Risk of decline in functional activities in dementia with Lewy bodies and Alzheimer disease

We examined the risk of 1-year decline in 4 everyday activities in patients with dementia with Lewy bodies (DLB), relative to patients with Alzheimer disease (AD). Data were from the National Alzheimer's Coordinating Center, gathered from 32 Alzheimer's Disease Centers. Participants (n=1880) were: aged 60+ years, demented with a primary clinical diagnosis of probable AD or DLB, and had a global Clinical Dementia Rating of 0.5 to 2. The activities were measured with the Functional Activities Questionnaire. In modified Poisson regression models adjusted for demographics, baseline activity, years from symptom onset, cognitive impairment, and comorbidities; DLB participants aged 67 to 81 years had 1.5 to 2 times increased risk of decline in performing basic kitchen tasks, engaging in games/hobbies, and paying attention/understanding, relative to AD participants of the same age (P<0.05). There was no significant difference between AD and DLB participants beyond this age range. For decline in ability to go shopping alone, there was also no significant difference between AD and DLB participants. In summary, the functional course of DLB, relative to AD, may depend on the age of the patient. These findings may provide anticipatory guidance to families and healthcare providers, which may be useful in the planning of care strategies.     

A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia

OBJECTIVES: To compare the frequency and clinical correlates of neuropsychiatric symptoms in patients with Parkinson's disease (PD) with and without dementia and in those with dementia with Lewy bodies (DLB). METHODS: Neuropsychiatric symptoms during the month prior to assessment were assessed in clinically diagnosed PD patients with dementia (PDD; n = 48) and without dementia (PDND; n = 83) and in 98 DLB patients (33% autopsy confirmed) using standardized instruments. RESULTS: Delusions and hallucinations were significantly more common in DLB (57% and 76%) than PDD (29% and 54%) and PDND (7% and 14%) patients (p < 0.001). In all groups, auditory and visual hallucinations and paranoid and phantom boarder delusions were the most common psychotic symptoms. Frequency of major depression and less than major depression did not differ significantly between the three groups. Clinical correlates of hallucinations in PD were dementia (odds ratio (OR) = 3.9; 95% confidence interval (CI) 1.5-10.4) and Hoehn-Yahr stage 3 or more (OR 3.4; 95% CI 1.0-12.0), whereas no significant clinical correlates of hallucinations were found in DLB patients. CONCLUSIONS: Delusions and hallucinations occur with increasing frequency in PDND, PDD and DLB patients, but the presentation of these symptoms is similar. These findings support the hypothesis that psychiatric symptoms are associated with cortical Lewy bodies or cholinergic deficits in the two disorders.     

Accounting for functional loss in Alzheimer's disease and dementia with Lewy bodies: Beyond cognition

BackgroundThe relative contributions of cognitive, motor, and behavioral deficits to the impairment of physical or instrumental activities of daily living (ADLs) may differ in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).MethodsMultiple linear regression analyses were used to identify the amount of variability in physical self-maintenance and instrumental ADL ratings predicted by cognitive, motor, and behavioral indices separately for patients with autopsy-diagnosed DLB (n = 39) or AD (n = 39).ResultsMotor dysfunction accounted for significant variance in physical ADLs in DLB (R² change = 0.17), whereas behavioral (R² change = 0.23) and motor dysfunction (R² change = 0.13) accounted for significant variance in AD. Motor (R² change = 0.32) and cognitive (R² change = 0.10) dysfunction accounted for significant variance in instrumental ADLs in DLB, whereas cognitive (R² change = 0.36) and behavioral (R² change = 0.12) dysfunction accounted for significant variance in AD.ConclusionsCognitive, motor, and behavioral deficits contribute differently to ADL changes in DLB and AD. Thus, treatments designed to ameliorate a certain aspect of AD or DLB (e.g., cognitive dysfunction) may have a larger impact on everyday functioning in one disorder than the other.     

The progression of cognitive impairment in dementia with Lewy bodies, vascular dementia and Alzheimer's disease

BACKGROUND: Little is known about the rate of progression or associations of cognitive impairment in dementia with Lewy bodies (DLB), or the associations of accelerated decline. METHOD: Dementia patients from a case register were evaluated at baseline and 1 year follow-up using the Cambridge Assessment for Mental Disorders in the Elderly, section B (CAMCOG) and the Mini-Mental State Examination (MMSE) to determine the rate of cognitive decline. Operationalized clinical diagnoses were applied (NINCDS ADRDA for Alzheimer's disease (AD), NINCDS AIRENS for vascular dementia (VaD) and consensus criteria for DLB). RESULTS: One hundred and ninety-three patients completed annual MMSE schedules (AD, 101; DLB, 64; VaD, 38), of whom 154 completed the CAMCOG. The magnitude of cognitive decline (MMSE, 4-5 points; CAMCOG, 12-14 points) was similar in each of the dementias. The strongest predictor of accelerated cognitive decline in DLB was the apolipoprotein E4 allele (17.5 vs 8.3 points decline on the CAMCOG). CONCLUSION: Over 1 year, DLB, VaD and AD patients had similar rates of cognitive decline overall. Apolipoprotein E4 may be an important predictor of more rapid decline in DLB.     

Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies

BACKGROUND: There have been no previous studies on the role of inflammation in the brain for the second most common dementing disorder, dementia with Lewy bodies. OBJECTIVE: To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains. DESIGN AND MAIN OUTCOME MEASURES: Post-mortem tissue collection from a brain donor program using standardized diagnostic criteria. Brains collected from January 1, 1993, through December 31, 1996, were screened and selected only for the presence or absence of tau neuritic plaques. Results of immunohistochemistry for HLA-DR were quantified using area fraction counts. Counts were performed by investigators who were unaware of the diagnosis. Results were compared across groups using analysis of variance and posthoc testing. SETTING: A medical research institute in Sydney, Australia. PATIENTS: Eight brains with DLB and without the tau neuritic plaques typical of AD, 10 brains with AD and no Lewy bodies, and 11 nondemented controls without significant neuropathological features were selected from a consecutive sample. RESULTS: Compared with AD, DLB demonstrated significantly less inflammation in the form of HLA-DR-reactive microglia in all cortical regions (P<.001, posthoc). The level of inflammation in DLB was comparable to that seen in controls (P=.54, post hoc). CONCLUSIONS: Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.     

Cerebral metabolism, cognition, and functional abilities in Alzheimer disease

Patients with Alzheimer disease (AD) exhibit profound difficulties in completing instrumental activities of daily living (IADLs), such as managing finances, organizing medications, and food preparation. It is unclear which brain areas underlie IADL deficits in AD. To address this question, we used voxel-based analysis to correlate the performance of IADLs with resting cerebral metabolism as measured during [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging in 44 patients with AD. Poorer ability to complete IADLs was associated with hypometabolism in right-sided cortical regions, including the parietal lobe, posterior temporal cortex, dorsolateral prefrontal cortex, and frontal pole. Follow-up path analyses examining anatomically defined regions of interest (ROI) demonstrated that the association between metabolism and IADLs was mediated by global cognition in frontal ROIs, and partially mediated by global cognition in the parietal ROI. Findings suggest that hypometabolism of right sided brain regions involved in executive functioning, visuospatial processing, attention, and working memory underlie functional impairments in patients with AD.     

The characterisation and impact of 'fluctuating' cognition in dementia with Lewy bodies and Alzheimer's disease

BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in all the major dementias, particularly dementia with Lewy bodies (DLB) where it is one of three core clinical diagnostic features. The purpose of this study was to characterise FC and determine its impact upon activities of daily living. METHODS: Forty matched subjects (15 DLB, 15 AD, 10 elderly controls) were assessed using the activities of daily living scale (ADLD), the cognitive drug research (CDR) computerised neuropsychological test battery and a semi-standardised assessment of FC. The CDR battery was completed three times across a 1-week period, to evaluate variability in attention, visuospatial ability, working memory and delayed recall. RESULTS: There was a strong positive correlation between clinical FC scores and total mean ADLD. Measures of cognitive variability also demonstrated strong significant correlations with independent clinical severity ratings of FC across several cognitive domains. These associations were most powerful between attentional measures and clinical FC ratings. CONCLUSIONS: Although attention is the cognitive domain which fluctuates most markedly, other cognitive domains are also affected. FC also has a significant independent impact on activities of daily living.     

Low alpha-synuclein 126 mRNA levels in dementia with Lewy bodies and Alzheimer disease

Alpha-synuclein, a main component of Lewy bodies in synucleinopathies and senile plaques in Alzheimer disease, is centrally involved in neurodegeneration. Three different isoforms (alpha-synuclein 112, 126, and 140) resulting from alternative splicing have been described so far. The present study explores alpha-synuclein 126 mRNA expression levels in the prefrontal cortex of six patients with dementia with Lewy bodies, eight patients with Lewy body variant of Alzheimer disease, eight patients with Alzheimer disease, and 10 controls. Relative alpha-synuclein 126 expression levels were determined by real-time polymerase chain reaction with competimer technology. Alpha-synuclein 126 mRNA expression was markedly decreased in the three dementias in comparison with controls, suggesting an important role of this alpha-synuclein isoform in the normal brain.     

Attention and fluctuating attention in patients with dementia with Lewy bodies and Alzheimer disease

BACKGROUND: Attentional deficits are described in the consensus clinical criteria for the operationalized diagnosis of dementia with Lewy bodies (DLB) as characteristic of the condition. In addition, preliminary studies have indicated that both attentional impairments and fluctuation of attentional impairments are more marked in patients with DLB than in patients with Alzheimer disease (AD), although neuropsychological function has not previously been examined in a large prospective cohort with confirmed diagnostic accuracy against postmortem diagnosis. METHODS: A detailed evaluation of attention and fluctuating attention was undertaken in 155 patients with dementia (85 with DLB and 80 with AD) from a representative hospital dementia case register and 35 elderly controls using the Cognitive Drug Research Computerized Assessment System for Dementia Patients computerized neuropsychological battery. Operationalized clinical diagnosis was made using the consensus criteria for DLB and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD. High levels of sensitivity and specificity have been achieved for the first 50 cases undergoing postmortem examination. RESULTS: The groups were well matched for severity of cognitive impairments, but the AD patients were older (mean age, 80 vs 78 years) and more likely to be female (55% vs 40%). Patients with DLB were significantly more impaired than patients with AD on all measures of attention and fluctuating attention (for all comparisons, t > or = 2.5, P<.001), and patients from both dementia groups were significantly more impaired than elderly controls for all comparisons other than cognitive reaction time, which was significantly more impaired in DLB patients than controls but was comparable in controls and AD patients. There were, however, significant associations between the severity of cognitive impairment and the severity of both attentional deficits and fluctuations in attention. CONCLUSIONS: This large prospective study confirms that slowing of cognitive processing, attention, and fluctuations of attention are significantly more pronounced in DLB and AD patients, although fluctuating attention is common in patients with moderate-to-severe AD. Deficits of cognitive reaction time appear to be specific to DLB, except in severe dementia. A detailed evaluation of attentional performance could make an important contribution to differential diagnosis, although the results need to be interpreted within the context of the overall severity of cognitive deficits.     

Quantification and characterization 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.     

Spatial metabolic profiles to discriminate dementia with Lewy bodies from Alzheimer disease

Journal of Neurology - To differentiate dementia with Lewy bodies (DLB) from Alzheimer disease (AD) using a single imaging modality is challenging, because of their common hypometabolic findings....     

Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease

BACKGROUND: Reductions in cholinergic function occur in Alzheimer disease (AD) and dementia with Lewy bodies and correlate with cognitive decline. However, whether such alterations appear in early-stage disease is unclear. OBJECTIVE: To examine the timing of cholinergic deficits in AD and dementia with Lewy bodies. METHODS: Autopsy series of 89 patients with AD and 50 patients with the Lewy body variant of AD (LBV). Stage of disease was stratified according to results of the last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. We analyzed choline acetyltransferase (ChAT) activity in the midfrontal, superior temporal, and inferior parietal cortices. RESULTS: Although compared with a normal control group ChAT activity was decreased in the AD and LBV cohorts, ChAT activity reduction for the LBV cohort was much greater. Moreover, although the decline in ChAT activity in the AD cohort compared with the normal control group was significant only for patients in later stages of the illness, the decline in the LBV cohort was significant for those who died with mild-stage disease. When less impaired patients in each cohort (MMSE, > or = 10) underwent separate analysis, the relationship of ChAT activity with the MMSE score was strong and significant for the LBV cohort alone. CONCLUSIONS: Although cholinergic deficits are seen in both AD and LBV, loss of ChAT activity is less severe and occurs later in the clinical course of AD. Conversely, in LBV, loss of ChAT activity is already prominent in the earliest stages of the illness, suggesting that cholinergic replacement therapy may be more effective in LBV than in AD, especially in mild-stage disease.     

Prodromal autonomic symptoms and signs in Parkinson's disease and dementia with Lewy bodies

Pathologic staging systems suggest that autonomic dysfunction may be an early manifestation of Parkinson's disease and dementia with Lewy bodies. However, direct evidence is limited, and no prospective studies have measured when autonomic dysfunction starts before disease. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder are at very high risk of developing neurodegenerative synucleinopathy, providing an opportunity to directly observe the development of autonomic dysfunction from prodromal stages of neurodegeneration. Patients with idiopathic REM sleep behavior disorder were followed annually in a prospective cohort that was established in 2004. Urinary, orthostatic, erectile, and constipation symptoms and systolic blood pressure drop from lying to standing were assessed annually. Patients who eventually developed defined synucleinopathy were compared with age‐matched controls. The evolution of autonomic measures was assessed with regression analysis to determine when markers first deviated from control values. Sensitivity and specificity of autonomic markers for identification of prodromal disease were calculated. Of 91 patients, 32 developed disease. In prodromal stages, there was substantial autonomic dysfunction observable at least 5 years before diagnosis. On regression analysis, autonomic dysfunction appeared to progress slowly over prodromal periods. The estimated onset of autonomic dysfunction ranged from 11 years to 20 years, and systolic drop (20.4 years) and constipation (15.3 years) had the earliest estimates. Systolic drop, erectile dysfunction, and constipation could identify disease up to 5 years before diagnosis with sensitivity ranging from 50% to 90%. By directly observing development of neurodegenerative synucleinopathy, we confirmed that autonomic dysfunction can occur early in neurodegenerative synucleinopathy, even as long as 20 years before defined disease. © 2013 Movement Disorder Society