Faculty Bibliography

OBJECTIVE: To identify personality traits that distinguish dementia with Lewy bodies (DLB) from Alzheimer disease (AD). METHODS: We examined 290 participants enrolled in a longitudinal study (nondemented control = 34, DLB = 128, AD = 128) followed to autopsy. As part of the annual interview with the collateral source, the clinician asked about specific changes in personality, interests, and drives based on items from the Blessed Dementia Scale (BDS). Statistical analysis was performed using chi(2) and Fisher exact tests. Factor analysis was performed to determine underlying structure and receiver operating characteristic curves assessed the ability for each of three derived factors to discriminate DLB from AD. RESULTS: The sample was evaluated for a mean of 4.8 visits (range 1 to 14) with a mean age of 77.6 +/- 9.9 years. The participants' cognitive status ranged from nondemented (Clinical Dementia Rating [CDR] 0) through all stages of dementia (CDR > or = 0.5). Personality traits that distinguished DLB included diminished emotional responsiveness (p = 0.004), relinquishing hobbies (p = 0.01), growing apathy (p = 0.03), and purposeless hyperactivity (p = 0.003). Factor analyses of the BDS revealed a PASSIVE factor (diminished emotional responsiveness, relinquished hobbies, growing apathy, and purposeless hyperactivity) explaining 10.4% of variance and that DLB was more likely to manifest these personality traits than AD (p = 0.001). The PASSIVE factor discriminated DLB from AD (area under the curve = 0.61, 95% CI: 0.54 to 0.68, p = 0.006). Any change in personality is associated with the presence of visual hallucinations. CONCLUSIONS: Our results suggest that incorporating a brief, simple inventory of personality traits may improve the identification of individuals with dementia with Lewy bodies

OBJECTIVE: To test the ability of patients to rate their own cognitive ability using the AD8 compared with informant and clinician ratings of cognitive status. DESIGN, SETTING, AND PATIENTS: The AD8 was administered to 325 consecutive participant-informant dyads enrolled in a longitudinal study at Washington University School of Medicine between April 4, 2005, and December 15, 2005. The number of AD8 items endorsed by the participant was compared with informant answers and an independently derived Clinical Dementia Rating. MAIN OUTCOME MEASURE: Strength of association was measured with Spearman (rho) and intraclass correlation coefficients. Receiver operator characteristic curves assessed the discriminative properties of the AD8. RESULTS: The mean age of participants and informants was 72.8 years (range, 43-104 years) and 66.4 years (range, 24-101 years), respectively. The Clinical Dementia Rating was correlated with both informant (rho = 0.75, P<.001) and participant (rho = 0.34, P<.001) AD8 scores. Participants' AD8 scores had adequate agreement with informants' AD8 scores (intraclass correlation coefficient, 0.53; 95% confidence interval, 0.41-0.62) and correlated with subjective complaints of memory problems (rho = 0.47, P<.001) but not with estimates of symptom duration. The area under the receiver operator characteristic curve for the informant AD8 was 0.89 (95% confidence interval, 0.86-0.93); for the participant AD8, it was 0.78 (95% confidence interval, 0.68-0.78). CONCLUSIONS: The AD8 is a brief measure that, when completed by an informant, differentiates nondemented from demented individuals. We now demonstrate that a self-completed AD8 also differentiates nondemented from demented individuals, although the utility was better in mildly impaired individuals compared with more demented individuals. In the absence of a reliable informant, the AD8 may be asked of the participant to gain an understanding of their perception of cognitive status

OBJECTIVE: To combine the AD8, a brief informant interview, with performance measures to develop a brief screening tool to improve detection of cognitive impairment and dementia in general practice. DESIGN: The AD8 was administered to informants. Clinicians conducted independent patient evaluations and administered the Clinical Dementia Rating Scale and a 30-minute neuropsychological battery. Logistic regression was used to determine the best combination of brief tests to correctly classify patients as having no dementia, uncertain dementia, or dementia. The area under the receiver operator characteristic curve (AUC) evaluated the discriminative ability of the combined tests. PATIENTS/SETTING: Patients (n = 255) were consecutive referrals to a dementia clinic. Patients had a mean +/- SD age of 73.3 +/- 11.3 years, with 13.7 +/- 3.0 (mean +/- SD) years of education. The sample was 56% women; 77% of patients were white. Main Outcome Measure Dementia classification. RESULTS: A model combining the AD8 interview (odds ratio, 1.91; 95% confidence interval, 1.6-2.3) and the Consortium to Establish a Registry for Alzheimer Disease 10-item Word List Recall (odds ratio, 1.43; 95% confidence interval, 1.2-1.7) predicted dementia with 91.5% correct classification (AUC = 0.968; 95% confidence interval, 0.93-0.99). A cutoff of 2 or greater on the AD8 and less than 5 items remembered on the Word List Recall was sensitive (94%) and specific (82%). For cognitive impairments not meeting dementia criteria, combining AD8 (odds ratio, 2.31; 95% confidence interval, 1.3-4.0) and Word List Recall (odds ratio, 1.42; 95% confidence interval, 1.1-1.8) was most predictive (AUC = 0.91; 95% confidence interval, 0.8-1.0). Using the same cutoffs as those used for dementia gave the best combination of sensitivity (85%) and specificity (84%). CONCLUSION: Combining the AD8 interview with the Word List Recall improves the ability to detect the presence of dementia. The AD8 can be administered to an informant and, when combined with Word List Recall, is a powerful yet brief method of detecting cognitive impairment

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse 'Lewy body disorders' as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases

OBJECTIVE: To establish the validity, reliability, and discriminative properties of the AD8, a brief informant interview to detect dementia, in a clinic sample. METHODS: We evaluated 255 patient-informant dyads. We compared the number of endorsed AD8 items with an independently derived Clinical Dementia Rating (CDR) and with performance on neuropsychological tests. Construct and concurrent validity, test-retest, interrater and intermodal reliability, and internal consistency of the AD8 were determined. Receiver operator characteristic curves were used to assess the discriminative properties of the AD8. RESULTS: Concurrent validity was strong with AD8 scores correlating with the CDR (r = 0.75, 95% CI 0.63 to 0.88). Construct validity testing showed strong correlation between AD8 scores, CDR domains, and performance on neuropsychological tests. The Cronbach alpha of the AD8 was 0.84 (95% CI 0.80 to 0.87), suggesting excellent internal consistency. The AD8 demonstrated good intrarater reliability and stability (weighted kappa = 0.67, 95% CI 0.59 to 0.75). Both in-person and phone administration showed equal reliability (weighted kappa = 0.65, 95% CI 0.57 to 0.73). Interrater reliability was very good (Intraclass correlation coefficient = 0.80, 95% CI 0.55 to 0.92). The area under the curve was 0.92 (95% CI 0.88 to 0.95), suggesting excellent discrimination between nondemented individuals and those with cognitive impairment regardless of etiology. CONCLUSION: The AD8 is a brief, sensitive measure that validly and reliably differentiates between nondemented and demented individuals. It can be used as a general screening device to detect cognitive change regardless of etiology and with different types of informants

OBJECTIVE: To determine whether dementia with Lewy bodies (DLB) progresses more rapidly than Alzheimer disease (AD). METHODS: We compared 315 participants (63 with DLB and 252 with AD) enrolled in a prospective longitudinal study of memory and aging with annual clinical and cognitive assessments and followed until death. The main outcome measure was dementia progression to institutionalization and death. Neuropathologic examinations were performed on all participants in this study. Subject classification (DLB vs AD) was based on neuropathology. RESULTS: Patients with DLB had an increased risk of mortality vs patients with AD (hazard ratio [HR] 1.88, 95% CI: 1.4 to 2.5). The median survival time for DLB was 78.0 years and for AD was 84.6 years (chi(2) = 19.9, p < 0.001) with significant modification effects due to gender (HR 1.51, 95% CI: 1.0 to 2.3) and the presence of at least 1 APOE epsilon4 allele (HR 1.50, 95% CI: 1.0 to 2.2). Survival after dementia onset was also different between DLB and AD (7.3 vs 8.5 years; chi(2) = 5.4, p < 0.02). DLB cases had similar risks of institutionalization and survival in long-term care facilities to AD cases. Self-reports of depression and the presence of extrapyramidal signs were important covariates. The rate of cognitive decline as measured by psychometric performance and clinical staging methods did not differ between DLB and AD. CONCLUSIONS: Dementia with Lewy bodies (DLB) increases the risk of mortality compared with Alzheimer disease (AD), but the two groups did not differ in rate of cognitive decline. The greater risk for noncognitive disease progression for DLB compared with AD suggests clinically meaningful differences for the two disorders

Dysferlin is a transmembrane protein that is highly expressed in muscle. Dysferlin mutations cause limb-girdle dystrophy type 2B, Miyoshi myopathy and distal anterior compartment myopathy. Dysferlin has also been described in neural tissue. We studied dysferlin distribution in the brains of patients with Alzheimer disease (AD) and controls. Twelve brains, staged using the Clinical Dementia Rating were examined: 9 AD cases (mean age: 85.9 years and mean disease duration: 8.9 years), and 3 age-matched controls (mean age: 87.5 years). Dysferlin is a cytoplasmic protein in the pyramidal neurons of normal and AD brains. In addition, there were dysferlin-positive dystrophic neurites within A beta plaques in the AD brain, distinct from tau-positive neurites. Western blots of total brain protein (RIPA) and sequential extraction buffers (high salt, high salt/Triton X-100, SDS and formic acid) of increasing protein extraction strength were performed to examine solubility state. In RIPA fractions, dysferlin was seen as 230-272 kDa bands in normal and AD brains. In serial extractions, there was a shift of dysferlin from soluble phase in high salt/Triton X-100 to the more insoluble SDS fraction in AD. Dysferlin is a new protein described in the AD brain that accumulates in association with neuritic plaques. In muscle, dysferlin plays a role in the repair of muscle membrane damage. The accumulation of dysferlin in the AD brain may be related to the inability of neurons to repair damage due to A beta deposits accumulating in the AD brain

OBJECTIVE: To determine which clinical features best characterize Parkinson disease dementia (PDD), compared with Alzheimer disease (AD) and dementia with Lewy bodies (DLB), and to determine the pathologic basis for PDD. METHODS: We examined 103 participants enrolled in a longitudinal study (nondemented control = 10, PD = 42, DLB = 20, AD = 31) who were followed to autopsy using standardized protocols. We characterized the features of PDD using published criteria for AD and DLB as a framework. Statistical analysis was performed using chi(2) and Fisher exact tests, Kaplan-Meier curves, and logistic regression models. RESULTS: The sample's mean age was 74.0 years (range 53 to 91 years), and individuals were followed for a mean of 3.4 visits (range 1 to 12 visits). During longitudinal follow-up, 83% of subjects with PD developed dementia, defined as a Clinical Dementia Rating score of >or=0.5. Features that distinguished PDD from AD included cognitive fluctuations (p = 0.001), visual (p < 0.001) and auditory (p = 0.006) hallucinations, depression (p = 0.003), and sleep disturbance (p = 0.003). These PDD features were identical to those observed for DLB. The pathologic substrates for PDD included DLB (38%), AD (32%), and nigral LB alone (24%). Clinical predictors of PDD were visual hallucinations (odds ratio [OR] 21.3; 95% CI: 1.5 to 309.6) and male gender (OR 9.6; 95% CI: 1.3 to 71.4). CONCLUSIONS: Parkinson disease dementia (PDD) shares identical clinical features with dementia with Lewy bodies (DLB); both entities can be distinguished from Alzheimer disease. The presence of PDD/DLB features at any time during the course of PD is highly predictive of dementia and the presence of LB at autopsy; in particular, male gender and visual hallucinations in PD predict dementia