Mary Ganguli

Analysis of genetic polymorphisms in the transforming growth factor-β1 gene and the risk of Alzheimer's disease

Abstract. Alzheimers disease (AD) is a complex disease involving several genetic and environmental components. Genetic studies have yet to identify all the genes involved in the pathogenesis of AD. Transforming growth factor-β1 (TGF-β1) is a candidate gene for AD. It is a multifunctional cytokine whose overexpression has been shown to promote the deposition of amyloid-β peptide. The goal of this study was to investigate the association of three polymorphisms in TGF-β1 with the risk of AD. Two of the polymorphisms are located in the 5 region at positions –800 (G→A) and –509 (C→T), and the third is in exon 5 at codon 263 (Thr→Ile). We screened DNA samples from 428 sporadic, late-onset patients and 421 controls by PCR-based assays. There was no statistically significant difference in genotype or allele frequency distributions between cases and controls for the –800 or codon 263 polymorphisms (P=0.38 and P=0.60, respectively). The overall genotype distribution at the –509 site was significantly different between cases and controls. (P=0.017). The frequency of the –509/TT genotype was significantly higher in AD patients than controls (P=0.015). We further tested whether this polymorphism may alter the regulation of the TGF-β1 gene using dual luciferase reporter assay. We subcloned the 5 flanking region, which contained the –509 C/T polymorphic sites, in front of the firefly luciferase reporter gene in pGL-3 basic vector and co-transfected with the pRL-CMV vector containing Renilla luciferase gene as a control for transfection efficiency in COS-1 cells. The activity of each promoter allele was directly measured by the ratio of firefly luciferase activity to Renilla luciferase activity. The –509 T allele was associated with marginally higher transcriptional activity of TGF-β compared with the –509 C allele (P=0.051). These data suggest that the –509 polymorphism of TGF-β1 may be modestly associated with the risk of AD. However, these data should be interpreted with caution as the differences associated with the –509 alleles in both the genetic association and the transfection studies were modest.

Use of Prescription Medications in an Elderly Rural Population: The Movies Project

Objective To determine the pharmacoepidemiology of prescription drug use in a rural elderly community sample, specifically the numbers and categories of medications taken and the factors associated with them. Design Cross-sectional community survey. Setting The mid-Monongahela Valley of southwestern Pennsylvania. Participants An age-stratified random sample of 1360 community-dwelling individuals, aged 65 years and older. Measures Self-reported use of prescription drugs, demographic characteristics, and use of health services. Results Nine hundred sixty-seven participants (71%) reported regularly taking at least one prescription medication and 157 (10%) reported taking five or more medications (median 2.0, range 0–13). Women took significantly more medications than men (median 2.0, range 0–13 and median 1.0, range 0–9, respectively; p = 0.01). The use of a greater number of medications was independently and statistically significantly associated with older age, hospitalization within the previous 6 months, home health care in previous year, visit to a physician within the previous year, and insurance coverage for prescription medication. Individuals older than 85 years were significantly more likely to be taking cardiovascular agents, anticoagulants, vasodilating agents, diuretics, and potassium supplements. Significantly more women than men were taking nonsteroidal antiinflammatory drugs, antidepressants, potassium supplements, and thyroid replacement medications. Conclusions Both the number and the types of prescription medications vary with age and gender. The demographic and health service use variables associated with greater medication use in the community may help define high-risk groups for polypharmacy and adverse drug reactions. Longitudinal studies are needed.

Twelve-year depressive symptom trajectories and their predictors in a community sample of older adults.

INTRODUCTIONnThe aim of this study is to understand the long-term course and outcomes of depressive symptoms among older adults in the community by examining trajectories of depressive symptoms over time and identifying profiles of depressive symptoms predicting different trajectories.nnnMETHODnWe measured depressive symptoms biennially for up to 12 years, using the modified Center for Epidemiological Studies-Depression (mCES-D) scale, in 1260 community-based adults aged 65+ years. We determined latent trajectories of total mCES-D scores over time. We identified symptom profiles based on subgroups of baseline depressive symptoms derived from factor analysis, and examined their associations with the different trajectories.nnnRESULTSnSix trajectories were identified. Two had one or no depressive symptoms at baseline and flat trajectories during follow-up. Two began with low baseline symptom scores and then diverged; female sex and functional disability were associated with future increases in depressive symptoms. Two trajectories began with high baseline scores but had different slopes: the higher trajectory was associated with medical burden, higher overall baseline score, and higher baseline scores on symptom profiles including low self-esteem, interpersonal difficulties, neurovegetative symptoms, and anhedonia. Mortality was higher among those in the higher trajectories.nnnCONCLUSIONSnIn the community at large, those with minimal depressive symptoms are more likely to experience future increases in symptoms if they are women and have functional disability. Among those with higher current symptom levels, depression is more likely to persist over time in individuals who have greater medical burden and specific depressive symptoms.

Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition.

OBJECTIVEnThe authors sought to identify patterns and associations of prescription and over-the-counter sedative-hypnotic use in an older, rural, blue-collar, community-based cohort in southwestern Pennsylvania over 10 years.nnnMETHODSnA group of 1,627 individuals age 65 and over were recruited and assessed during 1987-1989 and re-assessed during approximately biennial waves. Data included sleep medications, demographics, depressive symptoms, sleep complaints, and cognitive functioning (Mini-Mental State Exam [MMSE]).nnnRESULTSnAt Waves 1 through 5, the mean age of the cohort increased from 73.4 to 80.5 years. Use of prescription sedative-hypnotics (primarily benzodiazepines) increased from 1.8% to 3.1%, and over-the-counter sedative-hypnotic use (primarily diphenhydramine) increased from 0.4% to 7.6%. At Wave 5 (1996-1998), 8.17% of the sample reported using diphenhydramine as a sleep aid. After adjusting for age and sex, diphenhydramine use was associated with higher education and more depressive symptoms, the latter becoming nonsignificant after controlling for initial insomnia. MMSE became significantly associated with diphenhydramine use when 143 subjects with dementia were excluded from the analysis.nnnCONCLUSIONnAs the cohort aged, prescription sedative-hypnotic use remained relatively stable, whereas over-the-counter sedative use, principally diphenhydramine, increased substantially. The association of this drug with cognitive impairment in persons without dementia highlights its potential for causing adverse reactions in older adults.

Cognitive Decline and Mortality in a Community‐Based Cohort: The Monongahela Valley Independent Elders Survey

OBJECTIVES: To compare, in a longitudinal cohort study, declines in specific cognitive domains on their ability to predict time to death, in the presence and absence of dementia, and to explore an explanatory role for vascular disease.

Elders with dementia living in the community with and without caregivers: an epidemiological study.

BACKGROUNDnPrevious studies of dementia and family caregiving have focused on individuals seeking diagnosis and treatment, and have rarely been conducted in representative community samples. Identifying demented individuals participating in a community survey, we determined (a) the factors associated with demented elderly living alone; (b) the factors associated with the demented elderly having caregivers; (c) the factors associated with increased levels of burden among caregivers of persons with dementia.nnnPOPULATION AND METHODSnDuring an epidemiological survey of a mostly rural U.S. community, the authors identified 116 noninstitutionalized elderly individuals with dementia. These individuals were classified into those living alone and those living with others; both groups were further classified into those with and without identifiable family caregivers. Characteristics of both caregivers and care recipients were examined.nnnRESULTSnApproximately a third of the subjects with dementia lived alone, and only half of them had caregivers. The average age of the caregivers was 67.4 years, and 73% of them were women. Almost half of the caregivers were spouses, whereas almost a third were offspring, of the demented individuals. Over two thirds of caregivers lived with the subjects. Female caregivers were significantly younger than male caregivers. Multivariate analyses revealed that subjects with dementia who were living alone were independently and significantly more likely to be women and to have dementias of shorter duration, lesser severity, and lesser functional impairment than those living with others. Demented subjects with caregivers were more likely to have greater dementia severity, functional impairment, and cognitive impairment and more current cognitive and behavioral symptoms than those without caregivers. Demented subjects whose caregivers reported higher levels of burden were more likely to be women and to have greater dementia severity, functional impairment, and cognitive impairment and more current symptoms than those whose caregivers had no/minimal burden.nnnCONCLUSIONSnThese results draw attention to the problems of persons with dementia living alone, particularly those without caregivers. Our data also provide epidemiological confirmation of previous clinical/volunteer studies of dementia caregiving, as well as a preliminary assessment of need in the community at large. Living arrangements and caregiver issues should be taken into account when planning services for the elderly.

Engagement in Reading and Hobbies and Risk of Incident Dementia: The MoVIES Project

Objective: To examine whether there is an association between engagement in reading and hobbies and dementia risk in late life. Methods: A total of 942 members of a population-based, prospective cohort study were followed biennially to identify incident dementia cases. Cox proportional hazards models were used to estimate the risk of dementia in relation to baseline total number of activities and time commitment to reading and hobbies. Results: A lower risk for dementia was found for a greater number of activities and for a high (about 1 hour each day) compared with low (less than 30 minutes each day) weekly time commitment to hobbies, independent of covariates. Only the protective effect of hobbies remained after methods were used to minimize bias due to potential preclinical dementia. Conclusion: Engaging in hobbies for 1 or more hours every day might be protective against dementia in late life.

Sustained Benzodiazepine Use in a Community Sample of Older Adults

OBJECTIVES: To identify factors associated with sustained benzodiazepine use in older adults.

Genetic polymorphism in the cathepsin G gene and the risk of Alzheimer's disease.

Alzheimers disease (AD) is a complex disease with the possible involvement of several genes. The APOE*4 allele has been documented to be a major risk factor for sporadic late-onset AD, but it is neither necessary nor sufficient to cause the disease. Cathepsin G, a serine protease found commonly in the azurophillic granules of neutrophils, has been reported to possess some beta-secretase like properties, and thus may be involved in the processing of amyloid precursor protein (APP). Recently, an A-->G polymorphism has been reported in exon 4 of the cathepsin G gene, which changes the codon AAC ((125) Asp) to AGC ((125)Ser). In this study, we have investigated the association of this polymorphism with sporadic late-onset AD. We screened DNA samples from 464 late-onset AD cases and 310 age-matched controls. No significant association was seen between this polymorphism and AD. When the data were stratified by the APOE*4 carrier status, no significant difference was seen either. Our data show no effect of this cathepsin G polymorphism in AD. Characterization of additional polymorphisms in this gene may provide more conclusive answers.