Regional differences in rates of dementia: MRC-CFAS.
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Biomedical subjects
Lenore J Launer
Publications and source records attributed to Lenore J Launer.
Atorvastatin therapy lowers circulating cholesterol but not free radical activity in advance of identifiable clinical benefit in the treatment of mild-to-moderate AD.
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.
Activities of Daily Living↗
The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study.
Cerebral white matter lesions are frequently observed on magnetic resonance imaging (MRI) scans in elderly people and are associated with stroke and dementia. Elevated blood pressure is presumed one of the main risk factors, although data are almost exclusively derived from cross-sectional studies. We assessed in 10 European cohorts the relation between concurrently and previously measured blood pressure levels, hypertension, its treatment, and severe cerebral white matter lesions. In total, 1805 nondemented subjects aged 65 to 75 years were sampled from ongoing community-based studies that were initiated 5 to 20 years before the MRI. White matter lesions in the periventricular and subcortical region were rated separately using semiquantitative measures. We performed logistic regression analyses adjusted for potential confounders in 1625 people with complete data. Concurrently and formerly assessed diastolic and systolic blood pressure levels were positively associated with severe white matter lesions. Both increases and decreases in diastolic blood pressure were associated with more severe periventricular white matter lesions. Increase in systolic blood pressure levels was associated with more severe periventricular and subcortical white matter lesions. People with poorly controlled hypertension had a higher risk of severe white matter lesions than those without hypertension, or those with controlled or untreated hypertension. Higher blood pressure was associated with an increased risk of severe white matter lesions. Successful treatment of hypertension may reduce this risk; however, a potential negative effect of decreasing diastolic blood pressure level on the occurrence of severe periventricular white matter lesions should be taken into account.
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Fasting insulin and incident dementia in an elderly population of Japanese-American men.
OBJECTIVE: To evaluate the association of fasting insulin level to incident dementia in a cohort of elderly men. METHODS: Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese-American men, aged 71 to 91 years in 1991. Serum insulin was measured in 1991 and participants were grouped based on their insulin levels. Dementia was ascertained in 1991, 1994, and 1996 according to international guidelines. The 2,568 men dementia-free in 1991 were reexamined in 1994 and 1996; 244 new cases of dementia were diagnosed. Survival analysis with age as the time scale was used to estimate the risk (hazard ratio [HR] and 95% CI) for incident dementia associated with levels of insulin. RESULTS: The risk of dementia was increased at the two extremes of the insulin distribution (lower and upper 15th percentiles). Compared to the rest of the cohort subjects in the lowest 15th percentile and highest 15th percentile had an increased risk for dementia (HR = 1.54, CI 1.11 to 2.11 and HR = 1.54, CI 1.05 to 2.26). In men with insulin levels <22.2 mIU/L the risk for dementia decreased with increased levels of insulin (HR = 0.76, CI 0.72 to 0.79 for each increase of one logarithmic unit -2.72 mIU/L of insulin). In men with insulin levels >/=22.2 mIU/L the risk for dementia increased with increasing levels of insulin (HR = 1.64, CI = 1.07 to 2.52 for each 2.72 mIU/L). CONCLUSIONS: Both low and high levels of insulin are associated with an increased risk of developing dementia.
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Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study.
Hippocampal atrophy (HA) is usually attributed to the neurofibrillary tangles and neuritic plaques of Alzheimer disease. However, the hippocampus is vulnerable to global ischemia, which may lead to atrophy. We investigated the association of midlife blood pressure (BP) and late-life HA in a sample of Japanese-American men born between 1900 and 1919. BP was measured on 3 occasions between 1965 and 1971. In 1994 to 1996 a subsample underwent magnetic resonance imaging (MRI) of the brain. Hippocampal volume was estimated by manually drawing regions of interest on relevant scan slices; HA was defined as the lowest quartile of hippocampal volume. Also assessed on the MRI were cortical and subcortical infarcts, lacunes, and white matter hyperintensities. The risk (OR, 95% CI) was estimated for HA associated with systolic (<140 versus > or =140 mm Hg) and diastolic (<90 versus > or =90 mm Hg) BP and with antihypertensive treatment. Analyses were adjusted for sociodemographic factors, other cardiovascular risk factors, apolipoprotein E allele, and correlated brain pathology. Those never treated with antihypertensive medication had a significantly increased risk for HA (OR 1.7; CI=1.12; 2.65). The nontreated subjects with high systolic BP had an increased risk (OR=1.98; CI=0.89; 4.39) for HA. Results were similar for untreated men with high diastolic BP (OR=3.51; CI=1.26; 9.74). In conclusion, treatment with antihypertensive treatment modifies the association of BP and HA, such that high levels of BP adversely affect the hippocampus in persons never treated with antihypertensives.
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Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia Aging Study.
Antioxidants have been hypothesized to protect against Alzheimer's disease, but studies conducted in late life have been inconsistent. Risk factors measured in midlife may better predict dementia in late life because they are less affected by the disease process. The authors examined the association of midlife dietary intake of antioxidants to late-life dementia and its subtypes. Data were obtained from the Honolulu-Asia Aging Study, a prospective community-based study of Japanese-American men who were aged 45-68 years in 1965-1968, when a 24-hour dietary recall was administered. The analysis included 2,459 men with complete dietary data who were dementia-free at the first assessment in 1991-1993 and were examined up to two times for dementia between 1991 and 1999. The sample included 235 incident cases of dementia (102 cases of Alzheimer's disease, 38 cases of Alzheimer's disease with contributing cerebrovascular disease, and 44 cases of vascular dementia). Relative risks by quartile of intake were calculated using Cox proportional hazards models with age as the time scale, after adjustment for sociodemographic and lifestyle factors, cardiovascular risk factors, other dietary constituents, and apolipoprotein E e4. Intakes of beta-carotene, flavonoids, and vitamins E and C were not associated with the risk of dementia or its subtypes. This analysis suggests that midlife dietary intake of antioxidants does not modify the risk of late-life dementia or its most prevalent subtypes.
Age Distribution↗
Migraine as a risk factor for subclinical brain lesions.
CONTEXT: Clinical series have suggested an increased prevalence of cerebral infarction and white matter lesions (WMLs) in migraine patients. It is not known whether these lesions are prevalent in the general migraine population. OBJECTIVES: To compare the prevalence of brain infarcts and WMLs in migraine cases and controls from the general population and to identify migraine characteristics associated with these lesions. DESIGN: Cross-sectional, prevalence study of population-based sample of Dutch adults aged 30 to 60 years. PARTICIPANTS: Randomly selected patients with migraine with aura (n = 161), patients with migraine without aura (n = 134), and controls (n = 140), who were frequency matched to cases for age, sex, and place of residence. Nearly 50% of the cases had not been previously diagnosed by a physician. MAIN OUTCOME MEASURES: Brain magnetic resonance images were evaluated for infarcts, by location and vascular supply territory, and for periventricular WMLs (PVWMLs) and deep WMLs (DWMLs). The odds ratios (ORs) and 95% confidence intervals (CIs) of these brain lesions compared with controls were examined by migraine subtype (with or without aura) and monthly attack frequency (<1 attack, > or =1 attack), controlling for cardiovascular risk factors and use of vasoconstrictor migraine agents. All participants underwent a standard neurological examination. RESULTS: No participants reported a history of stroke or transient ischemic attack or had relevant abnormalities at standard neurological examination. We found no significant difference between patients with migraine and controls in overall infarct prevalence (8.1% vs 5.0%). However, in the cerebellar region of the posterior circulation territory, patients with migraine had a higher prevalence of infarct than controls (5.4% vs 0.7%; P =.02; adjusted OR, 7.1; 95% CI, 0.9-55). The adjusted OR for posterior infarct varied by migraine subtype and attack frequency. The adjusted OR was 13.7 (95% CI, 1.7-112) for patients with migraine with aura compared with controls. In patients with migraine with a frequency of attacks of 1 or more per month, the adjusted OR was 9.3 (95% CI, 1.1-76). The highest risk was in patients with migraine with aura with 1 attack or more per month (OR, 15.8; 95% CI, 1.8-140). Among women, the risk for high DWML load (top 20th percentile of the distribution of DWML load vs lower 80th percentile) was increased in patients with migraine compared with controls (OR, 2.1; 95% CI, 1.0-4.1); this risk increased with attack frequency (highest in those with > or =1 attack per month: OR, 2.6; 95% CI, 1.2-5.7) but was similar in patients with migraine with or without aura. In men, controls and patients with migraine did not differ in the prevalence of DWMLs. There was no association between severity of PVWMLs and migraine, irrespective of sex or migraine frequency or subtype. CONCLUSIONS: These population-based findings suggest that some patients with migraine with and without aura are at increased risk for subclinical lesions in certain brain areas.
Brain↗
Epidemiologic evidence of oxidative stress in the brain.
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Age Distribution↗
Epidemiology of white matter lesions.
This is an overview of the prevalence of, and risk factors for white matter lesions in older persons. The prevalence of white matter lesions is high and increases with age. Most risk factors that have been examined in association with white matter lesions are similar to those for cardiovascular disease, including elevated blood pressure, diabetes atherosclerosis, homocysteine levels, and markers of oxidative stress. The genetic contributions to white matter lesions are also reviewed.
Age Factors↗
Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study.
Diabetic patients are at increased risk for stroke, but little is known about the presence of other brain lesions. We studied the association of magnetic resonance imaging-detected brain lesions to diabetes in 1,252 individuals aged 65-75 years who were randomly selected from eight European population registries or defined working populations. All scans were centrally read for brain abnormalities, including infarcts, white matter lesions, and atrophy. We used a three-point scale to rate periventricular white matter lesions, and the volume of subcortical lesions was calculated according to their number and size. Subjective grading of cortical atrophy by lobe and summation of the lobar grades resulted in a total cortical atrophy score. The mean of three linear measurements of the ventricular diameter relative to the intracranial cavity defined the severity of subcortical atrophy. After adjustment for possible confounders, diabetes was associated with cortical brain atrophy but not with any focal brain lesions or subcortical atrophy. There was a strong interaction of diabetes and hypertension, such that the association between diabetes and cortical atrophy existed only in hypertensive but not in normotensive participants. Cognitive and pathological data are needed to determine the clinical significance of these findings as well as to understand the mechanisms underlying these associations.
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Nonsteroidal anti-inflammatory drugs and Alzheimer disease: what's next?
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Alzheimer Disease↗
Higher estrogen levels are not associated with larger hippocampi and better memory performance.
BACKGROUND: Estrogens may prevent cognitive decline and Alzheimer disease. Animal study findings have shown beneficial effects of estrogen on the brain, particularly on the hippocampus, a structure related to memory performance and early Alzheimer disease. OBJECTIVE: To investigate whether higher levels of endogenous estradiol in older women and men are associated with larger hippocampal volumes on magnetic resonance imaging and better memory performance. DESIGN AND SETTING: Cross-sectional analysis within the Rotterdam Scan Study, a population-based study in the Netherlands of elderly subjects who do not have dementia. PARTICIPANTS: Two hundred ten women and 202 men, aged 60 to 90 years, with plasma levels of total estradiol and, in part, 162 women and 149 men also with levels of bioavailable and free estradiol. MAIN OUTCOME MEASURE: Hippocampal volumes on magnetic resonance imaging and memory performance (delayed recall). RESULTS: Women with higher total estradiol levels had smaller hippocampal volumes and poorer memory performance -0.29 mL (95% confidence interval, -0.57 to -0.00) and -0.4 (95% confidence interval, -1.3 to 0.5) fewer words in delayed recall testing for the highest tertile compared with the lowest tertile. Similar inverse associations were found among bioavailable and free estradiol levels, hippocampal volumes, and memory. In men, no association was observed between estradiol levels and hippocampal volume, but a trend was found for higher levels of total estradiol to be associated with poorer memory performance. CONCLUSION: Our data do not support the hypothesis that higher levels of endogenous estradiol in older women and men are associated with larger hippocampal volumes and better memory performance.
Age Factors↗
Endogenous estradiol and risk of dementia in women and men: the Rotterdam Study.
We determined whether higher endogenous estradiol levels were associated with lower risk of dementia in older men and women not using hormonal replacement therapy, using a case-cohort design within the Rotterdam Study, a population-based follow-up study on chronic diseases, including dementia, in 7983 subjects aged 55 years or older, and ongoing since 1990. The analyses were based on a random subcohort of 508 women and 438 men, and on 76 women and 53 men with incident dementia. Cox proportional hazards models with robustly estimated standard errors showed that in women higher levels of total estradiol were associated with higher risk of dementia (age-adjusted hazard ratio per standard deviation increase 1.38; 95% CI 1.04-1.84). Age-adjusted HR's of Alzheimer's disease and vascular dementia associated with higher levels of total estradiol (per SD increase) were 1.24 (95% CI 0.87-1.76) and 2.19 (95% CI 1.22-3.92), respectively. Similar results were observed for bioavailable estradiol. Additional adjustments for potential confounders did not change the results substantially. In men, no clear association was observed between estradiol levels and risk of dementia or its subtypes. The findings do not support the hypothesis that higher levels of endogenous estradiol reduce risk of dementia, neither in women nor in men.
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Epidemiology of white-matter lesions.
White-matter lesions (WML) detected on MRI may reflect different pathologies, but, in older persons, are thought to be mainly of ischemic origin. WML increase in prevalence with age. Several cardiovascular risk factors and cognitive, emotional, and physical function consequences of WML have been identified. These are reviewed briefly in this report.
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Cigarette smoking and alcohol consumption in relation to cognitive performance in middle age.
In the elderly, cigarette smoking has been related to reduced cognitive performance and moderate alcohol consumption to increased cognitive performance. It is not clear whether these associations also exist in middle age. The authors examined these relations in a population-based cohort study of 1,927 randomly selected, predominantly middle-aged subjects aged 45-70 years at the time of cognitive testing and living in the Netherlands. From 1995 until 2000, an extensive cognitive battery was administered, and compound scores were calculated. Risk factors had been assessed approximately 5 years previously. Multiple linear regression analyses (in which one unit of the cognitive score = one standard deviation) showed that, after the authors adjusted for age, sex, education, alcohol consumption, and cardiovascular risk factors, current smokers had reduced psychomotor speed (beta = -0.159, 95% confidence interval: -0.071, -0.244; p = 0.0003) and reduced cognitive flexibility (beta = -0.133, 95% confidence interval: -0.035, -0.230; p = 0.008) compared with never smokers. This effect was similar to that of being approximately 4 years older. Alcohol consumption was related to increased speed and better flexibility, especially among women who drank 1-4 alcoholic beverages a day. In conclusion, among middle-aged subjects, current smoking was inversely and alcohol consumption positively related to psychomotor speed and cognitive flexibility. This finding suggests that actions to prevent cognitive decline can be taken in middle age.
Age Distribution↗
Vitamin E and C supplements and risk of dementia.
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Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study.
Inflammatory responses are associated with cardiovascular disease and may be associated with dementing disease. We evaluated the long-term prospective association between dementia and high-sensitivity C-reactive protein, a nonspecific marker of inflammation. Data are from the cohort of Japanese American men who were seen in the second examination of the Honolulu Heart Program (1968-1970) and subsequently were reexamined 25 years later for dementia in the Honolulu-Asia Aging Study (1991-1996). In a random subsample of 1,050 Honolulu-Asia Aging Study cases and noncases, high-sensitivity C-reactive protein concentrations were measured from serum taken at the second examination; dementia was assessed in a clinical examination that included neuroimaging and neuropsychological testing and was evaluated using international criteria. Compared with men in the lowest quartile (<0.34mg/L) of high-sensitivity C-reactive protein, men in the upper three quartiles had a 3-fold significantly increased risk for all dementias combined, Alzheimer's disease, and vascular dementia. For vascular dementia, the risk increased with increasing quartile. These relations were independent of cardiovascular risk factors and disease. These data support the view that inflammatory markers may reflect not only peripheral disease, but also cerebral disease mechanisms related to dementia, and that these processes are measurable long before clinical symptoms appear.
Alzheimer Disease↗
Demonstrating the case that AD is a vascular disease: epidemiologic evidence.
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.
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