Abstract: Background: Although the overall effects of cholinesterase inhibitors (CEIs) are limited, there could be a subpopulation of patients who experience unequivocal benefit. This study aimed to describe a clinical profile based on a combination of specific neuropsychological test scores and clinical symptoms associated with a favourable response to rivastigmine. Methods: A prospective cohort study was conducted in 53 patients who started rivastigmine treatment. Neuropsychological evaluation was performed at baseline and 6 months of treatment. Patients were labelled responders and non-responders based on change scores after 6 months in 3 clinical domains: cognition, activities of daily living and behaviour. Results: After 6 months 19 responders and 15 non-responders were identified. Variability in reaction time and Continuous Performance Test (CPT) scores differed significantly at baseline between groups. A previously defined cluster of 4 items of the Neuropsychiatric Inventory was correlated with therapeutic response. Conclusion: These findings suggest that patients who respond well to CEI therapy can be identified by deficits in attention, combined with a cluster of behavioural symptoms, including hallucinations, apathy, anxiety and psychomotor disturbances. This may constitute the clinical profile of cholinergic deficiency. Further prospective studies in larger populations are warranted to investigate whether this profile can be used to select patients who will benefit from CEIs. Copyright (c) 2007 S. Karger AG, Basel.
Abstract: BACKGROUND: Infection induces an acute phase response that is accompanied by non-specific symptoms collectively named sickness behavior. Recent observations suggest that microglial cells play a role in mediating behavioral changes in systemic infections. In animal models for sepsis it has been shown that after inducing lipopolysaccharide, LPS, microglia in the brain were activated. The aim of this study was to investigate whether activation of microglia can be detected in patients who died of sepsis. METHODS: In a case-control study brain tissue of 13 patients who died with sepsis was compared with that of 17 controls. Activated microglia were identified by expression of MHC-class II antigens and CD68. Microglia activation was analyzed by a semiquantitative score combining both the number of the immunoreactive cells and their morphology. RESULTS: In patients who died with sepsis there was a significant increase in activated microglia in the grey matter when stained with CD68 compared to controls. This effect was independent of the effect of age. CONCLUSION: This study shows for the first time in human brain tissue an association between a systemic infection and activation of microglia in the brain. Activated microglia during sepsis could play a role in behavioral changes associated with systemic infection.
Abstract: Apolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Down's syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-based sample of persons with DS (n=425), demented and non-demented. There was evidence that APOE varepsilon4 is correlated with the rate of decline in the social competence rating scale (SRZ) (p=0.04). In our population, we found overall a modest but not statistical significant effect on the prevalence of dementia (OR=1.57, 95%CI: 0.87-2.82). We did observed a significant long-term effect on the incidence of dementia (HR=4.66, 95%CI: 1.35-16.14), but for those with a follow-up less than 3 years the risk was not significantly increased: HR=0.83 (95%CI 0.35-1.94). When pooling our data in a meta-analysis, the APOE varepsilon4 allele shows a 1.59-fold (95%CI: 1.19-2.12) increase in risk of dementia in persons with DS. We conclude that APOE is influencing the risk of dementia in persons with DS.
Abstract: OBJECTIVES: The authors investigated prodromal delirium symptoms in elderly patients undergoing hip surgery. METHODS: This was a prospective cohort study in the setting of a large medical school-affiliated general hospital in Alkmaar, The Netherlands. Participants were patients undergoing hip surgery aged 70 and older at risk for delirium. Before surgery, patients were randomized to low-dose prophylactic haloperidol treatment or placebo. Daily assessments were based on patient interviews with the Mini-Mental State Examination and Digit Span test. The Delirium Rating Scale-Revised (DRS-R-98) was used to measure early symptoms during the prodromal phase before the onset of delirium. RESULTS: Data of 66 patients with delirium were compared with those of 35 at-risk patients who did not develop delirium: 14 of 66 patients (21%) had delirium on the day of surgery or early the day after, 32 of 66 (48%) on the second day, 14 of 66 on the third, and six of 66 (9%) on the fourth. The average DRS-R-98 total scores on day -4 to day -1 before delirium were 1.9 for the comparison group patients and 5.0, 4.3, 5.8, and 10.7 for patients with postoperative delirium. Multivariate analysis showed that the early symptoms memory impairments, incoherence, disorientation, and underlying somatic illness predict delirium. CONCLUSIONS: Most elderly patients undergoing hip surgery with postoperative delirium already have early symptoms in the prodromal phase of delirium. These findings are potentially useful for screening purposes and for optimizing prevention strategies targeted at reducing the incidence of postoperative delirium.
Abstract: The practice guideline 'Diagnosis and pharmaceutical treatment of dementia' emphasizes that a nosological diagnosis should be made and that it is important to assess the extent of need for care. The guideline recommends the use of diagnostic criteria for the various conditions that can cause dementia. With respect to ancillary investigations, the burden to the patient should be weighed against the benefits of increasing diagnostic confidence. Observation of the course of the disease, laboratory and cerebrospinal-fluid investigations, neuropsychological and EEG examinations, and neuroimaging all increase diagnostic confidence. Treatment with a cholinesterase inhibitor or memantine should always be embedded in a comprehensive-treatment protocol that includes explicit discussion of treatment goals and expectations at baseline, in combination with criteria for starting and stopping treatment. Guidelines for evaluating the effects of treatment with cholinesterase inhibitors or memantine are specified. If psychosis, depression or behavioural disturbances occur in patients with dementia, antidepressants, antipsychotics or anticonvulsants may be indicated.
Abstract: OBJECTIVES: To evaluate risk factors for postoperative delirium in a cohort of elderly hip-surgery patients and to validate a medical risk stratification model. DESIGN: Prospective cohort study. SETTING: Medical school-affiliated general hospital in Alkmaar, the Netherlands. PARTICIPANTS: Six hundred three hip-surgery patients aged 70 and older screened for risk factors for postoperative delirium. MEASUREMENTS: Predefined risk factors for delirium were assessed on admission. One point was assigned for each of four risk factors present, resulting in three groups: low, intermediate, and high risk. Baseline screening and assessment included the Mini-Mental State Examination, the standardized Snellen test for visual impairment, chart review to determine Acute Physiological and Chronic Health Evaluation II score, and blood urea nitrogen to creatinine ratio. The primary outcome was postoperative delirium, as defined using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Confusion Assessment Method criteria. All patients were screened daily for delirium. RESULTS: Incidence of delirium was 3.8% in the low-risk group (P<.001), 11.1% in the intermediate-risk group (P=.27, relative risk (RR)=3.0), and 37.1% in the high-risk group (P<.001, RR=9.8). Cognitive impairment at admission had the highest predictive value for postoperative delirium (coefficient of determination=0.15). Contrary to previous findings, age was an independent predictive factor for delirium. Moreover, postoperative delirium was four times as frequent in acute patients as in elective hip-replacement patients. CONCLUSION: The medical risk factor model is valid for elderly hip-surgery patients. Cognitive impairment, age, and type of admission are important risk factors for delirium in this surgical population.
Abstract: Cholinesterase inhibitors are widely prescribed in patients with Alzheimer's disease. Recently it has become clear that using these medications increases the risk of serious adverse events like cardiac arrhythmias, and some studies report a much-increased mortality in the treatment group on comparison with the placebo group. In the light of the at best, modest, treatment effects, we advocate that the safety of cholinesterase inhibitors should be the subject of continuing, intense scrutiny. Efforts should be made to delineate the profile of a true 'cholinergic deficiency syndrome', in order to be able to prescribe these medications to a group of patients in whom the benefits outweigh the risks.
Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) and Creutzfeldt-Jakob disease (CJD) share clinical features like cognitive decline, motor disturbances en psychiatric symptoms. Overlapping symptoms may cause physicians to mistake DLB for CJD. METHODS: Clinical data of 12 patients with autopsy-confirmed DLB who had been clinically suspected to suffer from CJD were analysed to investigate possible clinical features which led to misdiagnosis. RESULTS: There was an association in time between administering neuroleptics and rapid clinical deterioration in 8 out of 9 patients. CONCLUSION: It is suggested that the neuroleptic sensitivity in LBD fuelled the misdiagnosis of CJD in the presented series. Diagnostic confusion between CJD and DLB may have important clinical consequences and may lead to treatment restrictions.
Abstract: The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer's disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar A beta deposits. Recent neuropathological studies show a close relationship between fibrillar A beta deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in A beta metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.
Abstract: The amyloid plaques in Alzheimer's disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Abeta depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Abeta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while "later" neurodegenerative characteristics are not seen in these models. Next to the plaques, Abeta amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and medium-sized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed.
Abstract: OBJECTIVES: To study the effectiveness of haloperidol prophylaxis on incidence, severity, and duration of postoperative delirium in elderly hip-surgery patients at risk for delirium. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Large medical school-affiliated general hospital in Alkmaar, The Netherlands. PARTICIPANTS: A total of 430 hip-surgery patients aged 70 and older at risk for postoperative delirium. INTERVENTION: Haloperidol 1.5 mg/d or placebo was started preoperatively and continued for up to 3 days postoperatively. Proactive geriatric consultation was provided for all randomized patients. MEASUREMENTS: The primary outcome was the incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Confusion Assessment Method criteria). Secondary outcomes were the severity of delirium (Delirium Rating Scale, revised version-98 (DRS-R-98)), the duration of delirium, and the length of hospital stay. RESULTS: The overall incidence of postoperative delirium was 15.8%. The percentage of patients with postoperative delirium in the haloperidol and placebo treatment condition was 15.1% and 16.5%, respectively (relative risk=0.91, 95% confidence interval (CI)=0.6-1.3); the mean highest DRS-R-98 score+/-standard deviation was 14.4+/-3.4 and 18.4+/-4.3, respectively (mean difference 4.0, 95% CI=2.0-5.8; P<.001); delirium duration was 5.4 versus 11.8 days, respectively (mean difference 6.4 days, 95% CI=4.0-8.0; P<.001); and the mean number of days in the hospital was 17.1+/-11.1 and 22.6+/-16.7, respectively (mean difference 5.5 days, 95% CI=1.4-2.3; P<.001). No haloperidol-related side effects were noted. CONCLUSION: Low-dose haloperidol prophylactic treatment demonstrated no efficacy in reducing the incidence of postoperative delirium. It did have a positive effect on the severity and duration of delirium. Moreover, haloperidol reduced the number of days patients stayed in the hospital, and the therapy was well tolerated.
Abstract: The amyloid plaques in Alzheimer's disease (AD) brains are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that Abeta deposits in AD brains are closely associated with a locally induced, non-immune mediated, chronic inflammatory response. Clinicopathological and neuroradiological studies show that activation of microglia is a relatively early pathogenic event that precedes the process of neuropil destruction in AD. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins that are colocalized with Abeta plaques, are genetic risk factors of AD. Epidemiological studies have also shown that the use of classical nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent the risk of AD but clinical trials with anti-inflammatory drugs in AD patients were negative. These findings indicate that anti-inflammatory agents can be helpful in the prevention but not in the treatment of AD. So, pathological, genetic and therapeutic studies suggest that inflammatory mechanisms are most likely involved in the early steps of the pathological cascade. In the autosomal dominant inherited forms of AD the primary factor is the increased production of Abeta1-42 resulting into fibrillar Abeta deposition that elicits a brain inflammatory response. The etiology of the sporadic forms is yet unknown but this subtype is considered to be heterogeneous and multifactorial in its pathogenesis. Here we review the evidence that inflammation related events could be a critical etiological factor in certain forms of the sporadic AD.
Abstract: Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14% of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45%) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55% of its origin is still unknown.
Abstract: The DJ-1 gene is associated with autosomal recessive early-onset Parkinsonism, most likely through its role in defense against oxidative stress. Oxidative stress is not only involved in Parkinson's disease, but also in other neurodegenerative disorders, such as dementia. We assessed the presence of a 14 kb DJ-1 deletion in 191 patients with dementia, ascertained from the genetically isolated population where the first kindred with DJ-1 related Parkinsonism was originally identified. The control group consisted of 129 non-demented subjects. We found the deletion in two patients and one control. There was no evidence for an increased risk of dementia in carriers. All subjects were heterozygous for the deletion and related to a common ancestor within eight generations. Our results suggest it is unlikely that haploinsufficiency in the DJ-1 gene imparts an increased risk for dementia.
Abstract: The revised version of the practice guideline 'Dementia' from the Dutch College of General Practitioners provides a sound and comprehensive overview, and a practical guideline especially for the period following the diagnostic evaluation. The advice on the issues of whether to refer patients and whether to start symptomatic drug treatment is stated in rather general terms. Therefore, for most general practitioners it will still be difficult to decide how best to act on these issues. The fact that the cognitive examination is treated as part of the history taking will, most probably, negatively affect the quality of the diagnostic evaluation.
Abstract: The growing global disease burden attributable to dementia has strongly stimulated research activities. However, patients with dementia that are included in clinical research are systematically younger than patients from the general population. This large age gap perhaps indicates a lack of methodological rigour, but, more importantly, has the potential to affect the interpretation of research finding-eg, those relating to neuropathology, apolipoprotein E polymorphisms, the effects of cholinesterase inhibitors, and many other issues relevant to patients with dementia. Research on dementia has a lot to gain from the study of patients that more appropriately reflect the population at risk.
Abstract: Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer's disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electroencephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer's disease, Lewy body dementia and Parkinson's disease and to respond well to cholinesterase inhibitor therapy.
Abstract: Based on observations from neuropathology, epidemiology, and in vitro and animal experiments, the inflammatory component of Alzheimer's disease (AD) has been considered a compelling target for therapeutic intervention. However, a summary of all published trial reports to date suggests that AD patients do not benefit from treatment with anti-inflammatory drugs. In this brief review, we try to reconcile these sobering trial results with recent observations from basic research and epidemiology that continue to strengthen the idea that inflammatory mechanisms play an important role in the pathogenesis of AD. We review the possibilities that (1) not all components of the inflammatory response in AD are detrimental, (2) beneficial effects of anti-inflammatory drugs may not be mediated by inflammatory pathways, and (3) the timing of the intervention should be in the earliest stages of the pathogenesis of AD, perhaps even before the first symptoms emerge.We conclude that studies on primary prevention of AD are the logical next step in testing the inflammatory hypothesis of AD.
Abstract: Cholinesterase inhibitors are licensed for the treatment of dementia in Alzheimer's disease. In clinical practice, these drugs have little effect on the cognitive symptoms of dementia. Several studies report a beneficial effect of cholinesterase inhibitors on neuropsychiatric symptoms. We hypothesise that symptoms such as the impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome. It is postulated that this syndrome crosses boundaries of nosological entities and occurs in various neurodegenerative diseases. Symptoms resulting from cholinergic deficiency might be a much better target for treatment than cognitive deficits.
Abstract: Problems in the Netherlands with respect to the reimbursement of memantine have led the patient organization 'Alzheimer Nederland' to establish an emergency fund. Several trials have documented the limited, but consistent beneficial effects of memantine in severely demented patients. It is not clear which subgroup of patients might benefit the most. The drug seems to have dopamimetic and antidepressant effects which might explain its overall effect. The publicity surrounding memantine contributes to an atmosphere in which patients and care providers have to explain why they are not yet using 'anti-dementia drugs'. This should be avoided. Patients can expect to gain more benefit from ongoing, thorough and independent investigations than from hastily established emergency funds to finance the use of a drug with a limited and poorly defined efficacy.
Abstract: Creutzfeldt-Jakob disease (CJD) is a rare, neurodegenerative disorder belonging to the spongiform encephalopathies. A variant form (vCJD) is most likely the result of infection with the agent that causes bovine spongiform encephalopathy (BSE). Diagnostic information can be obtained by EEG, testing cerebrospinal fluid for the presence of the 14-3-3 protein, MRI, brain biopsy, tonsil biopsy, and postmortem brain examination. Some tests, such as MRI and postmortem brain examination, can be used to distinguish between CJD and vCJD. Pathological prions in a tonsil biopsy are only found with vCJD. In the Netherlands, there are four known cases of iatrogenic CJD. On the basis of certain exposure to BSE via the food chain, cases of vCJD are also to be expected. Chloropromazine and mepacrine are known to inhibit the formation of pathological prion conformations, but clinical trials have not yet been carried out.
Abstract: Many disorders, such as Alzheimer's disease and diabetes, are characterised by the misfolding and aggregation of proteins. Pepys et al. described a new approach of destabilizing these aggregates by removing an associated protein, serum amyloid P. This offers opportunities for treating amyloidosis and possibly other protein folding diseases. Understanding the mechanism of this unique disease process and the different elements involved is necessary for future drug development.
Abstract: OBJECTIVE: Evaluation of the initial experiences with rivastigmine in Alzheimer's disease. DESIGN: Retrospective. METHOD: Data were collected from patients with Alzheimer's disease who were treated with rivastigmine between 1 October 1998-30 November 1999 at the Memory Disorders Outpatients Clinic at the Academic Medical Centre or the Slotervaart Hospital, both in Amsterdam, the Netherlands. Before, and 6 months after treatment, the course of the disease was evaluated using clinimetric scales relating to cognitive functions, behavioural abnormalities and instrumental daily functions. The treatment results were considered to be 'favourable' if they corresponded with a disease course seen in less than 10% of untreated Alzheimer patients. RESULTS: During the study period, 53 patients were treated, 36 women and 17 men, with a mean age of 77 years (range: 57-89). Follow-up data were incomplete for four patients. Of the remaining patients, 27 (55%; 95% CI: 40-69) withdrew from treatment during the first 6 months, mainly because of gastrointestinal side-effects. Of the other 22 patients (45%; 31-60) 18 continued with rivastigmine treatment (18/49 = 37%; 23-52), and in three of these patients the disease course was favourable (3/49 = 6%; 1-17). CONCLUSION: In daily practice, over 50% of the patients were unable to tolerate rivastigmine. Structured evaluation of treatment efficacy was feasible in this population. Treatment with rivastigmine seemed to be beneficial in a small proportion of the patients.
Abstract: Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Abeta and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Abeta and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Abeta plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders.
Abstract: OBJECTIVE: To study whether an algorithm that includes additional diagnostic information could increase the specificity of the 14-3-3 protein testing in patients suspected to suffer from Creutzfeldt-Jakob disease (CJD). DESIGN: The development of a diagnostic algorithm. METHOD: The 14-3-3 protein was tested in the cerebrospinal fluid from 69 consecutive patients suspected of having CJD. On the basis of a former study and literature research, a diagnostic algorithm was constructed, which restricted the indication for performing the 14-3-3 protein test. RESULTS: By taking into consideration the findings of neuroimaging and routine cerebrospinal fluid examination prior to 14-3-3 testing, the specificity increased to 97% (95%-CI: 85.5-99.9) thus changing the prior probability of having CJD of 35% to a posterior probability of 75-100%, in the case of a positive test result. CONCLUSION: Determining the presence of 14-3-3 protein is a highly sensitive and specific marker for sporadic CJD when used in combination with imaging and cerebrospinal fluid examination.
Abstract: Rivastigmine was recently licensed for treatment of Alzheimer's disease on the basis of large double-blind placebo-controlled clinical trials. However, it is difficult to determine the clinical relevance for individual patients from the results of this type of clinical trial. With the help of standardised measurements in individual patients the clinical relevance can be better established. In order to avoid extra burden on patients, caregivers and doctors, these measurements should be simple. A combination of three clinimetrical scales for cognition, ability to perform daily activities and behaviour, which takes about 15 min to complete, appears to be efficient. Comparison of these data with data from a group of untreated Alzheimer's patients can give an impression of the efficacy of the medication. With the use of goal-attainment scaling, measurements can be individualised even more. This approach allows the clinician, in consultation with the caregiver and the patient, to make an informed decision about whether or not to continue treatment.
Abstract: BACKGROUND: Results of epidemiological studies, neuropathological observations, and in-vitro experiments all suggest that inflammatory mechanisms contribute to the destructive lesions in Alzheimer's disease. We aimed to establish the effect of the anti-inflammatory drug hydroxychloroquine on the progression of dementia. METHODS: We did a double-blind, parallel-group, multicentre trial in which we randomly assigned 168 patients with early Alzheimer's disease to hydroxychloroquine (200 or 400 mg dependent on bodyweight), or placebo for 18 months. Outcome measures were related to activities of daily living, cognitive function, and behavioural abnormalities. Analysis was by intention to treat. RESULTS: At 18 months, mean scores for the interview for deterioration in daily life in dementia in patients on hydroxychloroquine (22.6 [SD 11.4]) did not differ from those for patients on placebo (21.3 [10.5]). Also, mean scores on the cognitive subscale of the Alzheimer's disease assessment scale were closely similar in hydroxychloroquine (26.4 [14.9]) and placebo (25.7 [14.3]) treated patients, as were behavioural changes, measured by the revised memory and behavioural problems checklist (36.3 [12.0] and 34.2 [12.4], respectively). Explorative analyses did not suggest any specific subgroup that benefited from hydroxychloroquine. The frequency and nature of serious adverse events and side-effects were much the same in both groups. 155 (92%) patients completed all assessments over the entire study. INTERPRETATION: Anti-inflammatory treatment with hydroxychloroquine for 18 months does not slow the rate of decline in minimal or mild Alzheimer's disease.
Abstract: Creutzfeldt-Jakob disease (CJD) can be transmitted through human growth hormone or gonadotrophin administration, dura mater or cornea transplantation, depth EEG monitoring and the use of contaminated neurosurgical instruments. We describe the first two dura mater associated CJD cases in the Netherlands. Ten and fourteen years before the onset of symptoms both patients received a Lyodura implantation. Findings are discussed in light of the growing epidemic of CJD among dura mater recipients.
Abstract: Electroencephalography (EEG) bands may have different clinical or physiological correlates at initial diagnosis of Alzheimer's disease (AD). We studied 163 consecutive patients with probable (n = 105) and possible (n = 58) AD with measurements of cognitive function (CAMCOG), regional cerebral blood flow (rCBF) with single photon emission computed tomography using technetium-99m-labeled hexamethylpropylene amine oxime, and computed tomography (CT). Lower CAMCOG scores were significantly and most strongly associated with lower parieto-occipital and fronto-central alpha power. In a separate analysis of cognitive domains, disturbances in language, praxis, attention, and abstraction were also significantly and most consistently related to decrease in alpha power. Presence of cortical atrophy as measured on CT showed some statistically significant relations with EEG bands, but these associations were not consistent. Lower temporal and parietal rCBF were significantly related to lower parieto-occipital alpha activity. Presence of leukoaraiosis was significantly associated with lower beta values, but also with higher absolute theta and delta activity. The results suggest that alpha on EEG is most closely linked to cognitive function and rCBF, while beta and theta activity more likely reflect lower cortical or subcortical changes. Our study thus provides evidence that the EEG bands reflect differential pathophysiologic changes in AD.
Abstract: In Alzheimer disease brains, the amyloid plaques are closely associated with a locally induced, nonimmune-mediated, chronic inflammatory response without any apparent influx of leukocytes from the blood. The present findings indicate that in cerebral A beta diseases (Alzheimer disease, Down syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch type), the clinical symptoms are determined to a great extent by the site of inflammatory response. It was found that the formation of the amyloid-microglia complex seems to be a relatively early pathogenic event that precedes the process of severe destruction of the neuropil. The idea that inflammation is implicated in Alzheimer pathology has received support from the epidemiologic studies indicating that the use of anti-inflammatory drugs can prevent or retard the Alzheimer disease process. In this contribution, we review the relationship between inflammation and clinical manifestation and the opportunities for anti-inflammatory treatments in Alzheimer disease.
Abstract: The authors describe the clinical characteristics, MRI abnormalities, and molecular findings in a patient with a novel variant of a two-octarepeat insertion mutation in the prion protein gene. This patient presented with moderately progressive dementia of presenile onset and gait ataxia. MRI showed extensive cortical atrophy and white matter abnormalities. The mutation consists of a two-octarepeat insertion mutation and irregularities in the nucleotide sequence of the octarepeat region.
Abstract: OBJECTIVE: To study the sensitivity and specificity of 14-3-3 testing in a prospective series of patients suspected of having Creutzfeldt-Jakob disease (CJD). BACKGROUND: The 14-3-3 protein immunoassay on CSF has favorable test characteristics as a premortem diagnostic tool in CJD. However, the 14-3-3 protein is a normal cellular protein expressed in various tissues, and its presence in CSF reflects extensive destruction of brain tissue as in CJD, but also in ischemic stroke and meningoencephalitis. METHODS: 14-3-3 was tested in the CSF of a prospective series of 110 consecutive patients suspected of having CJD. RESULTS: The sensitivity was 97% and the specificity was 87% in this series. False-positive results were mainly caused by stroke and meningoencephalitis. CONCLUSION: The 14-3-3 protein is a highly sensitive and specific marker for CJD when used in the appropriate clinical context.
Abstract: Correct classification of patients with dementia is pertinent to proper interpretation of research findings. However, the history of Alzheimer's disease (AD) is characterized by a continuing debate on its nosological status. Cerebrovascular pathology, Lewy bodies, or hippocampal sclerosis in combination with neuropathological signs of AD of only limited severity results in a disease that is essentially different from severe, purely degenerative AD. The clinical signs, course of the disease, and pathological correlates in elderly patients suffering from "mixed dementia of the Alzheimer type," may differ from those with "purely degenerative Alzheimer's disease" as encountered in relatively young patients. Both clinicians and researchers have much to gain from a perspective that acknowledges the differences between these subgroups of AD patients. It may provide a more realistic perspective, and it holds promise for new opportunities for prevention and treatment.
Abstract: We determined the relationship between regional cerebral blood flow (rCBF) measured with single-photon emission tomography (SPET) and decline in cognitive function and survival in Alzheimer's disease. In a prospective follow-up study, 69 consecutively referred patients with early probable Alzheimer's disease (NINCDS/ADRDA criteria) underwent SPET performed at the time of initial diagnosis using technetium-99m-labelled hexamethylpropylene amine oxime. Neuropsychological function was assessed at baseline and after 6 months and survival data were available on all patients, extending to 5.5 years of follow-up. Lower left temporal (P<0.01) and lower left parietal (P<0.01) rCBF were statistically significantly related to decline in language function after 6 months. The association between left temporal rCBF and survival was also statistically significant (P<0.05) using Cox proportional hazards regression analysis. Performing analysis with quartiles of the distribution, we found a threshold effect for low left temporal rCBF (rCBF<73.7%, P<0. 01) and high risk of mortality. In this lowest quartile, median survival time was 2.7 years (follow-up to 5.2 years), compared with 4.4 years in the other quartiles (follow-up to 5.5 years). Kaplan-Meier survival curves showed statistically significant (P<0. 05, log rank test) survival curves for the lowest versus other quartiles of left temporal rCBF. All results were unaffected by adjustment for age, sex, dementia severity, duration of symptoms, education and ratings of local cortical atrophy. We conclude that left temporal rCBF predicts decline in language function and survival in patients with early probable Alzheimer's disease, with a threshold effect of low rCBF and high risk of mortality.
Abstract: Dementia is reversible in a minority of patients, and these should be diagnosed but without subjecting the majority with irreversible disease to an excessive set of investigations. Should a battery of ancillary investigations be performed routinely in dementia? Or can these tests be carried out as clinically indicated? Three arguments are important to answer this question. (a) Reversible dementia is rare: about 1% of cases. (b) If the clinical criteria for diagnosing primary degenerative disease are used consistently, the results of investigations can be predicted with sufficient accuracy, except those of blood tests. (c) Treatment of reversible dementia has the best results in its most frequent causes: depression and drug intoxication; however, treatment of medical and surgical causes of dementia may also be effective. Based on these three considerations, we propose the following guideline in the setting of a memory clinic: to perform blood tests in every patient with dementia, but also to perform other tests, such as electroencephalography (EEG) and computed tomography (CT), as clinically indicated.
Abstract: BACKGROUND: We studied whether heterogeneous profiles of cognitive function are relevant to survival in patients with early Alzheimer's disease. METHODS: CAMCOG subscales of cognitive function were used as predictors of survival, together with gender in 157 consecutively referred patients with early Alzheimer's disease. Statistical analysis was performed with Cox proportional hazards analysis and Kaplan-Meier survival curves. Survival rates were compared with those in the general population. RESULTS: Eighty patients (51%) died during the follow-up that extended to 5.7 years, with a median survival of 4.4 years after entry. Only the praxis subscore was statistically significant related to survival (P < 0.0001). Its predictive power was based on only two items, including copying ability for a spiral and a three-dimensional house, independent of age, sex, education, overall CAMCOG score, dementia severity and symptom duration. Kaplan-Meier curves for the combined score of these items (0, 1, or 2) showed three groups with significantly different survival rates for both men and women. Comparison of gender specific survival rates with data from the general population showed that excess mortality was statistically significant (P < 0.01) higher in men (51%) than in women (21%) after follow-up extending to 5 years. CONCLUSIONS: A simple test of copying ability defines subgroups of AD patients with large differences in survival rates. This suggests that parietal lobe impairment is an important predictor of mortality in AD. Also, the course of AD may be more benign in women than in men.
Abstract: OBJECTIVE: We investigated the diagnostic value of the visually assessed electroencephalogram (EEG) in patients with mild Alzheimer's disease (AD), using the grand total of EEG (GTE) score. METHODS: Forty-nine non-demented control subjects with and without minimal cognitive impairment from the general population and 86 probable AD patients (NINCDS-ADRDA criteria), consecutively referred to a memory clinic, participated in this study. RESULTS: Frequency of rhythmic background activity (P<0.05), diffuse slow activity (P<0.001), and reactivity of the rhythmic background activity (P<0.001) were statistically significant related to the diagnosis control subject or AD patient, using logistic regression analysis with adjustment for age and sex. When these subscores were used to confirm the diagnosis of AD, thus at high specificity of 89.1% (GTE cut-off point of 3), the sensitivity was 44.6% and positive predictive value was 88.1%. Incremental ruling-in and ruling-out curves showed a maximum diagnostic gain of 38% for a positive test result at a prior probability ranging from 30 to 40%. At high pretest probability levels of 80-90%, the diagnostic gain for a positive test result was low, varying from 7 to 14%. CONCLUSION: In conclusion, the visually assessed EEG may give a clinically meaningful contribution to the diagnostic evaluation of AD when there is diagnostic doubt.
Abstract: OBJECTIVE: To determine whether measures of quantitative spectral electroencephalography (EEG) can predict survival in patients with early Alzheimer disease. DESIGN: Prospective cohort study; median duration of follow-up was 4.4 years in survivors and 2.6 years in nonsurvivors. Cox proportional hazards models, with adjustment for age and sex were used to estimate relationships between EEG measures and survival. Log relative percentage values of EEG bands were used as predictors. SETTING: Outpatient university memory clinic. PARTICIPANTS: One hundred one consecutively referred patients with early probable Alzheimer disease according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria were studied with EEG at the time of diagnosis. The mean age of the patients was 79.2 years, which was higher than in previous EEG studies. MAIN OUTCOME MEASURE: Mortality. RESULTS: Fifty-one patients (50.5%) died during follow-up, with a median survival time in all patients of 4.1 years. The following EEG variables were significantly associated with increased risk of mortality: from parieto-occipital leads, higher theta (hazard ratio, 2.05; 95% confidence interval, 1.15-3.66; P<.05), lower alpha (hazard ratio, 0.43; 95% confidence interval, 0.25-0.76; P<.01), and lower beta (hazard ratio, 0.38; 95% confidence interval, 0.22-0.68; P<.001) activity; and from frontocentral leads, higher theta activity (hazard ratio, 2.07; 95% confidence interval, 1.17-3.66; P<.05). Stepwise Cox regression analysis showed that loss of parieto-occipital beta (P<.01) and alpha (P<.05) power were independent and significant predictors of mortality. Both beta (12.6-35.4 Hz) and alpha (7.5-12.5 Hz) activity remained significantly associated with mortality after adjustment for education, dementia severity, symptom duration, level of cognitive function, presence of extrapyramidal symptoms or hallucinations, presence of vascular risk factors, and presence of leukoaraiosis or local cortical atrophy. CONCLUSIONS: Decreases of beta and alpha activity on quantitative spectral EEG are independent predictors of mortality in patients with early Alzheimer disease. In the clinical context, the use of EEG technology for prediction of survival in individual patients remains to be determined.
Abstract: OBJECTIVE AND BACKGROUND: Frontotemporal dementia (FTD) is a common, non-Alzheimer's dementia. Its familial occurrence has been reported, but the frequency of positive family history is unknown. METHODS: We carried out a nationwide genetic-epidemiologic study of FTD in the Dutch population of 15 million people. The family history of dementia was analyzed in 74 FTD patients and 561 age- and gender-matched control subjects. RESULTS: We found one or more first-degree relatives with dementia before age 80 in 38% (28 of 74) of FTD patients, but only in 15% (84 of 561) of control subjects. Ten percent of FTD patients had two or more first-degree relatives with dementia compared with 0.9% of the control subjects. Seven percent of FTD patients showed the ApoE4E4 genotype versus 2.3% of the control subjects. The first-degree relatives of FTD had a risk of 22% for dementia before age 80 compared with 11% in relatives of control subjects. The age of onset of dementia in affected first-degree relatives of FTD patients (60.9+/-10.6 years) was significantly lower than among affected relatives of control subjects (72.3+/-8.5 years). The first-degree relatives of FTD patients were 3.5 times (95% CI, 2.4 to 5.2) more at risk for developing dementia before age 80 than relatives of control subjects. The hazard ratio in the subgroup with unknown linkage to chromosome 17 was 2.4 (95% CI, 1.5 to 3.7). CONCLUSION: This study documents the importance of genetic factors in a proportion of FTD patients with the age at onset of dementia in first-degree relatives being 11 years earlier than in the general population.
Abstract: Global clinical impression (GCI) of change is assumed to integrate aspects of both cognitive and noncognitive functioning. We evaluated 140 consecutive patients with probable (n = 90) and possible (n = 50) early Alzheimer's disease at baseline and after 6 months with measurements of global cognitive function (CAMCOG), behavior, activities of daily living, and burden of the caregiver. After 6 months, both the clinician (GCI-clin) and the caregiver (GCI-care) rated clinical change on a 3-point scale (worse, no change, improved). Data were analyzed with multiple polychotomous logistic regression, adjusted for age and sex. Change in global cognitive function and GCI-care were significantly and independently related to GCI-clin, while changes in activities of daily living and in behavior were significantly and independently associated with GCI-care. The findings suggest a double dissociation. Change in cognition appears to be the major determinant of the clinician's global impression but not change in behavioral and functional parameters, while global impression of the caregiver is primarily based on change in behavioral and functional measures but not on change in cognition.
Abstract: We investigated whether an index based on clinical features, electroencephalogram and computed tomography is useful to predict survival in early Alzheimer's disease. One hundred and sixty-three consecutively referred patients to an outpatient memory clinic and first diagnosed with Alzheimer's disease (105 'probable' and 58 'possible', NINCDS-ADRDA criteria) were studied and outcome measure was death. Cox proportional hazards regression analysis and Kaplan-Meier survival curves were used to investigate relations between baseline parameters and survival. Eighty-four patients (51. 5%) died during the follow-up period that extended to 5.8 years, with a median duration of survival after entry of 4.3 years. Baseline factors that were statistically significant and independently related to increased risk of mortality were high age, male sex, poor cognitive function as measured with the CAMCOG, low alpha and beta power on electroencephalogram, and temporoparietal atrophy on computed tomography scan. These results were independent of the diagnosis probable or possible Alzheimer's disease. Based on the coefficients from the regression equation, we computed a survival index for each patient and we constructed three groups according to tertiles of this index. After 5.2 years of follow-up, survival curves showed a low mortality group with 81.7% patients alive (median survival at least 5.7 years), an intermediate mortality group with 35.9% patients alive (median survival 3.8 years), and a high mortality group with no patients alive (median survival 2.3 years). Log rank tests were statistically significant for comparisons between all three groups. We conclude that an overall index combining demographic, cognitive, electroencephalogram and computed tomography features is a strong predictor of survival in early Alzheimer's disease.
Abstract: Although the sporadic form of Alzheimer's disease is the most common, rare familial variants exist. Approximately 50% of these cases are caused by a mutation in the presenilin genes. Mutations in presinilin genes give rise to Alzheimer's disease in a dominant pattern of inheritance with an early age of onset (< 60 years). Both presenilins (PS-1 and PS-2) are transmembrane proteins localized in the intracellular membranes of the endoplasmatic reticulum and Golgi apparatus. This suggests they play a role in transport or sorting of proteins in the cell. Different lines of evidence directly link presenilin to the formation of beta-amyloid, an important constituent of senile plaques. PS-1 has an essential function during development: mice lacking intact PS-1 are not viable. In addition, structural and functional homologies have been identified between presenilins and Notch signal transduction pathways, which play a role in development. The discovery of the presenilin mutations has provided a new angle to Alzheimer's disease research. Eventually, this will probably greatly contribute to knowledge of the pathogenesis of the disease and in time support the development of novel therapeutic strategies.
Abstract: Several cholinesterase inhibitors have recently become available for Alzheimer's disease. To reach consensus about their relevance and use in daily practice, a meeting with clinical experts was organised by the section of Geriatric Psychiatry of the Dutch Society for Psychiatry. So far, available drugs have only very modest effects on cognitive functioning and clinical impression, compared with placebo. The question whether these effects are clinically relevant cannot be answered yet. Awaiting the results of further studies, it was decided not to use cholinesterase inhibitors on a routine basis but to limit prescription of these drugs to research setting or under well-controlled conditions with regard to diagnosis and evaluation. Furthermore, prescription must be limited to mild or moderately severe dementia caused by 'probable Alzheimer's disease'. Proper evaluation in the individual patient is still an unresolved problem. Therefore, n = I protocols are to be designed. These should include the use of appropriate and standardised instruments measuring cognitive functions, behavioural functions and activities of daily life. The skills and experience required will be available in specialised and multidisciplinary units for dementia. Pharmaceutical treatment for Alzheimer's disease must be integrated with all other available forms of patient care.
Abstract: The relation between quantitative spectral electroencephalogram (qEEG) parameters and subsequent rate of cognitive, functional, and behavioral decline in 82 consecutive patients with early probable Alzheimer disease (NINCDS-ADRDA criteria) was examined in a prospective study. The qEEG was performed at initial examination and global cognitive function, activities of daily living, and behavior were assessed at initial evaluation and after a period of 6 months. Using multiple linear regression analysis, higher frontocentral and parieto-occipital theta values, lower parieto-occipital beta values, and lower peak frequency were significantly associated with more decline in global cognitive function over the follow-up period. In addition, lower parieto-occipital beta values were significantly related to more decline in activities of daily living. These associations were independent of demographic (age, sex, and education) and disease characteristics [initial Cambridge Examination for Mental Disorders of the Elderly Cognitive test (CAMCOG) or Mini-Mental State Examination scores, estimated duration of symptoms, estimated prior rate of decline, and dementia severity]. In a separate multiple logistic regression analysis, prediction of rapidly progressive decline, defined as 8 or more points decline in CAMCOG scores (n = 21), could be made with parieto-occipital and frontocentral beta values. The results suggest that slowing on qEEG is a marker for subsequent rate of cognitive and functional decline in mildly demented AD patients, independent of demographic or disease characteristics.
Abstract: It is widely accepted that excess disability (treatable coexisting physical disorders and psychiatric phenomena) is common in demented patients, and should be looked for carefully and treated properly, as it may result in improvement. This idea, however, does not state what investigations should be performed and what kind of improvement can be expected. Therefore, we studied prospectively in elderly outpatients with early Alzheimer's disease the prevalence of excess disability, the results of medication treatment, and the added value of investigations for diagnosis, treatment, and outcome after clinical examination. Outcome was assessed clinically and clinimetrically (using instruments with regard to cognition, disability in daily functioning, behavior, and caregiver burden). Excess disability was present in 66% of patients. Medication treatment was effective with regard to target symptoms, but (partial) reversal of dementia did not occur. Only blood tests produced unexpected results with consequences for treatment and outcome. Positive treatment effects often resulted from clinical examination only. We recommend blood tests in all patients; other investigations can be performed on clinical indication.
Abstract: Dementia has a reversible cause in some cases, and these should be diagnosed without over-investigating the many patients with irreversible disease. We prospectively studied the prevalence of reversible dementia in a memory clinic, determined the added value of investigations compared with clinical examination and assessed the outcome of treatment of potentially reversible causes by measuring (1) cognition, (2) disability in daily functioning, (3) behavioural changes and (4) caregiver burden. Two hundred patients aged 65 years and over were examined, using the CAMDEX-N. If they were demented, the probable cause was diagnosed clinically and confirmed or excluded by a standard set of investigations, which were done in all patients. Of the patients, 170 (mean age 79.2 years) were demented; 31 were treated for potentially reversible causes. At follow-up after 6 months, no patients showed complete reversal of dementia. Five patients improved on clinical impression, but only one on clinical measurement. Thirty patients were cognitively impaired, but not demented; seven were treated. Judged clinically, three patients improved, but on assessment only one did so; she recovered completely. Blood tests often produced diagnostic results that were not expected clinically, but electroencephalography and computed tomography of the brain did not. None of the investigations had an effect on outcome of dementia after treatment. We conclude that in elderly patients referred to a memory clinic, the prevalence of reversible dementia is of the order of 1%, if outcome after treatment is assessed by a standardized measurement. We recommend blood tests in all patients, to detect not only metabolic causes of dementia but also co-morbidity possibly worsening the dementia. Other investigations can be performed on clinical indication. Clinical evaluation remains the mainstay of diagnosis in dementia.
Abstract: Dementia is one of the most common organic mental syndromes, usually caused by Alzheimer's disease (AD) or vascular dementia (VD) or both. Regarding AD we review the state or the art of the cholinergic approach and discuss some future options regarding preventive and nonsymptomatic strategies. Therapy for VD will consist mainly in influencing and preventing cerebrovascular pathology, because operational criteria for the diagnosis have only recently been proposed and are being discussed widely. One of the crucial problems here lies in the distinction between VD and AD and the recognition that the two disorders may be coexistent more often than assumed; the role of white matter changes seems to be particularly important. The same goes for the recognition that AD ist not a single entity. The question of heterogeneity may be solved when different therapeutic strategies are found for different subtypes. The focus of future plans should be on preventive strategies combined with an early diagnosis.
Abstract: During the last year the knowledge of the transmission of prion diseases has increased. New diagnostic methods were developed: investigation of cerebrospinal fluid for the 14-3-3 protein and tonsillar biopsy to detect protease resistant prion protein. Indirect evidence of a causal relation between new variant Creutzfeldt-Jakob disease (nvCJ) and bovine spongiform encephalopathy (BSE) is accumulating, although epidemiological data do not indicate that the incidence of CJ is increasing.
Abstract: Three patients with a severe symptomatic carotid stenosis developed headache, epileptic seizures and focal neurologic deficits several days after carotid endarterectomy. CT of the brain revealed hypodensities, indicative of cerebral oedema with haemorrhagic components. This is caused by cerebral hyperperfusion, a complication after carotid endarterectomy as a result of increased cerebral perfusion on the side of the operated carotid stenosis. Dysfunction of the cerebral autoregulation believed to be the cause of this hyperperfusion. Sometimes these complications are incorrectly attributed to one of the better known types of stroke.
Abstract: OBJECTIVE: To describe experiences with the diagnosis of Creutzfeldt-Jakob disease (CJD). SETTING: Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands. DESIGN: Descriptive. METHODS: By retrospective analysis of patient files and follow-up data case histories were studied of ten patients diagnosed since 1980 as having CJD. RESULTS: Follow-up of two patients (who recovered) led to rejection of the diagnosis of CJD. Symptoms and results of ancillary investigations of the remaining eight patients were similar to those in large patient series from the literature. CONCLUSIONS: On the basis of our experience and data from the literature we conclude that a classification can be made of three degrees of probability of the diagnosis CJD: possible (rapidly progressive dementia with or without myoclonus); probable (if the clinical syndrome is accompanied by triphasic complexes in the EEG and/or hyperintense basal ganglia or (parts of) the cerebral cortex on T2-weighted MRI images); and certain (vacuolisation, neuronal loss and gliosis on neuropathological examination).
Abstract: Routine determination of serum vitamin B12 levels is generally recommended as part of the screening of demented patients, based on the notion that vitamin B12 deficiency is one of the causes of reversible dementia. We studied the effects of vitamin B12 replacement therapy in a prospective longitudinal study at a memory clinic, with special emphasis on assessment of severity of dementia: not only cognitive deterioration, but also disability in the activities of daily life, behavioural problems, and the burden experienced by the caregiver were examined using instruments of proven validity. In a series of 170 consecutive patients with dementia, subnormal serum vitamin B12 levels were found in 26 cases (15%); all but one fulfilled diagnostic criteria for possible Alzheimer's disease. Cobalamin supplementation was given to all patients and the effect was evaluated after 6 months. When the size and pattern of individual change scores, and the mean change scores on all instruments were taken into account, functioning after replacement therapy was not improved. When change scores of treated patients were compared with those of patients with Alzheimer's disease (n = 69), vitamin B12 replacement did not result in slowing of the progression of dementia. Contrary to widely accepted beliefs, subnormal serum vitamin B12 levels are not a (quantitatively) important cause of reversible dementia.
Abstract: Deposition of fibrillar amyloid beta protein (A beta) is increased in brains of patients with Alzheimer's disease. Concentrations of A beta were measured in cerebrospinal fluid with an enzyme-linked immunosorbent assay in 10 neurological patients free from neurodegenerative disease, 28 patients with Parkinson's disease, and 18 patients with probable Alzheimer's disease. Levels of A beta in cerebrospinal fluid were not significantly different among these groups. This observation suggests that concentrations of soluble A beta in cerebrospinal fluid as measured in this study do not reflect the amount of fibrillar, aggregated A beta in the brain of patients with Alzheimer's disease.
Abstract: Based on the observation of bilateral temporoparietal hypoperfusion in Alzheimer's disease (AD), single photon emission computed tomography (SPECT) is advocated by some as a powerful diagnostic tool in the evaluation of demented patients. We studied whether routine brain SPECT in elderly, mildly demented outpatients increases the a priori diagnostic sensitivity and specificity of a careful clinical examination. 99mTc-HMPAO SPECT imaging was performed in 110 patients for a first evaluation for dementia. A semiquantitative measure of temporoparietal (TP) perfusion was calculated as the ratio of the activity in the temporoparietal cortex to activity in the cerebellum. A diagnosis of probable AD according to the McKhann criteria was made in 68 patients (mean age of 79.3 years) based on the results of a clinical examination, ancillary investigations and a 6-month follow-up. TP perfusion was significantly lower in AD patients than in 18 age-matched, non-demented controls. However, at a specificity of 89%, sensitivity was only 43% for detecting probable AD. The clinicians judged that SPECT had contributed to the final diagnosis in only 8% of the demented patients investigated. Routine brain SPECT in elderly, mildly demented outpatients does not contribute substantially to diagnostic accuracy after a careful clinical examination using current diagnostic criteria. Clinical guidelines have to be developed for the use of SPECT in patients with (suspected) dementia.
Abstract: We conducted an interobserver study to assess agreement on visual rating of medial temporal lobe atrophy on coronal T1-weighted MRI. A total of 100 studies of elderly individuals, using two different MRI techniques (spin echo and inversion recovery sequences), were analysed by four raters (three neurologists and one neuroradiologist) using a five-point rating scale. Complete agreement was found in 37% of the total sample. Interobserver agreement as expressed by kappa values was 0.44 (95% CI = 0.34-0.54) and 0.51 (95% CI = 0.41-0.61) for the two techniques. After dichotomizing medial temporal lobe atrophy into present or absent, a post hoc analysis revealed higher complete agreement (70%), with kappa values of 0.59 (95% CI = 0.51-0.67) and 0.62 (95% CI = 0.48-0.075), for the two techniques (all four raters). From this study we conclude that visual rating of medial temporal lobe atrophy on MRI in the coronal plane yields fair to good agreement among observers. We recommend this type of visual rating for use in clinical settings when a quick judgement on the presence of medial temporal lobe atrophy is needed.
Abstract: The prevalence of clinical signs and neuropathological findings of Alzheimer's disease (AD) is high in Down's syndrome (DS). In the general population, the apolipoprotein E (ApoE) epsilon 4 isoform is an important risk for AD. We studied the allelic frequencies of ApoE in 26 DS cases fulfilling clinical diagnostic criteria for AD and in 26 DS controls matched for age, sex, and premorbid level of mental retardation. A meta-analysis of data available in the literature was used for comparison with allele frequencies in other AD and control populations. ApoE type 2, 3, or 4 allele frequencies were not significantly different in AD-DS cases and DS controls. The ApoE epsilon 4 frequency in DS cases with AD (0.14; CI, 0.06-0.26) was significantly lower than in any other AD population studied so far and it is within the range of nondemented controls from the general population. These findings suggest that ApoE epsilon 4 does not significantly affect the pathogenesis of AD in DS patients.
Abstract: The clinical features and disease course of six patients from a family with autosomal dominant inheritance of presenile dementia and a hypokinetic syndrome are described. In the past, these patients have carried diagnoses of Pick's disease, Huntington's disease, Parkinson-dementia, and one patient was described as suffering from a 'peculiar type of presenile dementia' in a case report. In the two cases examined, the most distinctive neuropathological features were extensive globular deposits of periodic acid-Schiff plus diastase (PAS)-positive material, having tinctural properties of amyloid only to a limited degree, in the cerebellum and cerebral cortex. These globules stained positively with antibodies against prion protein. Southern blot of MspI-digested genomic DNA showed an abnormal band of approximately 950 bp in all three patients from which material was available. Direct sequencing of the abnormal allele revealed an insert consisting of eight extra 24-nucleotide repeats in the patients, which was absent in a healthy first degree relative who was considered well beyond the age of onset of symptoms in this family. The nucleotide sequence of the abnormal insert of 192 bp was different from that of a previously described insert of equal length. Adding to previous descriptions of mutations in the prion protein gene, this report emphasizes the clinical, neuropathological and genetic heterogeneity of inherited prion disease.
Abstract: Cerebral deposition of amyloid-beta protein (A beta) is central to the pathogenesis of Alzheimer's disease (AD). Increasing age is one of the few definitively established risk factors for this disease. The concentration of A beta was measured in cerebrospinal fluid (CSF) with a sensitive enzyme-linked immunosorbent assay in 18 adult neurological patients free from neurodegenerative disease. CSF A beta increased with age, yielding a significant correlation of 0.84. This observation suggests that increased levels of A beta in CSF may be an index of age-related changes in the processing of the amyloid-beta precursor protein resulting in an increased risk for AD.
Abstract: Alzheimer's disease is aetiologically heterogeneous, but the pathogenesis is often considered to be initiated by the deposition of amyloid fibrils, followed by neuritic tau pathology and neuronal death. A variety of inflammatory proteins has been identified in the brains of patients with Alzheimer's disease post mortem. In this article, Piet Eikelenboom and colleagues review evidence to suggest that the inflammatory processes are intimately involved in several crucial events in the pathological cascade. This suggests possibilities for the treatment of Alzheimer's disease with anti-inflammatory drugs.
Abstract: Tremor, e.g. in Parkinson patients, often shows large spontaneous fluctuations in severity over the day, to such an extent that a short observation is usually not sufficient to assess the overall severity or the effect of a treatment. Since momentary impressions of the tremor can thus be misleading, long-term ambulatory recordings would be helpful in the evaluation of severity and treatment effectiveness. As existing methods for long-term tremor registration have several shortcomings, a new method is proposed: an algorithm was designed to discriminate tremor from other movements and to describe the amount (i.e. the proportion of tremor or movements per time unit) as well as the intensity (i.e. average acceleration amplitude) of the two types of movement. In the evaluation of the severity of tremor both the amount and intensity of tremor episodes are of importance. The algorithm was tested on 24-h analog tape recordings of wrist-movement in 10 young and 10 aged controls, as well as in 8 patients with tremor--both before and after a tremor relieving thalamotomy. The algorithm scored movements as 'tremor' exclusively in patients prior to the operation. Fluctuations in tremor severity over the day were detected, and tremor could be discriminated from non-pathological movements. Moreover, following thalamotomy, motor slowing (bradykinesia) was detectable using this algorithm. Based on these test results, a miniaturized device in wrist-watch format is now being developed for long-term registrations.
Abstract: Circadian rhythms are already present in the fetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the fetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the fetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of maternal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the fetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin.
Abstract: Studies into the value of examination of the cerebrospinal fluid (CSF) in diagnosing Alzheimer's disease are reviewed. The diagnostic utility of about 60 substances including CSF measures related to classical neurotransmitters, (neuro)peptides, proteins, amino-acids, trace elements, and constituents of senile plaques and neurofibrillary tangles is evaluated. Technical, methodological, and ethical issues relevant to this kind of studies are discussed. None of the CSF constituents studies so far, has a proven diagnostic utility. Increased knowledge concerning macromolecular changes in the brain and improved immunochemical techniques make the outlook for a diagnostic test for Alzheimer's disease on CSF promising.
Abstract: In the study of dementia four distinct categories of instruments can be distinguished: instruments to examine cognitive dysfunction, to measure the severity of dementia, to assess disturbances in daily behaviour, and instruments to make a differential diagnosis of dementia. The Cambridge Examination for Mental Disorders of the Elderly (CAMDEX), published in 1988, incorporates these four categories in a single comprehensive interview schedule. Items related to the diagnosis of clouded/delirious state, depression and other psychiatric symptoms are also included. The Dutch version (CAMDEX-N) and accompanying software for data analysis and for scientific research were developed. Items were added to the section on physical and neurological examination, and to the section on ancillary investigations. The software can be adapted to future developments in dementia research.
Abstract: In 12 ambulant patients with a clinical diagnosis of probable Alzheimer's disease, a 12-week, double-blind, placebo-controlled study with 100 mg/day tetrahydroaminoacridine (THA) and 10 g/day lecithin is reported. The aim of the study was to find whether treatment would result in an improvement of cognition, of functioning in daily life, decrease of behavioural disturbances, and decrease in burden experienced by the carers. Two of the six THA-treated patients demonstrated an increase on cognitive test scores with a moderate increase in the other outcome measurements. There was, however, no difference between the two groups in any outcome measurement after treatment. In addition, we found a reversible rise of liver transaminases in 4 of 6 patients in the treated group. This pilot study is too small to draw definite conclusions on the use of THA alone or in combination with lecithin. Our results suggest, however, that semi-structured interviews with the carers may be of value in the evaluation of treatment effects in patients with Alzheimer's disease.
Abstract: OBJECTIVE: To review studies on cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) in order to answer the question whether CSF contains a specific marker which can be used to support a clinical diagnosis of AD. DATA SOURCES: Studies identified through an English-language literature search using MEDLINE (1966 to 1990) and a review of bibliographies of relevant articles. STUDY SELECTION: All studies on CSF in AD patients were selected. Double publications on the same original data were not included. Otherwise, no particular selection was made. DATA EXTRACTION: The diagnostic utility of more than 60 substances, including CSF measures related to classical neurotransmitters, (neuro)peptides, proteins, amino acids, purines, trace elements, and constituents of senile plaques and neurofibrillary tangles, is evaluated. Clinical epidemiological criteria for deciding on the usefulness of new diagnostic methods are emphasized in this analysis. DATA SYNTHESIS: Concentrations of some CSF constituents are consistently found to be significantly changed in AD. However, overlap with data of control populations and methodological shortcomings in study design, limit the diagnostic value of all CSF measurements reviewed. CONCLUSIONS: None of the CSF constituents studied so far can be used in support of the diagnosis of AD. However, increased knowledge concerning macromolecular abnormalities in amyloid containing plaques and neurofibrillary tangles makes the outlook for a diagnostic test for AD on CSF promising.
Abstract: The suprachiasmatic nucleus (SCN) of the hypothalamus is considered to be the endogenous clock of the mammalian brain, regulating circadian rhythmicity of a great number of physiological and behavioural parameters. Numerous studies have shown that the circadian organization in the rat is progressively disturbed in senescence. However, a recent study by Peng et al.17 using conventionally stained material, revealed no decrease in overall SCN cell number of senescent rats. Their results have now been confirmed in this study. In addition, an increase in SCN volume (P = 0.02) and nucleus diameter (P = 0.001) and an overall decrease in cell density (P = 0.006) was observed. All these parameters seem to confirm the absence of a general degeneration in the senescent SCN. However, the major aim of the present study was to determine whether a well-defined population of neurons, i.e. the vasopressinergic (AVP) cells of the SCN, shows changes with aging. Immunocytochemical staining with antivasopressin and morphometry revealed a decrease of 31% (P = 0.007) in the number of these SCN neurons, whereas the remaining vasopressin cells became larger (P = 0.001). There were no statistical significant differences between rats housed in standard cages and those housed in an enriched environment in either age group, but the groups were relative small. Changes in either the number or stainability of SCN vasopressin neurons may be a morphological correlate of changed circadian rhythms in senescence.
Abstract: To assess whether or not environmental changes may continue to affect measures relating to cortical size, the size of the cerebral cortex of young adult (7 to 8 months) and old (32 to 33 months) "standard" and "enriched" rats were compared. Enriched rats were housed in large cages during 10 weeks and had access to many different objects; age-matched controls remained in standard laboratory cages. Effects on the cerebral cortex were small; a significant increase in cortical thickness at one, albeit different, site in both age groups was observed. Significant correlations were not present between environmentally induced changes in sleep parameters (recorded in the same rats prior to the present experiment) and the small change in cortical size. The results do, however, support the hypothesis that a certain amount of plasticity of the cerebral cortex is preserved in old age.
Abstract: Sleep-wakefulness rhythms were recorded for at least 5 consecutive days in young adult (n = 6; 5-8 months) and old (n = 4; 30-32 months) rats. During the continuous recordings the rats were maintained in isolated cabins under constant temperature and constant dim, red light. The period length and amplitude of the free-running circadian rhythms of wakefulness (W), slow wave sleep (SWS) and desynchronized sleep (DS) were estimated by means of a cosine curve fitting program. Age-related amplitude differences were absent under the constant recording conditions. The circadian period of the W- and DS-rhythms, however, was significantly shorter in the old rats. These results are consistent with the notion that circadian organization is changed in old age.
Abstract: The effects of aging and housing in an enriched environment were assessed in young adult (4-7 months) and old (27-31 months) male Brown Norway rats by conducting 24-h sleep-wake recordings. Comparison of recordings made in rats of different ages, housed in a standard laboratory environment, revealed a reduction of the time spent in slow wave and desynchronized sleep during the light period in the old rats. Furthermore in the old rats, sleep was more fragmented and the amplitude of the circadian sleep-wake rhythm was reduced. In both age groups, housing in an enriched environment resulted in an increase of the time spent in slow wave and desynchronized sleep during the light period. Old "enriched" rats showed an additional alleviation of the senescence-related shortening of sleep cycles and desynchronized sleep epochs. The reduction of the circadian sleep-wake amplitude observed in old age was, however, not affected by the differential housing period. It is concluded that the similarity of the changes in sleep pattern in young and old rats after increased environmental complexity may reflect a preserved capacity of the senescent nervous system to adapt to environmental changes.
Abstract: Visual and auditory evoked potentials were studied in the occipital, temporal, prefrontal and cingulate areas of the rat cerebral cortex. We found that both prefrontal and cingulate areas can respond to more than one sensory modality. The latencies of the response to light and sound, though slightly longer in these associative areas than in the two primary cortical regions, were still within the range of early sensory evoked responses (i.e. less than 50 ms).
Abstract: The effects of aging and of housing in an enriched environment on performance in an 8-arm radial maze were evaluated in young adult (7-8 months) and old (30-33 months) male Brown-Norway rats, using a procedure in which the rats were confined for 8 s to the central platform of the maze between consecutive choices. Although the old rats attained a level of performance which was clearly above change, they were shown to perform worse than the young rats. No performance differences were found between differentially housed rats of the same age group. In a second experiment recovery cycles of visual evoked potentials were determined in the same rats by using paired flashes with an interstimulus time of 400, 300, 200, or 100 ms. Recovery was consistently smaller in the old rats as compared to the young ones. No correlation could be demonstrated, however, between radial maze performance or housing condition and recovery functions of the visual evoked potentials. This finding indicates that a decline in visual sensitivity cannot readily explain the impaired radial maze performance of old rats. Evidence which suggests that age-related hippocampal changes play a major role in the radial maze performance deficit is discussed.
Abstract: In order to study whether or not the age-related changes in the sleep pattern observed in humans also occur in rats, young adult (4 months) and old (22 months) male Wistar rats were implanted with EEG and EMG electrodes for 24 h on-line registration by means of an automatic sleep-classifier. During the 12 h light period, the old rats as compared to the young adult ones showed a significant increase of the time spent awake and a decrease of active sleep time. Furthermore, the light-dark ratio was decreased in the old rats for wakefulness and active sleep. Off-line analysis of the EEG during quiet sleep and active sleep revealed no differences between the two age groups. These results suggest the existence of a number of considerable age-related changes in the sleep pattern of adult rats, which are comparable to those observed in humans.
