Mild cognitive impairment--no benefit from vitamin E, little from donepezil.
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Alzheimer Disease↗
Biomedical subjects
Deborah Blacker
Publications and source records attributed to Deborah Blacker.
Family-based association between Alzheimer's disease and variants in UBQLN1.
BACKGROUND: Recent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22. METHODS: We evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects). We then tested the single-nucleotide polymorphisms showing a positive result in an independently identified set of 217 sibships discordant for Alzheimer's disease (Consortium on Alzheimer's Genetics [CAG] sample; 489 subjects) and assessed the functional effect of an implicated single-nucleotide polymorphism in brain tissue from 25 patients with Alzheimer's disease and 17 controls. RESULTS: In the NIMH sample, we observed a significant association between Alzheimer's disease and various single-nucleotide polymorphisms in UBQLN1. We confirmed these associations in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer's disease. CONCLUSIONS: Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.
ATP Binding Cassette Transporter 1↗
Delusions and hallucinations are associated with worse outcome in Alzheimer disease.
BACKGROUND: Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality. OBJECTIVE: To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD. DESIGN, SETTING, AND PARTICIPANTS: A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors. MAIN OUTCOME MEASURES: Cognitive (Columbia MMSE score of < or =20/57 [approximate Folstein MMSE score of < or =10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of > or =10), institutionalization equivalent index, and death. RESULTS: During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14). CONCLUSIONS: Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.
Aged↗
Psychiatric genetics: a survey of psychiatrists' knowledge, opinions, and practice patterns.
OBJECTIVE: Knowledge about the genetic basis of psychiatric illness is growing rapidly, and psychiatrists may be called upon to incorporate this information into clinical practice. The goal of this study was to assess psychiatrists' familiarity with and attitudes toward genetic information. METHOD: We surveyed 844 participants, the majority of whom were psychiatrists, attending a continuing medical education course in the fall of 2002 and measured knowledge, opinions, and current practice patterns in regard to psychiatric genetics. RESULTS: Responses were received from 352 psychiatrists (54% of those surveyed). Most psychiatrists correctly answered fewer than half of survey items assessing general and psychiatric genetic knowledge. While 83% considered it their role to discuss genetic information with patients and families, fewer than 25% felt prepared or competent to do so. In response to hypothetical questions regarding genetic testing, a substantial proportion of psychiatrists indicated willingness to use such tests for diagnostic clarification, as well as presymptomatic and even prenatal risk prediction. The majority of respondents expressed interest in further genetics education. CONCLUSIONS: Our results suggest that psychiatrists view genetic information as clinically relevant, but have limitations in knowledge that may impact the incorporation of psychiatric genetics into clinical practice.
Attitude of Health Personnel↗
Family-based association tests for survival and times-to-onset analysis.
In this paper, we discuss family-based association test (FBATs) relating genetic data to survival and time-to-onset data. We show how the standard logrank and Wilcoxon statistics can be used with family data to develop tests of association. We prove that the FBAT-logrank approach can be identical to the proportional hazard approach discussed in Mokliatchouk et al. (2000). Further, using simulation studies, we compare the power of the logrank, Wilcoxon and an approach developed for censored exponential data (Euro J Hum Gen 2001; 9:301-306). Based on the results of the simulation study, we suggest rules of thumb about which statistics to use in a given situation. An application of all three tests to an Alzheimer study illustrates the practical relevance of our discussion.
Age of Onset↗
Medial temporal lobe function and structure in mild cognitive impairment.
Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognition of stimuli afterward. MTL regions of interest were identified from each individual's structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.
Aged↗
A QTL genome scan of the metabolic syndrome and its component traits.
BACKGROUND: Because high blood pressure, altered lipid levels, obesity, and diabetes so frequently occur together, they are sometimes collectively referred to as the metabolic syndrome. While there have been many studies of each metabolic syndrome trait separately, few studies have attempted to analyze them combined, i.e., as one composite variable, in quantitative trait linkage or association analysis. We used genotype and phenotype data from the Framingham Heart Study to perform a full-genome scan for quantitative trait loci underlying the metabolic syndrome. RESULTS: Heritability estimates for all of the covariate-adjusted and age- and gender-standardized individual traits, and the composite metabolic syndrome trait, were all fairly high (0.39-0.62), and the composite trait was among the highest at 0.61. The composite trait yielded no regions with suggestive linkage by Lander and Kruglyak's criteria, although there were several noteworthy regions for individual traits, some of which were also observed for the composite variable. CONCLUSION: Despite its high heritability, the composite metabolic syndrome trait variable did not increase the power to detect or localize linkage peaks in this sample. However, this strategy and related methods of combining correlated individual traits deserve further investigation, particularly in settings with complex causal pathways.
Adult↗
Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin.
Alpha-2-Macroglobulin (A2M) is a highly plausible candidate gene for Alzheimer's disease (AD) in a region of chromosome 12 that has numerous independent reports of genetic linkage. We previously reported that a 5 bp deletion in A2M was associated with AD in a subset of the National Institute of Health (NIMH) Genetics Initiative AD family sample. Efforts to replicate this association finding in case - control samples have been largely negative, while those in family samples have been more positive. We hypothesized that variable findings regarding this deletion, along with variable reports of association with V1000I, another polymorphism in the gene, result from linkage disequilibrium in the area as well as ascertainment differences between family-based and case-control studies. Thus, we resequenced the A2M locus to identify novel polymorphisms to test for genetic association with AD. We identified seven novel polymorphisms and tested them in the full NIMH sample of 1439 individuals in 437 families. We found significant genetic association of the 5 bp deletion and two novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remain significantly associated with AD even after correction for multiple testing. Taken together, these findings, and the positive reports in other family-based studies, continue to support a potential role for A2M or a nearby gene in AD. However, the negative case - control studies suggest that any underlying pathogenic polymorphisms have a modest effect, and may operate primarily among individuals with a family history of AD.
Aged↗
Results of a high-resolution genome screen of 437 Alzheimer's disease families.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.
Aged↗
Analysis of metabolic syndrome phenotypes in Framingham Heart Study families from Genetic Analysis Workshop 13.
Twelve teams of investigators constituted a group which analyzed phenotypes related to metabolic syndrome, making use of the available longitudinal measurements from the family component of the Framingham Heart Study or the simulated data, as distributed by Genetic Analysis Workshop 13 (GAW13). Body mass index, obesity, lipid abnormalities, glucose, or combinations of these traits were analyzed by this group. A wide variety of approaches were taken to construct phenotypes from the longitudinal measurements, including considering single or multiple cross-sectional time points, single ages, minimum values, maximum values, means, other lifetime values, ever/never dichotomy, or age at onset of some threshold value. Approaches also differed in the family structures utilized (sib pairs to full extended pedigrees), the genetic data considered (two-point or multipoint), and the statistics calculated (model-free and parametric), and led to a diverse set of analyses being performed. Inferences were made about heritability, and attempts were made to map underlying genes. Over 40 genome-wide linkage analyses were conducted. Despite the broad range of approaches, several regions of the genome were repeatedly identified across multiple analyses.
Cardiovascular Diseases↗
Hypothyroidism and hyperthyroidism in anxiety disorders revisited: new data and literature review.
BACKGROUND: The need for thyroid screening of patients presenting with panic disorder (PD), social phobia (SP) or generalized anxiety disorder (GAD) remains uncertain. METHODS: We examined thyroid histories and serum testing in 169 patients, 92 with PD, 48 with SP, and 29 with GAD. Combined prevalence rates of hyperthyroidism and hypothyroidism were compared with expected rates (2.7%) derived from the population based Whickham Survey. Data from previously published studies were also compared with these expected rates. RESULTS: In our sample, only 2/169 patients had thyroid dysfunction detected by serum testing, but 5/169 [1/92 (1%) with PD, 1/48 (2%) with SP, and 3/29 (10%) with GAD], all currently euthyroid, reported a history of thyroid disease. The rates were statistically significant only for GAD (10.4%; z = 2.56, p = 0.01). However, combining prior PD studies that examined both thyroid history and test results with our data also suggests significantly elevated rates of thyroid dysfunction (6.5%; z = 4.69, p < 0.0001). LIMITATIONS: As with previous data, the 95% confidence interval for our findings is broad, reflecting the instability of low rates of illness in relatively small samples. Further, methods for obtaining thyroid histories and tests were not uniform. CONCLUSIONS: Despite relatively low yields on serum testing, lifetime prevalence of thyroid dysfunction does appear elevated for GAD and PD, with minimal data addressing this issue for SP. The data support the need to query GAD and PD patients regarding thyroid history and perform serum testing in those without prior testing.
Adolescent↗