Associations of circulating saturated long-chain fatty acids with risk of mild cognitive impairment and Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

BACKGROUND: No study has examined the associations between peripheral saturated long-chain fatty acids (LCFAs) and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This study aimed to examine whether circulating saturated LCFAs are associated with both risks of incident MCI from cognitively normal (CN) participants and incident AD progressed from MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: We conducted analysis of data from older adults aged 55-90 years who were recruited at 63 sites across the USA and Canada. We examined associations between circulating saturated LCFAs (i.e., C14:0, C16:0, C18:0, C20:0) and risk for incident MCI in CN participants, and incident AD progressed from MCI. FINDINGS: 829 participants who were enrolled in ADNI-1 had data on plasma saturated LCFAs, of which 618 AD-free participants were included in our analysis (226 with normal cognition and 392 with MCI; 60.2% were men). Cox proportional-hazards models were used to account for time-to-event/censor with a 48-month follow-up period for the primary analysis. Other than C20:0, saturated LCFAs were associated with an increased risk for AD among participants with MCI at baseline (Hazard ratios (HRs) = 1.3 to 2.2, P = 0.0005 to 0.003 in fully-adjusted models). No association of C20:0 with risk of AD among participants with MCI was observed. No associations were observed between saturated LCFAs and risk for MCI among participants with normal cognition. INTERPRETATION: Saturated LCFAs are associated with increased risk of progressing from MCI to AD. This finding holds the potential to facilitate precision prevention of AD among patients with MCI. FUNDING: National Institutes of Health.

Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer's disease (AD) dementia phenotype.

Dietary calcium and magnesium intake and risk for incident dementia: The Shanghai Aging Study.

Introduction: Calcium (Ca), magnesium (Mg), or the calcium to magnesium (Ca:Mg) ratio may affect the risk of dementia via complex mechanisms. The aim of this study was to evaluate the association of dietary Ca, Mg, and Ca:Mg ratio with dementia risk at the prospective phase of the Shanghai Aging Study. Methods: We analyzed data from 1565 dementia-free participants living in an urban community who had measurements of dietary Ca and Mg intake derived from a food frequency questionnaire at baseline and incident dementia during follow-up. Results: Over the 5-year follow-up, 162 (10.4%) participants were diagnosed with incident dementia by Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. Participants with the lowest tertile of dietary Ca (<339.1 mg/day) and Mg (<202.1 mg/day) had the highest incidence rates of dementia (3.3/100 person-years for Ca, 3.3/100 person-years for Mg) compared to those with higher Ca and Mg intake. In the subgroup with Ca:Mg ratios ≤ 1.69, Mg intake >267.5 mg/day was related to an increased risk for dementia (adjusted hazard ratio: 3.97, 95% confidence interval: 1.29-12.25). Conclusions: Our findings suggest that high dietary intake of Mg is associated with an increased risk of dementia mainly among older adults with low Ca:Mg intake ratios. Proper balance of Ca to Mg in the diet may be critical to the relationship between Mg intake and risk of dementia. Highlights: Participants with the lowest tertile of dietary calcium (Ca) and magnesium (Mg) had the highest incidence rates of dementia.In the subgroup with Ca:Mg ratios ≤1.69, Mg intake >267.5 mg/day was related to an increased risk for dementia.Balance of Ca to Mg in diet may be critical to the relationship between Mg intake and risk of dementia.

Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial.

BACKGROUND: Deterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). OBJECTIVE: To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). METHODS: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. RESULTS: Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). CONCLUSION: Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer's disease.Clinical Trial Registry number and website: #100106 https://clinicaltrials.gov/ct2/show/NCT03265483.

Smaller Head Circumference Combined with Lower Education Predicts High Risk of Incident Dementia: The Shanghai Aging Study.

INTRODUCTION: An important index of brain reserve is the maximal attained brain size, which can be estimated by measuring the head circumference (HC). We investigated the association of HC and education with incident dementia in a population-based study of Chinese older adults. METHODS: We conducted a prospective follow-up study of 1,659 non-demented participants with a mean age of 71.5 years. Characteristics and anthropometry of the participants were collected at baseline. Consensus diagnoses for dementia were made using DSM-IV criteria based on functional, neurological, and neuropsychological assessments. RESULTS: We identified 168 new-onset dementia cases after a mean of 5.2 years of follow-up. Participants with smaller HC combined with low educational attainment had a significantly higher risk of incident dementia than those with larger HC who had completed more than 12 years of education (adjusted hazard ratio 4.48, 95% CI 2.47-8.12). DISCUSSION/CONCLUSION: Our results suggest that smaller HC in combination with low education leads to a markedly increased risk of dementia.

Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes.

STUDY OBJECTIVES: To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aß42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer's disease (AD) elderly. METHODS: Longitudinal study with mean follow-up time of 2.52 ± 0.51 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF Aß42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA. RESULTS: In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B = .06, 95% CI = .02, .11 and B = .08, 95% CI = .05, .12, respectively) and decrease in CSF Aß42 levels (B = -2.71, 95% CI = -3.11, -2.35 and B = -2.62, 95% CI = -3.23, -2.03, respectively); as well as increases in CSF T-tau (B = 3.68, 95% CI = 3.31, 4.07 and B = 2.21, 95% CI = 1.58, 2.86, respectively) and P-tau (B = 1.221, 95% CI = 1.02, 1.42 and B = 1.74, 95% CI = 1.22, 2.27, respectively); compared with OSA- participants. No significant variations in the biomarker changes over time were seen in the AD group. CONCLUSIONS: In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

Sleep, Cognitive impairment, and Alzheimer's disease: A Systematic Review and Meta-Analysis.

Study Objectives: Mounting evidence implicates disturbed sleep or lack of sleep as one of the risk factors for Alzheimer's disease (AD), but the extent of the risk is uncertain. We conducted a broad systematic review and meta-analysis to quantify the effect of sleep problems/disorders on cognitive impairment and AD. Methods: Original published literature assessing any association of sleep problems or disorders with cognitive impairment or AD was identified by searching PubMed, Embase, Web of Science, and the Cochrane library. Effect estimates of individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated using random effects models. We also estimated the population attributable risk. Results: Twenty-seven observational studies (n = 69216 participants) that provided 52 RR estimates were included in the meta-analysis. Individuals with sleep problems had a 1.55 (95% CI: 1.25-1.93), 1.65 (95% CI: 1.45-1.86), and 3.78 (95% CI: 2.27-6.30) times higher risk of AD, cognitive impairment, and preclinical AD than individuals without sleep problems, respectively. The overall meta-analysis revealed that individuals with sleep problems had a 1.68 (95% CI: 1.51-1.87) times higher risk for the combined outcome of cognitive impairment and/or AD. Approximately 15% of AD in the population may be attributed to sleep problems. Conclusion: This meta-analysis confirmed the association between sleep and cognitive impairment or AD and, for the first time, consolidated the evidence to provide an "average" magnitude of effect. As sleep problems are of a growing concern in the population, these findings are of interest for potential prevention of AD.

Seroprevalence of cutaneous human papillomaviruses (HPVs) among men in the multinational HPV Infection in Men study.

Data on cutaneous human papillomavirus (HPV) seroprevalence are primarily derived from skin cancer case-control studies. Few studies have reported the seroprevalence of cutaneous HPV among healthy men. This study investigated the seroprevalence of cutaneous HPV types and associated risk factors among men residing in Brazil, Mexico and the USA. Six hundred men were randomly selected from the HPV Infection in Men study. Archived serum specimens were tested for antibodies against 14 cutaneous HPV genotypes, ß-HPV types (5/8/12/14/17/22/23/24/38/48), α-HPV 27, γ-HPV 4, µ-HPV1 and ν-HPV 41 using a glutathione S-transferase L1-based multiplex serology assay. Risk factor data were collected by a questionnaire. Binomial proportions were used to estimate seroprevalence, and logistic regression to examine factors associated with seropositivity. Overall, 65.4 % of men were seropositive to ≥1 of the 14 cutaneous HPV types, and 39.0 % were positive for ≥1 ß-HPV types. Seroprevalence was 8.9, 30.9, 28.6 and 9.4 % for α-HPV 27, γ-HPV 4, µ-HPV 1 and ν-HPV 41, respectively. In multivariate analyses, seropositivity for any cutaneous HPV type was associated with higher education [adjusted odds ratio (AOR) 1.75; 95 % confidence interval (CI) 1.08-2.83], and seropositivity of any ß-HPV type was significantly associated with increasing age (AOR 1.72; 95 % CI 1.12-2.63, for men aged 31-44 years vs men aged 18-30 years). Other factors associated with various type-specific cutaneous HPV seropositivity included country, circumcision and lifetime number of male sexual partners. These data indicate that exposure to cutaneous HPV is common. Future studies are needed to assess the role of cutaneous HPV in diseases.

Seroprevalence and Associated Factors of 9-Valent Human Papillomavirus (HPV) Types among Men in the Multinational HIM Study.

BACKGROUND: Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. Recently a 9-valent HPV (9vHPV) prophylactic vaccine was licensed. Seroprevalence prior to vaccine dissemination is needed for monitoring vaccine effectiveness over time. Few studies have assessed the seroprevalence of 9vHPV types in men. OBJECTIVES: To investigate the seroprevalence of 9vHPV vaccine types and associated risk factors among men residing in Brazil, Mexico, and the United States. METHODS: Six hundred men were randomly selected from the HPV Infection in Men (HIM) Study. Archived serum specimens collected at enrollment were tested for antibodies against nine HPV types (6, 11, 16, 18, 31, 33, 45, 52 and 58) using a glutathione S-transferase (GST) L1-based multiplex serologic assay. Socio-demographic, lifestyle and sexual behavior data at enrollment were collected through a questionnaire. Binomial proportions were used to estimate seroprevalence and logistic regression was used to examine factors associated with seropositivity of type-specific and grouped (i.e. 9vHPV, high-risk 9vHPV, low risk 9vHPV, and five-additional) HPV types. RESULTS: Overall, 28.3% of men were seropositive for at least one of the 9vHPV vaccine types, 14.0% for at least one of the seven high-risk types (16, 18, 31, 33, 45, 52 and 58) and 11.2% for at least one of the five high-risk types (31, 33, 45, 52 and 58) not included in the quadrivalent HPV vaccine, and 17.4% for at least one of the low-risk types (6/11). In multivariate analyses, odds ratios adjusted (AOR) for country of residence, age, marital status, smoking, number of anal sex lifetime partners, compared to men with no anal sex lifetime partners, men with ≥2 partners were more likely to be seropositive for grouped HPV [(9vHPV: AOR 2.52; 95% confidence interval (CI) 1.40-4.54), (high-risk 9vHPV: AOR 2.18; 95%CI: 1.05-4.50) and (low-risk 9vHPV: AOR 2.12; 95%CI: 1.12-4.03)], and individual HPV types 6, 16, 33 and 58 with AORs ranging from 2.19 to 7.36. Compared to men aged 18-30 years, men older than 30 years were significantly more likely to be seropositive for any high-risk 9vHPV, in addition to individual types 18 and 45; and compared to never smokers, current smokers were more likely to be seropositive to 9vHPV, low-risk 9vHPV and HPV 6. In contrast, married men were less likely to be seropositive to any high-risk 9vHPV and individual HPV types 18 and 31 when compared to single men. CONCLUSIONS: These data indicate that exposure to the nine HPV types included in the 9vHPV vaccine is common in men and that seropositivity to 9vHPV vaccine types is associated with older age and the lifetime number of anal sex partners. Nine valent HPV vaccination of males and females has the potential to prevent HPV related diseases and transmission in both sexes.

Seroprevalence of Cutaneous Human Papillomaviruses and the Risk of External Genital Lesions in Men: A Nested Case-Control Study.

BACKGROUND: A variety of cutaneous human papillomaviruses (HPV) are detectable in genital epithelial lesions in men and non-melanoma skin cancer patients. It remains unclear whether these viruses are associated causally with skin lesions. To date, no study has prospectively examined the association between cutaneous HPV seropositivity and development of external genital lesions (EGLs) in men. OBJECTIVES: To examine the association between seropositivity to cutaneous HPV types and the risk of subsequent development of EGLs. METHODS: A nested case-control study including 163 incident EGL cases and 352 EGL-free controls in the HPV Infection in Men (HIM) Study cohort was conducted. Cases were ascertained at each of up to 10 biannual clinical visits and verified through biopsy and pathological diagnoses. EGLs were categorized as condyloma, suggestive of condyloma, penile intraepithelial neoplasia (PeIN), and other EGLs. Archived serum specimens collected at baseline were tested for antibodies against 14 cutaneous HPV types (ß types (5, 8, 12, 14, 17, 22, 23, 24, 38, and 47), α type 27, γ type 4, µ type 1, and ν type 41) using a GST L1-based multiplex serology assay. Socio-demographic and sexual behavior data were collected through a questionnaire. Using logistic regression, adjusted odds ratios (AOR) and 95% confidence intervals (CI) were estimated. RESULTS: Overall, seropositivity to ≥1 cutaneous HPV type (any-HPV) and ≥1 ß types (any-ß) was 58.3% and 37.5% among other EGL cases, 71.6% and 46.8% among condyloma, 66.8% and 50.0% among PeIN, and 71.9% and 38.4% among controls, respectively. Type-specific seropositivity was most common for ɤ-HPV 4, µ-HPV 1, and ß-HPV 8. No statistically significant association was observed between any-HPV, any-ß, and type-specific HPV seropositivity and subsequent development of EGLs across all pathological diagnoses. CONCLUSIONS: Overall, seropositivity to cutaneous HPV was common among men; however, it appears that cutaneous HPV is not associated with the development of genital lesions in men.

Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia.

OBJECTIVE: Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS: A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS: Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P < 0.001). CONCLUSIONS: Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

Occupational Characteristics and Patterns as Risk Factors for Parkinson's Disease: A Case Control Study.

BACKGROUND: Associations have been reported between the risk of Parkinson's disease (PD) and employment in certain fields. Most studies have focused on toxic exposures as potential causal explanations. However, PD also has been associated with personality characteristics that may influence occupational choices and patterns. OBJECTIVE: This study evaluates the role of personality as indicated by occupational choices and employment patterns in the risk for PD. METHODS: In-person interviews were conducted to assess occupational histories and early-adult personality indicators among 89 PD patients and 99 controls. RESULTS: PD cases had fewer lifetime jobs than controls (mean for cases = 4.38 ± 2.20; mean for controls = 5.00 ± 2.26; p = 0.03). Among women, PD was positively associated with more complex work with people (OR = 1.45, 95% CI 1.12-1.89), representing a 95% increased risk for PD comparing women with the greatest complexity of work with those requiring the least complexity of work with people. Women PD cases also performed less complex work with things compared with controls (OR = 0.69 (95% CI 0.53-0.90)), translating into a 13-fold increased risk for PD among women whose work involved the least complex work with things compared with the most. The numbers of jobs and job types were associated with taking more activity risks as a young-adult (r = 0.19, p = 0.02; r = 0.26, p = 0.001, respectively). CONCLUSIONS: Cases with PD held fewer lifetime jobs compared with controls. Occupational complexity was associated with the risk for PD among women, but not men. Further consideration of the possible influence of personality on occupational choices is warranted.

Prevalence of mild cognitive impairment in an urban community in China: a cross-sectional analysis of the Shanghai Aging Study.

BACKGROUND: Substantial variations in the prevalence of mild cognitive impairment (MCI) have been reported, although mostly in Western countries. Less is known about MCI in the Chinese population. METHODS: We clinically and neuropsychologically evaluated 3141 community residents ≥60 years of age. Diagnoses of MCI and its subtypes were made using standard criteria via consensus diagnosis. RESULTS: Among 2985 nondemented individuals, 601 were diagnosed with MCI, resulting in a prevalence of 20.1% for total MCI, 13.2% for amnestic MCI (aMCI), and 7.0% for non-amnestic MCI (naMCI). The proportions of MCI subtypes were: aMCI single domain (SD), 38.9%; aMCI multiple domains (MD), 26.5%; naMCI-SD, 25.0%; and naMCI-MD, 9.6%. The prevalence of aMCI-MD increased rapidly with age in women APOE ε4 carriers (from 60 to 69 years to ≥80 years, 3.1%-33.3%, P < .001). CONCLUSIONS: Our findings suggest that 20% of Chinese elderly are affected by MCI. Prospective studies in China are needed to examine progression to dementia and related risk factors.

The Shanghai Aging Study: study design, baseline characteristics, and prevalence of dementia.

BACKGROUND: To establish a prospective cohort to enumerate the prevalence, incidence and risk factors for dementia and mild cognitive impairment (MCI) among residents aged ≥60 in an urban community of Shanghai, China. METHODS: Participants received clinical evaluations including physical measurements, demographic and lifestyle questionnaires, physical and neurologic examinations, and neuropsychological testing. Urine and blood samples were collected, aliquoted, and stored. DNA was extracted for Apolipoprotein (APOE) genotyping. Diagnoses of dementia and MCI were made using standard criteria via consensus diagnosis. RESULTS: Among 3,141 participants aged ≥60, 1,438 (45.8%) were men. The average age of participants was 72.3 years (SD 8.1), and they had an average of 11.6 years (SD 4.4) of education. The most common chronic disease of participants was hypertension (56.4%). The frequencies of APOE-​ε2, ε3 and ε4 were 7.9, 82.7 and 9.4%, respectively. We diagnosed 156 (5.0%, 95% CI 4.3-5.8%) participants with dementia. The prevalence rates of Alzheimer's disease and vascular dementia were 3.6% (95% CI 3.0-4.3%) and 0.8% (95% CI 0.5-1.1%). CONCLUSIONS: The Shanghai Aging Study is the first prospective community-based cohort study of cognitive impairment in China, with a comparable study design, procedures, and diagnostic criteria for dementia and MCI to most previous cohort studies in developed countries.

Incidence rates of dementia, Alzheimer disease, and vascular dementia in the Japanese American population in Seattle, WA: the Kame Project.

There are few studies on the incidence of dementia in representative minority populations in the United States; however, no population-based study has been conducted on Japanese American women. We identified 3045 individuals aged 65+ with at least 1 parent of Japanese descent living in King County, WA in the period 1992 to 1994, of whom 1836 were dementia-free and were examined every 2 years (1994 to 2001) to identify incident cases of all dementias, Alzheimer disease (AD), vascular dementia (VaD), and other dementias. Cox regression was used to examine associations with age, sex, years of education, and apolipoprotein (APOE)-ε4. Among 173 incident cases of dementia, the overall rate was 14.4/1000/y, with rates being slightly higher among women (15.9/1000) than men (12.5/1000). Rates roughly doubled every 5 years for dementia and AD; the age trend for VaD and other dementias was less consistent. Sex was not significantly related to incidence of dementia or its subtypes in adjusted models. There was a trend for an inverse association with increasing years of education. APOE-ε4 was a strong risk factor for all dementias [hazard ratio (HR)=2.89; 95% confidence interval (CI), 1.88-4.46], AD (HR=3.27; 95% CI, 2.03-5.28), and VaD (HR=3.33; 95% CI, 1.34-8.27). This study is the first to report population-based incidence rates for both Japanese American men and women.

Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS) is caused by gene-environment interactions. Mutations in genes underlying familial ALS (fALS) have been discovered in only 5-10% of the total population of ALS patients. Relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron death leading to the syndrome of ALS, although exposure to chemicals including lead and pesticides, and to agricultural environments, smoking, certain sports, and trauma have all been identified with an increased risk of ALS. There is a need for research to quantify the relative roles of each of the identified risk factors for ALS. Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid ß-N-methylamino-L-alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems. Rigorous epidemiologic studies could determine the risks associated with exposure to cyanobacteria, and if combined with genetic analysis of ALS cases and controls could reveal etiologically important gene-environment interactions in genetically vulnerable individuals.

Associations of welding and manganese exposure with Parkinson disease: review and meta-analysis.

OBJECTIVE: To examine associations of welding and manganese exposure with Parkinson disease (PD) using meta-analyses of data from cohort, case-control, and mortality studies. METHODS: Epidemiologic studies related to welding or manganese exposure and PD were identified in a PubMed search, article references, published reviews, and abstracts. Inclusion criteria were 1) cohort, case-control, or mortality study with relative risk (RR), odds ratio (OR), or mortality OR (MOR) and 95 confidence intervals (95% CI); 2) RR, OR, and MOR matched or adjusted for age and sex; 3) valid study design and analysis. When participants of a study were a subgroup of those in a larger study, only results of the larger study were included to assure independence of datasets. Pooled RR/OR estimates and 95% CIs were obtained using random effects models; heterogeneity of study effects were evaluated using the Q statistic and I(2) index in fixed effect models. RESULTS: Thirteen studies met inclusion criteria for the welding meta-analysis and 3 studies for the manganese exposure meta-analysis. The pooled RR for the association between welding and PD for all study designs was 0.86 (95% CI 0.80-0.92), with absence of between-study heterogeneity (I(2) = 0.0). Effect measures for cohort, case-control, and mortality studies were similar (0.91, 0.82, 0.87). For the association between manganese exposure and PD, the pooled OR was 0.76 (95% CI 0.41-1.42). CONCLUSIONS: Welding and manganese exposure are not associated with increased PD risk. Possible explanations for the inverse association between welding and PD include confounding by smoking, healthy worker effect, and hormesis.

Changes in brain volume and cognition in a randomized trial of exercise and social interaction in a community-based sample of non-demented Chinese elders.

Physical exercise has been shown to increase brain volume and improve cognition in randomized trials of non-demented elderly. Although greater social engagement was found to reduce dementia risk in observational studies, randomized trials of social interventions have not been reported. A representative sample of 120 elderly from Shanghai, China was randomized to four groups (Tai Chi, Walking, Social Interaction, No Intervention) for 40 weeks. Two MRIs were obtained, one before the intervention period, the other after. A neuropsychological battery was administered at baseline, 20 weeks, and 40 weeks. Comparison of changes in brain volumes in intervention groups with the No Intervention group were assessed by t-tests. Time-intervention group interactions for neuropsychological measures were evaluated with repeated-measures mixed models. Compared to the No Intervention group, significant increases in brain volume were seen in the Tai Chi and Social Intervention groups (p < 0.05). Improvements also were observed in several neuropsychological measures in the Tai Chi group, including the Mattis Dementia Rating Scale score (p = 0.004), the Trailmaking Test A (p = 0.002) and B (p = 0.0002), the Auditory Verbal Learning Test (p = 0.009), and verbal fluency for animals (p = 0.01). The Social Interaction group showed improvement on some, but fewer neuropsychological indices. No differences were observed between the Walking and No Intervention groups. The findings differ from previous clinical trials in showing increases in brain volume and improvements in cognition with a largely non-aerobic exercise (Tai Chi). In addition, intellectual stimulation through social interaction was associated with increases in brain volume as well as with some cognitive improvements.

The UCHL1 S18Y polymorphism and Parkinson's disease in a Japanese population.

UCHL1 plays an important role in the ubiquitin-proteasome system and is a biologically plausible candidate gene for Parkinson's disease (PD). However, results from genetic association studies of the UCHL1 S18Y polymorphism have been equivocal. Meta-analyses indicate that the polymorphism's risk effect might be restricted to Asian populations and early-onset disease. To further explore the role of UCHL1 in PD, we genotyped S18Y in 605 PD patients and 1620 controls of Japanese ancestry. We did not find evidence of an association in the overall sample (SY vs. SS: adjusted OR=1.11, P=0.37; YY vs. SS: adjusted OR=1.01, P=0.94). In the early-onset stratum, however, we observed a trend toward a reduction in risk for those with the Y allele (SY vs. SS, adjusted OR, 0.75; 95% CI, 0.47-1.20; YY vs. SS, OR, 0.64; 95% CI, 0.36-1.14; trend test, P=0.12). These results indicate that, if involved in PD, the S18Y variant is not a major determinant of risk and its effect might be restricted to early-onset disease.