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Biomedical subjects

E B Larson

Publications and source records attributed to E B Larson.

At least 55 records · Page 3Linked to original sources
PubMed1998

The human FE65 gene: genomic structure and an intronic biallelic polymorphism associated with sporadic dementia of the Alzheimer type.

The FE65 protein binds to the intracellular domain of the beta-amyloid precursor protein (betaPP) and may modulate the internalization of betaPP. This gene is highly expressed in regions of the brain specifically affected in dementia of the Alzheimer type (DAT). As a prelude to further investigations of the role of FE65 in the metabolism of betaPP and in the pathogenesis of DAT, we have determined the entire genomic structure and sequence of human FE65 and have discovered several polymorphisms in this gene. Human FE65 contains 14 exons ranging in size from 6 to 735 bp. All splice sites conform to consensus sequences except for the donor site of intron 10. The 5' end of FE65 mRNA was identified by rapid amplification of the cDNA 5' end and is 31 bp longer than the previously published cDNA sequence. The 5'-flanking region of this gene is TATA-less and is very GC-rich with at least five putative Sp1 binding sites. In comparison to the genomic rat FE65 sequence, the human FE65 5'-untranslated region is 134 bp longer and has an extra exon (exon 1, 86 bp). To identify mutations/polymorphisms of the coding regions of this gene, we performed blinded analysis of 457 Caucasian case-control samples from a large epidemiological study of sporadic DAT. Screening was conducted by single-strand conformation polymorphism. Four minor variants were found within the coding region, with frequencies between 0.002 and 0.015; two of the four result in amino acid substitutions. The more informative biallelic polymorphism (a trinucleotide deletion and a single base substitution) was found within intron 13 (84 bp), which interrupts two exons encoding the betaPP binding site. The frequency of the minor allele in this intron was 0.097 in DAT cases and 0.161 in controls (chi2=7.78, P=0.0054). Having at least one copy of the minor allele was associated with a decreased risk for DAT (chi2=9.20, P<0.005, odds ratio=0.49, 95% CI 0.31-0.77). Multivariate analysis showed that this association was independent of the APOE genotype. These results suggest that either FE65 itself or a closely linked gene influences the pathogenesis of sporadic DAT. The interaction of FE65 with betaPP and the association of a FE65 polymorphism with DAT lend credence to the hypothesis that the metabolism of betaPP is central to the pathogenesis of common sporadic forms of DAT.

Aged↗
PubMed1998

Wandering: a significant problem among community-residing individuals with Alzheimer's disease.

This study evaluated the frequency, predictors, and effects of wandering in a population-based sample of 193 individuals with Alzheimer's disease (AD). Although wandering occurred in subjects at all levels of cognitive impairment, analysis of variance indicated that for the group as a whole, greater frequency of wandering was associated with significantly more impairment in cognition, day-to-day functioning, and behavior. Caregiver distress also increased significantly with increased frequency of wandering. Logistic regression modeling identified functional impairment and disruptive behavior problems as the strongest independent predictors of wandering occurring within the past week. Cluster analysis revealed four characteristic groups of wanderers that represented a continuum of wandering frequency, each having a unique pattern of other behavioral disturbances. Based on this analysis, we recommend further evaluation and the development of possible treatment strategies that address the individual differences found among AD patients who wander.

Aged↗
PubMed1998

Prevalence and subtypes of dementia in a rural Chinese population.

We conducted a single-stage community-based study of dementia on all registered residents > or =65 years in age in a rural Chinese community. Neurologists conducted semistructured interviews and examined all participants; they also interviewed family members in cases where dementia was suspected. The diagnosis was made by consensus according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM-III-R). Among the 2,055 contacted individuals, 1,736 (84.5%) participated in the study and 44 ( 13 men and 31 women) were diagnosed as having dementia, including 35 (80%) with probable Alzheimer disease (AD) and 3 (7%) with vascular dementia (VsD). The rates of dementia were 0.5% for ages 65-74 years, 2.9% for ages 75-84 years, and 12.0% for ages 85-101 years. The overall rate was 2.5% for age > or =65 years. After controlling for age, neither a lack of formal education nor being a woman was a risk factor for dementia. At 2-year follow-up, 30 of the 44 demented participants had died, yielding a 2-year survival rate of 32%. The present results corroborated our previous findings of lower prevalence rates of dementia among the Chinese than among Western populations, and both genetic and sociocultural factors may have contributed to the low rates. The lack of neuroradiological imaging studies in the present study may have contributed to the finding of an unusually low rate of VsD.

Aged↗
PubMed1998

Management of Alzheimer's disease in a primary care setting.

This article covers a broad topic from the pragmatic point of view of a primary care physician. The perspective is that of a primary care physician who teaches resident physicians and students in a medical school and for almost 20 years has conducted clinical research in patient care settings, including a large Health Maintenance Organization in Seattle, Washington. This article addresses four general areas that are important for the management of dementia in primary care settings: recognition and diagnosis, treatment in the community (treatment before a person becomes permanently or semipermanently institutionalized), treatment as the disease progresses, and minimization of excess disability.

Aged↗
PubMed1998

Occupational exposures to solvents and aluminium and estimated risk of Alzheimer's disease.

OBJECTIVES: To study the role of occupational exposures to solvents and aluminium in the aetiology of Alzheimer's disease (AD). An industrial hygienist rated exposure. METHODS: 89 subjects diagnosed with probable AD were matched by age, sex, and type of informant to 89 controls. Subjects were identified from a large health maintenance organisation in Seattle, WA. A complete occupational history was obtained from spouses of cases and controls as well as from controls themselves. After the interview an industrial hygienist, blinded to case-control status, rated exposures. RESULTS: Non-significant associations were found between AD and ever having been occupationally exposed to solvents (odds ratio (OR) 1.77, 95% confidence interval (95% CI) 0.81 to 3.90) and aluminium (OR 1.46, 95% CI 0.62 to 3.42). Although an increasing risk was found with increasing number of years of exposure to solvents, there was an inverse association between exposure intensity and AD, and measures of cumulative exposure taking into account both intensity and duration of exposure were not significant. Analysis of the age at which half the cumulative exposure to solvents was achieved showed that an older age incurred a greater risk of AD than a younger age. However, the total amount of exposure carried no risk. CONCLUSIONS: The results suggest that lifetime occupational exposure to solvents and aluminium are not likely to be important risk factors for Alzheimer's disease.

Aged↗
PubMed1998

Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease.

BACKGROUND: The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-epsilon4 homozygotes have an earlier age at onset, increased amyloid burden, and decreased acetylcholine levels--findings that suggest differences in disease severity or rate of progression. Studies of genotype differences in rate of decline, however, have produced negative results that may be due to methodologic biases. The current study examined rate of decline in the largest sample of APOE-genotyped AD patients for whom longitudinal cognitive data have been reported. METHODS: Newly diagnosed patients with probable AD (n = 201) comprised four genotype groups: epsilon2/3 (n = 14), epsilon3/3 (n = 75), epsilon3/4 (n = 82), and epsilon4/4 (n = 30). The Dementia Rating Scale (DRS) was administered at baseline and then annually for 1 to 6 years (mean, 2.5 years). For each subject, a DRS slope was calculated reflecting annual rate of decline. Rate of decline as measured by DRS slope differed according to genotype, with the effect modified by DRS score (p < 0.014). At the mean DRS score observed in our sample (DRS = 105), the epsilon4/4 group had an increased rate of decline (11.9 points per year) relative to the epsilon2/3 (5.8 points per year; p < 0.003), epsilon3/3 (9.3 points per year; p < 0.076), and epsilon3/4 (9.6 points per year; p < 0.055) groups. At a lower DRS score (DRS = 80), even larger differences were observed among genotypes; the epsilon4/4 group had a increased rate of decline (22.2 points per year) relative to the epsilon2/3 (9.7 points per year; p < 0.0006), epsilon3/4 (15.8 points per year; p < 0.020), and epsilon3/3 (18.2 points per year; p < 0.173) groups. The epsilon2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105. CONCLUSIONS: APOE-epsilon4 homozygosity is associated with a faster rate of cognitive decline, whereas the epsilon2 allele slows disease progression. These findings suggest that APOE plays a mechanistic role in the progression of AD, and is not simply related to disease onset.

Age of Onset↗
PubMed1998

Exercise and activity level in Alzheimer's disease: a potential treatment focus.

This article provides information on the baseline health and physical function of 30 individuals with Alzheimer's disease (AD); describes a community-based program designed to increase balance, flexibility, strength, and endurance in these persons by the training of caregivers to facilitate and supervise exercise activity; and documents the adherence of these subjects and their caregivers to this intervention. Subjects were recruited from an ongoing, community-based Alzheimer's Disease Patient Registry, and met NINCDS-ADRDA criteria for probable or possible AD. Caregivers were family members living with the demented individuals in the community. Physical performance was measured using walking speed, functional reach, and standing balance. Health status was measured with the Medical Outcomes Study Short Form, the Sickness Impact Profile, and caregiver reports of subject's restricted activity days, bed disability days, falls, and exercise participation. Baseline data indicated that persons with AD were impaired on measures of physical performance and function, compared to published data on nondemented older adults. During a 12-wk treatment period, caregivers were taught to guide their demented charges in an individualized program of endurance activities (primarily walking), strength training, and balance and flexibility exercises. Adherence data indicated that 100% of the subjects were compliant with some exercise recommendations, and one-third completed all assigned exercises during the training period. Caregivers were able to learn and direct subjects during scheduled exercise activities. These findings indicate that the integration of exercise training into the care of persons with AD is both needed and feasible. Further research is currently underway to determine the efficacy of this approach for reducing additional physical disability in these individuals.

Activities of Daily Living↗
PubMed1997

Estrogen replacement therapy and cognitive function in postmenopausal women without dementia.

The epidemiologic evidence for an association between estrogen and cognitive function among healthy postmenopausal women remains controversial. Equivocal findings may be explained, in part, by differences in the methodologic approaches of these studies. Overall, the evidence for a positive relationship comes primarily from randomized clinical trials. These trials suggest an acute effect on specific tests of recent verbal memory and tasks incorporating concept formation and reasoning. The potential long-term effects of estrogen in slowing or delaying the age-related decline in cognitive function require further study. More data are needed to determine the effects of estrogen replacement therapy on cognitive function, independent of changes in mood and depressive symptoms. In addition, evidence suggests that progesterone may mitigate the beneficial effects of estrogen on mood. Research should be undertaken to determine the interactive effects of estrogen and progesterone on cognitive function. Lastly, there should be continued investigation by both epidemiologic and basic neuroscientific studies to further elucidate the specific cognitive domains that may respond to estrogen.

Cognition↗
PubMed1997

Long-term outcome in acute myocardial infarction patients admitted to hospitals with and without on-site cardiac catheterization facilities. MITI Investigators. Myocardial Infarction Triage and Intervention.

BACKGROUND: Previous studies have documented the strong association between availability of on-site cardiac catheterization facilities and increased use of coronary angiography in patients with acute myocardial infarction (AMI). Although these studies have shown little influence of the availability of catheterization labs on hospital mortality, no long-term follow-up has been reported. METHODS AND RESULTS: From a cohort of 12,331 AMI patients admitted to 19 Seattle area hospitals, we compared long-term outcome in 7985 patients admitted to hospitals with and 4346 patients admitted to hospitals without on-site catheterization labs. During the index hospitalization, patients admitted to hospitals with on-site catheterization were more likely to undergo coronary angiography (67.1% versus 39.3%, P<.0001), coronary angioplasty (32.5% versus 13.2%, P<.0001), or coronary bypass surgery (12.5% versus 9.5%, P<.0001). At 3-year follow-up, patients admitted to hospitals with on-site catheterization labs were more likely to undergo postdischarge angiography (19.2% versus 15.2%, P=.0001) and coronary angioplasty (11.6% versus 8.2%, P<.0001). This was associated with approximately $2500.00 per patient in higher cumulative costs. Despite this higher rate of procedure use, there was no association between admission to a hospital with on-site catheterization facilities and lower long-term mortality (multivariate hazard ratio, 1.0; 95% CI, 0.93 to 1.1., the hazard being associated with admission to hospitals with on-site catheterization facilities). CONCLUSIONS: In an urban area with unconstrained patient transfer mechanisms and high overall cardiac procedure use rates, AMI patients admitted to hospitals without on-site catheterization facilities were managed with fewer procedures during hospitalization and follow-up. This more conservative treatment approach was not associated with any observed increase in long-term mortality.

Aged↗
PubMed1997

Head injury and risk of Alzheimer's disease by apolipoprotein E genotype.

Head injury and apolipoprotein E (APOE)-epsilon 4 (e4) genotype have each been associated with increased risk of Alzheimer's disease. If APOE-e4 affects neuronal viability and branching, and if response to head injury differs in e4 patients, then the association between head injury and Alzheimer's disease may vary with the presence of the e4 allele. The authors examined this association in a case-control study conducted between 1987 and 1995 among enrollees of the Group Health Cooperative of Puget Sound, a health maintenance organization in Seattle, Washington. Proxy informants reported prior head injury with loss of consciousness for 32 of 349 patients with probable Alzheimer's disease and for 16 of 342 control subjects of similar age and sex who had been randomly selected from the same population (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.1-3.8). Elevated risk was observed among men (OR = 4.2, 95% CI 1.5-11.5) but not among women (OR = 1.1, 95% CI 0.5-2.6). No significant variation in the head injury-Alzheimer's disease risk relation by APOE-e4 genotype was found among 230 cases and 309 controls (OR = 3.1 (95% CI 0.7-14.6) for persons with at least one e4 allele and OR = 2.0 (95% CI 0.8-5.2) for those without e4). Neither age, education, race, type of proxy informant, nor duration of relationship with the proxy confounded the association. Head injury with loss of consciousness, although uncommon in this sample, was associated with increased risk of Alzheimer's disease. APOE-e4 was an independent risk factor which neither modified nor confounded the association. Susceptibility to Alzheimer's disease as conferred by APOE-e4 does not appear to increase the risk associated with head injury.

Aged↗
PubMed1997

Progression to dementia in patients with isolated memory loss.

BACKGROUND: The diagnosis of dementia requires both memory loss and at least one other type of cognitive impairment. The natural history of patients with severe memory loss but no other type of cognitive impairment is poorly understood. We studied progression to dementia in patients with isolated memory loss. METHODS: From a registry of 811 patients with cognitive complaints, 21 patients with severe isolated memory loss of unknown cause were identified and followed up for a mean of 48 months. A comparison group of 198 patients on the same register was identified with newly recognised cognitive complaints but without dementia or isolated memory loss (mean follow-up 31 months). We did a range of neuropsychological tests at intake. FINDINGS: During follow-up, 48% (n = 10) of patients with isolated memory loss-developed dementia compared with 18% (n = 36) of the comparison group. Life-table analysis showed the mean times to a diagnosis of dementia was 3.77 years (95% CI 2.99-4.56) and 5.96 years (5.60-6.31), respectively (p = 0.01). The neuropsychological tests did not predict which patients would progress to dementia. INTERPRETATION: Patients with severe isolated memory loss have an increased risk of developing dementia and should be closely followed-up.

Adult↗
PubMed1997

Counting plaques and tangles in Alzheimer's disease: concordance of technicians and pathologists.

Our primary aim is to provide a descriptive approach to the analysis of counts of plaques and tangles by different readers. We wanted to find out whether subjects with minimal training can count plaques and tangles in histological specimens of patients with Alzheimer's disease and controls. Two experienced neuropathologists trained three student helpers to recognize plaques and tangles in slides obtained from autopsy material. After training, the students and pathologists examined coded slides from patients with Alzheimer's disease and controls. Some of the slides were repeated to provide an estimate of reliability. Each reader read four fields which were averaged to obtain estimates of plaque and tangle counts. Raters are compared on four aspects of concordance: location, scale, precision and accuracy. Precision and accuracy are combined to provide an estimate of concordance. We conclude that subjects with minimal training can be taught to count plaques and tangles. Concordance with the neuropathologists was somewhat greater for tangles. This paper also provides a methodology for comparing raters.

Aged↗
PubMed1997

Bilateral field interactions, hemispheric specialization and evoked potential interhemispheric transmission time.

The interrelationship between bilateral visual field processing, hemispheric specialization and interhemispheric transmission time (IHTT) was examined in two experiments in order to test two theories regarding callosal function and lateralized visual processing. Contrary to both theoretical speculations [Braun, Neuropsychology Review, Vol. 3, pp. 321-365, 1992] and a recent report [Nowicka et al., Neuropsychologia, Vol. 34, pp. 147-151, 1996], the directional asymmetry in evoked potential measures of IHTT did not vary with task differences in indices of hemispheric specialization. IHTT was faster from right to left hemispheres regardless of visual field advantage for the task. Similarly, patterns of correlation between IHTT and bilateral field advantage did not change between verbal and spatial matching tasks, despite differences in visual field advantage. Since the latter data did not consistently support the Brown and Jeeves [Neuropsychologia, Vol. 31. pp. 1267-1281, 1993] hypothesis, an alternative hypothesis involving hemispheric asymmetries in attention rather than processing specialization was proposed.

Adult↗
PubMed1997

Depressive disorders among older residents in a Chinese rural community.

BACKGROUND: Two recent surveys of depression among Chinese elderly people sampled different populations, used different case ascertainment methods and resulted in a seven-fold difference in prevalence rates. The present study was conducted to compare prevalence rates obtained with two commonly used methods in the same population, and to examine the risk factors for depression. METHODS: The target population included all residents aged 65 years and over in a rural Chinese community. Participants were interviewed for demographic and medical information, examined by a neurologist and administered Chinese versions of the Geriatric Depression Scale-Short Form (GDS-S), the Cognitive Abilities Screening Instrument (CASI) and an Activities of Daily Living (ADL) form. Individuals who screened positive on the GDS-S were also interviewed by a psychiatrist for diagnosis according to the DSM-III-R criteria. RESULTS: Among the 1313 participants, 26% screened positive on the GDS-S and 13% were diagnosed as having a depressive disorder, including 6.1% with major depression. Individuals with depressive disorders were more likely to have poor ADL scores, lower CASI scores, and chronic physical illnesses. They were also more likely to be female, older, illiterate and without a spouse, but adding these variables did not increase the overall association with the GDS-S score. CONCLUSIONS: Depression was quite common in this Chinese rural geriatric population. The prevalence rate was twice as high when judged by depression symptomatology rather than clinical diagnosis. The critical risk factors were functional impairments, poor cognitive abilities and the presence of chronic physical illnesses.

Activities of Daily Living↗