Douglas W. Scharre

Dementia with Lewy bodies: Reliability and validity of clinical and pathologic criteria

Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study.Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimers disease (AD) (n = 18), Parkinsons disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of >6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi squared = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement. NEUROLOGY 1996;47: 1403-1409

Cognitive and behavioral effects of quetiapine in Alzheimer Disease patients

In a prospective, open-label, 12-week pilot study in outpatients with probable Alzheimer disease (AD) with psychosis or aggressive behaviors, we used the Alzheimers Disease Assessment Scale–cognitive subscale (ADAS-cog) and the Neuropsychiatric Inventory (NPI) to evaluate the cognitive and behavioral effects of quetiapine. After receiving doses ranging from 50 to 150 mg, patients given quetiapine showed a significant decrease of delusions, aggression, and overall behaviors based on NPI scores at 6 and 12 weeks. ADAS-cog scores did not show a significant change over 12 weeks. This study provides initial evidence that quetiapine does not significantly worsen cognition in AD outpatients.

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial

IMPORTANCE Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. CONCLUSIONS AND RELEVANCE In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01584440.

Combination therapy of donepezil and vitamin E in Alzheimer disease

&NA; A retrospective chart review was performed on 130 patients from the Ohio State University Memory Disorders Clinic to examine the long‐term effects of combination therapy with donepezil and vitamin E on patients with Alzheimer disease. Subjects were included if they met National Institute of Neurological and Communicative Disorders and Stroke and Alzheimers Disease and Related Disorders Association criteria for probable Alzheimer disease, had taken at least 5 mg donepezil and at least 1000 U vitamin E daily, had at least a 1‐year follow‐up while continuing these medications, and had a Mini‐Mental State Examination score of 10–24. The Mini‐Mental State Examination was then recorded annually thereafter. These data were compared with the Consortium to Establish a Registry for Alzheimers Disease database for patients collected prior to the availability of these treatment options. Patients declined at a significantly lower rate as compared with the Consortium to Establish a Registry for Alzheimers Disease data. The long‐term combination therapy of donepezil and vitamin E appears beneficial for patients with Alzheimer disease. Future prospective studies would be needed to compare combination treatment to vitamin E and donepezil alone.

Self-administered Gerocognitive Examination (SAGE) A Brief Cognitive Assessment Instrument for Mild Cognitive Impairment (MCI) and Early Dementia

ObjectivesTo develop a self-administered cognitive assessment instrument to facilitate the screening of mild cognitive impairment (MCI) and early dementia and determine its association with gold standard clinical assessments including neuropsychologic evaluation. MethodsAdults aged above 59 years with sufficient vision and English literacy were recruited from geriatric and memory disorder clinics, educational talks, independent living facilities, senior centers, and memory screens. After Self-administered Gerocognitive Examination (SAGE) screening, subjects were randomly selected to complete a clinical evaluation, neurologic examination, neuropsychologic battery, functional assessment, and mini-mental state examination (MMSE). Subjects were identified as dementia, MCI, or normal based on standard clinical criteria and neuropsychologic testing. ResultsTwo hundred fifty-four participants took the SAGE screen and 63 subjects completed the extensive evaluation (21 normal, 21 MCI, and 21 dementia subjects). Spearman rank correlation between SAGE and neuropsychologic battery was 0.84 (0.76 for MMSE). SAGE receiver operating characteristics on the basis of clinical diagnosis showed 95% specificity (90% for MMSE) and 79% sensitivity (71% for MMSE) in detecting those with cognitive impairment from normal subjects. ConclusionsThis study suggests that SAGE is a reliable instrument for detecting cognitive impairment and compares favorably with the MMSE. The self-administered feature may promote cognitive testing by busy clinicians prompting earlier diagnosis and treatment.

Long-term effects of antidepressants on cognition in patients with Alzheimer's disease.

Purpose:  Approximately 25–40% of patients with Alzheimers disease (AD) may develop depression. Antidepressants are typically used to treat depression in this population. However, their effect on cognition has been rarely studied and the results are conflicting. In addition, the long‐term effects of antidepressants on cognition have not been studied. Therefore, the objective of the study was to evaluate the effects on cognition in patients with AD treated with antidepressants for at least 9 months.

Problem solving ability in patients with mild cognitive impairment.

Background and ObjectiveIt is important to determine which patients with mild cognitive impairment (MCI) are at risk for progression to dementia. The presence of mild impairments not restricted to the domain of memory may suggest such progression. Our goal is to determine how well a visuospatial problem solving task assessing the cumulative burden of frontal and posterior damage differentiates MCI patients from matched controls. MethodsTwenty-six patients with MCI [Clinical Dementia Rating (CDR) score of 0.5] and mini-mental state examination (MMSE) scores of at least 24/30, were compared with 20 age and education level matched controls without cognitive impairment. All patients were given the MMSE, Hopkins Verbal Learning Test (HVLT), Boston Naming Test (BNT), Rey Complex Figures copying (RCF), anagrams, and visuospatial problem solving battery (VPS). The VPS is a complex problem solving task, which we predicted would better discriminate patient groups than the relatively simpler tasks. ResultsDifferences existed between groups on most tasks, but logistic regression revealed that the VPS discriminated the 2 groups better than the other nonmemory cognitive tests. ConclusionsThe VPS, a problem solving task assessing the cumulative burden of frontal and posterior damage is more sensitive for detecting nonmemory impairments in MCI than other tasks. Future research will be needed to determine if impairment in the VPS is a sensitive predictor of progression to dementia or treatment response.

Blipped multi gradient-echo slice excitation profile imaging (bmGESEPI) for fast T*2 measurements with macroscopic B0 inhomogeneity compensation

With the rapid development of human MRI at field strengths ≥ 7 T, knowledge of T  2* relaxation times at such field strengths is needed to optimize acquisition parameters and understand relaxation mechanisms in many applications. However, standard T  2* measurements (e.g., using conventional multiecho gradient‐echo (GE) sequences) are affected by macroscopic static magnetic field (B0) inhomogeneities, which are particularly severe at high field strength. The multi‐GE slice excitation profile imaging (mGESEPI) method was developed for T  2* measurements in the presence of macroscopic B0 inhomogeneity, but it requires excessive acquisition times at field strengths ≥ 7 T. In this paper a more efficient technique, named blipped mGESEPI (bmGESEPI), is proposed. To demonstrate its advantages, T  2* maps were acquired using a conventional multiecho GE method, the mGESEPI method, and the bmGESEPI method in postmortem and in vivo human brains at 8 T. Magn Reson Med, 2006.

A pilot open-label trial of citalopram for restless activity and aberrant motor behaviors in alzheimer disease

OBJECTIVE In a prospective, open-label pilot study in probable-Alzheimer disease (AD) outpatients, the authors investigated the efficacy of citalopram to reduce restless activity and aberrant motor behaviors. METHODS Nineteen subjects were evaluated with Neuropsychiatric Inventory subscale and total scores. RESULTS There was a significant decline in aberrant motor behaviors and overall behavior problems at 4, 8, and 12 weeks. CONCLUSION This study provides initial evidence that citalopram may be effective in reducing aberrant motor behaviors in AD. However, because of the potential biases of an open-label study, these findings need to be confirmed in a larger, controlled trial.

Motor performance differentiates individuals with Lewy body dementia, Parkinson’s and Alzheimer’s disease

INTRODUCTION Differential diagnosis of dementia with Lewy bodies (DLB), Parkinsons disease with dementia (PDD), Parkinsons disease (PD) and Alzheimers disease (AD) is challenging. Comparative motor profiles of these neurodegenerative disorders may aid in earlier diagnosis but have not been extensively studied. METHODS Groups were rigorously matched by age, education, and sex. DLB/PDD participants were matched by Mini-Mental State Examination Score to individuals with AD and by Unified Parkinsons Disease Rating Scale motor scores to individuals with PD. Gait, balance, dual task walking and hand dexterity measures were compared between a combined group (n=21) of individuals with Lewy body dementia (LBD) consisting of those with DLB (n=11) and PDD (n=10) to individuals with PD (n=21) or AD (n=21). RESULTS Individuals at the same disease stage with LBD walked significantly slower with shorter stride lengths (p<0.05), demonstrated poorer balance on both the Tinetti and Berg Balance Scale, and poorer performance on dual-task and figure-of-eight walking compared to PD and AD (p<0.05 for all) groups. Upper extremity coordination on the 9-hole peg test differentiated LBD from both PD and AD and was the only motor test in which individuals with AD performed worse than those with PD. Tinetti balance subscores were significantly lower in PDD compared to DLB participants (10.4±2.3 versus 12.8±2.3; p=0.027). CONCLUSIONS Motor features distinguish individuals with LBD from those with AD and PD. Measures of gait, balance and finger dexterity provide an additional means of differentiating individuals with LBD from those with AD and PD.