Alzheimer Disease: Launer LJ

Launer LJ. · No affiliation provided · JAMA. · Pubmed #12783919 No free full text.

This publication has no abstract.

Launer LJ. · Laboratory for Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health, 7201 Wisconsin Avenue, Bethesda, MD 20892, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16917200 No free full text.

This publication has no abstract.

Launer LJ. · Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, 7201 Wisconsin Avenue, Suite 3C-309, Bethesda, MD 20892, USA. · Curr Diab Rep. · Pubmed #15663919 No free full text.

Abstract: Increasingly, data from epidemiologic studies suggest diabetes is a risk factor in old age for brain aging, including cognitive impairment and dementia. These associations may reflect a direct effect on the brain of hyperglycemia, or the effects of the diabetes-associated comorbidities of hypertension, dyslipidemia, or hyperinsulinemia. Epidemiologic data on diabetes and brain aging are reviewed. A brief overview is also given of the physiologic mechanisms supporting the epidemiologic data.

in 't Veld BA, Launer LJ, Breteler MM, Hofman A, Stricker BH. · Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. · Epidemiol Rev. · Pubmed #12762096 links to  free full text

This publication has no abstract.

Launer LJ. · Intramural Research Program, Laboratory of Epidemiology, Demography and Biometry, Neuroepidemiology Section, National Institute on Aging, 7201 Wisconsin Avenue, Gateway Building, Suite 3C-309, Bethesda, MD 20892-9205, USA. · Ageing Res Rev. · Pubmed #12039449 No free full text.

Abstract: Alzheimer's disease (AD) is the most frequent type of dementia in old age. The pathology of AD is not well understood. One hypothesis states that AD has a vascular basis. This hypothesis is controversial because AD has traditionally been studied and treated as a separate disease from vascular dementia. This article reviews the epidemiologic evidence supporting an association between AD and two major vascular risk factors-blood pressure and diabetes. Both methodologic and biologic explanations for these associations are discussed.

Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Petanceska S, Browne P, Wassar D, Johnson-Traver S, Lochhead J, Ziolkowski C. · SunHealth Research Institute, USA. · Curr Alzheimer Res. · Pubmed #15974900 No free full text.

Abstract: Cholesterol-induced production of amyloid beta (Abeta) as a putative neurotoxin in Alzheimer's disease (AD), along with epidemiological evidence, suggests that statin drugs may provide benefit in treatment of the disorder. We tested the effect of once daily atorvastatin calcium (80 mg; two 40 mg tablets) on cognitive and/or behavioral decline in patients with mild-to-moderate AD. The study was designed as a pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to study medication employing last-observation-carried-forward (LOCF) ANCOVA as the primary statistical method of assessment. Alternate statistical methods were employed to further explore the effect of atorvastatin treatment on progression of deterioration. Of the 98 individuals with mild-to-moderate AD (Mini-Mental State Examination score of 12-28) providing Informed Consent, 71 were eligible for randomization, 67 were randomized and 63 completed the 3-month visit and were statistically evaluable. The primary outcome measures were change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) performance and the Clinical Global Impression of Change (CGIC). Secondary outcome measures included the MMSE, Geriatric Depression Scale (GDS), the Neuropsychiatric Inventory (NPI) and the ADCS Activities of Daily Living inventory (ADCS-ADL). Tertiary outcome measures included levels of total circulating cholesterol, LDL and VLDL, and circulating activity of the free radical scavenger enzymes superoxide dismutase (SOD) and glutathione peroxidase (GpX). Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared to placebo, but did not elicit a difference in circulating SOD or GpX activities. The observed beneficial clinical effect reached significance for the GDS (p = 0.040) and the ADAS-cog at 6 months (p = 0.003), was all but significant for the ADAS-cog (p = 0.055) at 12 months, and was of marginal significance for the CGIC (p = 0.073) and NPI (p = 0.071) at 12 months when employing the primary statistical approach (ANCOVA with LOCF). Application of repeated measures ANCOVA statistics revealed the difference was significant for the CGIC and marginally significant for the ADAS-cog, but not significant for the other clinical indices. This evaluation indicated significant time-by-treatment interactions (altered progression) for the ADAS-cog and MMSE, but not the CGIC. Application of random intercept regression analysis revealed a significant difference for the CGIC, ADAS-cog and MMSE. Regression analysis also indicated that atorvastatin produced change in the slope of deterioration on the MMSE. Accordingly, atorvastatin therapy may be an effective treatment and may slow the progression of AD among mild-to-moderately affected patients.

Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. · Author Affiliations: Sun Health Research Institute, Sun City, AZ 85351, USA. · Arch Neurol. · Pubmed #15883262 links to  free full text

Abstract: BACKGROUND: Laboratory evidence of cholesterol-induced production of amyloid beta as a putative neurotoxin precipitating Alzheimer disease, along with epidemiological evidence, suggests that cholesterol-lowering statin drugs may favorably influence the progression of the disorder. OBJECTIVE: To determine if treatment with atorvastatin calcium affects the cognitive and/or behavioral decline in patients with mild to moderate Alzheimer disease. DESIGN: Pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40-mg tablets) or placebo using last observation carried forward analysis of covariance as the primary method of statistical assessment. PARTICIPANTS: Individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination score of 12-28) were recruited. Of the 98 participants providing informed consent, 71 were eligible for randomization, 67 were randomized, and 63 subjects completed the 3-month visit and were considered evaluable. MAIN OUTCOME MEASURES: The primary outcome measures were change in Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Global Impression of Change Scale scores. The secondary outcome measures included scores on the Mini-Mental State Examination, Geriatric Depression Scale, the Neuropsychiatric Inventory Scale, and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. The tertiary outcome measures included total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels. RESULTS: Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared with placebo. This beneficial effect reached significance for the Geriatric Depression Scale and the Alzheimer's Disease Assessment Scale-cognitive subscale at 6 months and was significant at the level of a trend for the Alzheimer's Disease Assessment Scale-cognitive subscale, Clinical Global Impression of Change Scale, and Neuropsychiatric Inventory Scale at 12 months assessed by analysis of covariance with last observation carried forward. CONCLUSION: Atorvastatin treatment may be of some clinical benefit and could be established as an effective therapy for Alzheimer disease if the current findings are substantiated by a much larger multicenter trial.

Launer LJ. · Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD 20892, USA. · Stroke. · Pubmed #19064803 No free full text.

This publication has no abstract.

Irie F, Masaki KH, Petrovitch H, Abbott RD, Ross GW, Taaffe DR, Launer LJ, White LR. · Pacific Health Research Institute, Honolulu, Hawaii, USA. · Arch Gen Psychiatry. · Pubmed #18678795 links to  free full text

Abstract: CONTEXT: The apolipoprotein E epsilon4 (APOE epsilon4) allele is a genetic risk factor for Alzheimer disease. Recently, depression has also become recognized as a risk factor for dementia. However, the possible effect of the APOE genotype on the association between depression and dementia is unexamined. OBJECTIVE: To examine the independent and combined effects of depression and APOE epsilon4 on the risk of dementia and its subtypes. DESIGN: The Honolulu-Asia Aging Study, a population-based prospective cohort study of Japanese American men. SETTINGS AND PARTICIPANTS: Depressive symptoms and presence of the APOE epsilon4 allele were assessed between March 1991 and October 1993 in 1932 cognitively healthy men aged 71 to 90 years. Incident cases of dementia were diagnosed during approximately 6 years of follow-up based on neurologic assessment at 2 repeated examinations (April 1994-April 1996 and October 1997-February 1999). MAIN OUTCOME MEASURES: Overall dementia, Alzheimer disease, and vascular dementia. RESULTS: The interaction of depression and APOE epsilon4 was statistically significant in the analytical models. Compared with men with neither APOE epsilon4 nor depression, the risk of dementia in nondepressed men with APOE epsilon4 was not significant (hazard ratio, 1.1; 95% confidence interval [CI], 0.6-1.8); however, depressed men without APOE epsilon4 had a 1.6-fold greater risk (95% CI, 0.8-3.0), whereas depressed men with APOE epsilon4 had a 7.1-fold greater risk (95% CI, 3.0-16.7) of dementia. For subtypes, we found similar increased risks of Alzheimer disease. CONCLUSIONS: The APOE epsilon4 status modifies the association between depressive symptoms and dementia in elderly men. Because individuals with depressive symptoms and the APOE epsilon4 allele had a markedly increased risk of dementia, one might be especially watchful for early signs of dementia in the older person with depression who is also positive for the APOE epsilon4 allele. Because this cohort includes only men, further investigation in women is required.

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #18334827 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate the quality of longitudinal statistical applications in published studies on Alzheimer's disease (AD). METHODS: A 21-item instrument, the Quality of Longitudinal AD Studies (QLADS), was developed by the research team (4 biostatisticians, 1 neuroepidemiologist, and 1 neurologist). All items were extensively discussed within the team for content validity. After pilot testing on 5 publications, the instrument was revised and tested for reliability with a sample of 40 published longitudinal AD studies randomly sampled from MEDLINE. RESULTS: Item-specific test-retest reliability coefficients for QLADS ranged from 0.53 to 1.00 with the associated standard error (SE) ranging from 0.02 to 0.13. The test-retest reliability for the overall score over the 21 items was high (intraclass correlation coefficient (ICC) = 0.94, 95% CI 0.90, 0.97). Item-specific inter-rater reliability coefficients for QLADS ranged from 0.46 to 1.00 with the associated SE ranging from 0.07 to 0.18. The inter-rater reliability for the overall score was also high (ICC = 0.87, 95% CI 0.77, 0.93). CONCLUSIONS: This study indicates that the quality of longitudinal statistical applications in AD publications can be reliably assessed.

Mohanty JG, Eckley DM, Williamson JD, Launer LJ, Rifkind JM. · Molecular Dynamics Section, National Institute on Aging, Baltimore, MD, USA. · Adv Exp Med Biol. · Pubmed #18290311 No free full text.

Abstract: Oxygen delivery requires that Red Blood Cells (RBCs) must be deformable to pass through the microcirculation. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormal extracellular deposition of beta-amyloid peptide (Abeta) and neuronal loss. We have analyzed RBC morphology in blood from subjects with AD and found that > 15% of the RBCs are elongated as compared to 5.9% in normal controls (p < 0.0001). To determine whether these morphology changes can be associated with the greater exposure of RBCs to AP in AD subjects, we investigated the in vitro effect of Abeta fibrils on blood. Morphological analysis of RBCs treated with Abeta1-40 or Abeta1-42 fibrils show 8.6% or 11.1% elongated cells, respectively. In contrast, only 2.9% or 1.3% of RBCs are elongated when blood is treated with buffer or mock fibrils generated from Abeta42-1. Elongated RBCs are expected to be less deformable. This prediction is consistent with our earlier studies showing impaired deformability of RBCs treated with Abeta fibrils. An additional factor previously reported by us, expected to impair the flow of RBCs through the microcirculation is their adherence to endothelial cells (ECs) when Abeta1-40 fibrils are bound to either RBCs or ECs. This factor would be more pronounced in AD subjects with elevated levels of Abeta on the vasculature. These results suggest that Abeta interactions with RBCs in AD subjects can result in impaired oxygen transport and delivery, which will have important implications for AD.

Xu Y, Valentino DJ, Scher AI, Dinov I, White LR, Thompson PM, Launer LJ, Toga AW. · Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095-1721, USA. · Neuroimage. · Pubmed #18280181 No free full text.

Abstract: Understanding the variability of the hippocampus in human brain research is essential. The effect of age on the hippocampus has been explored in several studies that have been focused on either normal aging or neural degeneration. Shape analysis of magnetic resonance imaging (MRI) provides morphological measures for brain structures. This study further investigates the age effects on hippocampal morphology in three groups (104 normal controls, 24 Alzheimer's disease (AD) and 14 vascular dementia (VaD) patients). By utilizing a parametric shape analysis of hippocampal MRI scans, each individual distance map is generated and analyzed statistically. Specifically, after eliminating similarity parameters (rotation, translation, and scaling) effects for each hippocampus, an individual distance map is generated from parametric hippocampal surfaces and medial axes. Then statistical methods, including regression, and permutation tests, are applied to detect the differences in hippocampal distance maps and volumes under the effect of age in each group. Statistical analyses reveal that the loss of hippocampal volume and changes in shape are more significantly related to aging in the control group than in AD/VaD. The results also show that the asymmetry of hippocampus in healthy subjects is greater than that in either of the disease groups. Our study shows that 3D statistical shape analysis could enhance the understanding of age effects on local areas of hippocampi. However, the sample sizes of disease groups are relatively low; further studies with more AD/VaD data are needed.

Irie F, Fitzpatrick AL, Lopez OL, Kuller LH, Peila R, Newman AB, Launer LJ. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave, Bethesda, MD, USA. · Arch Neurol. · Pubmed #18195144 links to  free full text

Abstract: BACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes. OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD. DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors. RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95% confidence interval, 1.46-10.40). CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.

Strozyk D, Launer LJ, Adlard PA, Cherny RA, Tsatsanis A, Volitakis I, Blennow K, Petrovitch H, White LR, Bush AI. · Albert Einstein College of Medicine, Department of Neurology, Bronx, NY, USA. · Neurobiol Aging. · Pubmed #18068270 No free full text.

Abstract: Abnormal interaction of beta-amyloid 42 (Abeta42) with copper, zinc and iron induce peptide aggregation and oxidation in Alzheimer's disease (AD). However, in health, Abeta degradation is mediated by extracellular metalloproteinases, neprilysin, insulin degrading enzyme (IDE) and matrix metalloproteinases. We investigated the relationship between levels of Abeta and biological metals in CSF. We assayed CSF copper, zinc, other metals and Abeta42 in ventricular autopsy samples of Japanese American men (N=131) from the population-based Honolulu Asia Aging Study. There was a significant inverse correlation of CSF Abeta42 with copper, zinc, iron, manganese and chromium. The association was particularly strong in the subgroup with high levels of both zinc and copper. Selenium and aluminum levels were not associated to CSF Abeta42. In vitro, the degradation of synthetic Abeta substrate added to CSF was markedly accelerated by low levels (2microM) of exogenous zinc and copper. While excessive interaction with copper and zinc may induce neocortical Abeta precipitation in AD, soluble Abeta degradation is normally promoted by physiological copper and zinc concentrations.

Laurin D, Masaki KH, White LR, Launer LJ. · Laval University Geriatrics Research Unit, Centre de recherche du CHA, and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada. · Circulation. · Pubmed #17967779 links to  free full text

Abstract: BACKGROUND: Measurement of the ankle-to-brachial index (ABI) is a noninvasive test to assess peripheral arterial disease. A low ABI is a strong correlate of cardiovascular disease and subsequent mortality. Evidence indicates the existence of vascular components in the pathogenesis of dementia. Here, we examine the association of ABI with dementia and subtypes. METHODS AND RESULTS: Data are from the Honolulu-Asia Aging Study (HAAS), a prospective community-based study of 3734 Japanese American men 71 to 93 years of age at baseline in 1991 to 1993. The analysis included 2588 men who were free of dementia at the first assessment, had an ABI measure, and were examined up to 2 more times for dementia between 1994 and 1999. The sample included 240 incident cases of dementia (144 of Alzheimer's disease, 46 of vascular dementia, and 50 of dementia of other causes). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from Cox proportional-hazards models with age as the time scale after adjustment for education, year of birth, high blood pressure, body mass index, diabetes mellitus, cholesterol concentration, smoking status, alcohol consumption, and apolipoprotein E epsilon4 allele. A low ABI was associated with an increased risk of dementia and vascular dementia (HR, 1.66; 95% CI, 1.16 to 2.37; and HR, 2.25; 95% CI, 1.07 to 4.73, respectively). ABI was weakly associated with Alzheimer's disease (HR, 1.57; 95% CI, 0.98 to 2.53), particularly in the apolipoprotein E epsilon4 carriers (HR, 1.43; 95% CI, 1.02 to 1.96). CONCLUSIONS: These results suggest that ABI, a measure of atherosclerosis, is associated with the incidence of total dementia, vascular dementia, and Alzheimer's disease in carriers of the apolipoprotein E epsilon4 allele.

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Bergmann KR, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #17878738 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate statistical applications in publications on Alzheimer's disease (AD). METHODS: Three instruments/checklists were developed: Assessment of Statistical Reporting (ASR; 44 items), Survey of Statistical Designs (SSD; 10 items), and Survey of Statistical Methods (SSM; 7 items). After a pilot testing on 5 AD publications, the instruments/checklists were revised and tested for reliability with a sample of 30 AD articles and for validity with another sample of 10 AD articles from MEDLINE. RESULTS: Item-specific test-retest and interrater reliability for ASR ranged from 0.29 to 1.0 with the associated standard errors (SEs) ranging from 0.01 to 0.31. The test-retest reliability (intraclass correlation coefficient = 0.94, 95% CI: 0.88-0.97) and the interrater reliability (intraclass correlation coefficient = 0.84, 95% CI: 0.69-0.92) for the overall score of ASR were high. The correlational validity of the ASR with a published checklist was also high (r = 0.74, SE = 0.24). The item-specific test-retest reliability in SSD and SSM ranged from 0.58 to 1.00 with the associated SEs ranging from 0.01 to 0.32. The item-specific interrater reliability in SSD and SSM ranged from 0.17 to 1.00 with the associated SEs ranging from 0.01 to 0.22. CONCLUSIONS: This study suggested that it was feasible to assess statistical applications in AD publications.

de Jong FJ, Masaki K, Chen H, Remaley AT, Breteler MM, Petrovitch H, White LR, Launer LJ. · Department of Epidemiology & Biostatistics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. · Neurobiol Aging. · Pubmed #17870208 No free full text.

Abstract: Thyroid dysfunction is associated with cognitive impairment and dementia, including Alzheimer's disease (AD). It remains unclear whether thyroid dysfunction results from, or contributes to, Alzheimer pathology. We determined whether thyroid function is associated with dementia, specifically AD, and Alzheimer-type neuropathology in a prospective population-based cohort of Japanese-American men. Thyrotropin, total and free thyroxine were available in 665 men aged 71-93 years and dementia-free at baseline (1991), including 143 men who participated in an autopsy sub-study. During a mean follow-up of 4.7 (S.D.: 1.8) years, 106 men developed dementia of whom 74 had AD. Higher total and free thyroxine levels were associated with an increased risk of dementia and AD (age and sex adjusted hazard ratio (95% confidence interval) per S.D. increase in free thyroxine: 1.21 (1.04; 1.40) and 1.31 (1.14; 1.51), respectively). In the autopsied sub-sample, higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. No associations were found for thyrotropin. Our findings suggest that higher thyroxine levels are present with Alzheimer clinical disease and neuropathology.

Williamson JD, Miller ME, Bryan RN, Lazar RM, Coker LH, Johnson J, Cukierman T, Horowitz KR, Murray A, Launer LJ, Anonymous00095. · Roena B. Kulynych Center for Memory, Cognition Research, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. · Am J Cardiol. · Pubmed #17599421 No free full text.

Abstract: Type 2 diabetes mellitus and cognitive impairment are 2 of the most common chronic conditions found in persons aged > or = 60 years. Clinical studies have shown a greater prevalence of global cognitive impairment, incidence of cognitive decline, and incidence of Alzheimer disease in patients with type 2 diabetes. To date, there have been no randomized trials of the effects of long-term glycemic control on cognitive function and structural brain changes in patients with type 2 diabetes. The primary aim of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) is to test whether there is a difference in the rate of cognitive decline and structural brain change in patients with diabetes treated with standard-care guidelines compared with those treated with intensive-care guidelines. This comparison will be made in a subsample of 2,977 patients with diabetes participating in the ongoing ACCORD trial, a clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) with support from the National Institute on Aging (NIA). Data from this ACCORD substudy on the possible beneficial or adverse effects of intensive treatment on cognitive function will be obtained from a 30-minute test battery, administered at baseline and 20-month and 40-month visits. In addition, full-brain magnetic resonance imaging will be performed on 630 participants at baseline and at 40 months to assess the relation between the ACCORD treatments and structural brain changes. The general aim of ACCORD-MIND is to determine whether the intensive treatment of diabetes, a major risk factor for Alzheimer disease and vascular dementia, can reduce the early decline in cognitive function that could later evolve into more cognitively disabling conditions. This report presents the design, rationale, and methods of the ACCORD-MIND substudy.

Launer LJ, Petrovitch H, Ross GW, Markesbery W, White LR. · Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, 7201 Wisconsin Ave., 3C-309 Bethesda, MD 20892, USA. · Neurobiol Aging. · Pubmed #17466414 No free full text.

Abstract: An increasing number of studies suggest a vascular contribution to Alzheimer's disease (AD). One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration (amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles) were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment.

Scher AI, Xu Y, Korf ES, White LR, Scheltens P, Toga AW, Thompson PM, Hartley SW, Witter MP, Valentino DJ, Launer LJ. · Department of Preventive Medicine and Biometrics, Uniformed Services University, Bethesda, MD 20814, USA. · Neuroimage. · Pubmed #17434756 No free full text.

Abstract: BACKGROUND: Hippocampal atrophy--particularly of the CA1 region--may be useful as a biomarker for Alzheimer's disease (AD) or the risk for AD. The extent to which the AD hippocampus can be distinguished in vivo from changes due to normal aging or other processes that affect the hippocampus is of clinical importance and is an area of active research. In this study, we use structural imaging techniques to model hippocampal size and regional shape differences between elderly men with incident AD and a non-demented comparison group of elderly men. METHODS: Participants are Japanese-American men from the Honolulu Asia Aging Study (HAAS). The HAAS cohort has been followed since 1965. The following analysis is based on a sub-group of men who underwent MRI examination in 1994-1996. Participants were diagnosed with incident AD (n=24: age=82.5+/-4.6) or were not demented (n=102: age=83.0+/-5.9). One reader, blinded to dementia diagnosis, manually outlined the left and right hippocampal formation using published criteria. We used 3D structural shape analysis methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal diameter between the AD cases and the non-demented comparison group. RESULTS: Mean total hippocampal volume was 11.5% smaller in the AD cases than the non-demented controls (4903+/-857 mm(3) vs. 5540+/-805 mm(3)), with a similar size difference for the median left (12.0%) and median right (11.6%) hippocampus. Shape analysis showed a regional pattern of shape difference between the AD and non-demented hippocampus, more evident for the hippocampal body than the head, and the appearance of more consistent differences in the left hippocampus than the right. While assignment to a specific sub-region is not possible with this method, the surface changes primarily intersect the area of the hippocampus body containing the CA1 region (and adjacent CA2 and distal CA3), subiculum, and the dentate gyrus-hilar region.

Launer LJ. · National Institute on Aging, Bethesda, MD 20892, USA. · Curr Alzheimer Res. · Pubmed #17430237 No free full text.

Abstract: Epidemiologic studies have provided important clues about the etiology, prognosis and options for prevention and treatment of AD, and sub-clinical changes in cognition and brain structure. A brief review is given of what we have learned from epidemiologic studies of risk factors and natural history. This is followed by a discussion of how these findings could inform the design of basic research strategies that may further the translation of bench science to the clinic and public health arena.

Stewart R, White LR, Xue QL, Launer LJ. · King's College London (Institute of Psychiatry), Section of Epidemiology, England. · Arch Neurol. · Pubmed #17210816 links to  free full text

Abstract: BACKGROUND: The relationship between total cholesterol levels and dementia is unclear. OBJECTIVE: To compare the natural history of change in total cholesterol across 26 years between men who did and did not develop dementia 3 years after the last measurement. DESIGN, SETTING, AND PARTICIPANTS: In the Honolulu-Asia Aging Study, 1027 Japanese American men had total cholesterol levels assayed on 5 occasions between 1965 and 1993 and were screened for dementia on 2 occasions between 1991 and 1996. MAIN OUTCOME MEASURE: The slope of 26-year change in serum total cholesterol levels was estimated by a repeated-measures analysis and was compared between men with incident dementia (n = 56) and those without dementia (n = 971) at the end of the follow-up period. RESULTS: Cholesterol levels in men with dementia and, in particular, those with Alzheimer disease had declined at least 15 years before the diagnosis and remained lower than cholesterol levels in men without dementia throughout that period. The difference in slopes was robust to adjustment for potential confounding factors, including vascular risk factors, weight change, alcohol intake, and use of lipid-lowering agents. CONCLUSION: A decline in serum total cholesterol levels may be associated with early stages in the development of dementia.

Marlowe L, Peila R, Benke KS, Hardy J, White LR, Launer LJ, Myers A. · Laboratorie of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD 20892, USA. · Neurodegener Dis. · Pubmed #17192720 No free full text.

Abstract: BACKGROUND: Insulin-degrading enzyme (IDE) polymorphism is hypothesized to regulate insulin levels as well as processes involved in neuronal compromise found in dementia. METHODS: We examined the association of IDE haplotypes with dementia and insulin levels in a single well-characterized cohort of Japanese-American men born between 1900 and 1919 and followed since 1965. In 1991, a fasting insulin was obtained; dementia cases were ascertained in 1991 and 1994 in a multi-stage procedure, diagnoses were made according to international guidelines. Five single-nucleotide polymorphisms were genotyped and used for haplotype analysis in a sample of 179 Alzheimer's disease cases, 104 vascular dementia cases and 516 controls nested in the total cohort. RESULTS: The global test for the haplotype effect on insulin levels was significant (p < 0.0001), adjusting for age, education, apolipoprotein epsilon4 status and fasting glucose. CONCLUSION: There was no association of IDE haplotypes with the risk of dementia. This study suggests IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimer's.

Peila R, White LR, Masaki K, Petrovitch H, Launer LJ. · Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Stroke. · Pubmed #16601212 links to  free full text

Abstract: BACKGROUND AND PURPOSE: The efficacy of treating older persons for hypertension remains controversial. Although clinical trials suggest no short-term harm, or some benefits, there are little data on the effect on cognitive function of long-term antihypertensive treatment. We evaluated the risk of dementia and cognitive decline associated with duration of antihypertensive treatment. METHODS: Data are from the Honolulu Asia Aging Study on Japanese American men followed since 1965. The subjects included in this analysis were hypertensive from midlife and dementia-free in 1991 (mean age 76.7 years). In 1991, 1994 and 1997, global cognitive function was assessed with the Cognitive Abilities Screening Instrument (CASI) and dementia by a standardized examination using international criteria. The sample was grouped by treatment duration (never-treated hypertensives (NTH), <5 years, 5 to 12 years, >12 years). Normotensive subjects up to 1991 were included in the analysis as a control group. RESULTS: For each additional year of treatment there was a reduction in the risk of incident dementia (hazard ratio [HR]=0.94, 95% CI, 0.89 to 0.99). The risk for dementia in subjects with >12 years of treatment was lower compared to NTH (HR for dementia=0.40; 95% CI, 0.22 to 0.75 and for Alzheimer disease HR=0.35; 95% CI, 0.16 to 0.78) and was similar to the normotensives. Nondemented subjects with 5 to 12 years of treatment had lower yearly CASI decline compared to NTH. CONCLUSIONS: Results suggest that in hypertensive men, the duration of the antihypertensive treatment is associated with a reduced risk for dementia and cognitive decline.

Hartley SW, Scher AI, Korf ES, White LR, Launer LJ. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Neuroimage. · Pubmed #16376107 No free full text.

Abstract: As population-based epidemiologic studies may acquire images from thousands of subjects, automated image post-processing is needed. However, error in these methods may be biased and related to subject characteristics relevant to the research question. Here, we compare two automated methods of brain extraction against manually segmented images and evaluate whether method accuracy is associated with subject demographic and health characteristics. MRI data (n = 296) are from the Honolulu Asia Aging Study, a population-based study of elderly Japanese-American men. The intracranial space was manually outlined on the axial proton density sequence by a single operator. The brain was extracted automatically using BET (Brain Extraction Tool) and BSE (Brain Surface Extractor) on axial proton density images. Total intracranial volume was calculated for the manually segmented images (ticvM), the BET segmented images (ticvBET) and the BSE segmented images (ticvBSE). Mean ticvBSE was closer to that of ticvM, but ticvBET was more highly correlated with ticvM than ticvBSE. BSE had significant over (positive error) and underestimated (negative error) ticv, but net error was relatively low. BET had large positive and very low negative error. Method accuracy, measured in percent positive and negative error, varied slightly with age, head circumference, presence of the apolipoprotein eepsilon4 polymorphism, subcortical and cortical infracts and enlarged ventricles. This epidemiologic approach to the assessment of potential bias in image post-processing tasks shows both skull-stripping programs performed well in this large image dataset when compared to manually segmented images. Although method accuracy was statistically associated with some subject characteristics, the extent of the misclassification (in terms of percent of brain volume) was small.