Biomedical subjects

Lenore J Launer

Publications and source records attributed to Lenore J Launer.

At least 19 recordsLinked to original sources

PubMed2007

Twenty-six-year change in total cholesterol levels and incident dementia: the Honolulu-Asia Aging Study.

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.

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PubMed2006

A TGF-beta1 polymorphism association with dementia and neuropathologies: the HAAS.

The transforming growth factor-beta1 (TGF-beta1) is involved in post-ischemic neuronal rescue and in beta-amyloid turn-over. We hypothesized that the risk for dementia and related neuropathologies is modified by the TGF-beta1 functional genetic variants. The association of the TGF-beta1+29T-->C polymorphism with dementia was examined in a sample of 261 cases and 491 controls from the Honolulu-Asia Aging Study, including 282 subjects with autopsy data. Dementia was assessed in 1991 and 1994 by a multi-step protocol and standardized diagnostic criteria. The analysis was adjusted for demographic and vascular factors. Compared to the TT genotype, the TC and the CC genotypes were associated with a reduced risk for vascular dementia (OR(TC)=0.28, 95% confidence interval (CI): 0.1-0.9; OR(CC)=0.28, CI: 0.1-0.9), microinfarcts (OR(CC)=0.31, CI: 0.13-0.71) and cerebral amyloid angiopathy (OR(CC)=0.48, CI: 0.2-0.9). The CC genotype was associated with an increase risk of neocortical plaques (OR(CC)=4.34, CI: 1.6-11.8). These preliminary data suggest that the TGF genetic variability may be important in the risk of vascular related dementia.

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PubMed2006

Reducing the risk of dementia: efficacy of long-term treatment of hypertension.

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.

Age Factors↗

PubMed2006

Sex hormones and neuropathology in elderly men: the HAAS.

Experimental studies suggest 17-beta estradiol (E2) and testosterone (T) may have neuroprotective properties that are associated with Alzheimer's and vascular pathology. However, there are limited studies correlating steroid hormones with autopsy findings in humans. In this community-based autopsy study of elderly men (n=232) participating in the Honolulu Asia Aging Study, we found a significant decrease of neurofibrillary tangles in the highest tertile of free serum estradiol [IRR=0.43 (0.3-0.7)] after controlling for age at blood draw, interval from blood draw until death, ApoE allele, and socio-demographic health factors. Higher Free-T levels were associated with a two-fold increased risk for micro infarcts [IRR=2.2; 95% CI (1.2-4.1)]. There was no association between sex hormones and amyloid plaques or cerebral amyloid angiopathy. This community-based autopsy study suggests that peripheral levels of sex hormones are associated with neurofibrillary tangles and micro-infarcts, but not with other neuropathologic markers of brain disease in elderly men.

Aged, 80 and over↗

PubMed2006

Brain stem and cerebellar hyperintense lesions in migraine.

BACKGROUND AND PURPOSE: Migraineurs are at increased risk of cerebellar infarcts and supratentorial white matter lesions. The prevalence, frequency, and distribution of infratentorial hyperintense lesions in migraine are unknown. METHODS: Migraineurs with aura (n=161), without aura (n=134), and controls (n=140) from a population-based sample of adults (30 to 60 years of age) were evaluated with MRI. RESULTS: Infratentorial hyperintensities were identified in 13 of 295 (4.4%) migraineurs and in 1 of 140 (0.7%) controls (P=0.04). Twelve cases had hyperintensities, mostly bilaterally, in the dorsal basis pontis. Those with infratentorial hyperintensities also had supratentorial white matter lesions more often. CONCLUSIONS: We found an increased prevalence of infratentorial (mostly pontine) hyperintensities in migraineurs from the general population. This extends the knowledge about vulnerable brain regions and type of lesions in migraine brains. A hemodynamic ischemic pathogenesis is likely, but further research is needed.

Adult↗

PubMed2006

Apolipoprotein E genotype and statins affect CRP levels through independent and different mechanisms: AGES-Reykjavik Study.

OBJECTIVE: C-reactive protein (CRP), an inflammatory marker, was linked to coronary heart disease (CHD) in the Reykjavik study cohort. Recent genetic studies have shown that the apolipoprotein E (APOE) epsilon4 allele is associated with lower CRP levels. Statin treatment has also been shown to lower CRP levels. In the Age Gene/Environment Susceptibility (AGES)-Reykjavik Study, we examined the association of APOE genotypes with CRP accounting for the effect of statin treatment, previous CHD and a mid-life measurement of erythrocyte sedimentation rate (ESR), an inflammatory marker associated with risk in this cohort. METHODS AND RESULTS: The first 2296 participants (mean age 76+/-6 years, 42% men) in the AGES-Reykjavik Study were genotyped for APOE CRP concentration was measured with a high sensitivity method. A general linear model was used to evaluate the association of APOE genotype to CRP levels. The frequencies of the APOE alleles are epsilon2=0.06, epsilon3=0.78 and epsilon4=0.16. CRP levels ranged from 0.2 to 56.6 mg/L, median 1.9 mg/L. Participants carrying one or two epsilon4 alleles have significantly lower CRP levels than non-carriers and this effect was observed in a dose-dependent manner. This trend is the same in users and non-users of statin treatment. CONCLUSIONS: This study suggests that the contribution of the epsilon4 allele towards lowering CRP levels is independent and may be by a different mechanism than how statins affect inflammation.

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PubMed2006

The effect of social engagement on incident dementia: the Honolulu-Asia Aging Study.

The authors examined whether low levels of social engagement in midlife and late life were associated with the risk of incident dementia in 2,513 Japanese-American men who have been followed since 1965 as part of the Honolulu Heart Program and the Honolulu-Asia Aging Study. In 1991, assessment of dementia began; incident dementia cases (n = 222) were diagnosed in 1994 and 1997. Social engagement was assessed in midlife (1968) and late life (1991). The relation between social engagement and dementia risk was examined using Cox proportional hazards models. No level of midlife social engagement was associated with the risk of dementia. In late life, compared with participants in the highest quartile of late-life social engagement, those in the lowest quartile had a significantly increased risk of dementia (hazard ratio = 2.34, 95% confidence interval: 1.18, 4.65). However, compared with those who were in the highest quartile of social engagement at both midlife and late life, only decreased social engagement from midlife to late life was associated with an increased risk of dementia (hazard ratio = 1.87, 95% confidence interval: 1.12, 3.13). Although low social engagement in late life is associated with risk of dementia, levels of late-life social engagement may already have been modified by the dementing process and may be associated with prodromal dementia.

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PubMed2006

Migraine and MTHFR C677T genotype in a population-based sample.

OBJECTIVE: Migraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype status. METHODS: We compared adult migraineurs with aura (MA; n = 187), without aura (MO; n = 226), and nonmigraineurs (n = 1,212) from the population-based Genetic Epidemiology of Migraine study. RESULTS: Compared with the wild-type genotype, the T/T genotype was associated with increased odds of MA (odds ratio [OR], 2.05; 95% confidence interval, 1.2-3.4; p < 0.006), with a trend of increasing numbers of T alleles (OR, 1.40; 95% confidence interval, 1.1-1.8; p < 0.007). ORs were slightly attenuated after adjusting for homocysteine. INTERPRETATION: Risk of MA is associated with MTHFR C674T homozygosity, independent of other cardiovascular risk factors.

Adult↗

PubMed2006

Endogenous sex hormones, cognitive decline, and future dementia in old men.

OBJECTIVE: To estimate the association of endogenous levels of bioavailable testosterone and estradiol with risk for cognitive decline and dementia in old men. METHODS: Within the population-based, prospective Honolulu-Asia Aging Study, 2,974 men, aged 71 to 93 years, without dementia were reexamined 3 times over an average of 6 years for development of dementia and cognitive decline. Cognitive decline was measured with the Cognitive Abilities Screening Instrument. Incident dementia was diagnosed according to standard criteria. A total of 134 men experienced development of Alzheimer's disease (AD; including 40 cases with contributing cerebrovascular disease) and 44 experienced development of vascular dementia. RESULTS: Adjusting for age and other covariates, testosterone was not associated with risk for dementia (using Cox regression analyses) or cognitive decline (using random coefficient analyses). However, higher levels of estradiol were associated with risk for AD (hazard ratio per standard deviation increase, 1.25; 95% confidence interval, 1.05-1.47) and AD with cerebrovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.02-1.38). Also, compared with the lowest tertile of estradiol, men in the middle and highest tertile of estradiol had 0.24 and 0.28 points lower Cognitive Abilities Screening Instrument scores, respectively, for each year increase in age. INTERPRETATION: In old men, endogenous testosterone levels are not associated with risk for cognitive decline and AD, whereas higher estrogen levels increase risk for cognitive decline and AD.

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PubMed2006

Cerebral changes on MRI and cognitive function: the CASCADE study.

The aging, non-demented brain undergoes several physiological changes, some of which may affect cognitive function. The goal of the present study was to examine the associations between subcortical and periventricular white matter hyperintensities (WMHs), cortical and subcortical atrophy, and cognitive function (episodic memory, word fluency, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, Cardiovascular Determinants of Dementia (CASCADE), in which magnetic resonance imaging (MRI) was performed on community-dwelling individuals. The study includes 1254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4+/-3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WMHS predicted lower performance in word fluency and the Stroop test (time), and subcortical atrophy predicted lower performance in motor speed and the Stroop test (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.

Age Distribution↗

PubMed2006

Insulin-degrading enzyme haplotypes affect insulin levels but not dementia risk.

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.

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PubMed2006

Brain aging in very old men with type 2 diabetes: the Honolulu-Asia Aging Study.

OBJECTIVE: Type 2 diabetes leads to cognitive impairment and dementia, which may reflect microvascular and macrovascular complications as well as neurodegenerative processes. There are few studies on the anatomical basis for loss of cognitive function in type 2 diabetes. The objective of this study was to investigate the association between type 2 diabetes and markers of brain aging on magnetic resonance images, including infarcts, lacunes, and white matter hyperintensities as markers of vascular damage and general and hippocampal atrophy as markers of neurodegeneration in Japanese-American men born between 1900 and 1919 and followed since 1965 in the Honolulu-Asia Aging Study. RESEARCH DESIGN AND METHODS: Prevalent and incident dementia was assessed. Associations between magnetic resonance imaging markers and diabetic status were estimated with logistic regression, controlling for sociodemographic and other vascular factors. RESULTS: The prevalence of type 2 diabetes in the cohort is 38%. Subjects with type 2 diabetes had a moderately elevated risk for lacunes (odds ratio [OR] 1.6 [95% CI 1.0-2.6]) and hippocampal atrophy (1.7 [0.9-2.9]). The risk for both hippocampal atrophy and lacunes/infarcts was twice as high in subjects with compared with those without type 2 diabetes. Among the group with type 2 diabetes, those with the longest duration of diabetes, those taking insulin, and those with complications had relatively more pathologic brain changes. CONCLUSIONS: There is evidence that older individuals with type 2 diabetes have an elevated risk for vascular brain damage and neurodegenerative changes. These pathological changes may be the anatomical basis for an increased risk of cognitive impairment or dementia in type 2 diabetes.

Aged, 80 and over↗

PubMed2005

Midlife pulse pressure and incidence of dementia: the Honolulu-Asia Aging Study.

BACKGROUND AND PURPOSE: Previous studies have shown that midlife systolic blood pressure (SBP) predicts late-life cognitive decline and incident dementia. This study explores whether this association is attributable to the pulsatile, ie, pulse pressure (PP), or the nonpulsatile component of blood pressure (BP). METHODS: Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese American men. Midlife BP was measured in 1971 to 1974 and dementia assessment was conducted in late-life. The 2505 men who were dementia free in 1991 and had complete follow-up data were re-examined for incident dementia in 1994 to 1996 and 1997 to 1999. Their age ranged from 71 to 93 years. Survival analysis with age as the time scale was performed to estimate the risk (hazard ratio [HR] and 95% CI) for incident dementia associated with mid- and late-life tertiles of PP and mean arterial BP, as well as SBP and diastolic BP categories. RESULTS: Over a mean of 5.1 years of follow-up, 189 cases (7.5%) of incident Alzheimer disease or vascular dementia were identified. After adjustment for cerebrovascular risk factors, dementia was significantly associated with SBP (HR 1.77; 95% CI, 1.10 to 2.84, for SBP > or =140 mm Hg compared with SBP <120 mm Hg), but not with PP tertiles. Limiting the analysis to those never treated with antihypertensives, high levels of all 4 BP components were significantly associated with dementia. In models with 2 BP components, only SBP remained significant in both the total sample and the never-treated subgroup (HR 2.29; 95% CI, 1.23 to 4.25, for SBP > or =140 mm Hg in total sample), whereas PP was not significantly associated with the risk for dementia. CONCLUSIONS: Midlife PP is not independently associated with dementia incidence. Midlife SBP is the strongest BP component predicting incident dementia.

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PubMed2005

Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA study.

In a previous study, migraine cases from the general population were found to be at significantly increased risk of silent infarct-like lesions in the posterior circulation (PC) territory of the brain, notably in the cerebellum. In this study we describe the clinical and neuroimaging characteristics of migraine cases with and without aura and controls with PC lesions. In total, 39 PC infarct-like lesions represented the majority (65%) of all 60 identified brain infarct-like lesions in the study sample (n = 435 subjects with and without migraine). Most lesions (n = 33) were located in the cerebellum, often multiple, and were round or oval-shaped, with a mean size of 7 mm. The majority (88%) of infratentorial infarct-like lesions had a vascular border zone location in the cerebellum. Prevalence of these border zone lesions differed between controls (0.7%), cases with migraine without aura (2.2%) and cases with migraine with aura (7.5%). Besides higher age, cardiovascular risk factors were not more prevalent in cases with migraine with PC lesions. Presence of these lesions was not associated with supratentorial brain changes, such as white matter lesions. The combination of vascular distribution, deep border zone location, shape, size and imaging characteristics on MRI makes it likely that the lesions have an infarct origin. Previous investigators attributed cases of similar 'very small' cerebellar infarcts in non-migraine patients to a number of different infarct mechanisms. The relevance and likelihood of the aetiological options are placed in the context of known migraine pathophysiology. In addition, the specific involvement of the cerebellum in migraine is discussed. The results suggest that a combination of (possibly migraine attack-related) hypoperfusion and embolism is the likeliest mechanism for PC infarction in migraine, and not atherosclerosis or small-vessel disease.

Adult↗

PubMed2005

Association of interleukin-1 gene polymorphisms with dementia in a community-based sample: the Honolulu-Asia Aging Study.

The interleukin-1 (IL-1) pro-inflammatory cytokine family participates in inflammatory processes and vessel damage involved in neurodegeneration. Recent studies suggest that Alzheimer's disease (AD) and vascular dementia (VaD) may share genetic risk factors. In this study, the frequency of polymorphisms in the genes coding for interleukin (IL)-1alpha, IL-1beta and the IL-1 receptor antagonist (RN) and their genotype associations with late-onset AD and VaD were determined in a Japanese-American cohort of men (n=931) participating in the Honolulu-Asia Aging Study (HAAS). A significant association was found between the IL-1beta (-511) and IL-1RN (+2018) polymorphisms and AD, suggesting that these variants confer an increased risk. Possessing the IL-1beta (-511) T/T genotype was also associated with VaD. There was no difference in the IL-1beta (+3953) frequency among the groups. Our results support the hypothesis that certain genetic variations contained within the IL-1 gene family contribute to the pathogenesis of dementia.

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PubMed2005

A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study.

BACKGROUND: The course of weight loss associated with dementia is unclear, particularly prior to and around the onset of the clinical syndrome. OBJECTIVE: To compare the natural history of weight change from mid to late life in men with and without dementia in late life. DESIGN AND SETTING: The Honolulu-Asia Aging Study, a 32-year, prospective, population-based study of Japanese American men who had been weighed on 6 occasions between 1965 and 1999 and who had been screened for dementia 3 times between 1991 and 1999. PARTICIPANTS: Of 1890 men (aged 77-98 years), 112 with incident dementia were compared with 1778 without dementia at the sixth examination (1997-1999). MAIN OUTCOME MEASURE: Weight change up to and including the sixth examination was treated as the dependent variable and estimated using a repeated measures analysis. RESULTS: Groups with and without dementia did not differ with respect to baseline weight or change in weight from mid to late life (first 26 years' follow-up). In the late-life examinations (final 6 years), mean age- and education-adjusted weight loss was -0.22 kg/y (95% confidence intervals, -0.26 to -0.18) in participants without dementia. Men with incident dementia at the same examination had an additional yearly weight loss of -0.36 kg (95% confidence interval, -0.53 to -0.19). This was not changed substantially with adjustment for risk factors for vascular disease or functional impairment and was significant for both Alzheimer disease and vascular dementia subtypes. CONCLUSIONS: Dementia-associated weight loss begins before the onset of the clinical syndrome and accelerates by the time of diagnosis. The potential impact on prognosis should be considered in the case of elderly persons at risk for dementia.

Age Factors↗

PubMed2005

Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results.

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.

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PubMed2005

Diabetes and brain aging: epidemiologic evidence.

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.

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