studied following intracisternal and subcutaneous administration in rodents. Behavioural manifestations of 5-hydroxytryptaminergic stimulation, including head twitches (mice), wet dog shakes (rats), forepaw treading, flat body posture, hindlimb splaying and Straub tail, were seen following the intracisternal (0.01-1.2 nmol) or subcutaneous (0.1-2.4 mumol kg-1) administration of senktide in both species. We conclude that stimulation of NK-3 receptors stimulates 5-hydroxytryptaminergic pathways in rodent brain, and that senktide may cross the blood-brain barrier in biologically significant amounts.
Abstract: Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of dystonia, a relative increase of other inputs to the pallidum may be important, such as those from the caudate and subthalamic nuclei.
Abstract: Apomorphine-induced yawning was studied in male rats with bilateral 6-hydroxydopamine lesions of the substantia nigra. Apomorphine 10, 20 and 50 micrograms/kg SC induced dose-dependent yawning in unoperated controls and animals with sham lesions. In the lesioned animals (in which the mean striatal dopamine depletion was 67%), the maximum yawning response rate was greatly attenuated with no evidence that the dose response curve was shifted in either direction. Furthermore, blockade of yawning in the lesioned animals was not simply due to suppression by other stereotyped behaviours, since there was no evidence of increased sniffing or chewing in these animals. These data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors and requires intact nigrostriatal projections.
Abstract: Behavioural responses to tachykinins were observed following intracisternal administration in mice. The synthetic NK-3 agonists senktide and L-363,851 caused behaviour typically associated with serotonergic stimulation, including head twitches, reciprocal forepaw treading and hindlimb splaying. Neurokinin B produced some features of the serotonin (5-HT) syndrome, while substance P, neurokinin A and eledoisin failed to elicit any such behaviours. Senktide-induced head twitches were prevented by pretreatment with the 5-HT2 antagonists ketanserin and ritanserin, while forepaw treading was attenuated by the 5-HT1 antagonists (-)-pindolol and methysergide. These data suggest that NK-3 agonists interact with central 5-HT mechanisms.
Abstract: Twenty-three persons at risk for Huntington's disease (HD) have been studied using a polymorphic human linked DNA marker (D4S10) and positron emission tomography (PET). We determined the likelihood of inheritance of the gene for HD in 13 persons, using DNA polymorphism studies. Of these, eight persons had a greater than 90% probability of being presymptomatic heterozygotes for HD. Three of these eight subjects had caudate glucose utilization detected by PET that was more than 2 standard deviations (SD) below the age-matched control mean. Measurement of caudate glucose utilization in the other five presumed presymptomatic heterozygotes revealed results between 1 and 2 SD below the mean. Five persons had a less than 10% likelihood of having inherited the abnormal gene for HD. Of these, four had normal rates of glucose utilization in the caudate nuclei. However, one individual with DNA results indicating a low risk of developing HD had abnormally low measures of caudate glucose utilization. This suggests that a recombination had occurred between the linked marker and the gene in this person. These studies suggest that PET studies of caudate glucose utilization may help to confirm results of DNA studies in some persons, and may provide an opportunity to detect when DNA results may be incorrect due to recombination.
Abstract: This article outlines a simple method for estimating the degree of cerebral atrophy and subsequent experimental control for the effects of cerebral atrophy on regional metabolic values measured with positron emission tomography. It is suggested that rather than correcting derived values for atrophy, less potential error is introduced by experimentally controlling for regional atrophy when possible. By treating the derived metabolic rates and the measure of atrophy as two separate variables, it is also possible to establish whether there actually is a demonstrable relationship between the two measures.
Abstract: The early clinical diagnosis of parkinsonism has been reviewed, together with consideration of investigations that may be helpful in certain cases. The controversial issues of management in early Parkinson's disease have been addressed, and some newer concepts of early diagnosis and management have been discussed, deriving from the study of a population of patients exposed to MPTP.
Abstract: Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by chorea of early onset with little or no progression. There is marked clinical variability in this disease with some subjects having onset in infancy and others with onset in early adulthood. In contrast to Huntington's disease (HD), there is no dementia. Computed tomography is normal in all subjects with no evidence of caudate nucleus atrophy. We present the results of positron emission tomography using 18F-2-fluorodeoxyglucose on three patients with this disorder from two families. Cerebral glucose metabolism in one patient was decreased in the caudate nucleus, as previously reported in HD. The other two persons from a second family showed a relative decrease in metabolic rates of glucose in the caudate when compared with the thalamus. It appears that caudate hypometabolism is not specific for HD. These findings suggest that the caudate nucleus may play a significant role in the pathophysiology of some persons with BHC.
Abstract: Regional cerebral glucose metabolism was studied in 16 patients with idiopathic torticollis, using positron emission tomography. Analysis of subcortical regions revealed no consistent focal abnormality of cerebral metabolic rate for glucose, but there was a bilateral breakdown of the normal relationships between the thalamus and basal ganglia. The findings suggest disruption of the pallidothalamic projections in this focal dystonia and may imply a disturbance of GABA.
Abstract: In a double-blind trial in 21 patients with spasmodic torticollis botulinum-A toxin produced both subjective and objective improvement, including significant pain relief in 14 of the 16 patients presenting with pain. Side-effects were more frequently reported during placebo administration and no significant systemic adverse reactions were noted.
Abstract: We studied 10 patients with early Huntington's disease and 7 normal age-matched controls with positron emission tomography (PET) using fluorodeoxyglucose. Subjects had little or no caudate nucleus atrophy and had not received any medications. The results demonstrated that hypometabolism of glucose preceded tissue loss. Furthermore, patients with minimal neurologic or psychiatric symptoms and no obvious CT changes may be differentiated from normal persons with high accuracy by PET. PET is helpful in the early diagnosis of Huntington's disease irrespective of the mode of presentation. PET may also be useful for preclinical detection and may supplement information from DNA studies.
Abstract: This article describes and partially validates a method for predicting whether an observed regional metabolic value is consistent with the observed value of another region. A regression equation was generated from a set of normal metabolic values, and then this equation was applied to patients with symptomatic Huntington's disease and patients at risk for this disorder. The results of the regression method were consistent with observations of the absolute rate for the normal subjects and Huntington's patients. For the at-risk patients, 6 of 18 were found to have reduced caudate metabolism relative to observed thalamic values. Since the initial scan, one of these identified at-risk individuals has developed symptomatic Huntington's disease. The method may be appropriate for other disorders where there are potential subgroups (e.g., schizophrenia) within a diagnostic category.
Abstract: We report two cases of serious intracerebral haemorrhage occurring in young women following their first use of oral medications containing catecholaminergic agents (phenylpropanolamine in combination with ephedrine or pseudoephedrine). Both women were previously well, and there was no evidence for systemic vasculitis, coagulopathy, aneurysm or arteriovenous malformation. Angiography in both cases, performed approximately forty hours following drug ingestion, revealed the beading pattern typical of that seen in previously reported cases of presumed amphetamine-induced "vasculitis." We believe that this arteriographic abnormality is non-specific and should not be construed as necessarily indicative of arteritis.
Abstract: The dopa analogue 6-fluorodopa (6-FD) used with positron emission tomography (PET) allows in vivo visualization of dopamine and its metabolites in nigrostriatal nerve endings. We have now found abnormal 6-FD scans in four subjects exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). None had parkinsonism. The results suggest subclinical damage to the nigrostriatal pathway. This is the first direct evidence that dopaminergic impairment can exist without clinical deficits. Here we discuss this finding in the context of the hypothesis that Parkinson's disease may stem from clinically silent damage to the substantia nigra, followed by slow attrition of neurones in this region because of its particular vulnerability to cell loss as a normal consequence of ageing.
Abstract: PHNO is a naphthoxazine compound with selective D2 agonist properties and a molecular structure unrelated to the morphine and ergot derivatives that have been used to treat Parkinson's disease. A double-blind, dose-ranging study on 8 patients showed that it is effective in the treatment of parkinsonism; its duration of effect of up to 6 h could make it useful for patients who experience wearing-off reactions with levodopa.
Abstract: We describe the clinical features and autopsy findings of an adult patient who had nemaline myopathy and an associated progressive cardiomyopathy. The spinal cord and the results of morphometric analysis of multiple peripheral nerves were normal. There was probable intrafusal fiber involvement, in addition to the typical histopathologic features of extrafusal fibers. Cardiac dysfunction was a prominent clinical and autopsy feature, but it has been infrequently recognized in this entity. Our findings suggest that there is a poor correlation between clinical and pathologic features in this disorder, and they support the need for careful cardiac evaluation of affected patients. Furthermore, the constellation of features favors a myopathic basis for the disease, in contradistinction to some previously expressed views.
Abstract: Bovine gastric mucosal microsomes synthesize prostaglandins from arachidonic acid but thromboxane B2 is the principal product. Thromboxane B2 synthesis occurs at an appreciable rate from endogenous precursor but more rapidly with added arachidonate. Nonsteroidal antiinflammatory drugs inhibited synthesis of prostaglandins and thromboxanes with the following decreasing order of potency: indomethacin, fenoprofen, acetylsalicylic acid, phenylbutazone, sulfinpyrazone, and acetaminophen.
