Matthew Walker

Quantifying fluctuation in dementia with Lewy bodies, Alzheimer’s disease, and vascular dementia

Background: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. Objectives: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. Method:— A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. Results: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). Conclusion: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.

Rapid eye movement sleep disturbances in Huntington disease.

BACKGROUNDnSleep disorders including insomnia, movements during sleep, and daytime sleepiness are common but poorly studied in Huntington disease (HD).nnnOBJECTIVEnTo evaluate the HD sleep-wake phenotype (including abnormal motor activity during sleep) in patients with various HD stages and the length of CAG repeats. Because a mild hypocretin deficiency has been found in the brains of some patients with HD (hereinafter referred to as HD patients), we also tested the HD patients for narcolepsy.nnnDESIGN AND PATIENTSnTwenty-five HD patients (including 2 premanifest carriers) underwent clinical interview, nighttime video and sleep monitoring, and daytime multiple sleep latency tests. Their results were compared with those of patients with narcolepsy and control patients.nnnRESULTSnThe HD patients had frequent insomnia, earlier sleep onset, lower sleep efficiency, increased stage 1 sleep, delayed and shortened rapid eye movement (REM) sleep, and increased periodic leg movements. Three HD patients (12%) had REM sleep behavior disorders. No sleep abnormality correlated with CAG repeat length. Reduced REM sleep duration (but not REM sleep behavior disorders) was present in premanifest carriers and patients with very mild HD and worsened with disease severity. In contrast to narcoleptic patients, HD patients had no cataplexy, hypnagogic hallucinations, or sleep paralysis. Four HD patients had abnormally low (< 8 minutes) daytime sleep latencies, but none had multiple sleep-onset REM periods.nnnCONCLUSIONSnThe sleep phenotype of HD includes insomnia, advanced sleep phase, periodic leg movements, REM sleep behavior disorders, and reduced REM sleep but not narcolepsy. Reduced REM sleep may precede chorea. Mutant huntingtin may exert an effect on REM sleep and motor control during sleep.

A comparison of sleep profiles in patients with dementia with Lewy bodies and Alzheimer's disease

Introduction. Sleep disturbances are common in healthy old age and in dementia syndromes. Polysomnography has demonstrated typical changes in both Alzheimers disease (AD) and dementia with Lewy bodies (DLB) with AD being characterised by sundowning and sleep apnoea and DLB patients showing more disturbances of movement control during sleep. The technical difficulties associated with EEG sleep recordings mean that polysomnography is not possible out of specialist centres.

Quantification and Characterisation of Fluctuating Cognition in Dementia with Lewy Bodies and Alzheimer’s Disease

Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.

Clinical and neuropathological correlates of apolipoprotein E genotype in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) represents the second commonest cause of dementia in the elderly following Alzheimer’s disease (AD). Whilst the presence of Lewy bodies is essential, DLB shares with AD the presence of senile plaques (SP), but neurofibrillary tangles (NFT) are not a necessary feature. The apolipoprotein E (APO E) Ε4 allele is the most consistently associated genetic risk factor for AD and has also been shown to associate with DLB. We have therefore analysed the APO E Ε4 allele in a large series of DLB cases coming to autopsy to: (1) determine if the Ε4 allele describes a similar risk in DLB development as in AD and (2) determine how APO E Ε4 allele status correlates with clinical and neuropathological findings in DLB, and in AD, as an indication of the role of APO E in underlying disease biology. Both DLB and AD share an increased Ε4 allele frequency, though in DLB the Ε2 allele frequency is not reduced and there is a relative lack of Ε4 homozygotes. In contrast to previous studies, no association of the Ε4 allele with age at onset or duration of disease was found in either disorders. In DLB cases, overall a significantly shorter duration of illness was observed when compared with AD cases, though no significant effect of the Ε4 allele on disease onset or duration was seen. The survival rate was reduced by the presence of the Ε4 allele in DLB, as with AD. No effect on SP or NFT counts was seen with the Ε4 allele, though DLB cases showed a lower SP burden in addition to the expected lower NFT counts. This study demonstrates that DLB shares the APO Ε4 allele with AD as a common risk factor, but that there are differences in the way the Ε4 allele affects the phenotypic expression of disease.