piperidines and Lewy-Body-Disease

There is a considerable overlap between Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). They present a challenge therapeutically, with regard to morbidity and mortality risk. In particular, symptoms of psychosis in these conditions augur a considerably increased burden. To date, there has been a myriad of prospective, retrospective and case studies examining the use of neuroleptics in the treatment of psychotic symptoms in PDD/DLB. Clozapine has the most robust evidence base however its use is limited by agranulocytosis risk and the associated need for frequent blood count monitoring. Quetiapine is more readily used, however, it has a more equivocal evidence base, in terms of efficacy. Other neuroleptics have thus far demonstrated mixed results with increased risk of extrapyramidal worsening. In addition to the atypical agents, the introduction of pimavanserin has provided another treatment option for Parkinson's Disease Psychosis (PDP), decreasing concern for deterioration in motor function. We await further research to confidently demonstrate its efficacy and safety in DLB psychosis. Cholinesterase inhibitors likely have a limited role in treating milder psychosis symptomatology in DLB and perhaps PDD. After review of the current literature for antipsychotic therapy in both PDD and DLB, we provide a logical framework for addressing psychotic symptoms in each condition.

Topics: Antipsychotic Agents; Humans; Lewy Body Disease; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.

Topics: alpha-Synuclein; Cholinesterase Inhibitors; Disease Management; Genetic Therapy; Humans; Lewy Body Disease; Parkinson Disease; Piperidines; Stem Cell Transplantation; Urea

Alzheimer's disease (AD) is a progressive condition that affects cognition, function, and behavior. Approximately 60-90% of patients with AD develop neuropsychiatric symptoms (NPS) such as hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior, sleep disturbances, appetite and eating changes, or altered sexual behavior. These noncognitive behavior changes are thought to result from anatomical and biochemical changes within the brain, and have been linked, in part, to cholinergic deficiency. Cholinesterase inhibitors may reduce the emergence of NPS and have a role in their treatment. These agents may delay initiation of, or reduce the need for, other drugs such as antipsychotics. This article summarizes the effects of donepezil, a cholinesterase inhibitor, on the NPS of dementia with emphasis on AD and dementia with Lewy bodies.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Lewy Body Disease; Piperidines; Psychotic Disorders

Dementia with Lewy bodies (DLB) is considered the second most common form of dementia in the elderly. The cognitive fluctuations, hallucinations and extrapyramidal symptoms and signs suggest simultaneous neurodegeneration in multiple neuronal pathways including both dopaminergic and cholinergic transmission. In the past few years, several small studies have demonstrated the benefit of acetylcholinesterase inhibitors (AChEIs) on the cognitive and behavioral symptoms of DLB. These drugs, by reversibly blocking the hydrolytic activity of AChE, increase the availability of synaptic acetylcholine. Neuropathological and neuroimaging studies demonstrated that cholinergic neurotransmission is more defective in DLB than in Alzheimer's disease (AD). Despite the relevance of AChEIs to DLB, there are no FDA-approved drugs for its management. The aim of this review is to summarize the literature on the application of donepezil in DLB. Although the results are inconclusive, when one compares and contrasts them to the results of the AD-donepezil trials, the effect size appears larger. Placebo-controlled, randomized, well-powered studies of adequate length are needed to avoid underutilization of a potentially efficacious drug.

Topics: Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Humans; Indans; Lewy Body Disease; Piperidines

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cholinesterase Inhibitors; Cognitive Dysfunction; Dementia; Disease Progression; Donepezil; Education, Medical, Continuing; Galantamine; Humans; Indans; Lewy Body Disease; Nootropic Agents; Peptide Fragments; Phenylcarbamates; Piperidines; Positron-Emission Tomography; Reference Standards; Rivastigmine; tau Proteins; Tomography, Emission-Computed, Single-Photon

Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement.. To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease).. The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials.. Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD).. Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0.. Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms. The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Lewy Body Disease; Neuroprotective Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

The first part of the present review describes the current status of elderly people with behavioral and psychological symptoms of dementia (BPSD) in the community and basic viewpoints for differentiating between different forms of dementia. Specifically, it focuses on four points among the data and research related to determining the current status of elderly people with BPSD. We also propose basic concepts for differentiating between the core symptoms of dementia and BPSD, BPSD and delirium, and agitation and delirium. In the second part of the present review, various aspects of the symptom 'agitation' are discussed based on the experience of our home visit medical service for people with dementia by describing two cases. In cases such as Case 1, where the subject was given high doses of antipsychotics, we believe the problem was that the physicians immediately abstracted all of the abnormal behavior in the subject's life as 'agitation', and provided treatment to the subject accordingly. In Case 2, where the subject had dementia with Lewy bodies (DLB), we propose that it is crucial to differentiate clearly between agitation and delirium. Both of these cases show the risks of focusing treatment simply on agitation. When BPSD occurs in a person with dementia, the burden on caregivers increases. At such times, physicians tend to side with the family rather than with the patient. However, medical care is intended to be for the afflicted person, and physicians should base their plans for medical intervention on this principle.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Caregivers; Delirium; Dementia; Diagnosis, Differential; Donepezil; Home Care Services; House Calls; Humans; Indans; Lewy Body Disease; Male; Nootropic Agents; Piperidines; Psychomotor Agitation; Tokyo

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are the two most common types of dementing neurodegenerative disease after Alzheimer's disease (AD). Both of these conditions are often diagnosed late or not at all.. Selective literature review.. The severe cholinergic and dopaminergic deficits that are present in both DLB and PDD produce not only motor manifestations, but also cognitive deficits, mainly in the executive and visual-constructive areas, as well as psychotic manifestations such as visual hallucinations, delusions, and agitation. The intensity of these manifestations can fluctuate markedly over the course of the day, particularly in DLB. Useful tests for differential diagnosis include magnetic resonance imaging and electroencephalography; in case of clinical uncertainty, nuclear medical procedures and cerebrospinal fluid analysis can be helpful as well. Neuropathological studies have revealed progressive alpha-synuclein aggregation in affected areas of the brain. In DLB, beta-amyloid abnormalities are often seen as well.. DLB should be included in the differential diagnosis of early dementia. If motor manifestations arise within one year (DLB), dopaminergic treatment should be initiated. On the other hand, patients with Parkinson's disease should undergo early screening for signs of dementia so that further diagnostic and therapeutic steps can be taken in timely fashion, as indicated. Cholinesterase inhibitors are useful for the treatment of cognitive deficits and experiential/behavioral disturbances in both DLB (off-label indication) and PDD (approved indication).

Topics: Aged; Brain; Cholinesterase Inhibitors; Cross-Sectional Studies; Dementia; Diagnosis, Differential; Diagnostic Imaging; Donepezil; Early Diagnosis; Humans; Indans; Lewy Body Disease; Mental Disorders; Neuropsychological Tests; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Topics: Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Lewy Body Disease; Nootropic Agents; Phenylcarbamates; Piperidines; Prognosis; Rivastigmine; Tacrine

Dementia and depression are serious causes of global impairment in the elderly. This review is aimed at finding pharmacological reports from 2007-2008 so as to examine whether new guidance is available to treat these patients.. Studies on Alzheimer's disease and Lewy body dementias show that cholinesterase inhibitors are still first line treatment for these diseases and memantine is indicated in moderate/severe Alzheimer's disease, whereas there is as yet no standard available treatment for frontotemporal dementias. Treatment of depression in the elderly shows the same results as in younger individuals, and cerebrovascular pathology is important for treatment resistance.. There is a need for new drugs that focus on treatment resistant and nonresponder individuals. Most studies are confirmation of previous reported results.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Drug Therapy; Evidence-Based Medicine; Geriatric Psychiatry; Humans; Indans; Lewy Body Disease; Parkinson Disease; Piperidines

Topics: Aged; Atrophy; Brain; Cholinesterase Inhibitors; Diagnosis, Differential; Diagnostic Imaging; Donepezil; Female; Humans; Indans; Lewy Body Disease; Piperidines; Reference Standards

Some randomized studies, mostly of short duration, have indicated that cholinesterase inhibitors (donepezil, rivastigmine and galantamine) may have a beneficial effect in Alzheimer's disease, vascular dementia and in dementia caused by Lewy body disease. The benefit of these drugs in clinical practice has not been satisfactorily documented.. Literature collected regularly for many years supplemented by extensive non-systematic searches of Pubmed and Embase.. Only in a few placebo-controlled, double-blind, randomised studies were the patients followed for more than one year. Several clinical tests were performed, among them the Mini Mental Status (MMS)-test, which is the most commonly used test in clinical practice. The three cholinesterase inhibitors led to statistically significant results, although of limited clinical relevance, in various forms of dementia.. Based on the results obtained it could be questioned whether the observed effects are of clinical significance. Only a small proportion of patients with Alzheimer's disease seem to benefit from the cholinesterase inhibitors tested, and it is difficult to predict who will in advance. Treatment should first be evaluated after 2-4 months and subsequently on a regular basis, and accepted clinical tests should be applied.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Dementia, Vascular; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Lewy Body Disease; Phenylcarbamates; Piperidines; Rivastigmine; Time Factors; Treatment Outcome

The efficacy of acetylcholinesterase (AChE) inhibitors for the treatment of dementia diseases has been established for both key cognitive symptoms and dementia-associated symptoms such as aggressiveness and the ability to perform activities of daily life. Presently three AChE inhibitors are approved for the treatment of mild to moderately severe Alzheimer dementia: donepezil, rivastigmine and galantamine. Rivastigmine is also approved for the treatment of Parkinson's dementia. The three substances differ in their efficacy and their pharmacological properties. AChE inhibitors should be used for long-term treatment. The clinical course should be monitored every six months.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia; Donepezil; Galantamine; Humans; Indans; Lewy Body Disease; Multicenter Studies as Topic; Neuroprotective Agents; Nootropic Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Time Factors

Treatments for the symptomatic relief of Alzheimer's disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer's disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued.

Topics: Acetylcholine; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Galantamine; Humans; Indans; Lewy Body Disease; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

In Denmark, Alzheimer drugs have been registered since 1997. Three cholinesterase inhibitors (donepezil, rivastigmin og galantamin) are approved mild to moderate Alzheimer's disease and one partial NMDA receptor antagonist (memantin) with the indication moderate to severe Alzheimer's disease. The treatment is symptomatic with a parallel shift of the course. The life expectancy does not seem to be altered. There is documented effect on the cholinesterase inhibitors of up to two years and for memantine for 6 months. New disease modifying agents are under clinical development.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Dementia, Vascular; Disease Progression; Donepezil; Evidence-Based Medicine; Galantamine; Humans; Indans; Lewy Body Disease; Memantine; Nootropic Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Community Mental Health Services; Diagnosis, Differential; Donepezil; Family; Female; Humans; Indans; Lewy Body Disease; Male; Memory; Piperidines; Social Support; Tomography, Emission-Computed, Single-Photon

Dementia with Lewy bodies (DLB) is a common cause of dementia with effects on cognition, mood, behavior, and function. Changes in the acetylcholine system have been reported in brains of patients with DLB, which provides a rationale for trials of acetylcholinesterase inhibitors in DLB. This review includes all English-language publications found via Medline and related to the efficacy and/or safety of these compounds in DLB. Preliminary data suggest that these compounds may be efficacious in DLB and that future randomized clinical trials are strongly needed. Methodological limitations of the existing data include small sample sizes, and the paucity of standardized psychometric measures.

Topics: Aged; Basal Ganglia Diseases; Behavior; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Cognition Disorders; Donepezil; Humans; Indans; Lewy Body Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Tacrine

Topics: Cholinesterase Inhibitors; Donepezil; History, 20th Century; Humans; Indans; Lewy Body Disease; Piperidines; Practice Guidelines as Topic

Topics: Aged; Antipsychotic Agents; Brain; Cholinesterase Inhibitors; Diagnostic Imaging; Donepezil; Dopamine Agonists; Humans; Indans; Lewy Body Disease; Male; Piperidines

To review the effect of cholinesterase inhibitors on the behavioural and neuropsychiatric symptoms of dementia and discuss the current clinical guidelines for the prescription of cholinesterase inhibitors in Australia.. This paper reports the case of a patient with clinical diagnosis of dementia with lewy bodies (DLB) who was referred to an old age psychiatry service for the treatment of severe visual hallucinations and behavioural problems.. Pharmacological treatment with olanzapine produced marked parkinsonism, agitation and confusion. A cholinesterase inhibitor, donepezil, was introduced. The introduction of donepezil was associated with cognitive improvement (mini-mental state examination [MMSE] increased from 23 to 27) and complete remission of behavioural symptoms.. That cholinesterase inhibitors may have a role in the management of behavioural symptoms of dementia and the current Australian PBS guidelines for prescribing cholinesterase inhibitors are clinically restrictive. This has clinical and ethical implications that need to be addressed by consumers, the medical community and regulating authorities.

Topics: Aged; Aged, 80 and over; Australia; Cholinesterase Inhibitors; Donepezil; Ethics; Hallucinations; Humans; Indans; Lewy Body Disease; Male; Mental Disorders; Piperidines

To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision.. Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres.. In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed.. Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria.

Topics: Aged; Aged, 80 and over; Consensus; Dementia; Donepezil; Female; Guideline Adherence; Humans; Indans; Lewy Body Disease; Male; Piperidines; Practice Guidelines as Topic; Psychiatric Status Rating Scales

To investigate whether increasing plasma donepezil concentration further improves cognitive function and neuropsychiatric symptoms without compromising safety in patients with dementia with Lewy bodies (DLB).. We analyzed data from a 12-week phase 3 trial of donepezil (5 and 10mg/day) in patients with DLB. The contribution of factors affecting plasma donepezil concentration was evaluated using multivariate regression analysis. The relationships between plasma donepezil concentration and efficacy (cognitive function as measured by the Mini-Mental State Examination [MMSE], hallucinations and cognitive fluctuation), or safety (blood pressure, pulse rate, body weight, and parkinsonism as measured by the Unified Parkinson's Disease Rating Scale part III) were assessed by scatterplots and Pearson correlation.. The data of 87 patients were used in the analyses. Plasma donepezil concentration increased proportionally with increasing dose from 5 to 10mg/day. The dose (contribution rate: 0.39, p<0.0001) and age (contribution rate: 0.12, p=0.0003) were statistically significant contributing factors affecting plasma donepezil concentration. Plasma donepezil concentration correlated significantly with improvement of MMSE score (p=0.040), but no significant correlations were found with the change in other tested parameters.. Plasma donepezil concentration correlated positively with change in cognitive function without affecting safety, and was affected mainly by dose and to a lesser extent by age. Therefore, for patients in whom safety concerns are not found at donepezil 5mg/day, increasing the dose to 10mg/day to increase plasma concentration is worthwhile to further improve cognitive function.

Topics: Aged; Aged, 80 and over; Blood Pressure; Body Weight; Cognition; Cytochrome P-450 CYP2D6; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Lewy Body Disease; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Pulse; Severity of Illness Index; Treatment Outcome

Based on Mini-Mental State Examination (MMSE) subitem scores, in dementia with Lewy bodies (DLB), we aimed to delineate features of cognitive impairment, identify cognitive domains improved by donepezil, and define a pretreatment cognitive profile likely to benefit from donepezil.. Pooled data were used from two randomized controlled trials of donepezil in DLB (n = 235). Baseline MMSE subitem scores were calculated for all patients. Mean changes in subitem scores at week 12 were compared between the placebo and the active group. Finally, the subgroup identification based on differential effect search (SIDES) method was applied.. Baseline subitem scores were relatively low for serial 7's, delayed recall, and copying. Significant improvement by donepezil was found for orientation, serial 7's, repetition, 3-step command, and copying. The subgroup with pretreatment scores of serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 were the best responders. MMSE change in subgroups increased as more of these three conditions were fulfilled.. Cognitive domains characteristically impaired in DLB are particularly improved by donepezil. The number of fulfilled conditions for serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 (likely to benefit score) may predict the response to donepezil in DLB patients.

Topics: Aged; Cognition; Donepezil; Drug Monitoring; Female; Humans; Indans; Lewy Body Disease; Male; Mental Recall; Mental Status and Dementia Tests; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB).. Using pooled datasets from phase 2 and 3, 12-week randomized, placebo-controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored.. The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean ± SD: -0.2 ± 4.3 and -0.6 ± 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity.. DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Datasets as Topic; Disease Progression; Donepezil; Female; Humans; Indans; Lewy Body Disease; Logistic Models; Longitudinal Studies; Male; Neuropsychological Tests; Piperidines

To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB).. This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout.. In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear.. The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks.

Topics: Aged; Aged, 80 and over; Data Interpretation, Statistical; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Lewy Body Disease; Male; Nootropic Agents; Parkinson Disease; Piperidines; Treatment Outcome

Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase 2 trial.. One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III.. Donepezil at 5 and 10 mg/day was significantly superior to placebo on both the MMSE (5 mg: mean difference, 3.8; 95% confidence interval [CI], 2.3-5.3; p < 0.001; 10 mg: mean difference, 2.4; 95% CI, 0.9-3.9; p = 0.001) and CIBIC-plus (p < 0.001 for each); 3 mg/day was significantly superior to placebo on CIBIC-plus (p < 0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p < 0.001) at 5 and 10 mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups.. Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Female; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome

Deficits in the cholinergic system are pronounced in dementia with Lewy bodies (DLB) and are more severe in patients with visual hallucinations (VHs). The aim is to identify the occipital glucose metabolism patterns by positron emission tomography (PET) and the changes following donepezil treatment. 13 DLB patients with VHs were enrolled in the study. After the first FDG-PET study, 5 mg/day donepezil was administered orally, and a second PET study was performed 3 months later. After donepezil administration, VHs disappeared completely in 6 patients, and the PET studies revealed significantly decreased glucose metabolism in the medial occipital cortex. These results suggest that VHs in DLB were associated with impaired glucose metabolism in the medial occipital cortex. Donepezil treatment may modify regional glucose metabolism.

Topics: Aged, 80 and over; Donepezil; Female; Glucose; Hallucinations; Humans; Image Interpretation, Computer-Assisted; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Nootropic Agents; Occipital Lobe; Piperidines; Positron-Emission Tomography

We examined attention-enhancing effects of the cholinesterase inhibitor donepezil in Dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) by means of open label study.. 22 DLBs and 23 PDDs were assessed over 20 weeks using the Cognitive Drug Research Computerized Attentional Tasks. We examined how much closer our patients moved towards being normal for their age by comparing them to a non-demented elderly control sample (n = 183, aged 71-75 years).. Donepezil treatment improved power of attention, continuity of attention and reaction time variability. The deficit in responses was moved towards normal by 38 and 56% for power of attention and 22 and 10% for continuity of attention in PDD and DLB, respectively.. Improvements in attention were found with donepezil in PDD and DLB.

Topics: Aged; Aged, 80 and over; Attention; Chi-Square Distribution; Cholinesterase Inhibitors; Cognition; Dementia; Donepezil; Female; Humans; Indans; Lewy Body Disease; Male; Mental Processes; Middle Aged; Nootropic Agents; Parkinson Disease; Piperidines; Reaction Time; Reference Values; Statistics, Nonparametric; Treatment Outcome

To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism.. Multicenter randomized, double-blind, placebo-controlled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n = 23), Parkinson disease (PD) with dementia (n = 9), or Alzheimer disease with parkinsonian features (n = 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment.. No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning.. Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Antiparkinson Agents; Antipsychotic Agents; Cholinesterase Inhibitors; Confounding Factors, Epidemiologic; Dementia; Dibenzothiazepines; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Parkinson Disease; Patient Selection; Piperidines; Placebo Effect; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Research Design; Severity of Illness Index; Treatment Failure

The objectives of the present study were first to determine the feasibility of conducting a randomized clinical trial of 5 mg/day donepezil in patients with mild to moderate dementia with Lewy bodies (DLB) and second, to obtain preliminary data of possible intervention effects. Twelve patients with probable DLB were evaluated at weeks 4, 8, and 12 using modified Neuropsychiatric Inventory (NPI) with an extra domain to additionally evaluate fluctuation in cognitive functions (NPI-11); the Japanese version of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog); and the Unified Parkinson's Disease Rating Scale (UPDRS). The NPI-11 scores were significantly improved at weeks 8 and 12 compared with baseline. Despite a significant improvement in ADAS-J-cog at week 4, no more improvement was noted thereafter. Deterioration was not noted in UPDRS scores. Donepezil is expected to be therapeutically useful and safe in treating DLB patients, indicating marked improvements in behavioral and psychological symptoms of dementia (BPSD) rather than in cognitive deficit, without deteriorating parkinsonism.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Donepezil; Feasibility Studies; Female; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB.. We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms.. The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment.. Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

Topics: Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Lewy Body Disease; Parkinson Disease; Piperidines; Treatment Outcome

This open label study was designed to assess the effects of donepezil treatment, its withdrawal and subsequent recommencement on cognitive functioning, behaviour and parkinsonian symptoms in patients with probable dementia with Lewy bodies (DLB) and with Parkinson's disease who subsequently developed dementia (PDD).. Eight patients with DLB and 11 with PDD were treated with up to 10 mg of donepezil daily for 20 weeks followed by a 6-week withdrawal period. The primary outcome measures were the Mini-Mental State Examination (MMSE), the total Neuropsychiatric Inventory (NPI) and the Unified Parkinson's Disease Rating Scale III. Testing was conducted before dosing, at week 20, at a withdrawal visit and 3 months after recommencement on donepezil.. Patients with DLB and PDD showed a significant improvement in cognition with treatment, loss of this improvement on withdrawal and restoration of treatment gains on recommencement. Both groups also demonstrated favourable, behavioural changes with treatment, PDD patients in particular deteriorating significantly after withdrawal. The only NPI symptom domain that showed a consistent significant response to both treatment (positive) and withdrawal (negative) was hallucinations. The medication was well tolerated and parkinsonian features did not alter significantly over the testing sessions.. Our results suggest that treatment with donepezil improves cognition and hallucinations without increasing parkinsonian symptoms, and its sudden withdrawal is usually detrimental, producing acute cognitive and behavioural decline. Although recommencement on donepezil appears to reverse this deterioration we do not advise its abrupt discontinuation in this population.

Topics: Cholinesterase Inhibitors; Dementia; Donepezil; Drug Administration Schedule; Humans; Indans; Lewy Body Disease; Neuropsychological Tests; Nootropic Agents; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

In several retrospective post-mortem studies, patients meeting clinical criteria for Alzheimer's disease (AD) who gained the greatest cognitive benefit from treatment with an acetylcholinesterase (AChE) inhibitor were found to have neocortical Lewy bodies accompanying classical AD neuropathology. This 'dementia with Lewy bodies' (DLB) subtype manifests both parkinsonian and psychopathologic features that set it apart from 'pure' AD (hereafter called AD). In the present preliminary study, 16 dementia patients were prospectively categorized as having DLB versus AD. Subjects were also categorized according to their profile on surface electromyographic (EMG) measures demonstrated in prior work to be analogues of clinically observed parkinsonian extrapyramidal signs (EPS). All patients were prescribed the AChE inhibitor donepezil (5 mg per day). At baseline and at 6 months, patients underwent cognitive testing with the Mini-Mental State Examination (MMSE) while caregivers assessed their psychopathologic status using the Behavioral Symptoms in Alzheimer's Disease (BEHAVE-AD) scale. The tester was blinded to the AD versus DLB classification of the patients. AD cases (N=12) had only a slight increase in cognitive scores, while DLB patients' (N=4) mean MMSE scores increased to a significantly greater degree. Furthermore, patients categorized by EMG as EPS positive (N=8) attained an increase in their mean MMSE score from baseline to 6 months that differed significantly from a decline in MMSE observed among their EPS negative (N=4) counterparts. For all subjects, an increase in MMSE scores across 6 months of treatment correlated with a decline in BEHAVE-AD scores.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Electromyography; Female; Humans; Indans; Lewy Body Disease; Male; Middle Aged; Motor Skills Disorders; Piperidines; Prospective Studies; Treatment Outcome

The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [. Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [. Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated nondiffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices.. The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.

Topics: Acetylcholine; Aged; Aged, 80 and over; Cerebral Cortex; Cross-Sectional Studies; Female; Fornix, Brain; Humans; Lewy Body Disease; Male; Nerve Net; Piperidines; Positron-Emission Tomography; Thalamus

Psychosis is common among patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Limited data exist on the most effective therapies.. Retrospective cohort study comparing patients with PD or DLB initiated on quetiapine or pimavanserin for psychosis. Primary outcome was time to discontinuation of pimavanserin or quetiapine using Kaplan-Meier survival analysis. We hypothesized the rate of antipsychotic discontinuation would be lower in the pimavanserin group. Subjects were included if the indication for treatment was psychosis and excluded if there was a history of major mental illness or no follow up data were available.. Forty-seven patients were included in the quetiapine cohort and 45 in the pimavanserin cohort. Patients in the pimavanserin cohort were more likely to have a diagnosis of DLB (33% vs. 11%, P = 0.01) and to have been prescribed an antipsychotic previously (62% vs. 6%, P < 0.01); otherwise, the groups were similar. Time to discontinuation analysis, which accounts for efficacy, safety and tolerability, revealed a lower early pimavanserin discontinuation rate and a higher late pimavanserin discontinuation rate (HR < 1 before day 43, HR > 1 after day 43; P = 0.04). There was no difference in mortality in the pimavanserin group compared to the quetiapine group (HR 0.37, 95% CI 0.06 to 2.45; P = 0.88). More individuals had a documented secondary indication for taking quetiapine than pimavanserin (38% vs. 4%; P = 0.001).. Accounting for efficacy, safety and tolerability, pimavanserin may be more clinically useful for promptly managing psychosis, while quetiapine may confer additional secondary benefits long-term.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Cohort Studies; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Urea

Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.

Topics: alpha-Synuclein; Animals; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Lewy Body Disease; Mice; Mice, Transgenic; Multiple System Atrophy; Neurons; Parkinson Disease; Piperidines; Protein Aggregation, Pathological; Protein Folding; Pyrazines; Pyrimidines; Retina

Cholinergic alterations in dementia with Lewy bodies (DLB) have been widely documented in postmortem studies, whereas in vivo studies are sparse, particularly at the subcortical level. We used. Twelve healthy volunteers (median age, 72 y; interquartile range, 6.25 y) and 11 DLB patients (median age, 76 y; interquartile range, 10.50 y) underwent a dynamic. Compared with BP. Our results confirm the existence in DLB of cholinergic alterations, reaching both cortical and subcortical levels, including the Ch5 pathway and the striatum. Alterations in cholinergic transmission in the anterior cingulate cortex could be closely associated with the development of apathy.

Topics: Aged; Aged, 80 and over; Brain; Cholinergic Neurons; Female; Humans; Lewy Body Disease; Male; Neural Pathways; Piperidines; Radiopharmaceuticals; Tetrahydronaphthalenes; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Vesicular Acetylcholine Transport Proteins

We investigated whether donepezil, a cholinesterase inhibitor, can be used to treat sleep disturbances in patients with dementia with Lewy bodies (DLB). Sleep disturbances were evaluated with the sleep disturbances item of the Neuropsychiatric inventory (NPI) and an actigraph in 16 DLB patients and 24 normal elderly control (NC) subjects. The presence/absence of nine kinds of sleep symptoms, such as dream enactment, were also evaluated in the DLB patients. The DLB patients were then given 5mg/day donepezil for 14 weeks and evaluated again. Eight of the 16 DLB patients had some sleep disturbances before taking donepezil. The actigraphy data indicated that average activity count per minute in sleep (AAC), which reflects body activity at night, was significantly higher and total sleep time was significantly longer in DLB patients than in NC subjects. The NPI sleep disturbances score significantly improved and the number of DLB patients who had sleep disturbances decreased after taking donepezil. The actigraphy results indicate that the sum of all wake epochs within the sleep period, which reflects the degree of fragmented sleep, and the AAC decreased in the DLB patients after donepezil treatment. These results indicate that donepezil treatment reduced sleep disturbances in DLB patients.

Topics: Actigraphy; Aged; Aged, 80 and over; Delusions; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indans; Lewy Body Disease; Male; Mental Status Schedule; Motor Activity; Piperidines; Sleep Deprivation; Treatment Outcome

As with other types of dementia, the behavioral and psychological symptoms of dementia (BPSD) can make caregiving difficult for patients with dementia with Lewy bodies (DLB). We hypothesized that administration of donepezil at an increased dose of 10 mg/day might dose-dependently improve BPSD in DLB patients with relapse, after their symptoms had been controlled initially by donepezil therapy at the standard dose.. The present study was as an open-label trial. We enrolled 24 patients with DLB (diagnosed according to the Consortium on Dementia with Lewy Bodies Guideline-Revised) who experienced a relapse of BPSD despite treatment with donepezil at the standard dose (5 mg/day). The donepezil dose for these patients was increased to 10 mg/day, and we evaluated the efficacy and safety of this dose escalation strategy.. The Neuropsychiatric Inventory (NPI) scores for BPSD showed statistically significant improvements as a result of the increased dosage, except those for anxiety and euphoria, disinhibition, irritability/lability. High-dose donepezil therapy caused gastrointestinal symptoms in 4 patients, but there were no life-threatening adverse events, such as arrhythmias, or no exacerbation of parkinsonian symptoms.. We found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD.

Topics: Aged; Aged, 80 and over; Behavior; Behavioral Symptoms; Cholinesterase Inhibitors; Cognition; Dementia; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indans; Lewy Body Disease; Male; Middle Aged; Piperidines; Severity of Illness Index; Treatment Outcome

Differential diagnosis between Lewy body disease and Alzheimer´s disease might be difficult because of similarities of clinical symptoms in both neurodegenerative diseases. DatSCAN is a modern functional neuroimmaging method which differentiates between this similar diseases and helps in correct treatment strategy. We report our positive experience with DatSCAN in differentiating Lewy body disease from Alzheimer´s disease. This is a case report of a woman with Lewy body disease, initially diagnosed as Alzheimer´s disease. DatSCAN neuroimmaging method was used in differential diagnosis of dementia. Memory impairment, impaired activities of daily living, sleep and behavioral disturbances were present in our case. Donepezil was well tolerated, but haloperidol administration was followed by development of severe dystonia. DatSCAN showed deficient dopaminergic presynaptic transport in substantia nigra and striatum. This finding is typical for Lewy body disease not for Alzheimer´s disease. DatSCAN neuroimmaging is a suitable method for differentiating Lewy body disease from Alzheimer´s disease. Deficient dopaminergic presynaptic transport in substantia nigra and striatum is typical for Lewy body disease.

Topics: Aged, 80 and over; Alzheimer Disease; Czech Republic; Diagnosis, Differential; Donepezil; Female; Humans; Indans; Lewy Body Disease; Piperidines; Synaptic Transmission; Tomography, X-Ray Computed

The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans.. Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment.. A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not.. These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency.

Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Atrophy; Cognition Disorders; Donepezil; Entorhinal Cortex; Female; Hippocampus; Humans; Indans; Language; Lewy Body Disease; Magnetic Resonance Imaging; Male; Mental Recall; Neuropsychological Tests; Nootropic Agents; Piperidines; Software; Temporal Lobe; Verbal Behavior

To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[(11) C]-methyl-4-piperidyl acetate (MP4A) and PET in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).. Participants were 14 DLB patients, 25 AD patients and 18 age-matched healthy controls (HC). All subjects underwent PET scans and MP4A to measure regional brain AChE activity. We performed anatomical standardization of each brain image, and k3 values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k3 images in frontal, temporal, parietal and occipital cortices, and in anterior and posterior cingulate gyri (ACG and PCG). In each VOI, the differential diagnostic performance between AD and DLB of k3 values was assessed by area under the curve (AUC) of the receiver-operating characteristic. Voxel-based statistical analyses were also performed.. Mean cortical AChE activities in AD patients (-8.2% compared with normal mean) and DLB patients (-27.8%) were lower than HCs (p < 0.05, p < 0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p < 0.001). All regional brain AChE activities of defined VOIs except ACG were able to well discriminate DLB from AD, and notably performance was the most significant in PCG (AUC = 0.989, 95% CI: 0.965-1.000).. Brain cholinergic deficit is consistently prominent in DLB compared with AD. PET measurement of brain AChE activity may be useful for the differential diagnosis between DLB and AD.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Case-Control Studies; Cerebral Cortex; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Piperidines; Positron-Emission Tomography; ROC Curve

Although cholinesterase inhibitors have been frequently used in the treatment of Alzheimer disease, its effects on serum cholinesterase concentrations have been rarely described. We described significant depression of serum cholinesterase levels due to cholinesterase inhibitor toxicity from redundant use of donepezil and rivastigmine in a 78-year-old man. Recovery of serum cholinesterase level was noted upon drug discontinuation and cholinergic symptom resolution. Serum cholinesterase level can be used as a biomarker for central cholinesterase inhibitor toxicity.

Topics: Aged; Bradycardia; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Humans; Indans; Lewy Body Disease; Male; Miosis; Parkinson Disease; Phenylcarbamates; Piperidines; Rivastigmine

Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimer's disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB.

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Amnesia; Bayes Theorem; Carbon Radioisotopes; Cognitive Dysfunction; Female; Humans; Lewy Body Disease; Male; Middle Aged; Piperidines; Positron-Emission Tomography

Topics: Cholinesterase Inhibitors; Conflict of Interest; Donepezil; Drug Costs; Humans; Indans; Lewy Body Disease; Neuropsychological Tests; Piperidines

Previous studies using magnetic resonance imaging (MRI) showed that dementia with Lewy bodies (DLB) had less atrophy in some medial temporal structures than Alzheimer's disease (AD). However, very few studies have focused on the entorhinal cortex, which is closely related to episodic memory. We compared the degree of entorhinal cortex atrophy between the two types of dementia using the voxel-based specific regional analysis system for AD (VSRAD) targeting this region.. The subjects consisted of 60 patients with DLB and 210 patients with AD. The degree of entorhinal cortex atrophy was quantified by application of the VSRAD to MRI data, and a Z score >2 was defined as significant atrophy.. The DLB group had significantly lower Z scores than the AD group (mean ± SD: 2.25 ± 1.10 vs. 2.85 ± 1.33, p < 0.01). The analysis of covariance with possible confounding factors as covariates also showed that Z scores were significantly lower in the DLB group than in the AD group (p < 0.01). The proportion of patients with atrophy was significantly lower in the DLB group than in the AD group (53 vs. 72%, p < 0.01).. The present study using the VSRAD suggests that DLB shows less atrophy in the entorhinal cortex than AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Data Interpretation, Statistical; Donepezil; Entorhinal Cortex; Female; Humans; Image Processing, Computer-Assisted; Indans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Nootropic Agents; Piperidines; Sex Characteristics

Here, we report a case of rapid eye movement sleep behavioural disorder in an elderly patient with dementia with Lewy bodies. Pretreatment polysomnography revealed atonia during rapid eye movement sleep, absence of sleep spindles and loss of slow-wave sleep. Administration of donepezil, an acetylcholinesterase inhibitor, markedly improved delusional symptoms and cognitive function. Pretreatment polysomnography performed after donepezil administration revealed a considerable number of sleep spindles. The effects of cholinergic modulation induced by donepezil seemed to cause remarkable improvement in mental status, incorporating associated with sleep spindles generated by the thalamocortical circuit involved in this patient.

Topics: Aged, 80 and over; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Humans; Indans; Lewy Body Disease; Piperidines; Polysomnography; Psychiatric Status Rating Scales; REM Sleep Behavior Disorder; Sleep, REM; Treatment Outcome

Topics: Aged; Brain; Cholinesterase Inhibitors; Cross-Sectional Studies; Dementia; Diagnosis, Differential; Diagnostic Imaging; Donepezil; Early Diagnosis; Evidence-Based Medicine; Humans; Indans; Lewy Body Disease; Mental Disorders; Neuropsychological Tests; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Dyskinesia, Drug-Induced; Female; Humans; Indans; Lewy Body Disease; Piperidines; Syndrome

We reported a patient with probable dementia with Lewy bodies (DLB) showing cervical dystonia during treatment with donepezil. A 78-year-old female had been treated with donepezil 5 mg/day for 18 months. The patient admitted to our hospital because of severe antecollis. Antecollis disappeard three weeks after discontinuation of donepezil. Five months later the patient received donepezil 3-5 mg/day for disease progression. The patient showed laterocollis again after a month-treatment with donepezil. Physical examination and labolatory tests were nomal. Magnetic resonance imaging of the neck showed no abnormal finding, but electromyography revealed dystonic changes in the neck muscles. Three weeks after discontinuation of donepezil, laterocollis disappeared. These findings suggest that treatment with donepezil induced cervical dystona in a patient with DLB.

Topics: Aged; Donepezil; Electromyography; Female; Humans; Indans; Lewy Body Disease; Piperidines; Torticollis

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Hallucinations; Humans; Indans; Lewy Body Disease; Piperidines

We discuss a case of a 67-year-old male with dementia with Lewy bodies (DLB) that was initially suspected as Creutzfeldt-Jakob disease (CJD) or another type of encephalopathy, because he showed rapidly progressive deterioration, myoclonus, gait disturbance and a decline in activities of daily living. The present study describes a clinically atypical case with probable DLB and reviews similar cases in the literature, and we propose a rapidly progressive clinical subtype of DLB.

Topics: Aged; Brain Ischemia; Cholinesterase Inhibitors; Creutzfeldt-Jakob Syndrome; Diagnosis, Differential; Donepezil; Hallucinations; Humans; Indans; Lewy Body Disease; Male; Mental Status Schedule; Neuropsychological Tests; Occipital Lobe; Parietal Lobe; Piperidines; Tomography, Emission-Computed, Single-Photon

To compare efficacy of different cholinesterase inhibitors (ChEIs) for treating patients with dementia with Lewy bodies (DLB).. Retrospective comparison of three independent clinical studies of ChEI treatment using donepezil, galantamine or rivastigmine in patients with DLB.. Data was obtained from open label trials of donepezil and galantamine and a placebo controlled randomized trial of rivastigmine in DLB. Changes in Mini Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) and United Parkinson's Disease Rating Scale (UPDRS-III) scores were compared between the three treatments at 12 and 20 weeks.. All ChEIs significantly improved cognitive and neuropsychiatric measures. Reduction in the total NPI score appeared significantly greater after donepezil treatment. There was no significant increase in UPDRS-III scores.. It is unclear to what extent these findings reflect true differences between ChEIs or are due to methodological artefacts of comparing different studies. There is so far no compelling evidence that any one ChEI is better than the other in treating DLB but head to head comparative studies of different ChEIs are warranted to clarify this.

Topics: Aged; Analysis of Variance; Cholinesterase Inhibitors; Clinical Trials as Topic; Data Interpretation, Statistical; Donepezil; Female; Galantamine; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Phenylcarbamates; Piperidines; Psychiatric Status Rating Scales; Rivastigmine; Treatment Outcome

Dementia with Lewy Bodies (DLB) is the second most common form of dementia in the elderly. Core features of the DLB are fluctuating cognitive symptoms, visual hallucinations and spontaneous parkinsonism. The clinical diagnostic criteria are very useful in the differentiation between DLB and Alzheimer's disease. The deficits in cholinergic neurotransmission are pronounced and associated with cognitive and psychotic symptoms. An 83 years old patient with DLB showed well formed recurrent visual hallucinations and fluctuating cognition and attention. There was no response to treatment with atypical neuroleptics. The patient responded within few days to treatment with Donepezil. Both cognitive and behavioural symptoms were improved significantly.

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Hallucinations; Humans; Indans; Lewy Body Disease; Male; Mental Disorders; Piperidines; Treatment Outcome

Cholinesterase inhibitors (ChEIs) are effective symptomatic treatments in dementia with Lewy bodies (DLB), although effects on pathologic mechanisms are unknown. In the first human autopsy study examining the impact of ChEI treatment on brain pathology, we compared treated patients with DLB with matched untreated patients for cortical beta-amyloid (Abeta) and tau pathologies. Treated patients with DLB had significantly less parenchymal Abeta deposition, which is relevant to disease management and treatment of dementia patients using ChEI.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Autopsy; Cerebral Cortex; Cholinesterase Inhibitors; Clinical Trials as Topic; Cohort Studies; Donepezil; Drug Evaluation; Female; Galantamine; Humans; Indans; Lewy Body Disease; Male; Middle Aged; Neuroprotective Agents; Phenylcarbamates; Piperidines; Prospective Studies; Rivastigmine; Tacrine; tau Proteins; Tauopathies

(1) Three cholinesterase inhibitors are marketed in France for the treatment of Alzheimer's disease: donepezil, galantamine and rivastigmine. Tremor and dystonia are known adverse effects of cholinesterase inhibitors. (2) In patients with Parkinson's disease who have cognitive disorders, or in patients with Lewy body dementia, exacerbations of parkinsonism and tremor have been observed during treatment with cholinesterase inhibitors at normal doses. The disorders were reversible on withdrawal of the cholinesterase inhibitor. (3) Withdrawal of cholinesterase inhibitors should be considered if gait disorders, falls or parkinsonism occur or worsen during treatment.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Dystonia; France; Galantamine; Humans; Indans; Lewy Body Disease; Parkinson Disease; Phenylcarbamates; Piperidines; Tremor

A double-blind randomized trial evaluated the efficacy and tolerability of rivastigmine and donepezil in patients with Alzheimer's disease (AD) over 2 years. Baseline data indicated that some patients had symptoms suggestive of concomitant Lewy body disease. This retrospective analysis investigated whether AD patients with and without symptoms suggesting concomitant Lewy body pathology demonstrated different responses to therapy.. AD patients were divided by the presence/absence of symptoms suggestive of concomitant Lewy body disease. These were identified by a concomitant diagnosis of dementia with Lewy bodies and/or use of anti-parkinsonian medication at baseline. Baseline characteristics, demographics, changes on efficacy parameters and adverse event (AE) frequencies were calculated for rivastigmine- and donepezil-treated patients. Efficacy parameters were the Severe Impairment Battery (SIB), Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS), Neuropsychiatric Inventory (NPI) and AD Cooperative Study Activities of Daily Living scale (ADCS-ADL). Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population.. Both populations reached mean doses of rivastigmine and donepezil that were within therapeutic ranges. Nine hundred and ninety-four AD patients received study drug, of whom 49 (4.9%) had symptoms suggestive of concomitant Lewy body disease (25 rivastigmine, 24 donepezil). In this subpopulation, changes from baseline after 2 years of treatment with rivastigmine were significantly better than those seen with donepezil on the SIB, MMSE and ADCS-ADL (ANCOVA or Wilcoxon analyses, p < 0.05, ITT-LOCF). Statistical significance was not maintained in non-ITT-LOCF analyses, except for EP analyses on the SIB and ADCS-ADL (both p < 0.05). Rivastigmine also provided significantly better functioning than donepezil in patients without Lewy body pathology, as shown by a significant treatment difference at endpoint on the ADCS-ADL (p < 0.05, ITT-LOCF; not maintained in non-ITT-LOCF analyses). NPI changes from baseline did not differ significantly between treatment groups. AD patients with symptoms suggestive of concomitant Lewy body disease receiving rivastigmine or donepezil experienced fewer gastrointestinal side effects, leading to fewer discontinuations due to AEs, compared with patients without Lewy body pathology.. In this retrospective analysis, AD patients who had symptoms suggestive of concomitant Lewy body disease appeared to show greater treatment responses to rivastigmine than to donepezil, and experienced fewer adverse events under either drug, compared with patients without Lewy body pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Lewy Body Disease; Male; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Retrospective Studies; Rivastigmine; Treatment Outcome

The authors explored the neural substrate of visual hallucinations in dementia with Lewy bodies (DLB) by investigating changes in regional cerebral blood flow (rCBF) and psychiatric symptoms, before and after cholinesterase inhibitor treatment. Twenty subjects with DLB were treated with donepezil for a 12-week period. Hallucinations attenuated while receiving therapy, whereas occipital rCBF focally increased, suggesting that functional visual association cortex deficits may cause visual hallucinations in patients with DLB.

Topics: Aged; Aged, 80 and over; Cerebrovascular Circulation; Donepezil; Female; Hallucinations; Humans; Indans; Lewy Body Disease; Male; Occipital Lobe; Piperidines; Regional Blood Flow; Tomography, Emission-Computed, Single-Photon

Lewy body disease is a common cause of dementia. Pharmacological therapies for the symptomatic treatment of this disorder are few and largely consist of acetylcholinesterase inhibitors. No guidelines exist regarding poor response or intolerability with such medications. This report discusses a case of an elderly woman with a diagnosis of probable Lewy body dementia who had significant improvement with donepezil but discontinued it due to side effects. She was switched to rivastigmine which she tolerated and which had a similar clinical response. The process of switching is discussed in light of the lack of specific guidelines.

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Lewy Body Disease; Neuroprotective Agents; Phenylcarbamates; Piperidines; Rivastigmine; Sweating

Fluctuations in consciousness and visual hallucinations are common neuropsychiatric features of dementia with Lewy bodies and Parkinson's disease dementia. To investigate potential neural correlates, we compared how changes in brain perfusion over a 1-year period were related to changes in the severity of these key clinical features. We recruited 29 subjects with either Parkinson's disease with dementia (15 subjects) or dementia with Lewy bodies (14 subjects). Cerebral perfusion was measured using HMPAO SPECT at baseline, and repeated 1 year later. The presence of hallucinations (Neuropsychiatric Inventory), severity of fluctuations in consciousness (fluctuation assessment scale) and cognitive ability (CAMCOG) were assessed at both time points. After controlling for changes in cognitive ability and effect of cholinesterase medication, we found a significant correlation between an increase in perfusion in midline posterior cingulate and decrease in hallucination severity. There was also a significant correlation between increased fluctuations of consciousness and increased thalamic and decreased inferior occipital perfusion. We have identified important neural correlates of key clinical features in Lewy body dementia and postulate that the associations can be understood through the influence of the cholinergic system on attention.

Topics: Aged; Cholinesterase Inhibitors; Consciousness Disorders; Donepezil; Female; Hallucinations; Hemodynamics; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Oximes; Piperidines; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

Clinicopathophysiological differences between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) remain obscure. Our goals were to determine whether characteristic findings of electroencephalogram (EEG) power and coherence in DLB and a differential pathophysiological mechanism of quantitative EEG existed between DLB and AD. The group consisted of 15 patients with AD or DLB and 12 age-matched controls. Original EEG signals were recorded from 14 scalp electrodes positioned according to the International 10-20 System, using digitally linked earlobes as a reference. Although EEG power spectral analysis showed increasing EEG power density in patients with DLB in the delta and theta bands, such a difference did not exist in patients with AD. Compared with AD, the delta and theta band intrahemispheric coherence values in the fronto-temporo-central regions were higher in DLB. In the beta band, AD was lower than DLB in almost all temporo-centro-parieto-occipital regions. Comparing the mean power value between patients with/without donepezil treatment, there was a significantly lower EEG power density in the delta and theta bands in DLB subjects taking donepezil than in subjects not taking donepezil, whereas there was no significant difference in AD patients. These results suggest that cholinergic dysfunction is stronger in DLB than AD.

Topics: Aged; Algorithms; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Electroencephalography; Female; Functional Laterality; Humans; Indans; Lewy Body Disease; Male; Piperidines

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) overlap in phenomenology and neurochemical deficits. We hypothesised they would not differ in their response to the cholinesterase inhibitor donepezil.. We recruited 70 subjects, 30 DLB and 40 PDD, in an open label study to compare the efficacy of donepezil in these two patient groups. They were assessed at baseline, 4, 12 and 20 weeks. The main outcome measures were the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) and motor sub-section of the Unified Parkinson's Disease Rating Scale (UPDRS III).. PDD patients were younger than DLB and had more severe parkinsonism at baseline. The groups were similar on all other variables of interest. By 20 weeks the mean MMSE score increased by 3.9 points in the DLB group and by 3.2 points in PDD. The mean NPI score reduced by 14.6 points for DLB and 12.0 points for PDD. These treatment effects were all significant compared to baseline (p < 0.001) but there were no significant between-group treatment differences (MMSE p = 0.56, NPI p = 0.39). UPDRS III motor scores did not change significantly from baseline values in either group. Although adverse effects were common (69%) they were usually mild and 64 patients (91%) completed the study. The four patients who did withdraw with adverse effects all had a PDD diagnosis.. Donepezil produced similar improvements in cognition and behaviour in DLB and PDD. This supports the hypothesis that the two disorders are closely related clinically and neurobiologically. Larger scale, placebo controlled clinical trials are needed to provide an evidence base to guide the clinical use of cholinesterase inhibitors in Lewy body disease.

Topics: Age Factors; Aged; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Parkinson Disease; Piperidines; Severity of Illness Index; Treatment Outcome

Delayed disease progression and symptomatic improvement occur with cholinesterase inhibitors (ChEIs) in dementia with Lewy bodies (DLB). In this study, complications (insomnia, dyskinesias, agitation, and delirium) occurred in three patients switched from donepezil to galantamine. The authors describe evidence-based recommendations for ChEI switchover in DLB.

Topics: Aged; Cholinesterase Inhibitors; Disease Progression; Donepezil; Galantamine; Humans; Indans; Lewy Body Disease; Male; Mental Status Schedule; Neuropsychological Tests; Piperidines

Recently recognized as an entity separate from Alzheimer's disease (AD) and Parkinson's disease with dementia, dementia with Lewy bodies (DLB) is a frequent cause of dementia. It is characterized by progressive cognitive decline and attention deficits, but in contrast to AD, the cognitive changes typically fluctuate over time. Patients with DLB often experience Parkinson-like spontaneous motor features as well as recurrent visual hallucinations. Another frequent finding in DLB is rapid eye movement (REM) sleep disorder. Ideally, each of the major symptom domains associated with DLB (behavioral, motor, and cognitive) would be treated, but drug interactions in these patients are a serious concern. In addition, many patients with DLB are hypersensitive to neuroleptics, which can induce severe extrapyramidal and other symptoms--sometimes ending in death. Compared with conventional neuroleptics, the newer atypical antipsychotic agents may be associated with lower rates of extrapyramidal side effects. Cholinergic deficits in DLB are even more severe than in AD, whereas the extent of cerebral atrophy and neuronal damage may be less. These observations and emerging clinical data support the treatment of DLB with acetylcholinesterase inhibitors. Encouraging results have been obtained from studies of DLB patients treated with rivastigmine, donepezil, and galantamine, but large-scale, controlled trials are needed to confirm the efficacy and safety of acetylcholinesterase inhibitors in patients with DLB.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Brain; Carbamates; Cholinesterase Inhibitors; Diagnosis, Differential; Donepezil; Galantamine; Humans; Indans; Lewy Body Disease; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Treatment Outcome

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Lewy Body Disease; Neuroleptic Malignant Syndrome; Piperidines

To describe the assessment and treatment of an elderly woman with parkinsonism, progressive memory and cognitive deficits, and visual hallucinations.. The patient presented with a 10-year history of hand tremors, an 8-year history of short-term memory problems, and a 3-4-year history of visual hallucinations. Treatment with donepezil and rivastigmine (successively) did not produce the desired benefits. Then she was started on galantamine 4 mg b.i.d. (escalated to 8 mg b.i.d.).. The patient's social interaction improved and cognitive decline appeared to be stabilized; hallucinations and agitation were also better controlled.. By current criteria, this subject would be labeled as having Parkinson's disease with dementia, although she exhibited the core features of dementia with Lewy body disease. As suggested in previous studies, cholinesterase inhibitors may be effective in treating psychotic symptoms; however, all currently available agents may not be equally effective.

Topics: Aged; Aged, 80 and over; Carbamates; Cognition Disorders; Donepezil; Drug Resistance; Female; Galantamine; Hallucinations; Humans; Indans; Lewy Body Disease; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Psychomotor Agitation; Rivastigmine; Social Behavior

Topics: Acetylcholine; Aged; Basal Ganglia; Cholinesterase Inhibitors; Disease Progression; Donepezil; Dopamine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Indans; Lewy Body Disease; Parkinsonian Disorders; Piperidines

We report a 75-year-old Japanese woman with probable dementia with Lewy bodies (DLB). At the age of 64, she showed left hand resting tremor, and gradually developed bradykinesia, and rigidity. She was diagnosed as having parkinsonism and took medication. At the age of 70, she showed hallucination and dementia. As she had developing cognitive dysfunction and hallucination and parkinsonism, she was diagnosed to have probable DLB. At the age of 75, after administration of donepezil, she showed severe psychosis and worsened parkinsonism, and was admitted to hospital. On neurological examination, she showed severe rigidity and akinesia, and behavioral immobility like "waxy flexibility" or motiveless resistance to maintenance of rigid posture against attempts to be moved. The phenomena, she presented as motor abnormalities, were thought to be catatonia. In consideration of clinical course, her catatonia and worsened parkinsonism was thought to be induced by donepezil and she was stopped the administration of donepezil. After treatment with trihexiphenizil, she had improvement of motor abnormalities and worsened parkinsonism. It is important to recognize that donepezil may induce catatonia on the patients of parkinsonism with severe dementia.

Topics: Aged; Catatonia; Donepezil; Female; Hallucinations; Humans; Indans; Lewy Body Disease; Nootropic Agents; Parkinsonian Disorders; Piperidines

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Lewy Body Disease; Piperidines

Topics: Aged; Antipsychotic Agents; Dibenzothiazepines; Donepezil; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Female; Hallucinations; Humans; Indans; Lewy Body Disease; Male; Nootropic Agents; Piperidines; Quetiapine Fumarate

Dementia with Lewy bodies (DLB) is often associated with REM sleep behavior disorders (RBD) characterized, in contrast to the usual paralysis of REM sleep, by violent motor and verbal activity.. The pharmacological management of RBD was investigated in three DLB patients treated with clonazepam, a benzodiazepine used as an antiepileptic, or donepezil, a cholinesterase inhibitor.. All three patients had marked improvement. The pharmacodynamic mechanisms underlying the efficacy of the two drugs might be due to facilitator effect on the pedunculopontine nucleus, a key structure in the physiology of REM sleep.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Benzodiazepines; Cholinesterase Inhibitors; Clonazepam; Donepezil; Dose-Response Relationship, Drug; Female; Globus Pallidus; Humans; Indans; Lewy Body Disease; Locus Coeruleus; Male; Mental Status Schedule; Middle Aged; Nerve Net; Pedunculopontine Tegmental Nucleus; Piperidines; REM Sleep Behavior Disorder; Sleep-Wake Transition Disorders; Sleep, REM; Treatment Outcome; Violence

To report a case of the successful use of donepezil for treatment of cognitive and noncognitive symptoms in a patient with dementia with Lewy bodies. CASE SUMARY: An 86-year-old white woman with dementia was experiencing early-onset significant fluctuation of her cognitive status, functional impairment, visual hallucinations, aggression, and parkinsonism. She was intially diagnosed with Alzheimer disease and Parkinsons disease and prescribed donepezil 5 mg/d and benztropine 1 mg twice daily. On reexamination of the case by a neurologist, the diagnoses were revised to dementia with Lewy bodies. The benztropine was discontinued, and donepezil was increased to 10 mg/d. The patient's cognitive and functional status significantly improved, as did her visual hallucinations.. This case supports previous reports of the marked responsiveness of patients with dementia with Lewy bodies to acetylcholinesterase inhibitors. This may be explained by the marked cholinergic deficit observed in patients with dementia with Lewy bodies and the evidence linking cognitive as well as noncognitive symptoms to this deficit.. The present case suggests that patients with dementia with Lewy bodies respond well to acetylcholinesterase inhibitors. Controlled trials are necessary to further define the role of these drugs for this disease.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Lewy Body Disease; Nootropic Agents; Piperidines

Measurement of cerebral acetylcholine esterase (AChE) activity is of clinical interest for the differential diagnosis of memory disorders and dementia. We developed and tested a non-invasive method for quantitation of regional cortical AChE activity with carbon-11-labelled N-methyl-4-piperidyl acetate (11C-MP4A) that does not require arterial blood sampling. AChE activity was measured in terms of the rate constant for hydrolysis of 11C-MP4A (k3). The physiological model is based on the very high AChE activity in the basal ganglia, which are used as a reference structure. Non-invasive k3 was compared with k3 determined with a standard technique by fitting kinetic tissue and metabolite-corrected plasma data in nine subjects with and without dementia. Across all regional values, a very high correlation of 0.92 was found, with a tendency towards moderate underestimation of k3 by 5%-14% with the non-invasive technique as compared to the invasive technique. In addition to its advantages with respect to practicability, the new non-invasive technique overcomes problems of the invasive technique that are related to interindividual variation of delay times between cerebral and peripheral tracer arrival and measurement of very small amounts of non-hydrolysed tracer in plasma samples.

Topics: Acetates; Acetylcholinesterase; Aged; Algorithms; Alzheimer Disease; Basal Ganglia; Brain; Female; Humans; Lewy Body Disease; Male; Middle Aged; Piperidines; Radiopharmaceuticals; Tomography, Emission-Computed

The patient was a 68-year-old man with a 1-year history of delusions related to well-formed and detailed visual hallucinations. Bromperidol 12 mg was prescribed to treat his symptoms. After a diagnosis of dementia of Alzheimer's type was suspected, the patient received donepezil hydrochloride 5 mg. One week later, the patient's Parkinsonism deteriorated. One month later, the patient developed radical edema of the eyelids and the anterior neck, hypoproteinemia, and severe anteflexion of the body. One and a half months later, the patient developed malignant syndrome. His medication was discontinued and parenteral nutrition was started. The patient recovered from his malignant syndrome. However, 1 month later, his Parkinsonism had not improved. The patient received levodopa to treat his Parkinsonism and his symptoms subsequently improved. The hallucinations and systematized delusions returned. The patient's cognitive impairment deteriorated on one side. The aggravation of extrapyramidal symptoms and the development of malignant syndrome were believed to have been caused by the combination of bromperidol and donepezil hydrochloride and poor nutrition. Caution should be exercised when prescribing an antipsychotic drugs with donepezil hydrochloride.

Topics: Aged; Donepezil; Drug Therapy, Combination; Hallucinations; Haloperidol; Humans; Indans; Lewy Body Disease; Male; Neuroleptic Malignant Syndrome; Nootropic Agents; Piperidines

We present a 73-year-old man with probable dementia with Lewy bodies(DLB). At 65 years of age, he gradually developed bradykinesia, gait disturbance and mild amnesia. At 71 years of age, he noted resting tremor in bilateral hands, and amnesia and disorientation were exacerbated. He was diagnosed as having parkinsonism and took L-dopa/carbidopa at 100 mg/day. Since he developed hallucination and abnormal behavior 2 days after the initiation of the drug, he stopped taking L-dopa and was admitted to our hospital. A neurological examination on admission revealed moderate amnesia, disorientation, finger agnosia, constitutional apraxia, mask-like face, cogwheel rigidity, resting tremor in bilateral hands, and bradykinesia. Brain MRI showed mild brain atrophy, and single photon emission computerized tomography(SPECT) showed diffuse moderate hypoperfusion in bilateral cerebral cortex. As he had fluctuating cognitive dysfunction and parkinsonism, he was diagnosed to have probable DLB. As his dementia was exacerbated by trihexyphenidyl, an anti-cholinergic agent, at 2 mg/day, we treated him with donepezil, an anti-choline esterase agent, at 3-5 mg/day. His parkinsonism, including rigidity and bradykinesia, was markedly improved his dementia, consisting of amnesia and disorientation. Electroencephalography (EEG) improved in the organization of the dominant rhythm. The SPECT improved in the blood perfusion of the bilateral frontal lobe as well as cognitive function and parkinsonism were maintained by donepezil for 6 months after discharge. A therapeutic efficacy of donepezil for DLB has recently been reported. It is notable that donepezil was beneficial not only for cognitive dysfunction but also for parkinsonism in the present case with probable DLB.

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Electroencephalography; Humans; Indans; Lewy Body Disease; Male; Parkinson Disease; Piperidines

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Lewy Body Disease; Male; Piperidines; Psychotic Disorders

Dementia with Lewy bodies (DLB) has been associated with important behavioural disturbances, such as psychotic symptoms. Unfortunately, neuroleptic sensitivity in these patients limits effective pharmacological management of these symptoms. Seven patients, five male and two female (mean age 75.3+/-4.7 years, range 68-81), diagnosed with DLB were treated with the acetylcholinesterase inhibitor donepezil (5-10 mg once daily) to determine its effect on treating behavioural disorders. Although the intended length of treatment was a minimum of 8 weeks, only three patients completed 8 weeks of therapy, one patient completed 6 weeks, two patients completed 4 weeks and one patient was discontinued after 5 days. The primary outcome (behavioural disturbances) was measured prospectively by the Neuropsychiatric Inventory (NPI), while other outcomes included cognition (Mini-Mental State Examination (MMSE)) and Clinical Global Impression. Three of the seven subjects showed marked improvement in behaviour, with NPI scores dropping significantly over time. Donepezil therapy was discontinued prematurely in three of the cases due to insufficient response and/or adverse events. Overall, five of the seven patients were rated at least minimally improved in behavioural symptoms. Our experience with donepezil in this group of patients shows promise. Given the limited experience with this agent in treating behavioural disorders associated with DLB, further studies are warranted.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Lewy Body Disease; Male; Nootropic Agents; Piperidines; Social Behavior Disorders; Survival Analysis; Treatment Outcome

Topics: Aged; Diagnosis, Differential; Donepezil; Female; Hallucinations; Humans; Indans; Lewy Body Disease; Nootropic Agents; Piperidines; Syndrome; Vision Disorders

Sundowning, manifested as a recurring increase in restlessness and agitation in the evening, is described in a 71-year-old man with clinically diagnosed dementia with Lewy bodies. An objective measure of activity using the activity electronic monitoring technique indicated a marked increase in activity level during the evening compared to earlier in the day. After treatment with donepezil, a cholinesterase inhibitor, ratings of behavioural symptoms improved. In addition, there was a marked reduction in evening activity and an increase in daytime activity. Cognition and parkinsonism also improved. Possible explanations for this finding are discussed.

Topics: Aged; Cholinesterase Inhibitors; Circadian Rhythm; Donepezil; Humans; Indans; Lewy Body Disease; Male; Piperidines; Psychomotor Agitation; Treatment Outcome

Memory and attention are cognitive functions that depend heavily on the cholinergic system. Local activity of acetylcholine esterase (AChE) is an indicator of its integrity. Using a recently developed tracer for positron emission tomography (PET), C-11-labeled N-methyl-4-piperidyl-acetate (C11-MP4A), we measured regional AChE activity in 4 non-demented subjects, 4 patients with dementia of Alzheimer type (DAT) and 1 patient with senile dementia of Lewy body type (SDLT), and compared the findings with measurements of blood flow (CBF) and glucose metabolism (CMRGlc). Initial tracer extraction was closely related to CBF. AChE activity was reduced significantly in all brain regions in demented subjects, whereas reduction of CMRGlc and CBF was more limited to temporo-parietal association areas. AChE activity in SDLT was in the lower range of values in DAT. Our results indicate that, compared to non-demented controls, there is a global reduction of cortical AChE activity in dementia.. Dementia, cholinergic system, acetylcholine esterase, positron emission tomography, cerebral blood flow, cerebral glucose metabolism.

Topics: Acetates; Acetylcholinesterase; Aged; Alzheimer Disease; Brain; Brain Stem; Carbon Radioisotopes; Cerebellum; Cerebrovascular Circulation; Corpus Striatum; Female; Glucose; Humans; Lewy Body Disease; Male; Mental Status Schedule; Middle Aged; Piperidines; Reference Values; Regression Analysis; Thalamus; Tomography, Emission-Computed