Abstract: Neurosarcoidosis occurs in 5-15% of sarcoidosis cases. Approximately 50% of patients with neurosarcoidosis present with a neurological disease at the time sarcoidosis is first diagnosed. Spinal sarcoidosis is rare. We report the case of a 61-year-old man with a highly aspecific intramedullary lesion as the first manifestation of sarcoidosis. One year after the onset of neurological symptoms, the high levels of angiotensin-converting enzyme and the results of a total body gallium scan and bronchoalveolar lavage supported the diagnosis of sarcoidosis. Isolated single reports indicate that spinal neurosarcoidosis may be the initial manifestation of sarcoidosis. In our case, magnetic resonance imaging of the dorsal spine showed a largely aspecific lesion. Neurosarcoidosis should be considered in the differential diagnosis of intramedullary cord lesion with leptomeningeal enhancement; a systematic search for evidence of sarcoidosis should be mandatory in all cases for a correct diagnosis and early treatment.

Abstract: Psychiatric disorders are common in Parkinson's disease (PD) and hallucinations are observed in nearly 40% of PD patients. The involvement of dopaminergic system in the pathogenesis of psychosis has been sustained by most of the authors even if several evidences indicate that multiple neurochemical substrates might underlie psychosis in PD. In PD there is an extensive loss of serotoninergic raphe neurons and serotonin dysfunction had been implicated in the pathogenesis of many psychiatric disorders such as depression, schizophrenia, and in psychosis of patients with Alzheimer disease. The association of a serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the 5-HT2A receptor T102C polymorphism with psychosis in a group of patients with PD was investigated. No significant differences in the distribution of allele and genotype frequencies of the 5-HTTLPR (p>0.01) and 5-HT2A T102C (p>0.05) were found between patients and controls as well as between the patients' subgroups without and with psychosis. These data might suggest that 5-HTTLPR and 5-HT2A polymorphisms are not major susceptibility factors of psychotic symptoms in PD patients.

Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand (123)I-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included. METHODS: We did a phase III study in which we used a (123)I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0.80) and specificity (0.85) targets and prespecified lower thresholds (sensitivity 0.65, specificity 0.73) using one-sided binomial tests with a significance level of alpha=0.025. FINDINGS: Abnormal scans had a mean sensitivity of 77.7% for detecting clinical probable DLB, with specificity of 90.4% for excluding non-DLB dementia, which was predominantly due to Alzheimer's disease. A mean value of 85.7% was achieved for overall diagnostic accuracy, 82.4% for positive predictive value, and 87.5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's kappa=0.87). The procedure was well tolerated with few adverse events. INTERPRETATION: A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.

Abstract: We used a CAPSIT-based questionnaire to estimate the percentage of parkinsonian patients suitable for subthalamic nucleus (STN) deep brain stimulation (DBS) in a movement disorders clinic. We found that out of 641 consecutive PD patients only 1.6% fulfilled strict STN-DBS criteria. When we applied more flexible criteria, the percentage of eligibility increased to 4.5%. Most patients (60%) were ineligible because they did not satisfy multiple questionnaire items. Items related to disease severity were responsible for the largest number of exclusions. This knowledge will help make decisions on resource allocation in centres wishing to start DBS surgery.

Abstract: 2006, there was, no single instrument (questionnaire or scale) for attempting a comprehensive assessment of the wide range of nonmotor symptoms (NMS) of Parkinson's disease (PD). The PD nonmotor group, a multidisciplinary group of experts including patient group representatives developed and validated the NMS screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self completed screening tool designed to draw attention to the presence of NMS. In this paper, we present the results gathered from 545 patients using the definitive version of the NMSQuest highlighting the prevalence of the wide range of NMS flagged in the NMSQuest from consecutive PD patients in an international setting. (c) 2007 Movement Disorder Society.

Abstract: OBJECTIVES: To assess midbrain atrophy through morphometric (linear, surface and volumetric) measurements in patients with clinically diagnosed progressive supranuclear palsy (PSP) and to establish the most accurate measure to be implemented in routine magnetic resonance (MR) protocol in distinguishing PSP from healthy subjects and MSA-p (multiple system atrophy, parkinsonian form) patients. MATERIALS AND METHODS: We studied 15 patients with the diagnosis of probable PSP, seven patients with the diagnosis of probable MSA-p and 14 age-matched healthy volunteers. MR protocol includes a sagittal SE T1-weighted sequence for cross-sectional area and linear brainstem measurements and a 3D-FSPGR sequence for brainstem volume measurements. RESULTS: A highly significant difference in the antero-posterior midbrain diameter, area and volume in PSP compared with control subjects was found. Only a measurement of the midbrain area and pons area enabled one to distinguish between PSP and MSA-p. Receiver operating characteristic analysis revealed that the midbrain area has the highest diagnostic accuracy in distinguishing between PSP and other conditions, with a sensitivity of 100% and specificity of 90.5%. The addition of the midbrain area/pons area ratio (A(ms)/A(pn) ratio) measurement improves the specificity in distinguishing between PSP and MSA. CONCLUSIONS: Morphological indexes indicate midbrain atrophy in PSP patients The combination of the A(ms) and A(ms)/A(pn) ratio measurements allows to discriminate between PSP and other conditions.

Abstract: The objective of this study is to compare the occurrence of dementia among Parkinson's disease (PD) patients treated with amantadine (AM group) with those never exposed to it (NoAM group). PD dementia shares neuroanatomical and biochemical similarities with Alzheimer's disease (AD). Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist has been shown to be beneficial in AD. Memantine is a dimethyl derivative of amantadine, which also possesses NMDA receptor blocking properties. We hypothesized that amantadine could have a beneficial effect on the occurrence of PD dementia. PD patients attending the Movement Disorders Clinics in Hillel Yaffe, Asaf Harofe Medical Centers (Israel) and Pisa (Italy) were included. Taking the onset of dementia as the endpoint, survival curves for AM and NoAM patients were estimated by the Kaplan-Meier method. The study population consisted of 593 patients (age, 69.5 +/- 9.9 years; PD duration, 9.2 +/- 6.0 years; 263 patients (44%) amantadine treated). The endpoint of dementia was reached by 116 patients (20%). PD duration until dementia was significantly longer for AM patients (9.1 +/- 5.7 years) than for NoAM patients (5.9 +/- 4.6 years, P = 0.006). The duration of amantadine exposure positively correlated with PD duration until dementia (P = 0.0001). Survival analysis, taking dementia onset as endpoint, showed slower mental decline in AM patients (Log rank P = 0.0049, Wilcoxon P = 0.0024). Mini-Mental State Examination scores were significantly higher for AM patients than for the NoAM group (P = 0.01). Age of PD onset also significantly influenced the duration of PD until dementia. Amantadine use may delay the onset of dementia in PD patients and may attenuate its severity.

Abstract: Idiopathic Parkinson's disease (IPD) patients have abnormal visual evoked potentials (VEPs) and pattern electroretinograms (PERGs), attributed to dopaminergic transmission deficiency in visual pathway, probably the retina. VEP abnormalities are not reported in multiple system atrophy (MSA). The aim of this study was to investigate and compare chromatic (Ch) red-green (R-G) and blue-yellow (B-Y), and luminance yellow-black (Y-Bk) PERGs in patients with MSA and IPD. We investigated 6 MSA patients (mean age: 62+/-7.4 years) not undergoing any pharmacological treatment, as well as 12 early IPD patients (mean age: 60.1+/-8.3 years) and 12 age-matched normal observers. ChPERGs were recorded monocularly in response to full-field equiluminant R-G, B-Y and Y-Bk horizontal gratings. In MSA only responses to R-G stimuli showed minimal insignificant changes (slight but not significant amplitude reduction without any significant latency delay); no significant abnormality was detected for B-Y and luminance Y-Bk stimuli. By contrast, in IPD all responses were reduced in amplitude and delayed in latency, above all for B-Y stimuli. Present data indicate that both chromatic and achromatic PERGs are virtually unaffected in MSA, whereas in early IPD they are clearly impaired, suggesting different pathogenic retinal mechanisms and a useful simple tool for distinguishing MSA from IPD.

Abstract: Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease and have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old. In the latter case, dopamine agonists are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists lose efficacy over time and the number of patients remaining on agonist monotherapy decreases to less than 50% after 3 years of treatment. Thus, after a few years of treatment the majority of patients who started on dopamine agonists will be administered levodopa, in a combined dopaminergic therapy, in order to achieve a better control of motor symptoms.

Abstract: Several evidences suggest that cholinergic deficits may significantly contribute to dementia in Parkinson's disease (PDD) and acetylcholinesterase inhibitors (ChEIs) have been reported to improve cognitive symptoms in PDD, without worsening parkinsonism. Nineteen PDD patients underwent brain perfusion SPECT with (99m)Tc-ethyl cysteinate dimer after 6 months ChEIs treatment in order to evaluate the functional correlates of clinical improvement. A clear-cut cognitive improvement was reported in PDD patients with a significant improvement of ADAS-cog total score as well as of subscores exploring executive functions (p<0.01). MMSE total score did not significantly change after ChEIs but the subscore of attention significantly improved after therapy (p<0.01). No difference in motor performance as evaluated by UPDRS was reported. SPM analysis showed a significant increase of perfusion (p < 0.0001) in bilateral cingulate, and frontal regions after ChEIs. Our data confirm the efficacy of ChEIs in the treatment of dementia associated with PD mainly on attention and executive functions, and the functional findings indicate that this cognitive improvement could be associated with a sort of pharmacological frontal "re-afferentation".

Abstract: OBJECTIVE: To evaluate in a prospective longitudinal study the evolution of functional disability and the response to dopaminergic therapy in PD patients with and without autonomic involvement. METHODS: Sixty untreated consecutive patients with PD underwent autonomic cardiovascular function evaluation using the five autonomic tests of Ewing. An integrated index (Autonomic Score=AS), taking in account the results of all subtests, was calculated. Patients were treated with pergolide and bromocriptine during a 5-year follow-up until the level of functional disability was sufficient to warrant the initiation of levodopa therapy. RESULTS: Results of autonomic testing were compared with those of a group of age-matched healthy subjects. A value of AS>2 was considered as indicative of autonomic failure. Eighteen patients with PD (35%) showed AS>2 (autonomically impaired group=AI), the remaining 33 (65%) had AS<2 (nonautonomically impaired group=non-AI). During the follow-up levodopa was added to the treatment regimen of 10/18 (55%) patients in AI group, and 6/33 (18%) patients in non-AI group (p<.01). CONCLUSIONS: The increased occurrence of levodopa adjunct in autonomically impaired PD suggests that there is a more rapid deterioration of functional performance in parkinsonian patients with early autonomic involvement.

Abstract: OBJECTIVE: Multiple system atrophy (MSA) may be difficult to distinguish from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine growth hormone (GH) stimulation test in distinguishing between MSA and PD in large populations of patients. METHODS: We measured the GH response to arginine in 69 MSA (43 MSAp [parkinsonism as the main motor feature] and 26 MSAc [cerebellar features predominated]) patients, 35 PD patients, and 90 healthy control subjects. We used receiver-operating curve analysis to establish the arginine cutoff value that best differentiated between MSA and PD. RESULTS: The GH response to arginine was significantly lower (p < 0.01) in MSA than in either PD patients or control subjects. At a cutoff level of 4 microg/L, arginine distinguished MSAp from PD with a sensitivity and specificity of 91% and MSAc from PD with a sensitivity of 96% and specificity of 91%. The arginine test had a positive predictive value for MSA of 95%. The GH response to arginine was not affected by disease duration or severity, MSA motor subtype, pyramidal signs, response to dopaminergic therapy, or magnetic resonance imaging findings. INTERPRETATION: The GH response to arginine differentiates MSA from PD with a high diagnostic accuracy. The results suggest an impairment of cholinergic central systems modulating GH release in MSA.

Abstract: To provide evidence-based recommendations for the management of late (complicated) Parkinson's disease (PD), based on a review of the literature. Complicated PD refers to patients suffering from the classical motor syndrome of PD along with other motor or non-motor complications, either disease-related (e.g. freezing) or treatment-related (e.g. dyskinesias or hallucinations). MEDLINE, Cochrane Library and INAHTA database literature searches were conducted. National guidelines were requested from all EFNS societies. Non-European guidelines were searched for using MEDLINE. Part II of the guidelines deals with treatment of motor and neuropsychiatric complications and autonomic disturbances. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement ('good practice point') is made.

Abstract:

Abstract: The aim of the study was to provide evidence-based recommendations for the management of early (uncomplicated) Parkinson's disease (PD), based on a review of the literature. Uncomplicated PD refers to patients suffering from the classical motor syndrome of PD only, without treatment-induced motor complications and without neuropsychiatric or autonomic problems. MEDLINE, Cochrane Library and International Network of Agencies for Health Technology Assessment (INAHTA) database literature searches were conducted. National guidelines were requested from all European Federation of Neurological Societies (EFNS) societies. Non-European guidelines were searched for using MEDLINE. Part I of the guidelines deals with prevention of disease progression, symptomatic treatment of motor features (parkinsonism), and prevention of motor and neuropsychiatric complications of therapy. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement (good practice point) is made.

Abstract: Many of the motoric features that define Parkinson's disease (PD) result primarily from the loss of dopaminergic neurons of the substantia nigra. l-dopa remains at present the most powerful symptomatic drug for the treatment of this condition. However, motor complications of chronic l-dopa treatment have emerged as a major limitation of this therapy. Slowing or delaying the progression of the disease with neuroprotective therapies may delay the need for l-dopa. In the past few years, novel insight into the pathogenetic mechanisms of neurodegeneration in PD has been provided. Mitochondrial function deficiency, increased oxidative stress, apoptosis, excitotoxicity, and inflammation are part of the processes that ultimately result in neurodegeneration. Drugs that are now under clinical scrutiny as neuroprotectant include molecules that combine one or more of the following properties: (1) monoamine oxidase inhibition (rasagiline, safinamide); (2) mitochondrial enhancement (coenzyme Q10, creatine); (3) antiapoptotic activity; (4) anti-inflammatory activity; (5) protein aggregation inhibition; (6) neurotrophic activity. In advanced Parkinson's disease, the combination of disease progression and l-dopa therapy leads to the development of motor response complications, particularly wearing off, on off, dyskinesias and dystonias. The nonphysiologic pulsatile stimulation of striatal dopamine receptors, produced by the currently available dopaminergic drugs, may trigger a dysregulation of many neurotransmitter systems within the basal ganglia, mainly localized on medium spiny striatal neurons. These include alterations of glutamatergic, serotonergic, adrenergic and adenosine A(2A) receptors. Novel strategies for pharmacological intervention with nondopaminergic treatments hold the promise of providing effective control or reversal of motor response complications. Of particular interest are NMDA and AMPA antagonists or drugs acting on 5-HT subtype 2A, alpha2-adrenergic, and adenosine A(2) receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern of basal ganglia neurons, such as synaptic vesicle proteins, nonsynaptic gap junction communication mechanisms, or signal transduction systems that modulate the phosphorylation state of glutamatergic receptors.

Abstract: The aim of the study was to determine the clinical frequency and features of REM sleep behaviour disorder (RBD) in a large population of Parkinson's disease (PD) patients using defined diagnostic criteria both for RBD and PD. Six trained neurologists used a semistructured questionnaire based on ICSD-R diagnostic criteria for RBD to evaluate 200 PD patients and their caregivers. Interobserver reliability for the diagnosis of RBD was "substantial" (Kappa 0.65). Five patients were excluded from the study because of an MMSE lower than 25. The demographic and PD clinical features were compared in the clinically defined RBD group and in those without RBD (NRBD). Then the RBD features during the last year were analysed in the affected group. Out of 195 patients, 66 fulfilled the ICSD-R criteria for RBD; 62 patients reported RBD during the last year (frequency 31.8%). RBD features: two or more episodes per week in 35.5%; upper limb movements in 87%; lower limb movements in 79%; vocalisations during events in 85%. RBD onset was before PD in 27% of patients; 69% of the RBD group had injured themselves or their caregivers during sleep. According to multivariate analysis, RBD was associated with male gender, age and PD duration. Brief training and the use of a semistructured questionnaire may help the neurologist in dealing with sleep disturbances in PD patients. The search for RBD symptoms in PD is highly recommended, especially in patients with a long disease duration, the risk of sleep-related injuries being high.

Abstract: It has been proposed that European mitochondrial DNA (mtDNA) haplogroups J and K, and their shared 10398G single-nucleotide polymorphism (SNP) in the ND3 gene, are protective from Parkinson's disease (PD). We evaluated the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset (>50, <65 years of age) idiopathic PD vs two groups of ethnic-matched controls. Neither the frequencies of haplogroup J nor that of 10398G were significantly different. However, the frequency of haplogroup K was significantly lower in PD. Stratification by sex and age indicated that the difference in the distribution of haplogroup K was more prominent in >50 year old males. In spite of the common 10398G SNP, haplogroups J and K belong to widely diverging mitochondrial clades, a consideration that may explain the different results obtained for the two haplogroups in our cohorts. Our study suggests that haplogroup K might confer a lower risk for PD in Italians, corroborating the idea that the mitochondrial oxidative phosphorylation pathway is involved in the susceptibility to idiopathic PD.

Abstract: The epidemiology of multiple system atrophy (MSA) is scarcely known, and risk factors have not been definitely identified. We investigated the effect of family history for neurodegenerative diseases and environmental factors on MSA risk in a multicentric case-control study. A total of 73 MSA patients (42 men, 31 women; age, 64.3 +/- 8.1 years; disease duration, 4.8 +/- 3.9 years), 146 hospital controls (84 men, 62 women; age, 64.9 +/- 8.4 years), and 73 population controls (42 men, 31 women; age, 63.7 +/- 8.9 years) matched for sex, age (+/-3 years), and province of residence were enrolled consecutively at seven neurological centers from 1 January 1994 to 31 July 1998. The following variables were investigated: family history of neurodegenerative diseases, education, smoking habits, hobbies, and occupational history. Occupational history of farming was significantly more frequent among MSA cases than controls (OR adj = 2.52; 95% CI, 1.25 to 5.07, MSA vs. hospital controls; OR adj = 4.53; 95% CI, 1.68 to12.2, MSA cases vs. population controls). A dose-response analysis for years of farming corroborated this association. We recently found that smoking is significantly less frequent among MSA cases than controls (Vanacore et al. [2000] Neurology 54:114-119). Here, we report that the effects of farming and smoking on MSA risk do not interact. Our results suggest that occupational history of farming is a risk factor for MSA. Smoking and farming seem to influence MSA risk independently. Further epidemiological studies might provide clues on the etiopathogenesis of MSA.

Abstract: The authors studied four patients with parkinsonism carrying the fragile X premutation using SPECT with ([23)I]FP-CIT. They found evidence of preserved presynaptic nigrostriatal function, suggesting that parkinsonism in the X fragile premutation might be related to postsynaptic dopaminergic changes or different neurotransmitter alterations.

Abstract: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.

Abstract: Several lines of evidence, including an increased level of lipid peroxidation and the depletion of antioxidant molecules like as glutathione (GSH), indicate that oxidative stress plays an important role in the pathogenesis of several neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). We previously observed a significant increased level of DNA oxidative damage in peripheral blood cells of PD patients, with respect to controls, moreover, the activity of glutathione transferases (GSTs) measured in circulating plasma was higher in controls than in PD patients, suggesting a lower enzymatic protection in PD individuals. Among human GSTs, glutathione transferase A4-4 displays a high catalitic activity towards 4-hydroxy-2-nonenal (HNE), a marker of lipid peroxidation whose levels have been found significantly increased in the substantia nigra of Parkinson's disease patients, in respect to controls. We performed this study to determine the presence of allelic variants of functional interest in the coding region of the hGSTA4 gene on 60 PD patients and 60 healthy controls. By the combined effort of polymerase chain reaction/single-strand conformation polymorphisms (PCR/SSCP) techniques, we observed a single nucleotide polymorphism (SNP) G351A leading to the silent mutation Gln117Gln. No significant difference was observed in the distribution of this polymorphism between PD individuals and controls, moreover, we did not observe any other polymorphism in the hGSTA4 gene in our population. Further studies are required to test the role played by both factors regulating the level of the expression of the hGSTA4 gene and any possible post-translational modification of the protein, in the protection against oxidative damage in neuronal cells.

Abstract: Behavioural disturbances are frequently observed in Parkinson's disease (PD), including mood and anxiety disorders. The existence of a comorbidity between such psychiatric disorders in PD patients has been suggested only in a few studies. To assess the prevalence of mood and anxiety disturbances, and the rate of comorbidity of such disorders in PD. Secondary aim was to correlate the prevalence of psychiatric disorders in PD with age, sex, laterality of motor symptomatology, clinical features, severity of disease, age of onset and PD duration, and anti-parkinsonian therapy. Ninety consecutive PD outpatients, and 90 age- and sex-matched controls were included. All PD patients enrolled were non-fluctuating (21 de novo, 69 treated with levodopa or dopamine agonists). PD patients and controls with Mini Mental State Examination score <23 were excluded. Psychiatric diagnosis was performed by semistructured interview according with DSM-IV criteria and the severity of depressive and anxious symptoms was rated with clinical rating scales. Major depression was found in 21.1% PD patients vs. 3.3% controls (P < 0.01, chi-square analysis), dystimia in 18.8% PD patients vs. 4.4% controls (P < 0.05), panic disorders in 30% PD patients vs. 5.5% controls (P < 0.01). No difference in the prevalence of other anxiety disorders was observed between the two groups. The comorbidity of mood and anxiety disorders was found in 19.3% PD patients vs. 8.6% controls (P < 0.01). No correlation was reported between the prevalence of behavioural disturbances and any of the demographic, clinical or pharmacological data taken into account. Our findings might suggest the existence of a wide spectrum of psychiatric disorders in PD ranging from pure depressive disorders, comorbid depressive and anxiety disorders, and pure anxiety disorders, presumably linked to the same neurobiological substrate.

Abstract:

Abstract: OBJECTIVES: To evaluate the reliability and validity of the Short Parkinson's Evaluation Scale (SPES)/SCales for Outcomes in Parkinson's disease (SCOPA)-a short scale developed to assess motor function in patients with Parkinson's disease (PD). METHODS: Eighty five patients with PD were assessed with the SPES/SCOPA, Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) scale, and Schwab and England (S&E) scale. Thirty four patients were examined twice by two different assessors who were blinded to each other's scores and test executions. Additionally, six items of the motor section of the SPES/SCOPA were assessed in nine patients and recorded on videotape to evaluate inter-rater and intra-rater reliability. RESULTS: The reproducibility of the sum scores in the clinical assessments was high for all subscales of the SPES/SCOPA. Inter-rater reliability coefficients for individual items ranged from 0.27-0.83 in the motor impairment section, from 0.58-0.82 in the activities of daily living section, and from 0.65-0.92 in the motor complications section. Inter-rater reliability of the motor items in the video assessments ranged from 0.70-0.87 and intra-rater reliability ranged from 0.81-0.95. The correlation between related subscales of the SPES/SCOPA and UPDRS were all higher than 0.85, and both scales revealed similar correlations with other measures of disease severity. The mean time to complete the scales differed significantly (p<0.001) and measured 8.1 (SD 1.9) minutes for the SPES/SCOPA and 15.6 (SD 3.6) minutes for the UPDRS. CONCLUSION: The SPES/SCOPA is a short, reliable, and valid scale that can adequately be used in both research and clinical practice.

Abstract: The occurrence of parkinsonism in Alzheimer's disease (AD) is quite common, however the molecular and neurochemical changes underlying such extrapyramidal features in AD have been not fully understood. Post-mortem as well as in vivo imaging study have produced conflicting results as regards the existence of dopaminergic changes in AD. Aim of the present study was to investigate in vivo the nigro-striatal dopaminergic function in a group of AD patients with parkinsonism. Thirteen patients with AD and extrapyramidal features not related to past neuroleptic use (AD-P) underwent SPECT with 123I-FP-CIT, a ligand of dopamine transporter, and the data were compared with those obtained in 15 patients with Diffuse Lewy Body Dementia (DLBD), 20 patients with Parkinson's disease (PD), and 8 healthy elderly controls. The analysis of the data was performed by regions-of-interest approach and calculations of the striatal-to-non specific (occipital lobes) radioactivity ratios were made. The 123I-FP-CIT striatal uptake in patients with AD-P was similar to that obtained in the control population. Both the DLBD and PD groups showed significantly lower 123I-FP-CIT uptake in all striatal areas with respect to AD-P and control groups (p < 0.005). The lack of dopamine transporter changes in our series of AD-P patients can indicate that dopaminergic presynaptic function is preserved in this population and that different dopaminergic changes such as postsynaptic ones, or different neurotransmitter alterations might underlie the extrapyramidal features in AD.

Abstract: To date the aetiology of Parkinson's disease (PD) is unknown although both genetic susceptibility and environmental factors appear to play an important role in the development of the disease. Recent data have also indicated that chronic exposure to a common pesticide can reproduce the neurochemical, behavioral and neuropathological features of PD. The epidemiological studies previously carried on the prevalence of PD in population exposed to environmental factors have produced controversial results, probably because of different trial design and different analysis methods. A case-control retrospective study was conducted in a well-defined geographic area in Tuscany-Italy with the aim to identify environmental factors possibly related to PD. No significant difference between PD patients and control subjects was observed in time spent in rural or industrial residence, in well water drinking and in the exposure to herbicides and pesticides. A significant difference between patients with PD and controls was reported for cigarette smoking, controls resulting more likely cigarette smokers in comparison with PD patients. The present findings support the view of a protective effect of cigarette smoking and do not show any significant association between environmental factors and the risk of development of PD.

Abstract: Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Abstract: A median safinamide (SAF) dose of 70 mg/day (range 40 to 90 mg/day) increased the percentage of parkinsonian patients improving their motor scores by > or =30% from baseline (responders) after 3 months from 21.4% (placebo) to 37.5% (p < 0.05, calculated by logistic regression analysis). In a subgroup of 101 patients under stable treatment with a single dopamine agonist, addition of SAF magnified the response (47.1% responders, mean 4.7-point motor score decrease; p > or = 0.05). These results suggest that doses of SAF exerting ion channel block and glutamate release inhibition add to its symptomatic effect and warrant exploration of higher doses.

Abstract: Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for D(2) receptors indicated for use in both early and advanced Parkinson's disease and in hyperprolactinaemic disorders.Following oral administration, peak plasma concentrations of cabergoline are reached within 2-3 hours. Over the 0.5-7mg dose range, cabergoline shows linear pharmacokinetics in healthy adult volunteers and parkinsonian patients. Cabergoline is moderately bound (around 40%) to human plasma proteins in a concentration-independent manner; concomitant administration of highly protein-bound drugs is unlikely to affect its disposition. The absolute bioavailability of cabergoline is unknown.Cabergoline is extensively metabolised by the liver, predominantly via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P450-mediated metabolism appears to be minimal. The major metabolites identified thus far do not contribute to the therapeutic effect of cabergoline. A significant fraction of the administered dose undergoes a first-pass effect. Less than 4% is excreted unchanged in the urine. The elimination half-life of cabergoline estimated from urinary data of healthy subjects ranges between 63 and 109 hours. Mild to moderate renal and hepatic impairment, administration of food and the use of concomitant antiparkinsonian medications, such as levodopa and selegiline, have no effect on the pharmacokinetics of cabergoline.The pharmacokinetic properties of cabergoline allow once daily administration in patients with Parkinson's disease and twice weekly administration in patients with hyperprolactinaemia, making this drug advantageous over other dopaminergic agents in term of both therapeutic compliance and better symptom control.

Abstract: In this report we show that dextromethorphan, a non-opioid cough suppressant, prevents the neurodegeneration of dopaminergic neurons in the substantia nigra of mice treated with diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This effect is further substantiated by the assessment of dopamine (DA) content in the striatum of these animals. Dextromethorphan does not attenuate the striatal DA fall induced by MPTP alone but completely prevents DDC-induced enhancement after the combined treatment. Moreover, a study of DA metabolites has confirmed this neuroprotective property. The striatal levels of serotonin, which were studied as a control neuronal marker, did not change with any of the treatments administered. Furthermore, we show that dextromethorphan reduces the toxicity of glutamate against dopamine neurons in mesencephalic cell cultures. In line with previous data suggesting that dextromethorphan can prevent neuronal damage, our observations supply new evidence regarding the possibility of this compound being of therapeutic use in neurodegenerative diseases.

Abstract: Thirteen patients with multiple system atrophy underwent multimodality neurophysiological evaluation, including sphincteric needle electromyography (EMG), sacral reflexes, pudendal nerve terminal latency, pudendal (PSEPs) and tibialis posterior nerve somatosensory evoked potentials (TPSEPs), and perineal motor evoked potentials (PMEPs). EMG revealed denervation or neurogenic changes, with reduction in spontaneous tonic activity at rest and abnormal pudendal nerve terminal latency in 10 patients (76.9%); anal reflex was delayed in 7 patients (53.8%). TPSEPs scalp responses were clearly abnormal in 4 patients (30.7%), whereas PSEPs exhibited changes in 9 (69.2%): in 6 patients responses were delayed at lumbar level (46.2%), and in 5 over the scalp (38.4%). PMEPs showed an increase in latency with a mild prolongation of central motor conduction time (CMCT) in 2 cases (15.3%); 1 patient had prolonged latencies following both cortical and sacral stimulation, but a normal CMCT. Even if diagnostic yield is not improved using these investigations they provide evidence of multiple lesion sites other than Onuf's nucleus.

Abstract: Visual-spatial working memory (WM) impairment is frequently associated with the early stage of Parkinson's disease (PD). The aim of this study was to evaluate the performance of a group of PD patients in visual-spatial and visual-object WM tasks and to investigate the effect of administering the dopaminergic agonist apomorphine (experiment 1) or the dopamine precursor L-dopa (experiment 2) on the performance of tests assessing these functions. To study WM processes, the PD patients and age-matched normal controls were given an n-back task paradigm. In both experiments, the PD patients were submitted to two evaluations: one after a 12-hour therapy washout and the other 15 min after a subcutaneous infusion of apomorphine (average 0.04 mg/kg) or 20/30 min after L-dopa intake (200 mg p.o.). The apomorphine infusion had a worsening effect on reaction times in both visual-spatial and visual-object WM tasks, but it did not influence performance accuracy. Instead, L-dopa administration had a ameliorative effect on accuracy and reaction times in both visual-spatial and visual-object tasks. These results highlight the role of dopamine in the modulation of the WM function in PD patients.

Abstract: Tolcapone is a mixed (peripheral and central) catechol-O-methyltransferase (COMT) inhibitor, whereas entacapone is a preferential peripheral COMT inhibitor. Both drugs are able to decrease the peripheral conversion of L-DOPA into 3-O-methyl-DOPA and thereby increase plasma and cerebral levels of L-DOPA, the precursor of dopamine (DA). Tolcapone may also impair the extraneuronal catabolism of DA by inhibiting COMT activity in the brain. To evaluate the role played by peripheral and central COMT inhibition, we compared the effects of tolcapone and entacapone on COMT activity in peripheral tissues, and on striatal extracellular levels of L-DOPA and DA in rats. Tolcapone and entacapone, at the dose of 15 mg/kg p.o., were almost equally effective in inhibiting COMT activity in duodenum and liver. Tolcapone decreased striatal extracellular levels of homovanillic acid (HVA), thus confirming its central COMT inhibitory effect, whereas entacapone did not alter HVA efflux. Following L-DOPA/benserazide administration (50/15 mg/kg p.o.), both COMT inhibitors significantly increased striatal levels of L-DOPA and DA compared with saline. The levels of L-DOPA were similar after treatment with either COMT inhibitors, whereas the increase in DA output was significantly greater in rats given tolcapone compared to those given entacapone. We conclude that the blockade of central DA catabolism by tolcapone contributes to the greater increase in striatal DA levels achieved with this drug.

Abstract: The acute antidyskinetic effects of IV amantadine in HD were evaluated. A 2-hour IV infusion of amantadine or placebo was administered to nine patients with HD on two different days in a double-blind, randomized crossover fashion. All patients subsequently received oral amantadine unblinded for a 1-year period. A reduction of dyskinesia scores was reported during both IV and oral amantadine treatment (p < 0.05). No significant changes were observed in neuropsychological tests or psychiatric rating scales.

Abstract: BACKGROUND: It is accepted that orthostatic hypotension is a clinical marker for the diagnosis of multiple system atrophy, but conflicting data indicate that it may also be present in Parkinson disease (PD). OBJECTIVES: To evaluate the prevalence of autonomic cardiovascular impairment and orthostatic hypotension in a large group of patients with de novo PD, followed up for at least 7 years, to clinically confirm the diagnosis of the disease. METHODS: During a 2-year recruiting period, 60 untreated patients diagnosed as having idiopathic PD underwent autonomic cardiovascular function evaluation using the Ewing test. Patients subsequently received dopaminergic therapy and their condition was followed up for at least 7 years. RESULTS: Nine (15%) of 60 patients were excluded from the study because during the follow-up period a parkinsonian syndrome was diagnosed (5 had multiple system atrophy and 4 had progressive supranuclear palsy). Data from 51 patients with PD underwent final statistical analysis and the results were compared with those of 51 age-matched healthy control subjects who had taken the same battery of autonomic tests. A statistically significant difference was found in postural hypotension (P =.02) and deep breathing test results (P =.03) between patients and controls. Seven (14%) of 51 patients with PD and 3 (60%) of 5 patients with multiple system atrophy had a decrease of more than 20 mm Hg in systolic blood pressure on standing. CONCLUSIONS: Data from this study indicate a high prevalence of sympathetic and parasympathetic failure in patients with de novo PD, and when using a decrease of at least 20 mm Hg in systolic blood pressure, manometric orthostatic hypotension was found in 7 (14%) of the 51 patients with de novo PD.

Abstract: Excessive daytime somnolence is a common adverse effect of dopamine-agonist treatment of Parkinson's disease (PD). Many factors, such as age and sleep disturbances, could be involved in the pathogenesis of this phenomenon. However, pharmacokinetic factors have never been considered. In this open, prospective, pilot study, nine consecutive non-demented PD patients in early disease stages on monotherapy treatment with dopamine agonists and with no significant sleep problems, were enrolled. They were selected based on the presence of excessive daytime sleepiness induced by the dopaminergic treatment. A fast switch-over from the dopamine agonist currently used to a single equivalent dose of cabergoline, a long-acting dopamine agonist, administered at bedtime was performed. All patients were evaluated by means of UPDRS and Epworth Sleepiness Scale (ESS). A significant 70% reduction of daytime sleepiness was observed during the 3-month study compared with baseline. Data from this study suggest that both pharmacodynamic and pharmacokinetic mechanisms are involved in the pathophysiology of dopamine agonist-induced sleepiness.

Abstract: In Parkinson's disease (PD), the luminance pattern electroretinogram (PERG) is reported to be abnormal, indicating dysfunction of retinal ganglion cells (RGCs). To determine the vulnerability of different subpopulations of RGCs in PD patients, the authors recorded the PERG to stimuli of chromatic (red-green [R-G] and blue-yellow [B-Y]) and achromatic (yellow-black [Y-Bk]) contrast, known to emphasize the contribution of parvocellular, koniocellular, and magnocellular RGCs, respectively. Subjects were early PD patients (n = 12; mean age, 60.1 +/- 8.3 years; range, 46 to 74 years) not undergoing treatment with levodopa and age-sex-matched controls (n = 12). Pattern electroretinograms were recorded monocularly in response to equiluminant R-G, B-Y, and Y-Bk horizontal gratings of 0.3 c/deg and 90% contrast, reversed at 1Hz, and presented at a viewing distance of 24 cm (59.2 x 59 degree field). In PD patients, the PERG amplitude was significantly reduced (by 40 to 50% on average) for both chromatic and luminance stimuli. Pattern electroretinogram latency was significantly delayed (by about 15 ms) for B-Y stimuli only. Data indicate that, in addition to achromatic PERGs, chromatic PERGs are altered in PD before levodopa therapy. Overall, chromatic PERGs to B-Y equiluminant stimuli exhibited the largest changes. Data are consistent with previous findings in PD, showing that visual evoked potentials (VEP) to B-Y chromatic stimuli are more delayed than VEPs to R-G and achromatic stimuli. The results suggest that the koniocellular subpopulation of RGCs may be particularly vulnerable in early stages of Parkinson's disease.

Abstract: The clinical differentiation of Lewy body dementia (LBD) from Alzheimer's disease (AD) may be difficult. The aim of the present study was to assess the dopamine transporter function and the perfusional pattern in LBD and AD in vivo. Twenty patients with probable LBD and 24 with probable AD underwent on 2 separate days a brain perfusional SPECT with 99mTc-ECD and a SPECT with (123)I-FP-CIT, a ligand of dopamine transporter. In LBD a significantly ( p<0.0005) lower ratio of specific (bilateral caudate nucleus, putamen) to non-specific (occipital cortex) (123)I-FP-CIT binding than in AD was reported. Perfusional data (SPM analysis) showed a significant ( p<0.001) decrease of temporo-parietal blood flow in AD versus LBD, whereas in LBD a significant ( p<0.001) occipital hypoperfusion with respect to AD was reported. Our findings confirm that dopaminergic nigrostriatal function is impaired in LBD. The selective occipital hypoperfusion in LBD needs to be further investigated.

Abstract: Dopamine agonists are effective in the management of both advanced and early-stage Parkinson's disease. Unfortunately, randomized head-to-head comparative studies between the many different dopamine agonists now available are sparse. Indirect comparisons of dopamine agonists show that ergot derivatives, such as pergolide and cabergoline, are as effective as non-ergot derivatives, such as ropinirole and pramipexole, in ameliorating Parkinson's disease symptoms in patients in early or advanced stages of the condition. As far as safety and tolerability are concerned, no significant differences between dopamine agonists are found. However, some specific adverse events, such as somnolence and sleep attacks, seem less frequent in monotherapy studies with pergolide than in those with the non-ergot dopamine agonists; however, because of the lack of direct-comparison studies this cannot be proved conclusively. Randomized, controlled comparative studies between dopamine agonists are necessary to verify any possible differences in their effectiveness and tolerability in the treatment of Parkinson's disease.

Abstract: The idiopathic cerebellar ataxias (IDCA) comprise a wide spectrum of neurodegenerative diseases with heterogeneous neuropathology, characterized by the negativity of search for any known genetic mutation. On the basis of both their clinical presentation and their magnetic resonance imaging pattern, patients with IDCA can be subdivided into patients with a purely cerebellar syndrome and atrophy of the cerebellum (IDCA-C) and patients with additional noncerebellar symptoms and atrophy of both cerebellum and brainstem (IDCA-P). The aim of the present study was to evaluate the disaggregated contribution of brainstem and cerebellum in the control of eye movements, by means of an extensive battery of quantitative tests covering most oculomotor subfunctions related to lesions of the cerebellum and the brainstem. The smooth-pursuit movement analysis showed a decrease in gain and magnitude in both subgroups of IDCA with respect to normal controls, without any significant differences in the prevalence pattern between the two subgroups; the mean values of these parameters, however, were significantly lower in IDCA-P than in IDCA-C subjects in both gain (P < 0.01) and magnitude (P < 0.001). No statistically significant difference was observed between the two subgroups in the analysis of saccadic movements or in the other parameters investigated. The distinction between IDCA-P and IDCA-C subgroups has clinical implications, as a poorer prognosis is related to brainstem involvement, which may occur late in the course of the disease. Thus, the possibility to detect the brainstem involvement, also in association with cerebellar impairment, by a relatively simple eye-movement analysis, potentially useful mainly in follow-up investigations, needs to be evaluated further.

Abstract: The objective of this study was to develop a Parkinson's disease diary that evaluates a patient's difficulties in performing activities as a substitute for the amount of "on"- and "off"-time and to assess its clinimetric qualities. In this study, 84 patients with Parkinson's disease kept a diary for 2 or 3 periods of 5 days. Daily, five items were recorded across 11 time periods. Patients simultaneously recorded "on-off" in the traditional way. The diary was easily understood, and median recording time was 5-10 minutes a day. Clinimetric analysis showed that the diary could be reduced successfully to 3 days, in which five items (walking, transfers, manual activities, dyskinesias, and sleep) with four response options (no, slight, moderate, and severe difficulty) were assessed seven times daily. Sumscores of the first three items accurately predicted being "on" or "off" in 93% of the cases, making separate scoring of "on" and "off" unnecessary. The diary was internally consistent and showed good reproducibility. Construct validity with external measures was adequate, and comparisons between patients grouped by disease severity and by degree of fluctuations revealed significant differences in the expected directions. Taken together, this Parkinson's disease diary has a sound clinimetric basis, provides information on the extent of perceived disability, and thereby accurately reflects the severity of "off"-periods and the variability of motor fluctuations.

Abstract: PURPOSE: the aim of this experimental study was to evaluate the attention modulating actions on the polysynaptic component of blink reflex responses and especially of the R3 component in patients suffering from Parkinson's Disease (PD). To this end, a non-task warning paradigm was adopted. METHODS: attention processing was evaluated by means of a non-task paradigm in 55 patients suffering from PD. Subjects were presented with a visual 'warning' prestimulus and the blink reflex (BR) analyzed with special regard for any modulation of its polysynaptic components (R2-R3). RESULTS: The mean amplitude of the post-warning R3 component (PW-R3c) of 'de novo' PD patients was 62% of the corresponding component following unannounced stimuli, a figure which differs significantly from both treated PD patients (18.9%) and control subjects (15.4%). De novo patients subsequently started on L-dopa therapy exhibited a more pronounced inhibition of the R3 component after warning stimulus, as the PW-R3c percentage decreased. Inversely, treated patients whose therapy was withheld showed decreased inhibition of this component. Regarding R2, the mean PW-R2c in the de novo patients differed slightly from that of the treated patients (P<0.05), but not from that of the control subjects. Such a finding may be attributable to a specific effects on the excitability of the polysynaptic responses. CONCLUSIONS: Attention disorders in PD have been well documented by means of this kind of non-task warning paradigm, which appears to probe the modulation of the BR R3 component, even if the interpretation of this R3 changes suggesting a specific alteration of attention processing must be put forward extremely carefully, because something similar, but less evident, appears also for R2.

Abstract: Tardive dystonia represents a complication of long-term use of neuroleptics and its treatment is often unsatisfactory. Atypical neuroleptics appear to improve tardive dystonia, and cases of tardive dystonia successfully managed with clozapine have been reported. The aim of this open-label video-blinded study was to evaluate the antidystonic efficacy of olanzapine, a new atypical neuroleptic with a low risk of agranulocytosis, in a group of four patients (one man and three women) with tardive cervical dystonia. They developed severe dystonia after several years of neuroleptic treatment. Extensive laboratory evaluations, as well as neurophysiologic and neuroradiologic investigations, were negative. Olanzapine was started at a dose of 5 mg/d and increased up to 7.5 mg/d. All patients were evaluated at baseline and after 2, 4, 8, and 12 weeks of treatment, using the Toronto Western Spasmodic Torticollis Rating Scale, and videotaped. At the end of the trial, the videotapes were reviewed and scored by a blind observer. A self-rating visual analog scale completed the disability evaluation.A moderate to marked improvement in dystonia was observed in all patients, and significant differences were observed in Toronto Western Spasmodic Torticollis Rating Scale scores and videotape ratings after 8 and 12 weeks of treatment compared with the basal values (p < 0.05). The average percentage of improvement in Toronto Western Spasmodic Torticollis Rating Scale score and visual analog scale was 26.4% and 42.6%, respectively. No serious side effects were reported at the maximum dosage reached (7.5 mg/d). This study warrants a larger controlled study to conclusively demonstrate the efficacy of olanzapine in tardive dystonia.

Abstract: Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.

Abstract: The Short Parkinson's Evaluation Scale has been compiled and validated previously (Clinical Neuropharmacology, 1997). In the present study, we have assessed and compared the motor scoring of the Unified Parkinson's Disease Rating Scale and the Short Parkinson's Evaluation Scale in 23 patients (mean age, 61.8 years) with Parkinson's disease. Patients were 12 hours off medication at the beginning of the series. They were then given levodopa, 125 mg and 250 mg, on different days and were evaluated each 30 minutes for 2 hours. In addition, patients' motor skills (finger tapping and walking velocity) were measured at each time. Analysis of variance with repeated measures was applied. The results presented show that both scales have the same ability to measure levodopa-dose effect within time. In addition, Spearman's correlation coefficients showed a negative correlation between finger tapping and upper-limb impairment and a positive correlation between walking velocity and lower-limb impairment in both scales.In summary, the present results suggest that Short Parkinson's Evaluation Scale is a useful tool in assessing the effect of medication, having the advantage of being easier and quicker.

Abstract: Huntington's disease (HD) is characterized by chorea, cognitive and behavioral changes. Amantadine, a non-competitive NMDA receptor antagonist, has shown an antidyskinetic effect on levodopa-induced dyskinesias, which are known to have strict pathogenetic analogies with choreic hyperkinesias. The antidyskinetic efficacy of amantadine and its effects on cognitive and behavioural symptoms were evaluated. Eight HD patients received oral amantadine (100 mg tid) unblinded for a 1-year period. A significant reduction of dyskinesias was reported ( p<0.01). No changes were observed in neuropsychologic and psychiatric assessments after 6 and 12 months of therapy. These data may have relevance to the treatment of HD with amantadine.

Abstract: We investigated the presence of cytogenetic alterations in peripheral blood lymphocytes of Alzheimer's disease (AD) and Parkinson's disease (PD) patients. Detection of spontaneous structural and/or numerical chromosome damage has been assessed by micronucleus (MN) assay coupled with fluorescence in situ hybridization (FISH). The cytogenetic investigation was performed on 22 AD patients, 18 PD patients, and 20 controls. The spontaneous frequencies of micronuclei (MN) in human lymphocytes of both AD and PD patients were significantly higher than in controls. The majority of MN was composed of whole chromosomes in AD patients, while a prevalence of MN arising from chromosome breakage was observed in PD patients. Different molecular mechanisms underlie cytogenetic alterations observed in peripheral lymphocytes of AD and PD patients.

Abstract: Aceruloplasminemia is a recessive disorder characterized by anemia, iron overload, and neurodegeneration, caused by the absence of ceruloplasmin (Cp), a multicopper oxidase important for iron export. Few patients homozygous for loss of function mutations of the Cp gene have been reported. We describe a 62-year-old white woman with heavy liver iron overload, diabetes, anemia, and neurologic symptoms. She was compound heterozygote for 2 novel mutations that result in the absence of hepatocyte Cp: an adenine insertion at nucleotide 2917 causing a truncated protein and a C-G transversion causing a glutamine-->glutamic acid substitution at position 146. Although rare in whites, aceruloplasminemia should be considered in the differential diagnosis of unexplained anemia associated with iron overload, because these features anticipate progressive neurologic symptoms. We propose that anemia, secondary to the impaired macrophage iron release, plays a major role in hepatic iron overload through increased absorption mediated by the erythroid regulator.

Abstract: BACKGROUND: Postmortem studies suggest excessive free radical toxicity in the substantia nigra of patients with PD. Increased lipid peroxidation and oxidative DNA damage have been reported in the CNS. Markers of oxidative stress have been identified in the blood of patients with PD. OBJECTIVE: To assess the presence of spontaneous chromosome and primary or oxidative DNA damage in peripheral blood leukocytes of patients with untreated PD. METHODS: Patients with de novo PD (20) and control subjects (16), matched for age, sex, and smoking habits, underwent cytogenetic analysis using the human lymphocyte micronucleus assay coupled with the fluorescence in situ hybridization technique and the Comet assay. RESULTS: Compared with controls, patients with PD showed an increase in the incidence of spontaneous micronuclei (p < 0.001); single strand breaks (p < 0.001); and oxidized purine bases (p < 0.05). Fluorescence in situ hybridization analysis showed micronuclei harboring acentric fragments. CONCLUSIONS: There is chromosomal, primary DNA damage and oxidative DNA damage demonstrable in lymphocytes of patients with untreated PD.

Abstract: The authors studied the motor response to apomorphine before and 1 year after levodopa therapy in 12 patients with Parkinson's disease. At the 1-year evaluation, the basal tapping score, recorded after a 12-hour levodopa withdrawal, was higher compared with the test performed while patients were de novo, indicating the presence of a long-duration response to levodopa. The amplitude (net increase) of the motor response to apomorphine was similar before and during levodopa therapy. However, because of the better baseline, the maximal tapping score was higher during levodopa therapy. The duration and the latency of the motor response to apomorphine did not change. The presence of a short-duration response to apomorphine, in the presence of a long-duration response to levodopa, may imply that either different compartment (i.e., postsynaptic versus presynaptic) or transduction pathways are involved in such responses.

Abstract: Essential tremor (ET) is one of the most common movement disorders. However the pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidences suggested that the ET gene might contain a CAG expanded region. In a cohort of Italian ET patients Repeat Expansion Detection (RED) approach did not demonstrate large CAG expansions. We extended the study towards specific targets: the channel proteins hSKCa3 and CACNL1A4. Direct assessment of CAG stretches within these two genes did not demonstrate any CAG expansion in affected subjects. Also a case-control analysis failed to reveal any evidence of association, thus excluding these genes as a cause of ET.

Abstract: Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous amantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations.

Abstract: The kinematics characteristics of an upper arm extension of large amplitude (90 degrees) performed in the horizontal plane and the simultaneous activity of the shoulder muscles were recorded in 12 parkinsonian patients and in six normal control subjects. The movement, triggered by an acoustic "go" signal, was preceded by an isometric adduction. Within the whole population of individuals (n = 18) a strong, positive correlation was observed between the root mean square value of agonist EMG activity, evaluated during the acceleration phase of the movement, and both peak velocity and acceleration. In six patients tremor bursts at the frequency of 8-14 Hz (action tremor) were observed during the movement phase in the anterior, middle, and posterior deltoid: all these patients showed low root mean square values and were bradykinetic with respect to the control subjects. The remaining six patients did not show this action tremor during the movement phase. All but one had an agonist activation of normal duration and amplitude, showed high root mean square values, and performed well in the range of control subjects. We conclude that the inability to suppress the activity of pathological oscillator(s) responsible for the action tremor plays a fundamental role in the bradykinesia associated with Parkinson's disease.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly with a complex etiology due to the interaction between genetic and environmental factors. At least 15% of cases are inherited as an autosomal dominant mutation, but the majority are sporadic. We evaluated cytogenetic alterations, both spontaneous and chemical-induced [aluminium (Al) and griseofulvin (GF)], by means of the micronucleus (MN) test in lymphocytes or skin fibroblasts of 14 patients with sporadic and eight with familial Alzheimer's disease (FAD), respectively. The spontaneous MN frequencies of sporadic (20.8 +/- 9.2) and familial (20.7 +/- 4.6) AD patients are significantly higher than those of the respective control groups (9.0 +/- 6.8 and 6.7 +/- 3.4). In all AD patients, GF significantly increased the spontaneous MN frequency of somatic cells to a lesser extent (P < 0.05) as compared with the control group. Al treatment did not induce MN in AD patients. The results of the present study indicate that different types of somatic cells from sporadic and familial AD patients show comparable levels of spontaneous cytogenetic anomalies, and MN induction is partially reduced or lacking according to the type of chemical treatments.

Abstract: Available evidence on the practice of acute pharmacological challenge tests in parkinsonian patients was reviewed by a committee of experts, which achieved a general consensus. The published data deal mainly with the acute administration of levodopa and apomorphine in Parkinson's disease. Such challenge may serve different purposes, e.g., research, diagnosis, or tailoring of treatment. Unique protocols describing the clinical setting and practice parameters are not available. The present paper describes the scientific background and supplies practical guidelines, whenever possible, to perform and evaluate acute challenge tests in parkinsonian syndromes. With the appropriate indication and setting, acute challenge tests are useful in diagnosis and therapy of Parkinson's disease and related disorders.

Abstract:

Abstract: Several lines of evidence support the presence of DNA damage in somatic cells of Parkinson's disease (PD) patients due to the formation of free radical species. In order to detect spontaneous chromosome and primary or oxidative DNA damage, we performed the human lymphocyte micronucleus assay (HLMNA) and comet assay in 19 PD patients and 16 healthy controls. Compared with controls, PD patients showed a significant increase in: (I) spontaneous micronucleus (MN) frequency (p<0.001); (2) single strand break (SSB) levels (p<0.001); and (3) oxidized purine base levels (p<0.05). The chromosome damage and the increased levels of oxidized purine bases observed in our patients support the hypothesis of oxidative stress as a relevant factor in the pathogenesis of PD.

Abstract: As cancer development usually results from exposure to several environmental risk factors in interaction with the genetic susceptibility of the host, it could be of interest to investigate if neurodegeneration, as occurs in Parkinson's disease (PD) patients can be attributed at least partially, to environmental risk factors. There is growing evidence that oxidative stress could play a significant role as a risk factor in the aetiology and pathogenesis of neurodegenerative diseases, emphasising the need for new individual and human-based approaches. The aim of our research is to explore the relation between chromosome instability and oxidative stress biomarkers in Parkinson's disease using a variety of strategies. We determined peripheral markers for oxidative damage in PD by testing for spontaneous and induced chromosomal damage, DNA strand breaks, oxidised pyrimidines and altered purines both in peripheral blood and cultured lymphocytes. We also measured glutathione S-transferase activity in the plasma of patients and controls. Compared to healthy controls, PD patients show higher frequencies of micronuclei (17.2 +/- 4.8 vs. 9.0 +/- 3.4, p < 0.001) and a significant increase in the levels of single strand breaks (SSB). Significant differences were also obtained in the distribution of oxidised purine bases between the two groups. Preliminary data obtained by fluorescence in situ hybridization analysis showed that the percentage of centromere negative micronuclei is higher than that of centromere positive micronuclei. Glutathione S-transferase activity in plasma from PD patients and controls was also measured and the enzymatic activity in PD patients was lower than in healthy controls.

Abstract: Selective serotonin reuptake inhibitors (SSRIs) have been reported to be useful in the treatment of depression in patients with Parkinson's disease (PD). However, a few reports have suggested that SSRIs may worsen parkinsonian motor symptomatology and extrapyramidal side effects have been reported in depressed patients treated with SSRIs. So far, no prospective trial comparing the effects of different SSRIs in depressed patients with PD has been performed. The aim of the present study was to assess the effects of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) on motor performance and their efficacy on depression in a group of patients with PD. Sixty-two consecutive nondemented, nonfluctuating, depressed patients with PD were included in four treatment groups (15 patiens received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline). The evaluation of extrapyramidal and depressive symptomatology was performed with use of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory, and Hamilton Depression Rating Scale at baseline and after 1, 3, and 6 months. Fifty-two patients completed the study. UPDRS scores were not significantly modified by the add-on therapy with each of the SSRIs studied. A significant improvement in depressive symptoms from baseline to the end of the trial was obtained with all SSRIs (Beck and Hamilton scores improving; p < 0.05 according to an analysis of variance). Our findings suggest that SSRIs do not significantly worsen extrapyramidal symptomatology and may ameliorate depression in patients with PD.

Abstract: Multiple system atrophy (MSA) is a form of atypical parkinsonism with unknown etiology. The epidemiological studies conducted up to now on this disease are scarce. The incidence rate is about 0.6 cases per 100,000 persons per year. The prevalence rates show 4-5 cases per 100,000 persons. In Italy, about 4,900 prevalent cases have been estimated. The mean onset age is about 54 years; the median survival is 7-9 years. Only one case-control study has been performed on this disease. This study showed an increased risk of MSA associated with occupational exposure to organic solvents, plastic monomers and additives, pesticides and metals. Smoking habits seem to be less frequent in MSA cases (as in Parkinson's disease cases) than in healthy controls. Quinn's clinical criteria and those of the Consensus Conference promoted by the American Academy of Neurology are in fair agreement. We have performed a case-control study on 73 MSA cases, 146 hospital controls and 73 population controls.

Abstract: Parkinson's disease is a nosological entity of unknown origin for which, in some cases, a possible pathogenetic role for mitochondrial dysfunction has been postulated. Two young onset parkinsonian patients with mitochondrial DNA (mtDNA) deletions in skeletal muscle are reported on. Patient 1 also presented with increased blood creatine kinase and lactate concentrations and a family history which included a wide range of phenotypes affecting multiple systems. Patient 2 presented with multiple symmetric lipomatosis. Histopathological investigation showed ragged red fibres and COX negative fibres in muscle biopsies from both patients. The data support the hypothesis that mitochondrial DNA mutations may occur in some cases of parkinsonism, suggesting that a diagnosis of a mitochondrial disorder should be considered in the presence of consistent family history and clinical symptoms.

Abstract: Progressive supranuclear palsy (PSP) is a rare form of parkinsonism. The incidence rates are about 0.3-1.1 cases per 100,000 persons. The only two case-control studies performed up to now show conflictual results as regards education and residence in rural areas. Recently, a cluster of PSP and atypical parkinsonism has been observed in French Antilles. The hypothesis is that a consumption of both tropical fruit and herbal tea may be associated with PSP onset. Some PSP families with a probably autosomal dominant transmission have been described. A high frequency of a tau haplotype (H1/H1) associated with PSP is reported by some authors. The significance of this association is still not clear. We have performed a case-control study on 58 PSP cases, 116 hospital controls and 58 population controls.

Abstract: Proton MR spectroscopy (1H-MRS) has been previously performed in Parkinson's disease (PD) and parkinsonian syndromes to evaluate in vivo concentrations of basal ganglia and cerebral cortex metabolites such as N-acetylaspartate (NAA), choline (Cho), and creatine (Cr). However, this technique has never been used to evaluate motor cortex in untreated PD patients. In this study, single-voxel 1H-MRS of basal ganglia and motor cortex was carried out in 10 de novo patients with PD and 10 age-matched healthy controls. A significant reduction in the NAA/Cr ratio was observed in the motor cortex of PD patients compared with controls (p)<(0.01). Basal ganglia spectra did not allow any evaluation due to the presence of artefacts related to inorganic paramagnetic substances. The motor cortex reduction of the NAA/Cr ratio in de novo PD patients may reflect an altered neuronal functioning due to a loss of thalamocortical excitatory inputs and may represent an in vivo marker for the diagnosis of PD.

Abstract: Patients with Parkinson's disease (PD) in long-term levodopa therapy often complain of worsening of motor symptoms in the afternoon and evening. The pathophysiology of this phenomenon is not known. We evaluated the motor response to repeated doses of levodopa during a 12-hour period in 52 parkinsonian patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the study, all patients received standard doses of levodopa/carbidopa at 8:00 a.m., 12:00 noon, and 4:00 p.m. Motor measurements such as tapping test, walking time, and tremor score, and blood samples for levodopa and 3-O-methyldopa (3OMD) plasma analysis, were performed hourly. Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose, were compared. In de novo patients, we did not observe diurnal changes in motor score, whereas a progressive daytime worsening was visible in stable and wearing-off patients. No significant difference in levodopa pharmacokinetics after each levodopa dose was observed within each patient group, whereas 3OMD plasma levels significant increased with repeated levodopa administrations. However, no significant correlation between motor scores and 3OMD plasma levels was observed, suggesting that the diminishing motor response to afternoon and evening doses of levodopa in patients in long-term levodopa therapy does not relate to the pharmacokinetics of the drug. It is possible that this phenomenon may be an expression of the occurrence of tolerance to repeated doses of levodopa.

Abstract: OBJECTIVE: To evaluate smoking habits in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) in a multicenter case-control study to determine whether these two forms of atypical parkinsonism share the inverse association with smoking previously found in PD. BACKGROUND: No epidemiologic studies have been performed on smoking habits in MSA. A previous investigation in PSP revealed no differences in smoking habits between patients and hospital control subjects. METHODS: Seventy-six MSA patients, 55 PSP patients, 140 PD patients, and 134 healthy control subjects were enrolled consecutively at seven neurologic clinics from January 1, 1994, to July 31, 1998. Detailed information on smoking habits was obtained using a structured questionnaire. RESULTS: The comparison between frequencies of never-smokers versus ever-smokers (ex-smokers/current smokers; adjusted odds ratio [ORadj], 0.56; 95% CI, 0.29 to 1.06) and a dose-response analysis for never-smokers, moderate smokers (ORadj, 0.64; 95% CI, 0.31 to 1.32), and heavy smokers (ORadj, 0.47; 95% CI, 0.21 to 1.05) suggest that MSA patients smoke less than population control subjects. By contrast, the comparison of frequencies of never-smokers versus ever-smokers (ORadj, 0.91; 95% CI, 0.42 to 1.98) and a dose-response analysis for never-smokers, moderate smokers (ORadj, 0.68; 95% CI, 0.27 to 1.69), and heavy smokers (ORadj, 1.24; CI 95%, 0.51 to 3.06) revealed no differences in smoking habits between PSP patients and population control subjects. CONCLUSIONS: The fact that the inverse association with smoking found previously in PD is shared by multiple system atrophy but not by progressive supranuclear palsy lends epidemiologic support to the notion that different smoking habits are associated with different groups of neurodegenerative disease.

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Abstract: Mexiletine is an antiarrhythmic drug that has been reported to exert antidystonic properties. We performed an open-label study to collect further evidence of the antidystonic effect of mexiletine in spasmodic torticollis (ST) and to evaluate its possible use in generalized dystonia. We administered mexiletine to six patients with dystonia (three with generalized dystonia and three with ST) who had failed to respond to previous pharmacotherapy. The drug was started at a dose of 200 mg/d by mouth and increased up to a maximum dose of 800 mg/d. Patients were evaluated at regular intervals over a 6-week period with use of the Fahn & Marsden Dystonia Scale and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and videotaped. At the end of the trial, the videotapes were reviewed and scored by a blind observer. Patients were then followed for at least 1 year and evaluated every 3 months at the dose reached during the study period. No adverse effects were reported in five patients; in one patient, dizziness developed at the dosage of 800 mg/d, requiring a reduction of the dose. At the end of a 6-week period, a significant improvement in the rating scale for dystonia and in videotape ratings was observed after mexiletine treatment (p < 0.01). Our data indicate that mexiletine is a useful drug in dystonia treatment.

Abstract: Selective serotonin reuptake inhibitors have been used in the treatment of depression in patients with PD. Conflicting data as to whether selective serotonin reuptake inhibitors worsen parkinsonian motor symptomatology have been reported. In this study, the additional 6 months therapy with paroxetine 20 mg/d in a group of depressed patients with PD did not modify parkinsonian motor function (Unified Parkinson's Disease Rating Scale scores); however, in one patient, fully reversible worsening of tremor was observed. Depression, as evaluated by Beck Depression Inventory and Hamilton Depression Rating Scale, improved from baseline to final visit (p < 0.05 by analysis of variance).

Abstract: The kinetic parameters at equilibrium of peripheral benzodiazepine receptors in platelets, lymphocytes and granulocytes of 15 patients affected by migraine without aura were tested using [3H]PK 11195, a specific radioligand for this receptor and compared with the same number of healthy controls: a statistically significant increase (platelets 212%, lymphocytes 203%, granulocytes 171%, as absolute percentage) in the maximal number of binding sites (B(max)) in all three patient samples, compared with healthy controls was detected; on the contrary, the values of the dissociation constant (K(d)) at equilibrium do not show any statistically significant variations between the two groups. These data further confirm the presence of peripheral biochemical alterations in migraine without aura. As peripheral benzodiazepine receptors appear to be involved in the regulation of the mitochondrial respiratory chain, the observed increase in B(max) might be related to the mitochondrial anomalies found in migraine disorders.

Abstract: We investigated the prevalence of headache in a group of patients attending a psychiatric clinic because suffering from panic disorder, according to DSM-IV criteria. The psychopathological assessment was performed with the 'Panic Disorder/Agoraphobia Questionnaire' and the presence of headache was evaluated according to the criteria of the International Headache Society. The results showed that two-thirds of patients met the criteria for a diagnosis of headache, with migraine without aura being the most frequent form, followed by tension headache, while two patients only were affected by migraine with aura. When we compared panic patients with and without headache, those with headache had a longer duration of panic disorder, a higher number of attacks and a heavier family loading for panic disorder and headache. This suggests that the comorbidity of headache with panic disorder renders this condition more severe and possibly responsive to different treatments compared to panic disorder alone.

Abstract: Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 +/- 3.3 in 85 expanded alleles, with a range of 34-52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range -3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy.

Abstract: A multicenter study was carried out in 10 Italian Headache Centers to investigate the prevalence of psychosocial stress and psychiatric disorders listed by the IHS classification as the "most likely causative factors" of tension-type headache (TTH). Two hundred and seventeen TTH adult outpatients consecutively recruited underwent a structured psychiatric interview (CIDI-c). The assessment of psychosocial stress events was carried out using an ad hoc questionnaire. The psychiatric disorders that we included in the three psychiatric items of the fourth digit of the IHS classification were depressive disorders for the item depression, anxiety disorders for the item anxiety, and somatoform disorders for the item headache as a delusion or an idea. Diagnoses were made according to DSM-III-R criteria. At least one psychosocial stress event or a psychiatric disorder was detected in 84.8% of the patients. Prevalence of psychiatric comorbidity was 52.5% for anxiety, 36.4% for depression, and 21.7% for headache as a delusion or an idea. Psychosocial stress was found in 29.5% of the patients and did not differ between patients with and without psychiatric comorbidity. Generalized anxiety disorder (83.3%) and dysthymia (45.6%) were the most frequent disorders within their respective psychiatric group. The high prevalence of psychiatric disorders observed in this wide sample of patients emphasizes the need for a systematic investigation of psychiatric comorbidity aimed at a more comprehensive and appropriate clinical management of TTH patients.

Abstract: Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.

Abstract: Patients with essential tremor (ET) may not respond to commonly used drugs. Clozapine, an atypical neuroleptic drug, has been reported to improve postural Parkinson's disease tremor clinically resembling ET. The effects of a single dose of 12.5 mg clozapine and placebo were evaluated in a randomized, double-blind, crossover study in 15 drug-resistant patients with ET. Patient responders with more than 50% improvement after a single dose of clozapine subsequently received the drug (39+/-9 mg up to 50 mg) unblinded for a period of 15.8+/-7.7 months. Tremor was effectively reduced by a single dose of clozapine in 13 of 15 patients (p <0.01). Sedation was the only side effect reported during the clozapine test; however, the time course of sedation and of the antitremor effect were not coincident. A significant reduction of tremor was reported with chronic clozapine treatment (p <0.01) with no tolerance to drug antitremor effect, whereas sedation markedly decreased after 6-7 weeks of therapy. No clozapine-induced hematologic side effects were observed in our cohort of patients during long-term treatment. Our results suggest that in selected drug-resistant ET cases, clozapine should be considered before resorting to neurosurgical options.

Abstract: Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.

Abstract: To further investigate our finding of high levels of spontaneous aneuploidy in somatic cells of Alzheimer's disease (AD) patients (Migliore et al. 1997), we studied the molecular cytogenetics of eight patients with sporadic AD and six healthy controls of similar age. Cytochalasin B-blocked binucleated peripheral blood lymphocytes from the AD patients and unaffected controls were used to measure micronucleus induction or other aneuploidy events, such as the presence of malsegregation in interphase nuclei (representing chromosome loss and gain). Dual-color fluorescence in situ hybridization (FISH) with differential labeled DNA probes was applied. We used a probe specific for the centromeres of chromosomes 13 and 21 combined with a single cosmid for the Down's syndrome region (21q22.2) to obtain information on spontaneous chromosome loss and gain frequencies for both chromosomes (13 and 21). FISH data showed that AD lymphocytes had higher frequencies of chromosome loss (evaluated as fluorescently labeled micronuclei) for both chromosomes, as well as higher frequencies of aneuploid interphase nuclei, again involving both chromosomes, compared to control lymphocytes. However, aneuploidy for chromosome 21 was more frequent than for chromosome 13 in AD patients. This preferential occurrence of chromosome 21 in malsegregation in somatic cells of AD patients raises the hypothesis that mosaicism for trisomy of chromosome 21 could underlie the dementia phenotype in AD patients, as well as in elderly Down's syndrome patients.

Abstract: Cervical hyperextension injuries are common and are associated with significant morbidity. Clinically two syndromes are described: "acute" whiplash syndrome and "late" whiplash syndrome (in which the patients are still symptomatic after six months despite normal physical and radiological examination). In order to clarify the pathology of the persistent pain in late whiplash syndrome we performed a cervical spine magnetic resonance imaging (MRI) in 33 consecutive patients suffering from this condition. Twenty-six patients (78.8%) showed MRI abnormalities, the most common MRI finding (57.6%) was pre-existent spondylosis. Indeed, the group of patients with spondylosis and other MRI changes had higher clinical scores than those without MRI abnormalities as measured by a three-point grading system based upon the symptoms and signs shown. Several MRI changes, most of them already demonstrable by standard X-ray were seen among 33 patients suffering from late whiplash syndrome. Although no one of these findings appears to be specific and certainly related to the previous neck injury, they could represent a risk factor for a longer pain duration.

Abstract: The clinical and neuroradiological outcome of carbon monoxide (CO) intoxication was evaluated prospectively in 30 patients over a follow-up period of 3 years. Among the patients studied, 22 had been acutely exposed to CO while 8 were chronically exposed.One month after CO poisoning, 12 of the 22 patients with acute intoxication showed magnetic resonance imaging (MRI) abnormalities: 6 also had neurological sequelae and 6 were asymptomatic. The remaining 10 patients showed neither MRI abnormalities nor neurological sequelae. During the 3-year follow-up, 4 of the patients with both MRI abnormalities and neurological sequelae improved in both clinical features and MRI findings. One of the 6 asymptomatic patients with MRI abnormalities developed a progressive cognitive impairment 2 months after acute intoxication, with a concomitant severe worsening of the MRI lesions. Among the 10 patients with neither MRI abnormalities nor neurological sequelae, only 1 developed neurological sequelae after a clear period of 4 months.In the group of patients who experienced chronic CO intoxication, only 1 presented with a neuropsychiatric syndrome which improved at follow-up. Brain MRI showed white matter lesions which remained unchanged at control scan after 1 year.In conclusion, we observed that some patients with severe CO poisoning and neurological sequelae may fully regain normal functions after approximately 1 year. The presence of MRI lesions 1 month after CO poisoning did not accurately predict the subsequent outcome. The observation of a clear period longer than the usual 2-40 day interval in 2 patients should be considered for careful planning of follow-up and for prognosis in CO-poisoned patients.

Abstract: OBJECTIVE: To determine whether reported genetic association of polymorphisms in the CYP2D6, CYP1A1, N-acetyltransferase 2 (NAT2), DAT1, and glutathione s-transferase M1 (GSTM1) genes with PD were evident in a population of 176 unrelated patients with sporadic PD and to extend these findings to other disease groups (familial PD [n = 30], ALS [n = 50], multiple system atrophy [n = 38], progressive supranuclear palsy [n = 35], and AD [n = 23]). METHODS: A combination of allele-specific PCR and analysis of restriction fragment length polymorphisms were performed. RESULTS: We genotyped 1,131 individuals. After matching each patient with a control subject by age, sex, ethnicity, and geographic origin, there was no association of any allele/genotype with any of the six disease groups. There was an increased frequency of NAT2 slow acetylators in the ALS group compared with controls (70% versus 50%; OR 2.33 [95% CI, 1.03 to 5.30]), but this was not significant after adjusting for multiple testing. CONCLUSIONS: This is one of the most extensive candidate gene studies performed in PD and the first time that some of these loci have been studied in multiple system atrophy and progressive supranuclear palsy. In contrast with previous studies, we found no role for these polymorphisms in the etiology of PD, ALS, multiple system atrophy, progressive supranuclear palsy, or AD.

Abstract: The efficacy of flunarizine in migraine prophylaxis is confirmed in both open and controlled trials. However, it is unknown what factors may influence a good response to prophylaxis with flunarizine. The aim of this study was to determine the possible predictive factors for therapeutic responsiveness to 3 months' treatment with flunarizine. One-hundred headache patients treated with flunarizine were evaluated. We considered "responders" those patients who recorded a reduction in migraine frequency of 75% after treatment. Statistical analysis revealed four factors which might influence therapeutic responsiveness in our patients. Positive factors were a family history (p<0.01) and high intensity of pain (p<0.01); negative factors were frequent attacks (p<0.01) and a history of analgesic abuse (p<0.001). Patients with no previous history of analgesic abuse, low frequency of attacks at baseline, higher levels of migraine pain, and positive family history constitute the prototype of flunarizine long-term treatment responders.

Abstract: OBJECTIVE: To confirm whether a dinucleotide repeat sequence in an intron of the microtubule-associated protein tau is associated with progressive supranuclear palsy (PSP) in an independent study population and to establish an improved methodology for allelotyping. BACKGROUND: It has recently been reported that a genetic variant of tau, known as the A0 allele, was represented excessively in PSP patients when compared with control subjects. METHODS: In a multicenter study, the authors examined the allelic distribution of this dinucleotide repeat marker in a set of clinically ascertained PSP patients (n = 30), multiple system atrophy (MSA) patients (n = 35), and matched control subjects (n = 70). Individuals were allelotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The A0 allele was significantly overrepresented in the PSP patients (93.3% versus 76.4%; p = 0.0067; odds ratio [OR] = 4.33; 95% confidence interval [CI], 1.36 to 13.60), but not in the MSA patients. Likewise, A0 homozygotes were overrepresented in the PSP group (86.7% versus 61.1%; p = 0.02; OR = 4.14; 95% CI, 1.19 to 14.48) compared with control subjects. CONCLUSIONS: The findings of this study, which is the largest to date, support those of a previous investigation that used pathologically confirmed PSP patients. These data provide additional strong evidence that genetic variation at or near the tau gene plays an important role in the pathogenesis of PSP.

Abstract: With the aim of assessing dopaminergic responsiveness in essential blepharospasm, we investigated the effects of oral levodopa and subcutaneous apomorphine on blink reflex recovery cycle in 7 blepharospasm patients. We found that in blepharospasm the excitability of the blink reflex recovery cycle was increased compared with control subjects. The oral administration of levodopa/carbidopa (500/50 mg) did not significantly modify the blink reflex recovery cycle. The 50 micrograms/kg dose of apomorphine decreased the amplitude of conditioned responses at 300 and 500 ms, whereas the 10 micrograms/kg dose was ineffective. We conclude that the excitability of the blink reflex recovery cycle in blepharospasm is partly under dopaminergic control. The partial normalization of the blink reflex recovery cycle excitability observed with 50 micrograms/kg apomorphine is consistent with the reported clinical efficacy of the drug in this condition.

Abstract: The present review discusses species differences in relation to the effects produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); in particular, it focuses on recent evidence regarding the role of excitatory amino acids in experimental parkinsonism. The main aim of the review is to provide a phylogenetic perspective which may serve as a useful tool to study Parkinson's disease in rodents. Excitotoxicity might represent the final common pathway on which the actions of different neurotoxins, selectively directed towards nigrostriatal dompaminergic neurons, converge. This is clearly demonstrated in methamphetamine- and 6-dihydroxy-dopamine-induced parkinsonism. The role of excitotoxicity in the mechanism of action of MPTP is less clear. Although there are several species differences for MPTP it is possible to obtain in mice the same effects induced in MPTP-treated primates by combining acetaldehyde or diethyldithiocarbamate with MPTP administration. When mice are administered these combined treatments, the onset of experimental parkinsonism can be prevented using the same pharmacological agents (i.e. glutamate N-methyl-D-aspartate antagonists) that are effective in primates.

Abstract: The extensive use of the Unified Parkinson's Disease Rating Scale (UPDRS) has revealed low interrater reliability in some items and redundancy in others. In view of these shortcomings, we have structured a new scale that includes a zero-to three-point scale for each item in the evaluation of PD. The mental axis includes memory, thought disorders, and depression. Activities of daily living (ADL) includes eight items: speech, eating, feeding, dressing, hygiene, handwriting, walking, and turning in bed. The motor examination includes eight items: speech, tremor, rest and posture, rigidity, finger tapping, arising from chair, gait, and postural stability. Complications of therapy were also included: dyskinesias, dystonia, motor fluctuations, and freezing episodes, collected by history. In addition, a global scoring for motor fluctuations that should complement the Hoehn and Yahr Scale was incorporated. In this report, we present a statistical analysis of the ADL, motor evaluation, and complications of therapy sections. Concerning the interrater reliability mean, Kendall's W values were >0.9 for most of the items in the Short Parkinson's Evaluation Scale (SPES). Kendall's W <0.8 (motor evaluation) was found for two items of the SPES and nine items of the UPDRS. The mean interrater reliability for both scales across all seven centers (seven Kendall's W for seven centers) (Mann-Whitney test) showed no statistical differences between the scales. Spearman's correlations between items of both scales were significant. Factor analysis of the SPES and UPDRS data revealed a four-factor solution that explained approximately 60% of the data. All participating centers found the SPES easier to apply and quicker to complete, when compared with the UPDRS. The results obtained strongly favor the introduction of SPES for clinical practice.

Abstract: This study was aimed at assessing whether peripheral blood lymphocytes of patients with Alzheimer's disease (AD) show significant levels of aneuploidy and high percentages of cytogenetic events in vitro, indicating a predisposition to aneuploidy spontaneously, or after chemical treatment in vitro. A group of affected individuals and a group of unaffected, age-, sex- and smoking-habit-matched controls were identified. Lymphocytes were cultured for analysis of the following cytogenetic parameters: premature centromere division (PCD), satellite associations of acrocentric chromosomes (SA) and micronuclei (MN). In a subset of subjects, the fluorescence in situ hybridization (FISH) technique was combined with the MN assay, by means of a pancentromeric DNA probe for the detection of the presence of centric material. To evaluate the sensitivity to aneuploidogenic agents, in vitro treatment of lymphocytes of affected individuals was performed by adding griseofulvin, a chemical whose supposed target is microtubule-associated protein(s). Both the spontaneous frequency of MN and the frequency of PCD was significantly higher in patient cells than in controls. Furthermore, after application of the FISH technique, we found that the majority of MN were composed of whole chromosomes (because of the phenomenon of chromosome loss). Metaphase analysis for the detection of associative events between satellite regions of acrocentric chromosomes showed no differences between the two groups under study. Analysis of sensitivity to the aneuploidogen griseofulvin showed that the patient group was characterized by lower levels of MN induction compared with controls. Our data confirm that peripheral blood lymphocytes of AD patients are prone to undergo aneuploidy spontaneously in vitro and support the hypothesis that microtubule impairment might be associated with the disease.

Abstract: The effects of the acute administration of clozapine on parkinsonian mixed tremor (i.e., resting and postural tremors) were evaluated to establish clozapine's predictive value for long-term response and to determine if there is a difference in the pharmacologic responses of the two tremors. We also investigated the correlation between reduction of tremor and induction of sedation after acute and chronic administration of clozapine. Clozapine (12.5 mg) or placebo were administered po in a double-blind manner to 17 PD patients with mixed L-dopa-resistant tremors. Two patients did not reach 50% improvement and were considered nonresponders. The remaining 15 patients reported moderate to marked reduction of tremor. Responsive patients in the acute test moved on to a long-term, open clozapine add-on study receiving an average daily dose +/- SD of 45 +/- 9.6 mg for a period of 15.5 +/- 8.3 months. A significant reduction of both resting (p < 0.05) and postural (p < 0.05) tremors was observed under clozapine from the first week of treatment through the entire period of the study. There was no statistically significantly difference between the degree of improvement for resting and postural tremors after either single or chronic clozapine administration. Sedation was the only side effect reported after clozapine; however, the time courses of sedation and tremor reduction did not coincide in the acute or in the chronic experimental paradigm, where it decreased considerably in a few weeks in all patients. During long-term clozapine treatment, neither systemic side effects nor worsening of motor disability scores were noted. Thus we wish to propose an acute test or a therapeutic attempt, or both, with clozapine before defining a case of mixed parkinsonian tremor as resistant tremor and therefore resorting to a neurosurgical approach.

Abstract: Previous investigations on the mutual pharmacokinetic influence of L-dopa and dopamine agonists in Parkinson's disease (PD) have shown controversial results. Two studies of the possible clinical and pharmacokinetic interaction between L-dopa and cabergoline were performed in 10 patients with de novo PD and 12 patients with fluctuating PD. In the first study (de novo patients), cabergoline was administered at increasing dosages until the maximum dosage of 2 mg/day once a day for 8 weeks; subsequently L-dopa (250 mg/day) was added. Blood levels of cabergoline were assayed in two different days, before starting L-dopa, and 1 week thereafter. In the second 8-week study (fluctuating patients), cabergoline was added to the current L-dopa therapy (maximum dosage 4 mg/day once a day). Blood levels of L-dopa were measured in two different days, before cabergoline was added, and at the end of the study. In both studies motor performance was evaluated by means of the Unified Parkinson's Disease Rating Scale (motor examination) and the Clinical Global Impression Scale; on-off diaries of daily motor condition also were filled by fluctuating patients. In patients with de novo PD, cabergoline pharmacokinetic parameters were unmodified by the adjunct of L-dopa, except that the time to reach the peak concentration (Tmax) significantly increased after L-dopa. In patients with fluctuating PD, no modification of L-dopa pharmacokinetics was observed before and after cabergoline coadministration. Clinical evaluations confirmed that cabergoline is effective in the treatment of advanced PD as well as in the management of de novo patients.

Abstract: 3,4-Dihydroxyphenylacetic acid (DOPAC) is commonly considered to be the main dopamine (DA) metabolite produced by monoamine oxidase (MAO); however, the initial product of DA oxidation is 3,4-dihydroxyphenylacetaldehyde (DOPALD). Owing to technical difficulties in detecting DOPALD from a biological matrix, no studies have so far been performed to measure brain levels of this aldehyde in vivo. In this work, using transstriatal microdialysis in freely moving rats, we identified DOPALD by HPLC coupled to a coulometric detector. In chromatograms obtained from microdialysis samples, DOPALD appeared as a peak with a retention time coincident with that of the standards obtained via enzymatic and chemical synthesis. On the other hand, DOPALD was undetectable ex vivo from rat striatal homogenates. This discrepancy is probably due to the preferential extraneuronal localization together with the high reactivity of the aldehyde, which is rapidly removed by the dialysis probe, whereas the ex vivo procedure allows its condensation and enzymatic conversion. Measurement of DOPALD levels as a routine procedure might represent a reliable tool to evaluate DA oxidative metabolism directly, in vivo. Moreover, parallel detection of DOPALD and DOPAC levels in brain dialysate may make it possible to distinguish between the activity of MAO and aldehyde dehydrogenase. DOPALD, like many endogenous aldehydes, has been shown to be toxic to the cell in which it is formed. Therefore, in vivo measurement of DOPALD levels could highlight new aspects in the molecular mechanisms underlying both acute neurological insults and neurodegenerative diseases.

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Abstract: Frequent or regular intake of antimigraine drugs, including analgesics, constitutes a common cause of chronic daily headache. Discontinuation of symptomatic medication can produce an increase in head pain accompanied by withdrawal symptoms. We report the favourable outcome of treating a group of outpatients with the combination of amitriptyline, dexamethasone and sumatriptan. Dexamethasone (4 mg/day) was given intramuscularly for 2 weeks, amitriptyline orally at night (50 mg/day) for at least 6 months, and sumatriptan subcutaneously to treat acute headache attacks. Eighteen out of 20 patients abstained from drug abuse. Eleven of these 18 patients showed a marked reduction in headache frequency (at least 75% in relation to the basal value), and were considered "very good responders". The other seven patients experienced at least 50% reduction in headache frequency compared to baseline. This preliminary report suggests that drug-induced headache can be treated effectively in outpatients using dexamethasone, amitriptyline and sumatriptan in combination with significant benefit in everyday life conditions.

Abstract: A case of adult onset coeliac disease with IgA and severe vitamin E deficiencies, associated with cerebellar impairment and peripheral neuropathy, is described. Nerve conduction velocities, BAERs and SEP were altered. Brain nMR showed cortical atrophy mainly in the frontal and parietal regions. At ultrastructural examination, nerve biopsy showed a severe nerve fiber loss with presence of lipofuscin. Lipofuscin has been also found in skin and muscle biopsy. Duodenal biopsy showed villar atrophy with criptae hypoplasia. IgA, Apo A1 lipoprotein and cholesterol were decreased. Serum level of vitamin E was not detectable and its amount did not increase after an oral loading (2 g bolus). Parenteral vitamin E administration (900 mg/day) was able to normalize the plasma values only after 6 months of chronic administration of the drug in coincidence with a significant improvement of clinical and neurophysiological signs, and disappearance of lipofuscin storage in the skin biopsy.

Abstract: Various open and controlled studies have confirmed the antimigraine action of flunarizine, while the antimigraine properties of nimodipine are still open to controversy. Moreover, only a few studies include an additional follow-up after discontinuation of migraine prophylaxis with either drug. We carried out a single blind evaluation of the efficacy and tolerance of flunarizine (25 patients) in comparison with nimodipine (25 patients) and the long-term effect after discontinuation of a 6-month treatment. Both medications significantly reduced migraine frequently and severity. Flunarizine was more efficacious than nimodipine in reducing migraine frequency (p < 0.001), pain severity (p < 0.05), migraine index (p < 0.05) and corrected migraine index (p < 0.05). The positive effect lasted 8.4 +/- 4.0 months after discontinuation of flunarizine and 4.9 +/- 3.5 months after nimodipine (p < 0.05). Our results suggest that flunarizine is more effective than nimodipine in the prophylactic treatment of migraine. The positive effect after drug discontinuation lasts longer with flunarizine, compared to nimodipine.

Abstract: In the last 20 years dopamine agonists have been considered more and more helpful as primary therapy for Parkinson's disease (PD). Recently the neuroprotective activity and the therapeutic efficacy of a new ergot derivative, alpha-dihydroergocryptine (DHEC), has been highlighted. In the present work we resume the experimental and clinical data reported about this drug. The rationale for dopamine (DA) agonists as primary therapy for Parkinson's disease (PD) is based on the possibility to delay the onset of long term I-dopa syndrome (LTS) (King, 1992); moreover DA agonists seem to exert a neuroprotective effect on substantia nigra neurons. In fact, they stimulate DA receptors bypassing the degenerating nigrostriatal neurons and their metabolic machinery (Lieberman, 1992; Olanow, 1992); more recently, some studies have shown that these drugs have a direct protective effect too (Felten et al., 1992; Yoshikawa et al., 1994). In this minireview we resume the data reported about neuroprotective activity and therapeutic efficacy of a new ergot derivative, alpha-dihydroergocryptine (DHEC).

Abstract: Past epidemiological and clinical research has identified depression as the most common psychiatric disorder associated with headache. The present study carried out in a neurology headache clinic showed that the major associations were with current anxiety disorders, especially panic and related conditions. These findings were particularly true of the subgroup of migraine with aura; in the relatively few patients with mood disorders, depression was nearly always comorbid with panic or other anxiety disorders. Past history of depression was mainly a characteristic of the tension headache group. These data are compatible with the hypothesis that migraine, especially that with aura, panic disorder and some forms of depressive illness are part of the same spectrum.

Abstract: Studies on the influence of some dopamine agonists, particularly bromocriptine, on the pharmacokinetics of L-dopa have furnished contrasting results. Thus, any possible pharmacokinetic interaction should be taken into consideration when adding a new dopamine agonist to L-dopa treatment. In 12 Parkinson's disease (PD) patients with motor fluctuations, cabergoline was added in an 8-week study to their usual L-dopa/carbidopa therapy. Cabergoline was administered once a day at increasing doses of 0.5, 1, 2, and 3mg/day for a period of one week per dose, and 4mg/day for three weeks. Motor performance was assessed weekly evaluating the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS) and the patients' diaries of daily on-off time. Blood levels of both L-dopa and 3-O-methyldopa (3-OMD) were assayed by HPLC in two different days, over an 8-hour period, before initiating cabergoline and at the end of the study. The results of this study confirm that cabergoline is effective in the management of PD motor fluctuations without modifying L-dopa and 3-OMD pharmacokinetics.

Abstract: A single-blind, crossover study was carried out to compare the efficacy and safety of pergolide against that of bromocriptine in 57 patients with Parkinson's disease who showed a declining response to levodopa therapy. Patients were randomly assigned to receive either bromocriptine followed by pergolide, or pergolide followed by bromocriptine. Both drugs were administered for 12 weeks. Patients were assessed by a clinician blinded to treatment assignment using the New York University Parkinson's Disease Scale. The average daily dose of pergolide was 2.3 +/- 0.8 mg and of bromocriptine 24.2 +/- 8.4 mg. Addition of pergolide or bromocriptine resulted in a significant improvement in total scores when compared with the previous treatment of levodopa alone (pergolide, p = 0.0001; bromocriptine, p = 0.0005). Pergolide was more effective than bromocriptine in daily living scores (p = 0.02) and motor scores (p = 0.038). No differences in the incidence of dyskinesias, dystonias, or psychosis were observed between groups. Fewer adverse events were recorded in the pergolide group, and most patients and physicians preferred pergolide to bromocriptine. Pergolide as adjunctive therapy to levodopa was more effective than bromocriptine in this short-term trial.

Abstract: OBJECTIVES: To verify recent preliminary data indicating that white matter hyperintensities on magnetic resonance imaging are more abundant in patients with Parkinson's disease (PD) than in healthy subjects and to examine possible correlation between these abnormalities and clinical features of PD. DESIGN: Magnetic resonance imaging data on patients with PD and normal subjects were compared as to frequency, extent, and topographic location of white matter hyperintensities; moreover, in the PD group, we studied the possible correlation of white matter hyperintensities with clinical features such as severity, disease duration, and therapy. SETTING: The outpatient clinic of the Institute of Clinical Neurology and the Neuroradiology Unit of the University of Pisa (Italy). PATIENTS: We studied 102 nondemented patients with idiopathic PD and 68 sex- and age-matched healthy controls, all screened for absence of cerebrovascular risk factors. OUTCOME MEASURES: White matter hyperintensities were classified as periventricular hyperintensities and deep hyperintensities. Frequency, extent, and topographic location of both periventricular and deep hyperintensities were evaluated. The clinical parameters examined were disease duration, treatment type, and disease severity (using Hoehn and Yahr staging and the Unified Parkinson's Disease Rating Scale), as well as disease progression index (ratio between Hoehn and Yahr stage and disease duration). RESULTS: The frequency and the extent of periventricular hyperintensities were significantly higher in patients with PD than in healthy subjects. Moreover, within the PD group, the patients who had periventricular hyperintensities had significantly shorter disease duration and greater disease severity, ie, a higher disease progression index, than those who did not. CONCLUSION: These data suggest that periventricular hyperintensities may represent a marker for a clinical subtype of PD characterized by a more rapid neurodegenerative process.

Abstract: Muscle biopsy was performed in two patients with Hallervorden-Spatz disease and increased serum creatine kinase levels. Morphological analysis showed myopathic signs such as subsarcolemmal accumulation of myeloid structures, dense bodies and debris, endomysial macrophage activation, focal necrosis and fiber splitting. We emphasize the finding of muscle involvement in Hallervorden-Spatz disease, like in other forms of neuroacanthocytosis.

Abstract: The effect of the dopaminergic agonist apomorphine on blood velocity in the middle cerebral artery has been studied in patients with migraine, tension-type headaches, and healthy subjects by means of transcranial Doppler monitoring. Following the administration of apomorphine, systolic velocity and mean velocity significantly increased and pulsatility index significantly decreased in migraineurs compared to placebo and to the other groups of subjects. These changes were dose-dependent and showed a time-curved compatible with the pharmacokinetic profile of the drug. The different effect of apomorphine in migraineurs compared with controls and tension-type headache patients implies that migraineurs have increased sensitivity to dopaminergic stimuli and suggests that transcranial Doppler monitoring after apomorphine administration could be a useful tool in the evaluation of migraineurs.

Abstract: We investigated platelet 3H-imipramine (3H-IMI) binding, a putative peripheral serotonergic marker, and the activity of sulphotransferase (ST), an enzyme involved in the catabolism of catecholamines and phenolic compounds, in 14 patients suffering from migraine without aura (MWoA) and in 10 with tension-type headache (TH), as compared with a group of controls. The possible relationships between the biological parameters and clinical features were also examined. The results showed that the two groups of patients had a lower number of 3H-IMI binding sites and a lower activity of the thermolabile form of ST, which acts preferentially on monoamine substrates, than the healthy controls, with no intergroup differences. Significant correlations between psychopathological rating scales and characteristics of the illness were observed in the patients with TH. The decreased number of platelet 3H-IMI binding sites is suggestive of a presynaptic serotonergic dysfunction and confirms the involvement of 5HT in primary headaches. The reduced ST activity might produce changes in the level of sulphated biogenic amines, including dopamine and tyramine, which might have an additional role in the pathophysiology of some aspects of primary headache.

Abstract: In an open-label trial, we evaluated the efficacy of clozapine on abnormal involuntary movements in five patients with Huntington's chorea. We administered clozapine at increasing doses of 25, 50, and 150 mg/d for 3 weeks. Subjective self-evaluation of all patients reported reduction of chorea and improvement of daily living activities. At the end of the trial, all patients requested to continue with clozapine. Objective evaluation with the Abnormal Involuntary Movements Scale demonstrated in all patients moderate-to-marked reduction of abnormal involuntary movements without any significant side effects; the improvement was dose-dependent and markedly decreased 1 week after drug withdrawal.

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Abstract: We studied the effect of striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice on kainic acid (KA) evoked seizures. MPTP, 36 mg/kgp i.p. for 3 days, caused an 80% drop of striatal dopamine. Animals pretreated with MPTP, plus controls treated with saline, were challenged with five different convulsant doses of KA (3, 6, 12, 18 and 36 mg/kg i.p.). The seizures were monitored by electrographic recording and behavioral observation. MPTP pretreatment greatly attenuated the severity of the convulsions and the mortality induced by KA. The effect was mostly evident at the intermediate and at the high doses of KA. Surprisingly, no differences between the MPTP and control groups were found on the intensity and time course of the electrical seizures. Increment doses of KA resulted in a more severe electrographic seizure pattern in both the saline and the MPTP pretreated groups. Our data suggest that the dopamine depletion induced by MPTP does not alter the genesis of KA induced seizures, but may alter the function of cerebral structures involved in the control of seizure motor expression.

Abstract: The most frequently reported abnormal MRI finding in migraine is the presence of high signal white matter foci (WMF) on long TR images. Recently, WMF have been distinguished in periventricular WMF (PVF), when contiguous to ventricles, and deep WMF (DF), when far from these. DF, but not PVF, appear positively correlated with cerebrovascular risk factors and are called leukoaraiosis. In this study the MRI examination was performed in 129 consecutive migraine patients (83 of them had migraine without aura and 46 migraine with aura). In 19.3% of the migraineurs studied we observed WMF on T2 weighted images strictly localized in the deep white matter (DF). No PVF were observed. These findings were independent of the type of migraine and did not correlate with age, sex, disease duration, or frequency of attacks. The presence in a subgroup of migraineurs of leukoaraiosis (DF), for which a vascular genesis has been hypothesized, suggests that migraine could represent, a cerebrovascular risk factor in these patients.

Abstract: We compared the efficacy and safety of pergolide and bromocriptine in 57 patients with Parkinson's disease (PD) with a declining response to levodopa therapy in a single-blind, crossover study. Patients were placed randomly on the sequence bromocriptine-pergolide (12 + 12 weeks) or vice versa. Regular evaluations using the New York University Parkinson's Disease Scale were performed by a clinician blinded to treatment assignment. Patients' and clinicians' impressions also were recorded. The average daily dose of pergolide was 2.3 +/0- 0.8 mg, and that of bromocriptine was 24.2 +/- 8.4 mg. Significantly greater efficacy was demonstrated by both drugs as adjunctive therapy to levodopa compared with previous treatment of levodopa alone (pergolide, p = 0.0001; bromocriptine, p = 0.0005; Wilcoxon t test). Pergolide was more effective than bromocriptine in daily living scores (p = 0.020) and motor scores (p = 0.038). No difference in dyskinesias, dystonias, and psychosis was observed. Adverse events were more frequent in bromocriptine-treated patients. Most patients and physicians preferred pergolide to bromocriptine. Pergolide as adjunctive therapy to levodopa was more effective than bromocriptine in this short-term trial.

Abstract: The clinical diagnosis of idiopathic Parkinson's disease (IPD) remains difficult and is supported by a favorable response to levodopa, while failure to respond represents an exclusion criterion. Recently, the response to subcutaneous apomorphine has been suggested as a tool in predicting levodopa responsiveness in parkinsonian syndromes. We administered apomorphine at doses of 10, 50, and 100 micrograms/kg subcutaneously against placebo over two consecutive days in 37 patients with parkinsonism and evaluated the motor response for 90 min after each dose. Subsequently, we compared the motor response with the follow-up response to levodopa therapy and to a final diagnosis. Twenty-seven patients of 37 showed a positive response to apomorphine, and 10 had a negative response. All positive responses to the apomorphine test were obtained with 50 or 100 micrograms/kg doses. Because of the high frequency of side effects with the dose of 100 micrograms/kg, 50 micrograms/kg seems more useful. After an adequate period of levodopa/carbidopa therapy (12-month follow-up), 29 patients improved; 25 of these had demonstrated a positive response to the apomorphine test. The final diagnosis of IPD, made on the basis of an exhaustive clinical and neuroradiological evaluation and on the response to chronic levodopa therapy, was in good agreement with the response to the apomorphine test (predictivity of diagnosis, 86.4%). Our data indicate that subcutaneous apomorphine at the dose of 50 micrograms/kg is a useful tool in the differential diagnosis of parkinsonian syndromes.

Abstract: In the present study, we examined the effect of metadoxine on striatal levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites in male C57 Black mice. Striatal content was assayed after systemic administration of metadoxine ranging from 1 micrograms kg-1 to 500 mg kg-1. Striatal dopamine increased 1 h after treatment with metadoxine (150 mg kg-1), but the most notable effect was obtained 24 h after the drug administration. At this time a plateau was reached; the two major metabolites of dopamine showed the same trend. Seven days after metadoxine administration, striatal dopamine approached the control values. Over the same time intervals, striatal 5-HT increased to a lesser extent and 5-hydroxy-indoleacetic acid did not differ significantly from controls. Striatal dopamine increased significantly at a dose of 250 micrograms kg-1 up to a dose of 1 mg kg-1 metadoxine; no further increment was observed between 1 and 500 mg kg-1 metadoxine. Administration of each component at doses equimolar to 1 mg metadoxine showed that pyridoxine produced only a mild increase in striatal dopamine compared with controls. We suggest that the metadoxine-induced striatal dopamine increase is obtained by increasing synthesis of dopamine.

Abstract: We report a case of neuroleptic malignant syndrome (NMS) following abrupt reduction of chronic levodopa treatment in a 71 year old female parkinsonian patient. The NMS resolved within 24 hours of the addition of apomorphine to levodopa therapy.

Abstract: We administered apomorphine, a powerful dopaminergic agonist, subcutaneously to 25 untreated patients with parkinsonian features and evaluated motor response with the aim of discriminating idiopathic Parkinson's disease (IPD) from multiple system atrophy and progressive supranuclear palsy. The response to apomorphine was strongly predictive of responsiveness to subsequent levodopa follow-up and of the final diagnosis, made on the basis of both clinical and instrumental evaluation. Our data confirm that the apomorphine test is helpful in the differential diagnosis of IPD.

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Abstract: 390 patients with severe head injuries were treated with phenobarbital (PB) orally for a period of 12 months in order to determine whether this drug could reduce the incidence of posttraumatic epilepsy (PTE). An intramuscular PB dose of 2.5-3 mg/kg body weight per day was administered within 24 hours after the trauma; after 5 days, or longer if the coma persisted, the drug was administered orally. Maintenance dosage adjustments, when necessary, were based on serial plasma concentrations of the drug, sustained at between 5 and 30 micrograms/ml. 293 patients completed the study. 66% of these presented one risk factor, while 34% presented two or more. 6 patients (2.04%) had at least one seizure during the twelve months. Plasma drug levels at the time of the seizure, with one exception of 15 micrograms/ml, ranged from 20 to 28 micrograms/ml. The results of the study indicate that PB administered during the first twelve months after the trauma, even at relatively low doses, can have a prophylactic effect on PTE.

Abstract: The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57 black mice causes an acute seizure syndrome the severity of which is dose dependent; there is also a good correlation between the seizure inducing potential of MPTP and the neostriatal dopamine (DA) depletion caused by MPTP. The simultaneous administration of MPTP and MAO B inhibitors attenuates both epileptiform phenomena and neostriatal DA depletion. On the contrary diethyldithiocarbamate (DDC) exacerbates both responses. All these pharmacological manipulations are known to affect the accumulation of 1-methyl-4-phenylpyridinium ion (MPP+) the main metabolite of MPTP. Thus the present data support the hypothesis of a strict dependence of the epileptiform phenomena on the presence of MPP+. Furthermore the tight correlation existing between the severity of epileptic events and DA depletion suggests that the acute excitotoxic syndrome may contribute to the long-term toxicity of MPTP. *On leave from the Department of Neurology, University of Pisa, Pisa, Italy.

Abstract: Several cases of association between cerebellar ataxia and hypothyroidism have been reported, in which cerebellar symptoms regressed after euthyroid state was obtained, suggesting an etiologic relationship between hypothyroidism and ataxia. We present a further case of hypothyroidism and ataxia, with a peculiar positive family history for both thyroid and cerebellar disorders. Long-term replacement therapy with L-thyroxine determined the regression of hypothyroidism; however, no improvement in cerebellar symptoms was observed. The lack of response of the neurologic symptoms to L-thyroxine treatment suggests the absence of an etiological relationship between thyroid disease and cerebellar disease in this case.

Abstract: To evaluate the prevalence of epilepsy syndromes in a district in Northwest Tuscany (Vecchiano, 9,952 inhabitants) we identified all suspected cases (probable epilepsy) from several information sources: files of local doctors, prescriptions of antiepileptic drugs (AEDs), hospital files from the center for epilepsy at the University of Pisa, medical files from university and hospital departments in Pisa, and files of the school doctors and social workers in the district of Vecchiano. All persons suspected of having epilepsy were examined; 51 cases of epilepsy were found, i.e., a prevalence rate of 5.1 in 1,000. During a previous study performed in the same district with the "house-to-house" method, a lower rate was found. Our study confirms that use of different epidemiologic investigational methods can produce different results.

Abstract: Peripheral benzodiazepine (BDZ) receptors are located in a variety of tissues, including platelets, in the nuclear and/or mitochondrial membranes. We studied the density of peripheral BDZ receptors in platelets of 10 de novo Parkinson's disease (PD) patients, 18 PD patients treated with a levodopa/carbidopa combination, and in 15 healthy subjects matched for sex and age. The binding assay was conducted using [3H]PK 11195, a specific ligand for peripheral BDZ receptors. A significant decrease in the density of [3H]PK 11195 binding sites has been observed in PD patients with respect to controls (p less than 0.01), but not between de novo and treated PD patients. No correlation has been found between the decrease in density of [3H]PK 11195 binding sites in platelets and either the duration or severity of PD. Peripheral BDZ receptors are implicated in the regulation of mitochondrial respiratory function. Thus, their decrease in PD might parallel the abnormalities in mitochondrial function recently found in this neurologic disease.

Abstract: The occurrence of acute dystonic reactions (ADRs) due to domperidone administration in two young women is reported. In both patients, a typical polycystic ovary (PCO) syndrome was found. The possibility that the relative hyperestrogenism typical of PCO syndrome acted as a facilitating factor for ADR is discussed.

Abstract: Parkinson's disease (PD) patients show a good response to levodopa in the morning, and reduced duration or complete failure of response later in the day, but the pathophysiology of this phenomenon remains unclear. We evaluated motor performance hourly over a twelve-hour period in patients treated with levodopa/carbidopa (group A), with bromocriptine (group B), and in "de novo" patients (group C). At 8 am, 12 and 4 pm, group A patients received standard doses of levodopa/carbidopa, whereas patients of group B and C took, respectively, 5 mg bromocriptine and placebo. In "de novo" patients and in patients under bromocriptine we did not observe significant diurnal changes in motor score, whereas in patients under levodopa a progressive daytime worsening, which significantly correlated with progressive increase in 3-O-methyldopa plasma levels, was visible. These data seem to indicate a contributory role of pharmacokinetic or pharmacodynamic factors related to levodopa assumption, rather than to the underlying disease, in the afternoon worsening in PD.

Abstract: The secretion of gonadotropins and the role exerted by the endogenous opioid system on luteinizing hormone (LH) secretion were investigated in 6 postmenopausal women affected by idiopathic Parkinson's disease (PD) as well as in 6 age- and weight-matched normal postmenopausal women as controls. The mean plasma follicle-stimulating hormone (FSH) and LH levels were evaluated both under basal conditions and after 20 days of conjugated estrogen administration (1.25 mg/day). At the same time, the activity of the endogenous opioid system was evaluated, as well as the LH response to the 4-hour infusion of the opioid antagonist naloxone (1.6 mg i.v. bolus followed by 1.6 mg/h). Both before and during estrogen administration, plasma FSH levels were similar in the two groups of subjects, whereas plasma LH levels were significantly lower (p less than 0.01) in parkinsonian than in control women. In each subject estrogen administration significantly blunted (p less than 0.01) plasma FSH levels. Plasma LH levels were reduced only in controls (p less than 0.05), but not in women with PD. In each subject, before estrogen administration, the plasma LH levels did not vary during naloxone infusion. In control women after 20 days of estrogen administration, the plasma LH levels significantly increased during naloxone infusion (p less than 0.01). By contrast, in women with PD, conjugated estrogens failed to restore the LH response to naloxone. The present results suggest that the neurotransmitter mechanisms, which regulate LH secretion, are altered, and, in particular, the activity of the endogenous opioid system is deficient in women with PD.

Abstract: Neuroleptic drugs represent the current therapy for Huntington's chorea (HC). However neuroleptics can improve involuntary movements, but not functional performance and disease progression. Several clinical and experimental data suggest the existence of functional relationship between corticosteroids and extrapyramidal system. We administered dexamethasone to six choreics, all female. Dexamethasone was given i.m. at dose of 4 mg/die for 20 days and 8 mg/die for 20 days more. Dexamethasone at both the doses used, determined significant improvement (p less than 0.05) of dyskinesia, evaluated by AIMS, and manual dexterity, evaluated by Tapping test. Although at present it is not clear which mechanism are responsible for this of dexamethasone favourable effect, it might open new perspectives in HC therapy.

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Abstract: The effects of naloxone on side effects provoked by apomorphine (APO) administration in patients with parkinsonian syndrome have been studied. The group under study included eight patients with Parkinson's disease and four with parkinsonism who received 100 micrograms/kg s.c. APO acutely to test dopaminergic responsiveness. All patients were treated with 20 mg domperidone tablets t.i.d. and then for 2 consecutive days (in double blind fashion) were given a 2-hour i.v. saline infusion alone or with naloxone (8 mg) starting 30 min before APO administration. In both groups, naloxone delayed the appearance of sleepiness, and reduced the intensity of yawning, sleepiness, nausea, and vomiting as compared with saline. These findings indicate a potential usefulness of naloxone and other opioid antagonists in preventing acute APO side effects.

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Abstract: Plasma luteinizing hormone (LH) levels were significantly lower in 10 postmenopausal women with Parkinson's disease (PD) compared to age-matched controls. The remaining hypophyseal hormones and gonadal steroids were similar in PD patients and in controls, suggesting a selective alteration of hypothalamic dopaminergic mechanisms which regulate LH secretion.

Abstract: Several biochemical abnormalities in peripheral tissues have been reported in Alzheimer's disease (AD). With this in mind we studied platelet monoamine oxidase B (MAO B) activity and 3H-imipramine (IMI) binding in both AD patients and healthy subjects and found a significantly higher level of platelet MAO B activity and 3H-IMI Bmax values in the AD patients. In view of the part that MAO B plays in metabolizing serotonin (5HT) and of the relationship which exists between 3H-IMI binding and 5HT uptake, our results would suggest that with AD there occurs a complex dysfunction in the 5HT system, at least at a peripheral level.

Abstract: The role exerted by the endogenous opioid system on thermoregulation has been studied in six postmenopausal women affected by Parkinson's disease and in 6 age-matched, normal postmenopausal women, as controls. The women randomly received an infusion of the opioid antagonist naloxone (1.6 mg/h for 4 h) or of saline on two consecutive days. Body temperature, as evaluated by rectal temperature, was significantly lower (p less than 0.05) in Parkinsonian than in normal women, and it did not vary during saline infusion, in either groups. Naloxone infusion significantly reduced (p less than 0.01) body temperature in normal postmenopausal women, but it was unable to modify body temperature in women affected by Parkinson's disease. The low basal body temperature values and the inability of naloxone to exert a hypothermic effect in women suffering from Parkinson's disease seem to constitute further evidence for an impaired regulation of body temperature and impaired activity of the endogenous opioid system in this pathology.

Abstract: Motor neuron diseases (MND) associations with paraproteinemia, lymphoma, hexosaminidase A deficiency and heavy-metal intoxication are of great interest. A case of amyotrophic lateral sclerosis (SLA) associated with multiple myeloma (monoclonal IgG paraproteinemia and K light chains) is reported. The detection of abnormal protein in 1988 and the increase of its serum level during 1989 were strictly correlated with the beginning and the worsening of the neurological disease. Shy and coll. in 1986 affirmed that association of paraproteins with MND is probably not merely the fortuitous association of a common laboratory abnormality and an uncommon disease. The reported case provides elements for a causal association between paraproteinemia and MND.

Abstract: Flunarizine, a calcium antagonist widely used in the prophylactic treatment of migraine, may interfere with dopaminergic systems. Flunarizine therapy can in fact induce extrapyramidal side effects and can increase basal as well as stimulated prolactin levels. To better define the mechanism of flunarizine action in migraine, we studied prolactin and growth hormone responses to thyrotropin releasing hormone and sulpiride in 13 female migraineurs before and after 60 days of flunarizine therapy. The treatment did not modify basal prolactin and growth hormone levels, but prolactin response to thyrotropin releasing hormone was enhanced. A paradoxical increase of growth hormone to thyrotropin releasing hormone observed before therapy was blunted after flunarizine treatment. These data indicate a modulatory action of flunarizine on dopaminergic systems which might to some extent explain the antimigraine action of this drug.

Abstract: Monoamine oxidase B (MAO B) plays a pivotal role in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinsonism. An increased MAO B activity in platelets of patients with idiopathic Parkinson's disease (PD) is reported in this study. The possibility that high MAO B activity may represent a trait of vulnerability for PD by enhancing the neurotoxic effects of environmental compounds is discussed.

Abstract: Apomorphine is a powerful dopaminergic drug, able to improve cardinal symptoms of Parkinson's disease in few minutes, when injected subcutaneously. We administered different doses of apomorphine s.c. against placebo in 25 patients with a Parkinsonian syndrome, with the aim of discriminating Parkinson's disease from other Parkinsonism. A positive response to apomorphine was predictive (88%) of good responsiveness to levodopa therapy. Our data, together with those of other groups, indicate that apomorphine test is a useful tool in the diagnosis of Parkinsonian syndromes.

Abstract: Ten women with a documented history of catamenial epilepsy underwent a hormonal study to evaluate hypophyseal-gonadal function. Baseline values of luteinizing hormone, follicle-stimulating hormone and prolactin were similar in catamenial seizure patients and in control groups throughout a complete menstrual cycle. Stimulated secretions of the same hypophyseal hormones in catamenial seizure patients overlapped those of the controls. The luteal secretion ratio of progesterone to estradiol was significantly reduced in catamenial seizure patients versus normal controls. In a subgroup of catamenial seizure patients on antiepileptic therapy, luteal progesterone levels were remarkably decreased compared to normal and epileptic controls. These results indicate that catamenial epilepsy is characterized by an imbalance in ovarian steroid secretion and emphasize the need for an endocrinological assessment in these patients.

Abstract: Based on behavioral observation alone, poorly characterized paroxysmal motor abnormalities have been reported in mice after acute MPTP administration. This study investigated electroencephalographic (EEG) and behavioral effects of acute MPTP in young and older mice. Single MPTP injections (30 mg/kg i.p.) produced limbic and/or generalized seizures in older (6 mo) and frank epileptiform interictal hippocampal spikes in younger (6-8 wks) mice. These latter showed behavioral seizures only after the 3rd drug administration. Studies of the acute effects of MPTP must take in consideration that seizures "per se" modify brain biochemical and metabolic activity and alter the permeability of the blood brain barrier, adding several confounding variables.

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Abstract: Flunarizine (FLU) treatment has proved effective for migraine but there have been reports--though controversial--of depression and/or extrapyramidal signs and symptoms in cases of chronic therapy. It has been suggested that FLU may interfere with the activity of central dopaminergic systems. In this study, prolactin (PRL) secretion was chosen as a parameter for functional exploration of central dopaminergic systems in normal and migraineous women before and after FLU treatment. Five healthy women were given FLU (20 mg) and placebo per os, each for one day. A significance increase of serum PRL levels was found after FLU administration, but not after placebo. Ten women with common migraine underwent TRH stimulation test (200 micrograms i.v.) before and after a 30-day FLU therapy (10 mg per os). Basal PRL levels were not modified by the treatment, but TRH stimulated PRL values were significantly enhanced after a 30-day FLU therapy. These results seem to confirm the hypothesis that FLU interferes with central dopaminergic activity.

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Abstract: We studied the effectiveness of orally administered thyrotropin-releasing hormone (TRH) (40 mg/day) for 10 days against placebo in 11 patients with hereditary ataxias (HA). All patients completed the trial and none reported any noticeable side effects. A clinical rating scale for inherited ataxias and the Northwestern University Disability Scale for clinical disability showed no significant variation over the duration of the study. Manual dexterity, studied with the peg board test, showed a significant improvement after TRH compared with basal values, which persisted after washout. Eye movement alterations, as revealed by electroculography were reduced after TRH and washout when compared with placebo and basal scores. Hormonal monitoring showed only a transitory effect on the hypothalamus-hypophysis-thyroid axis. These results demonstrate that orally administered TRH has a mild but significant effect only on some cerebellar symptoms in HA.

Abstract: Persistent neurochemical changes consistent with parkinsonism have been reported in brains of mice treated with repeated high doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We now report that ethanol or acetaldehyde potentiate MPTP-induced damage to mouse striatum. One hour after the combined treatments (ethanol and MPTP or acetaldehyde and MPTP), the animals exhibited a marked and long-lasting catatonic posture and then returned gradually to apparently normal locomotion. Seven days after MPTP administration, depletion of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in mouse striatum were further potentiated in the group of animals treated with ethanol. This effect was more evident when the treatment was repeated twice and was dose-dependent. Acetaldehyde was more potent than ethanol in enhancing MPTP neurotoxicity. A single exposure to acetaldehyde before and during MPTP treatment produced a very consistent fall of DA, DOPAC and HVA but not serotonin (5HT) or 5-hydroxyindoleacetic acid (5HIAA) in the striatum. This suggests that ethanol effects on MPTP neurotoxicity might be related to acetaldehyde formation.

Abstract:

Abstract: Circulating basal prolactin (PRL) levels were evaluated in 126 subjects of both sexes with partial or generalized epilepsy, who were treated with phenobarbital (PB) alone or in combination with either phenytoin or benzodiazepines. A significant increase in PRL levels was observed in male, but not in female, patients compared with a sex- and age-matched healthy volunteer group. Circadian PRL secretion, studied in six male epileptic patients on PB monotherapy and in nine normal subjects, showed comparable 24-h PRL mean values and a preserved PRL surge during the night in both groups; however, a statistically significant additional peak was found in male epileptic subjects during the late afternoon. The cosinor analysis of the data, used to evaluate PRL rhythmicity, showed a disruption of the 24-h periodicity in epileptic subjects, while the 12-h periodicity was maintained. These results indicate that central and/or peripheral mechanisms involved in PRL secretion control are more sensitive to PB alone or in combination with other antiepileptic drugs in male than in female subjects. However, the changes of PRL secretion we found were small and unrelated to the different clinical conditions.

Abstract: 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a new neurotoxin that causes degeneration of the dopaminergic nigrostriatal neurons and induces a Parkinson-like state in several species, including humans and monkeys. The present study was designed to better characterize the properties of [3H]MPTP binding sites and to evaluate the interaction of MPTP with the oxidation of dopamine by monoamine oxidase (MAO) in an animal species (Saimiri Sciureus) shown to be lesioned by MPTP. Our data confirm the presence of high affinity and saturable binding sites for [3H]MPTP in the squirrel monkey. Specific binding with analogous characteristics also occurs in peripheral tissues. Various substances failed to inhibit the [3H]MPTP binding, whereas only MAO inhibitors (MAOI) were able to antagonize this binding to brain and peripheral tissues. In particular, deprenyl, a selective inhibitor of MAO type B enzyme, was relatively more potent as a displacer of [3H]MPTP from its binding sites both in brain and in peripheral tissues. Our results further suggest a correspondence between [3H]MPTP sites and MAO, particularly MAO-B, in monkey brain. Moreover, our data show that the oxidative deamination of dopamine is inhibited by MPTP in vitro. In conclusion, these data are consistent with the hypothesis of the involvement of MAO in the neurotoxic effects of MPTP, even though further experiments are necessary to better clarify the molecular mechanism of MPTP neurotoxicity.

Abstract: Our study demonstrates that 3H-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (3H-MPTP) specifically binds to platelet membrane sites in humans. This specific, high affinity and saturable binding has properties similar to those of 3H-MPTP binding to rat and monkey brain, with a higher affinity. Deprenyl, a specific inhibitor of MAO type B enzyme, was the most potent drug in displacing 3H-MPTP from platelet binding sites. Platelets are considered a good model for central aminergic neurons and are very rich with MAO enzymatic activity, exclusively of type B. Our findings support previous evidence indicating a correspondence between 3H-MPTP binding sites and MAO-B enzyme. Moreover the presence of 3H-MPTP binding sites on human platelets suggests the use of this peripheral tissue as a simple model to study at least partially the mechanisms of neurotoxic action of MPTP.

Abstract: Plasma estradiol (E2), progesterone (P), beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) were measured in the luteal phase of 8 patients affected by menstrually-related migraine (M) and in 3 cases of catamenial epilepsy (CE). Plasma P and E2 of the M patients were lower than in the CE group. Both beta-LPH and beta-EP showed a reduction in M patients near menses, while the opposite pattern was found in CE. These data demonstrate that premenstrual syndrome is sustained by different, neurobiological dysfunction even if endogenous opioids could be involved in both migraine and epilepsy.

Abstract: The hypothesis that catamenial epilepsy depends on abnormal rhythmic hormone activity in the hypothalamus-pituitary-gonadal axis has never been critically tested. No significant modifications in the secretory pattern of pituitary hormones, both basally and in response to stimulatory tests, were found in a group of catamenial epileptic women. On the contrary, our data showed a reduction of luteal phase progesterone secretion. These findings indicate that an imbalanced secretion of ovarian steroids plays a role in the catamenial exacerbation of epilepsy.

Abstract: The effects of carbamazepine (CBZ) on spontaneous secretion of prolactin (PRL) and after stimulation with thyrotropin releasing hormone (TRH) were evaluated. Volunteer subjects after acute CBZ administration, and epileptic subjects with complex partial seizures chronically treated with CBZ, were examined. In an epileptic group, CBZ did not change TRH stimulatory effect on PRL secretion. No appreciable changes of PRL spontaneous secretion were observed, and only a small increase of sleep-entrained values with preservation of the normal secretory circadian rhythm was noted, both in normal subjects and in epileptic subjects. This result could be explained by a serotoninergic activity of PRL changes produced by CBZ in these various conditions agrees with the absence of published reports of CBZ side effects associated with hyperprolactinemia.

Abstract: Terguride, a mixed agonist-antagonist of central dopamine receptors, was administered to eight patients with Parkinson's Disease. The clinical symptomatology of all patients improved significantly. The maximum neurological effect of terguride was noted at the highest daily dose (1.2 mg) after 21 days of treatment in all subjects, with a statistically significant average of 50.6% neurological improvement on the Webster scale in respect to admission. All single scores of the Webster scale decreased significantly: swing of the arms, facial expression, bradikinesia, rigidity and gait, particularly. No significant adverse reactions were observed during treatment. Our study in drug-free parkinsonian patients demonstrated that terguride is able to improve the neurological symptoms similar to DA agonists, but without their typical side effects.

Abstract: We used a new radioimmunological (RIA) kit for the assay of B subunit of creatine kinase enzyme (CK). This RIA system uses a specific antisera against the B subunit as ligant, human CK-BB labelled with 125I as tracer, and purified human CK-BB isoenzyme as standard. The mean (+/- SD) sensitivity obtained was 0.25 +/- 0.16 ng/tube and the between assay variability was about 9-10%. Serum levels of 113 normal subjects was not normally distributed. The 95% of values was found below 5 ng/ml. This new RIA is usefull in clinical practice when serum levels of CK-BB isoenzyme must be determined. This method is quickly and it is characterized by a good degree of precision, but the CK-MB isoenzyme cross-reacts for about 40% in this RIA system. Therefore, for the clinical diagnosis by means of this RIA it is necessary to rule out the concomitant elevations of serum CK-MB values.

Abstract: Gynecomastia developed in two epileptic patients some months after the addition of oral fluoresone 750 mg daily to the phenobarbital and phenytoin already being administered. The common systemic diseases that may give rise to gynecomastia were excluded. One of the patients presented hyperprolactinemia and a raised estrogen/androgen ratio but the hormone levels were not raised in the other. The onset of symptoms after fluorescence in both cases is highly suggestive, although the pathogenetic mechanism is not clear.

Abstract: Nocturnal sleep was poligraphycally recorded in three male patients aged 54-67, with progressive supranuclear palsy (PSP). All patients suffered from insomnia. In case 1 REM sleep was markedly reduced and spindles were less numerous than in normal subjects. In cases 2 and 3, EEG patterns were not distinguishable from those observed when the patients were awake. Sleep, therefore, was recognized only by constant observation of the patients. As seen in the literature EEG changes during sleep can be correlated to the severity of the clinical picture and the stage of evolution of the disease. EEG patterns of sleep in PSP are similar to those reported in patients with presenile dementia.

Abstract: Phenobarbital (PB) was tested for its efficacy in averting post-traumatic epilepsy (PTE) in patients with non-missile head injuries. The protocol envisaged the administration of PB throughout a period of two years in randomly assigned doses ranging from 0.5 to 1.5 and from 1.6 to 2.5 mg/kg/day. The study included neurologic examination, EEG and plasma PB levels. Ninety patients, 83 of whom with serious head injury followed the prescribed treatment for the entire period. Two adult patients manifested seizures 5 and 10 months after the trauma. They were being treated with doses over 1.5 mg/kg/day. Another patient had a seizure six months after the end of the prophylaxis. Low doses of PB and monitoring permitted a reduction of side effects. The low incidence of PTE indicates that PB has an efficient prophylactic effect. The results also show that a low dosage has a favourable effect.

Abstract:

Abstract: Plasma levels of luteinizing and follicle-stimulating hormones were measured for 24 hours in six subjects affected by constitutional stature delay associated with sexual maturation delay. The children in pubertal stage exhibited fluctuating plasma concentrations of these hormones which significantly increased during sleep, as in healthy pubertal subjects. Thus in this type of delayed puberty, the synchronization of augmented gonadotropin secretion with sleep develops later in chronologic age but it is strongly related to bone age.

Abstract:

Abstract: Six nocturnal polygraphic recordings were carried out in a young man with fibrillary chorea of Morvan, during the acute period of the disease. Sleep was remarkably fragmented by numerous and brief awakenings but the total sleep time fluctuated between 157 and 312 mins.; the sleep structure was altered by the almost total absence of stages 3,4 and REM. During the day, the subject had one or two periods of sleep (1-2 hours) and complained of being tired. The nocturnal awakenings were correlated by the patient with pain and burning dysaesthesiae of distal distribution that were more severe than those occurring during the day. The patient improved gradually, and five month later both sleep disturbances and other signs of disease had disappeared.