PubMed Health⌕ Search

Biomedical subjects

James E Galvin

Publications and source records attributed to James E Galvin.

17 recordsLinked to original sources
PubMed2025

Caregiver experiences after the death of a person with dementia with Lewy bodies: A mixed-methods analysis.

BackgroundDementia with Lewy bodies (DLB) is a common degenerative dementia, but no studies investigate bereaved caregiver experiences.ObjectiveTo investigate the experiences of caregivers three months after the death of persons with DLB using a mixed-methods approach.MethodsDyads of individuals with moderate-advanced DLB and their primary informal caregivers were followed prospectively every 6 months until the person with DLB died. Caregivers completed a study visit with questionnaires and a semi-structured interview ∼3 months later. Spearman correlation coefficients and Wilcoxon rank-sum tests evaluated the relationships of post-death measures with pre-death patient and caregiver variables. Thematic analysis was used to analyze the interviews.ResultsSeventy-three caregivers completed visits (mean 3.5 months post-death). Most of the caregivers were women (82.2%) and spouses (76.7%) or adult children (17.8%). Over 40% had scores indicating risk for clinical depression. Post-death caregiver experiences (depression, quality of life, grief, resilience) correlated with pre-death caregiver experiences. Post-death experiences did not associate with patient characteristics, disease-related symptoms, or healthcare services used in the last 6 months of life. Trajectories for caregiver measures from pre- to post-death visits varied widely. Interview themes included grief and sadness, anger, guilt and regret, relief, appreciation/gratitude, and adjusting to a new normal.ConclusionsThe finding that pre-death caregiving experiences have the strongest association with post-death experiences emphasizes the critical importance of accessible and evidence-based caregiver support before and after the death of a person with DLB. Research is needed to develop interventions for current and bereaved caregivers of individuals with DLB.Trial registration informationNCT04829656 (submitted 2021-03-22).

Caregivers↗
PubMed2006

Survival and mortality differences between dementia with Lewy bodies vs Alzheimer disease.

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.

Aged↗
PubMed2006

Validity and reliability of the AD8 informant interview in dementia.

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.

Adult↗
PubMed2006

Clinical phenotype of Parkinson disease dementia.

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.

Aged↗
PubMed2006

The muscle protein dysferlin accumulates in the Alzheimer brain.

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.

Aged, 80 and over↗
PubMed2006

Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra.

Parkinson's disease (PD) is the most common movement disorder. Major disease symptoms are due to the loss of dopaminergic (DA) neurons in substantia nigra (SN). The pathologic hallmark of PD is Lewy bodies (LBs) in the SN and the major protein in LBs is alpha-synuclein (AS). A plethora of evidence points towards the culpability of AS in the pathogenesis of PD including: (1) linkage of AS mutations to familial forms of PD, (2) triplication of the AS locus causing PD, and (3) overexpression of AS in transgenic mice and Drosophila leads to PD-like phenotypes. Studies of purified AS have revealed its ability to interact with diverse molecules including monoamines. Monoamine metabolism is associated with oxidative stress conditions that may contribute to DA-AS interactions promoting aggregation and neuronal damage. However, in order to explain the selective vulnerability of DA neurons there needs to be a link between DA metabolism and AS aggregation. Since only the DA neurons contain significant amounts of DA, this has been hypothesized to account for the selective vulnerability of SN neurons. However, DA itself may not be toxic at physiologic relevant doses, so it is probable that other DA metabolites may play a major role in AS aggregation. In this review, we discuss the role of the DA metabolite 3,4-dihydroxyphenylacetaldehyde to provide a plausible link between DA production and metabolism, AS aggregation and the pathogenesis of PD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

The alpha-synuclein mutation E46K promotes aggregation in cultured cells.

Parkinson's disease (PD) is characterized by the polymerization of wild-type (WT) or mutant alpha-synuclein (AS) into aggregates and fibrils, which are observed as Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients. However, inability to demonstrate aggregation in many cell culture systems is a major drawback for effective in vitro modeling of AS aggregation. Utilizing PCR-based cloning approach, we generated A30P, A53T, and the recently reported E46K encoding mutation in the KTKEGV repeat region of AS gene. While cloning E46K mutant, a glycine deletion mutation (E46KDeltaG) adjacent to the intended lysine mutation was serendipitously generated. Expression of mutant constructs and green fluorescent protein (GFP)-tagged mutant constructs in catecholaminergic SH-SY5Y (5Y) cells revealed 40% of AS-E46KDeltaG and 18% of AS-E46K transfected cells formed aggregates as compared to 12% in AS-A53T, 6% in AS-WT, and 2% in AS-A30P transfected cells. Western blot analysis demonstrated the formation of high molecular weight AS aggregates. Electron microscopic analysis of 5Y cells expressing the E46K and E46KDeltaG mutants demonstrated two distinct kinds of inclusions: Type I, which showed dense granular profile; and Type II, which were largely membranous vacuolar inclusions without granular material. These two inclusions are reminiscent of Lewy bodies and pale bodies observed in PD postmortem brain samples. Our results demonstrate that mutations in 4th KTKEGV repeat lead to higher propensity of aggregation of AS compared to other mutants.

Blotting, Western↗
PubMed2005

Verbal and visuospatial deficits in dementia with Lewy bodies.

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.

Aged↗
PubMed2005

Expression profiling in the aging brain: a perspective.

To evaluate molecular events associated with the aging process in animal models and human tissues, microarray analysis is performed at the regional and cellular levels to define transcriptional patterns or mosaics that may lead to better understanding of the mechanism(s) that drive senescence. In this review, we outline the experimental and analytical issues associated with high-throughput genomic analyses in aging brain and other tissues for a comprehensive evaluation of the current state of microarray analysis in aging paradigms. Ultimately, the goal of these studies is to apply functional genomics and proteomics approaches to aging research to develop new tools to assess age in cell- and tissue-specific manners in order to develop aging biomarkers for pharmacotherapeutic interventions and disease prevention.

Adult↗
PubMed2005

Neuroanatomical predictors of response to donepezil therapy in patients with dementia.

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.

Alzheimer Disease↗
PubMed2005

Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study.

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.

Aged↗
PubMed2004

Neurodegenerative diseases: pathology and the advantage of single-cell profiling.

The aggregation of neuronal proteins as inclusions is emerging as a common mechanistic theme in neurodegenerative diseases. The presence of these "disease-specific" pathologic changes in the brains of patients with neurodegenerative diseases assist pathologists in the diagnosis and characterization of dementing illnesses. However, these same inclusions may provide valuable clues toward understanding common pathologic roots and shared abnormalities in protein folding across disorders. Such an investigation will likely provide insights into disease mechanisms underlying neurodegenerative disorders characterized by abundant filamentous lesions. This review focuses on two themes: (i) Neurodegenerative disorders are characterized by shared and distinct histopathological and biochemical abnormalities, and (ii) the presence of abnormal protein aggregates may alter a gene, and hence protein expression in inclusion-bearing neurons predisposes them to dysfunction and eventual neuronal degeneration. The pathologic features of neurodegenerative diseases are first discussed followed by a rationale behind sampling mRNA species from single cells rather than from whole-brain homogenates to explore disease mechanisms.

Amyloid beta-Peptides↗
PubMedDate not supplied

Development of a population-based questionnaire to explore psychosocial determinants of screening for memory loss and Alzheimer Disease.

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.

Aged↗
PubMedDate not supplied

Cognitive change in Parkinson disease.

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.

Aged↗
PubMedDate not supplied

Expression profiling and pharmacotherapeutic development in the central nervous system.

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.

Central Nervous System↗