Alzheimer Disease: Galvin JE

Galvin JE. · No affiliation provided · J Am Med Dir Assoc. · Pubmed #19426934 No free full text.

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Galvin JE. · No affiliation provided · Neurology. · Pubmed #17846407 No free full text.

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Tarawneh R, Galvin JE. · Department of Neurology, Washington University School of Medicine, St Louis, MO 63108, USA. · Expert Rev Neurother. · Pubmed #17997699 No free full text.

Abstract: Lewy body dementia (LBD) is the second most common dementia after Alzheimer's disease (AD). LBD is characterized clinically by visual hallucinations, extrapyramidal symptoms, cognitive fluctuations and neuroleptic sensitivity. LBD and AD share many common features in pathology, genetics and biochemical alterations; however, correct clinical distinction between these disorders has prognostic and therapeutic implications. There are currently no definitive radiological or biological markers for LBD, but studies suggest that premorbid differences in cognitive domains and personality traits, differences in clinical presentation, and alterations in autonomic function and sleep may improve diagnosis. Cholinergic dysfunction plays a major role in both AD and LBD; however, dysfunction is greater in LBD. This may account for the more prominent hallucinations, and offers the possibility of a greater response to cholinesterase inhibitors in LBD. The treatment of LBD is symptomatic and is based on a limited number of clinical trials and extension of results from trials in AD. Current research is focused on the role of synuclein aggregation with possible roles for synuclein-derived peptides as aggregation inhibitors. Other approaches target amyloid, neuroinflammation, oxidative injury, proteolysis, lipid peroxidation and immunotherapies with variable results. Improved understanding of disease mechanisms may open new therapeutic avenues for LBD in the future.

Galvin JE. · Department of Neurology, Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO 63108, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17132978 No free full text.

Abstract: Parkinson disease (PD) is the most common neurodegenerative movement disorder, affecting 1 in 100 individuals over the age of 60. Dementia in the setting of PD (PDD) may be among the most debilitating symptoms associated with disease progression. Estimates of cognitive decline and dementia in PD suggest that up to 14% per year of patients over age 65 with PD will develop some cognitive impairment. Unfortunately, PDD is not well characterized and the relationship of PDD to Alzheimer disease remains unclear. PDD has been proposed as part of a spectrum with dementia with Lewy bodies, and PDD and dementia with Lewy bodies frequently coexist with Alzheimer disease. It is uncertain, however, whether there is a meaningful distinction between the different disorders. It has also been difficult to gain understanding of the interaction of motor and non-motor symptoms that affect quality of life in PD and confound cognitive and psychomotor performance. This review will examine the clinical, cognitive, neuropsychiatric features of cognitive deficits associated with PD, discuss their pathologic basis and propose avenues for future research.

Galvin JE, Ginsberg SD. · Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108,USA. · Alzheimer Dis Assoc Disord. · Pubmed #15592143 No free full text.

Abstract: Expression profiling data is available for many diverse tissues throughout the body, allowing for exciting hypothesis testing of critical concepts such as cellular development, differentiation, normative function, and disease pathogenesis. The central nervous system is an ideal structure to evaluate relationships between functional genomics and expression data. Recent developments in gene array technologies, specifically cDNA microarray platforms, have made it easier to try to understand the multiplicity of gene alterations that occur within the brains of animal models and postmortem human tissues. However, unlike structures have one principal cell type, the brain contains diverse populations of phenotypically distinct cell types. A goal of modern molecular and cellular neuroscience is to assay gene expression from homogeneous populations of cells within a defined region without potential contamination by expression profiles of adjacent neuronal subtypes and non-neuronal cells. This is a difficult task that demands a multidisciplinary approach that is highlighted in this review within the context of neurodegenerative pathology.

Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ. · University of California, San Diego, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #18695053 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

Csernansky JG, Wang L, Miller JP, Galvin JE, Morris JC. · Alzheimer's Disease Research Center, and Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA. · Arch Neurol. · Pubmed #16286546 links to  free full text

Abstract: BACKGROUND: Patients with dementia of the Alzheimer type (DAT) respond variably to treatment with acetylcholinesterase inhibitors. OBJECTIVE: To determine whether measures of hippocampal volume and shape predict the response to donepezil in patients with DAT. DESIGN: T1-weighted, magnetic resonance images were obtained from patients with DAT, who subsequently underwent treatment with donepezil. Brain-mapping algorithms were used to quantify hippocampal volume and shape, and growth curves were used to estimate clinical outcome. SETTING: A referral outpatient center specializing in treatment of dementia. PATIENTS: Thirty-seven patients with very mild or mild DAT received donepezil therapy for up to 4 weeks before magnetic resonance imaging and for 24 to 96 weeks after magnetic resonance imaging. INTERVENTION: Donepezil, 10 mg/d. MAIN OUTCOME MEASURE: Rate of change in the cognitive portion of the Alzheimer's Disease Assessment Scale total scores. RESULTS: Smaller hippocampal volume and inward variation of the lateral and inferomedial portions of the hippocampal surface were correlated with a poorer response to donepezil therapy. CONCLUSIONS: Measures of hippocampal volume and surface variation can be used to predict the response of patients with DAT to the acetylcholinesterase inhibitor donepezil.

Johnson DK, Storandt M, Morris JC, Langford ZD, Galvin JE. · Alzheimer Disease Research Center, Washington University, St. Louis, MO 63108, USA. · Neurology. · Pubmed #19029518 No free full text.

Abstract: OBJECTIVE: To re-examine proposed models of cognitive test performance that concluded separate factor structures were required for people with Alzheimer disease (AD) and older adults without dementia. METHODS: Five models of cognitive test performance were compared using multistep confirmatory factor analysis in 115 individuals with autopsy-confirmed AD and 191 research participants without clinical dementia from longitudinal studies at the Washington University AD Research Center. The models were then cross-validated using independent samples of 323 people with clinically diagnosed dementia of the Alzheimer type and 212 cognitively healthy older adults. RESULTS: After controlling for Alzheimer-specific changes in episodic memory, performance on the battery of tests used here was best represented in people both with and without dementia by a single model of one general factor and three specific factors (verbal memory, visuospatial ability, and working memory). Performance by people with dementia was lower on the general factor than it was by those without dementia. Larger variances associated with the specific factors in the group with dementia indicated greater individual differences in the pattern of cognitive deficits in the stage of AD. CONCLUSIONS: A hybrid model of general and specific cognitive domains simplifies cognitive research by allowing direct comparison of normal aging and Alzheimer disease performance. The presence of a general factor maximizes detection of the dementia, whereas the specific factors reveal the heterogeneity of dementia's associated cognitive deficits.

Galvin JE, Fu Q, Nguyen JT, Glasheen C, Scharff DP. · Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. · Alzheimers Dement. · Pubmed #18790462 No free full text.

Abstract: BACKGROUND: There is little information about how receptive older adults are to discuss memory problems with healthcare providers. Here we test the psychosocial factors explaining older adults' intention to undergo screening for Alzheimer disease (AD). METHODS: A population-based, random-digit dialing strategy surveyed 1,039 older adults. The Behavioral Model of Health Services Use was used as a conceptual framework for a questionnaire testing constructs from several behavioral theories. Structural equation modeling assessed the relationship of latent variables to each construct with goodness-of-fit indices. RESULTS: The study had an 82% response rate and 72% completer rate. The respondents' mean age was 62.7 +/- 10.2 years (range, 50 to 97 years). The sample was 67% women, 86% were white, and less than 40% had personal experience with AD. Respondents were nondemented (Short Blessed scores, 1.7 +/- 2.2). Predictors of intention to screen included perceived benefits (gamma = .35), knowledge of dementia (gamma = .26), self-efficacy (gamma = .23), preventive health behaviors (gamma = .17), and perceived susceptibility (gamma = .14). Knowledge was positively correlated with perceived benefits (phi = .29) and susceptibility (phi = .20). Preventive behaviors (phi = .20) were positively correlated with perceived benefits. Self-efficacy correlated positively with preventive behaviors (phi = .24) and perceived benefits (phi = .37) and negatively with perceived susceptibility (phi = -.11). Goodness-of-fit indices suggested a good fit of this model (root mean square error of approximation, .037; comparative fit index, 0.98; relative fit index; .96). DISCUSSION: Older adults who have knowledge of dementia and perceive benefit from diagnosis and treatment are more likely to exhibit willingness and confidence to be tested for cognitive problems. Individuals with high self-efficacy, perceived susceptibility, and positive preventive health behaviors are also more likely to exhibit intention. These constructs can now be used to develop interventions to evaluate cognitive health in the elderly.

Galvin JE, Meuser TM, Coats MA, Bakal DA, Morris JC. · Alzheimer Disease Research Center, Washington University School of Medicine, 4488 ForestPark, Suite 130, St. Louis, MO 63108, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18695592 No free full text.

Abstract: The Clinical Dementia Rating (CDR) is a common rating system used in clinical trials and longitudinal research projects to rate the presence and severity of cognitive problems in Alzheimer disease and related disorders. The interview process requires training and can be time-consuming. Here, we describe the validity, reliability, and discriminative ability of a computer-generated CDR using a personal digital assistant format. This project used clinical data from 138 archival and live evaluations (patient and informant interviews) collected for research purposes at Washington University to develop and test a software-based system for the administration and automatic scoring of the CDR. The system was programmed for use on a hand-held computer via the Palm Operating System. We developed domain-specific algorithms to quantify and translate clinical scoring decisions for the 3 cognitive (Memory, Orientation, Judgment and Problem Solving) and the 3 functional (Community Affairs, Home and Hobbies, Personal Care) domains of the CDR. An acceptable set of algorithms were developed using data from 104 research cases, reflecting a range of impairment levels (CDR 0 to 3) and expert scoring decisions. These algorithms were then tested for accuracy in a validation sample of 34 cases. The computer-generated CDR has excellent internal consistency (Cronbach's alpha ranging from 0.94 to 0.98) and interrater reliability (intraclass correlation coefficient ranging from 0.88 to 0.96). The computer-generated CDR showed excellent discrimination between demented and nondemented cases (Area under the curve=0.95; 95% confidence interval, 0.84-1.1). The computer-generated CDR using a Palm Operating System is easy to use, valid, and reliable. The level of agreement compares favorably to published interrater reliability data for the CDR. Software-based administration and automatic scoring of the CDR is a viable alternative to paper-based methods and may be useful in research and clinical settings, especially where electronic data management and reliability in scoring are critical.

Galvin JE, Cornblatt B, Newhouse P, Ancoli-Israel S, Wesnes K, Williamson D, Zhu Y, Sorra K, Amatniek J. · Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18317244 No free full text.

Abstract: Deficits in attention are present early in the course of Alzheimer disease (AD). Acetylcholine receptors are appealing molecular targets for intervention as cholinergic pathways are involved in the neurobiology of attention. For this reason, measures of attention were included in 2 independent, multicenter, randomized, parallel, controlled trials in subjects with AD comparing the effects of galantamine, an acetylcholinesterase inhibitor and postulated nicotinic receptor modulator, and donepezil, an acetylcholinesterase inhibitor. The attention battery of the Cognitive Drug Research computerized assessment system was used in both trials. Small magnitude, positive signals were observed for simple and choice reaction times for both compounds. Attention task performance tended to improve early for galantamine-treated subjects. A consistent temporal pattern of improvement was not observed in donepezil-treated subjects. Quantitative findings appeared more pronounced in subjects with moderate AD. Galantamine's proposed action as a nicotinic receptor modulator may bear on these findings. Improved attention may have positive effects on cognitive and functional outcomes for AD patients, although this hypothesis requires further study and validation.

Galvin JE, Malcom H, Johnson D, Morris JC. · Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA. · Neurology. · Pubmed #17536045 No free full text.

Abstract: 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.

Galvin JE, Roe CM, Morris JC. · Department of Neurology, Washington University, St Louis, Missouri 63108, USA. · Arch Neurol. · Pubmed #17502471 links to  free full text

Abstract: 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.

Galvin JE, Roe CM, Xiong C, Morris JC. · Departments of Neurology, Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park, Suite 130, St. Louis, MO 63108, USA. · Neurology. · Pubmed #17159098 No free full text.

Abstract: 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.

Williams MM, Xiong C, Morris JC, Galvin JE. · Department of Medicine, Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park, Suite 130, St. Louis, MO 63108, USA. · Neurology. · Pubmed #17159097 No free full text.

Abstract: 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.

Galvin JE, Pollack J, Morris JC. · Department of Neurology, Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA. · Neurology. · Pubmed #17101891 No free full text.

Abstract: 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.

Galvin JE, Palamand D, Strider J, Milone M, Pestronk A. · Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park, Suite 130, St Louis, MO 63108, USA. · Acta Neuropathol. · Pubmed #17024495 links to  free full text

Abstract: 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.

Galvin JE, Scharff DP, Glasheen C, Fu Q. · Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16917189 No free full text.

Abstract: Alzheimer disease research has focused on detecting the earliest signs of cognitive decline and efforts are ongoing to develop biomarkers and cognitive measures that reliably distinguish between nondemented and demented individuals. However, little is known about factors that may directly or indirectly influence screening behavior of older community-dwelling adults. We describe an iterative process for the development and formative evaluation of a questionnaire about dementia knowledge and screening behaviors in older adults to understand the psychosocial factors underlying intention to obtain dementia screening to profile individuals manifesting intention to undergo dementia screening compared to those who will not. The Behavioral Model of Health Services Use was used as a conceptual framework for a questionnaire with constructs from the Health Belief Model, Theory of Reasoned Action and Self-Efficacy. After pretesting, we used a random dialing strategy to test our questionnaire on a final sample of 1024 older Missourians. Internal consistency and construct validity were examined. Pretesting identified several potential problems that were improved with rewording. Cronbach alpha was greater than 0.6 (range 0.62 to 0.92) in all but one construct testing dementia knowledge, suggesting good to excellent internal consistency. Convergent (construct) validity was assessed using confirmatory factor analysis. All constructs but 3 demonstrated good validity. Addressing these issues will allow researchers to identify unique characteristics based on age, race, sex, socioeconomic differences and geographic location, and characterize barriers to screening programs to more effectively develop targeted community-based interventions.

Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC. · Eli Lilly and Company, Indianapolis, IN 46085, USA. · Neurology. · Pubmed #16505324 No free full text.

Abstract: LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta.

Johnson DK, Morris JC, Galvin JE. · Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA. · Neurology. · Pubmed #16247050 No free full text.

Abstract: OBJECTIVE: To investigate the cognitive decline in dementia with Lewy bodies (DLBs) and characterize the contribution of Lewy bodies (LBs) to cognitive impairment in the presence of concurrent Alzheimer disease (AD). METHODS: Cognitive deficits and rates of progression attributable to DLB and AD neuropathology were investigated in three groups of participants from the longitudinal cohort of the Alzheimer Disease Research Center at Washington University with autopsy-confirmed diagnoses of pure DLB (n = 9), mixed DLB/AD (n = 57), and pure AD (n = 66). Factor analysis was used to recover latent constructs in a comprehensive psychometric test battery, analysis of variance was used to test group differences on the observed dimensions, and random effects models were used to test longitudinal rates of cognitive decline. RESULTS: Patients with AD pathology performed worse on the verbal memory dimension. Patients with LB pathology performed worse on the visuospatial dimension. Combined pathology affected visuospatial performance but not verbal memory. The rate of cognitive decline in the DLB, DLB/AD combined, and the pure AD groups was equivalent. CONCLUSIONS: The comorbid presence of DLB and AD alters the cognitive presentation of visuospatial deficits in dementia but does not alter dementia progression. Both visuospatial and verbal abilities declined at similar rates across the three patient groups. DLB diagnosis may be improved, particularly when there is comorbid AD, by using domain-specific testing.

Galvin JE, Roe CM, Powlishta KK, Coats MA, Muich SJ, Grant E, Miller JP, Storandt M, Morris JC. · Department of Neurology, Alzheimer Disease Research Center, Washington University, St. Louis, MO 63108, USA. · Neurology. · Pubmed #16116116 No free full text.

Abstract: BACKGROUND: Brief measures that accurately discriminate normal cognitive aging from very mild dementia are lacking. Cognitive tests often are insensitive to very mild dementia. Informant-based measures may be more sensitive in detecting early dementia. OBJECTIVE: To identify informant-reported clinical variables that differentiate cognitively normal individuals from those with very mild dementia. METHODS: A 55-item battery of informant queries regarding an individual's cognitive status was derived from a semistructured interview and a consensus panel of dementia experts. The battery was evaluated with informants for 189 consecutive participants of a longitudinal study of memory and aging and compared with an independently obtained Clinical Dementia Rating (CDR) score for the participant. Multiple regression and receiver operator characteristic curves assessed subsets of the items to discriminate between CDR 0 (no dementia) and CDR 0.5 (very mild dementia). RESULTS: The final version (AD8) querying memory, orientation, judgment, and function was administered to an additional sample of 112 CDR 0 and 68 CDR 0.5 participants. Using a cut-off of two items endorsed, the area under the curve was 0.834, suggesting good to excellent discrimination, sensitivity was 74%, and specificity was 86% (prevalence of 0.38 for very mild dementia). Inclusion of 56 additional individuals with mild to severe dementia (increasing dementia prevalence to 0.53) increased sensitivity to 85%. CONCLUSIONS: The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

Galvin JE, Powlishta KK, Wilkins K, McKeel DW, Xiong C, Grant E, Storandt M, Morris JC. · Department of Neurology, Alzheimer's Disease Research Center, School of Medicine, Washington University, St Louis, MO 63108, USA. · Arch Neurol. · Pubmed #15883263 links to  free full text

Abstract: BACKGROUND: To understand the earliest signs of cognitive decline caused by Alzheimer disease (AD) and other illnesses causing dementia, information is needed from well-characterized individuals without dementia studied longitudinally until autopsy. OBJECTIVE: To determine clinical and cognitive features associated with the development of AD or other dementias in older adults. DESIGN: Longitudinal study of memory and aging. SETTING: Alzheimer's Disease Research Center, St Louis, Mo. MAIN OUTCOME MEASURES: Clinical Dementia Rating, its sum of boxes, and neuropathologic diagnosis of dementia. PARTICIPANTS: Eighty control participants who eventually came to autopsy. RESULTS: Individuals who did not develop dementia showed stable cognitive performance. Entry predictors of dementia were age, deficits in problem solving as well as memory, slowed psychomotor performance, and depressive features. Minimal cognitive decline occurred prior to dementia diagnosis, after which sharp decline was noted. Even individuals who were minimally cognitively impaired (Clinical Dementia Rating = 0.5) typically had neuropathologic AD at autopsy. Histopathologic AD also was present in 34% of individuals who did not have dementia at death; these individuals without dementia showed an absence of practice effects on cognitive testing. CONCLUSIONS: Increased age, depressive features, and even minimal cognitive impairment, as determined clinically by Clinical Dementia Rating sum of boxes and by slowed psychomotor performance, identify older individuals without dementia who develop dementia. Older adults who do not develop dementia have stable cognitive performance. The absence of practice effects may denote the subset of older adults without dementia with histopathologic AD, which may reflect a preclinical stage of the illness.

Burns JM, Galvin JE, Roe CM, Morris JC, McKeel DW. · Department of Neurology, Washington University, St. Louis, MO, USA. · Neurology. · Pubmed #15851730 No free full text.

Abstract: BACKGROUND: Extrapyramidal signs (EPS) are common in Alzheimer disease (AD) and increase in prevalence as AD advances. The neuropathologic substrate responsible for EPS in AD remains to be fully characterized. METHODS: Subjects had a clinical diagnosis of AD confirmed by neuropathologic examination. EPS during life were documented by clinical methods assessing bradykinesia, cogwheel rigidity, rest tremor, and parkinsonian gait. Subjects with EPS and previous neuroleptic exposure were excluded. Twenty-eight subjects were in the EPS group and 104 subjects were without EPS. Neuron loss, alpha-synuclein (ASYN)-labeled pathology, and tau-labeled pathology in the substantia nigra were measured using semiquantitative techniques such that higher scores represented increased pathologic burden. RESULTS: Presence of nigral ASYN-labeled pathology was more common (50 vs 28.9%; p < 0.05) in the EPS group than in those without EPS. There was more nigral neuron loss in the EPS group (1.50 vs 1.11 in no-EPS group; p < 0.05). Tau-labeled burden was not different by group comparisons; however, EPS onset at later stages of dementia severity was associated with increased tau-labeled pathology (Kendall tau-B = 0.48, p < 0.01) and this association remained after controlling for dementia severity at death. Additionally, moderate to severe tau burden was more common in the subgroup with "pure AD" (definite AD without other neuropathology) with EPS (81.8%) than cases without EPS (49.0%; p < 0.05). Four subjects with EPS (14.3%) had little to no significant nigral pathologic changes. CONCLUSIONS: Clinically detected extrapyramidal signs (EPS) in Alzheimer disease (AD) are associated with substantia nigra pathology including alpha-synuclein aggregation, hyperphosphorylated tau accumulation, and neuron loss that may account for the increasing prevalence of EPS as AD progresses. In some cases, limited nigral pathology suggests extranigral factors in the clinical symptoms of EPS.

Ginsberg SD, Galvin JE, Lee VM, Rorke LB, Dickson DW, Wolfe JH, Jones MZ, Trojanowski JQ. · Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. · J Neuropathol Exp Neurol. · Pubmed #10446806 No free full text.

Abstract: To evaluate whether in vivo accumulations of heparan sulfate caused by inborn errors in the metabolism of glycosaminoglycans lead to the formation of neurofibrillary tangles and/or senile plaques, as seen in Alzheimer disease (AD), we studied postmortem brains from 9 patients, ages 1 to 42 years, with mucopolysaccharidosis (MPS). The brains of patients with Hurler's syndrome (MPS I: n = 5) and Sanfilippo's syndrome (MPS III; n = 4) as well as from caprine MPS IIID and murine MPS VII models were evaluated by thioflavine-S staining and by immunohistochemistry using antibodies directed against heparan sulfate proteoglycans, hyperphosphorylated tau, amyloid-beta peptide precursor proteins (APP), and amyloid-beta peptides (A beta [1-40], and A beta [1-42]). A two-site sandwich enzyme-linked immunosorbent assay (ELISA) was also utilized to compare levels of total soluble and insoluble A beta (1-40) and A beta (1-42) obtained from temporal cortex of MPS patients. Although no neurofibrillary tangles, senile plaques, or tau-positive lesions were detected in any of the MPS brains studied here, antibodies directed against A beta (1-40) intensely and diffusely stained the cytoplasm of cells throughout the brains of the MPS patients and the caprine MPS model. The ELISA assay also demonstrated a significant 3-fold increase in the level of soluble A beta (1-40) in the MPS brains compared with normal control brains. Thus, at least some of the metabolic defects that lead to accumulations of glycosaminoglycans in MPS also are associated with an increase in immunoreactive A beta (1-40) within the cytoplasmic compartment where they could contribute to the dysfunction and death of affected cells in these disorders, but not induce the formation of plaques and tangles. Models of MPS may enable mechanistic studies of the role A beta and glycosaminoglycans play in the amyloidosis that is a neuropathological feature of AD.