Risk profiles for mild cognitive impairment vary by age and sex: the Sydney Memory and Ageing study.

OBJECTIVES: : To examine age- and sex-related differences in risk and protective factors for mild cognitive impairment (MCI) in community-based elderly individuals. DESIGN: : Cross-sectional study. SETTING: : The population-based Sydney Memory and Ageing Study. PARTICIPANTS: : A total of 757 nondemented, community-dwelling elderly individuals from an English-speaking background categorized as younger (70-79 years) or older (80-90 years). MEASUREMENTS: : Risk of MCI was determined for sociodemographic, lifestyle, and cardiac, physical, mental, and general health factors using age- (and sex-) adjusted multiple regressions comprising initially significant univariate factors. RESULTS: : The point prevalence of MCI within our sample was 39.1% overall: it was lowest in younger women (32.3%) and similar across men and older women (41.9%-43.6%). The risk of MCI across all participants was increased by the APOE ∊4 allele, high homocysteine, and heart disease; and decreased by better odor identification, visual acuity, and mental activity. Risk factors in all younger participants were slow 6-m walk, poor odor identification, and high homocysteine. Risk of MCI was associated in younger women with history of depression, less mental activity, slower 6-m walk, poorer visual acuity, and higher homocysteine; and in younger men with poorer odor identification and higher homocysteine. Older participants showed no significant risk factors for MCI, except for poorer visual acuity in men. Supporting these findings were statistically significant interactions that reflected the differences in risk factor profiles between age and/or sex groups. CONCLUSIONS: : Risk factors for MCI differ in men and women and vary with age. This has implications for preventing MCI and possibly dementia.

The Sydney Memory and Ageing Study (MAS): methodology and baseline medical and neuropsychiatric characteristics of an elderly epidemiological non-demented cohort of Australians aged 70-90 years.

BACKGROUND: The Sydney Memory and Ageing Study (Sydney MAS) was initiated in 2005 to examine the clinical characteristics and prevalence of mild cognitive impairment (MCI) and related syndromes, and to determine the rate of change in cognitive function over time. METHODS: Non-demented community-dwelling individuals (N = 1037) aged 70-90 were recruited from two areas of Sydney, following a random approach to 8914 individuals on the electoral roll. They underwent detailed neuropsychiatric and medical assessments and donated a blood sample for clinical chemistry, proteomics and genomics. A knowledgeable informant was also interviewed. Structural MRI scans were performed on 554 individuals, and subgroups participated in studies of falls and balance, metabolic and inflammatory markers, functional MRI and prospective memory. The cohort is to be followed up with brief telephone reviews annually, and detailed assessments biannually. RESULTS: This is a generally well-functioning cohort mostly living in private homes and rating their health as being better than average, although vascular risk factors are common. Most (95.5%) participants or their informants identified a cognitive difficulty, and 43.5% had impairment on at least one neuropsychological test. MCI criteria were met by 34.8%; with 19.3% qualifying for amnestic MCI, whereas 15.5% had non-amnestic MCI; 1.6% had impairment on neuropsychological test performance but no subjective complaints; and 5.8% could not be classified. The rate of MCI was 30.9% in the youngest (70-75) and 39.1% in the oldest (85-90) age bands. Rates of depression and anxiety were 7.1% and 6.9% respectively. CONCLUSIONS: Cognitive complaints are common in the elderly, and nearly one in three meet criteria for MCI. Longitudinal follow-up of this cohort will delineate the progression of complaints and objective cognitive impairment, and the determinants of such change.

Hormone replacement therapy, brain volumes and white matter in postmenopausal women aged 60-64 years.

Research on the structural and functional effects of hormone replacement therapy on the brain has produced inconsistent results. This paper reports on cross-sectional associations between hormone replacement therapy use and volumes of brain structures measured using magnetic resonance imaging in 213 postmenopausal women aged 60-64 years recruited from a large population study. Of these, 64 were current hormone replacement therapy users, 69 previous users and 80 had never used hormone replacement therapy. No differences were observed between groups in total grey matter, white matter, hippocampal or amygdalar volumes, severity or volume of white matter hyperintensities, or in different measures of brain atrophy. While acknowledging the limitations of a cross-sectional study, the results argue against hormone replacement therapy being protective against brain changes associated with ageing in women in their early 60s.

Metabolic Burden and Disease and Mortality Risk Associated with Impaired Fasting Glucose in Elderly Adults.

OBJECTIVES: To examine whether impaired fasting glucose (IFG) represents an intermediary condition between normal fasting glucose and diabetes mellitus and, specifically, whether elderly adults with IFG have higher disease burden, cardiovascular risk, and systemic inflammation and higher 2-year mortality and incident disease. DESIGN: Prospective observational study. SETTING: Population-derived cohort. PARTICIPANTS: Individuals with a mean age of 78.6 ± 4.7 (N = 945). MEASUREMENTS: Disease was ascertained using a standardized questionnaire at baseline and 2 years. Fasting metabolic, inflammatory, and oxidative metabolism markers were measured. Disease prevalence, cardiovascular risk, and biochemical markers were compared to determine disease burden and metabolic disturbances in IFG. Adjusted odds ratios (ORs) for 2-year all-cause mortality and incident disease were determined. RESULTS: IFG prevalence was 41%. Individuals with IFG had higher baseline rates of heart disease than those with normal fasting glucose (NFG), similar to that in individuals with diabetes mellitus. IFG was characterized by higher inflammatory markers and oxidative metabolism end products and was an intermediary between NFG and diabetes mellitus for triglycerides and malondialdehyde. Discriminant analysis showed that IFG was independently associated with stroke and higher triglycerides and oxidative stress. Two-year all-cause mortality was 3.9%. The 2-year adjusted ORs for all-cause mortality, incident cardiac disease, stroke, and cancer were similar between IFG and NFG, using both American Diabetes Association and World Health Organization IFG criteria. IFG did not predict secondary cardiac events, stroke, or cancer. CONCLUSION: IFG was an intermediary condition for heart disease, inflammation, and oxidative stress in elderly adults but not for 2-year incident disease or all-cause mortality. Longer-term prospective studies are needed to clarify whether IFG in elderly adults portends greater morbidity and mortality.

Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men.

BACKGROUND: High serum homocysteine (HCY) levels have been associated with thromboembolic cerebrovascular disease, but their relationship to microvascular disease is uncertain. Homocysteine also has a direct neurotoxic effect and has been linked to brain atrophy and an increased risk of Alzheimer disease. OBJECTIVE: To examine the relationship of HCY levels to brain and cognitive measures in a healthy community sample. DESIGN: Cross-sectional study. SETTING: Individuals residing in Canberra and Queanbeyan, Australia, who were participating in the longitudinal PATH Through Life Project. PARTICIPANTS: Individuals aged 60 to 64 years selected randomly from the community, 196 men and 189 women. MAIN OUTCOME MEASURES: Regression coefficients with HCY level as the putative determinant and various magnetic resonance imaging measures (brain atrophy index, ventricle-brain ratios, volume of periventricular and deep white matter hyperintensities) and cognitive measures (information processing speed, verbal memory, fine motor speed) as dependent measures. RESULTS: Homocysteine levels did not have a significant relationship with brain atrophy index or ventricle-brain ratios. High HCY levels were related to increased deep white matter hyperintensities but not periventricular white matter hyperintensities, after correcting for levels of folate, vitamin B(12), creatinine, and thyrotropin; hypertension; smoking; and diabetes, the relationship being significant only in men. Homocysteine levels were related to impairment in verbal memory and fine motor speed but not after the previously mentioned correction. CONCLUSIONS: Total HCY level is independently related to leukoaraiosis in middle-aged men, and this may be functionally relevant in the form of mild cognitive impairment. The remediation of hyperhomocysteinemia should begin early in life if its deleterious effects on the brain are to be prevented.

Oxidative stress is closely associated with insulin resistance in genotypes 1 and 3 chronic hepatitis C.

BACKGROUND: Chronic hepatitis C (CHC) infection is associated with insulin resistance and with oxidative stress, but the relationship between the two has not been thoroughly examined. PURPOSE: To evaluate the association between insulin resistance and oxidative stress in CHC patients. METHOD: In 115 CHC patients (68 with genotype 1 and 47 with genotype 3), the relationship between the serum concentration of malondialdehyde (MDA), a marker of oxidative stress and insulin resistance as defined by the homeostasis model (HOMA-IR) was examined. RESULTS: There was no significant difference in MDA levels between genotype 1- and genotype 3-infected subjects (12.882 vs. 12.426 ng/mL, p = 0.2). By univariate analysis, factors associated with HOMA-IR in both genotypes were oxidative stress as measured by MDA (p = 0.002), body mass index (BMI), portal activity, and fibrosis. Genotype-specific differences in HOMA-IR association were steatosis and triglycerides (TG) for genotype 1, and age and glutathione (GSH) for genotype 3. In a stepwise multiple linear regression analysis in both genotypes, MDA was a significant and independent predictor of HOMA-IR (p = 0.04). As expected, BMI and fibrosis were likewise independently correlated to HOMA-IR. In addition, MDA levels were higher (p < 0.001) and GSH levels were lower (p = 0.023) in insulin-resistant subjects compared to their insulin-sensitive counterparts. CONCLUSIONS: It is concluded that in CHC, oxidative stress is an independent predictor of HOMA-IR, irrespective of virus genotype. Further studies on the role of oxidative stress in the development of insulin resistance in CHC are warranted.

Risk factors for late-life cognitive decline and variation with age and sex in the Sydney Memory and Ageing Study.

INTRODUCTION: An aging population brings increasing burdens and costs to individuals and society arising from late-life cognitive decline, the causes of which are unclear. We aimed to identify factors predicting late-life cognitive decline. METHODS: Participants were 889 community-dwelling 70-90-year-olds from the Sydney Memory and Ageing Study with comprehensive neuropsychological assessments at baseline and a 2-year follow-up and initially without dementia. Cognitive decline was considered as incident mild cognitive impairment (MCI) or dementia, as well as decreases in attention/processing speed, executive function, memory, and global cognition. Associations with baseline demographic, lifestyle, health and medical factors were determined. RESULTS: All cognitive measures showed decline and 14% of participants developed incident MCI or dementia. Across all participants, risk factors for decline included older age and poorer smelling ability most prominently, but also more education, history of depression, being male, higher homocysteine, coronary artery disease, arthritis, low health status, and stroke. Protective factors included marriage, kidney disease, and antidepressant use. For some of these factors the association varied with age or differed between men and women. Additional risk and protective factors that were strictly age- and/or sex-dependent were also identified. We found salient population attributable risks (8.7-49.5%) for older age, being male or unmarried, poor smelling ability, coronary artery disease, arthritis, stroke, and high homocysteine. DISCUSSION: Preventing or treating conditions typically associated with aging might reduce population-wide late-life cognitive decline. Interventions tailored to particular age and sex groups may offer further benefits.

Factors predicting reversion from mild cognitive impairment to normal cognitive functioning: a population-based study.

INTRODUCTION: Mild cognitive impairment (MCI) is associated with an increased risk of developing dementia. However, many individuals diagnosed with MCI are found to have reverted to normal cognition on follow-up. This study investigated factors predicting or associated with reversion from MCI to normal cognition. METHODS: Our analyses considered 223 participants (48.9% male) aged 71-89 years, drawn from the prospective, population-based Sydney Memory and Ageing Study. All were diagnosed with MCI at baseline and subsequently classified with either normal cognition or repeat diagnosis of MCI after two years (a further 11 participants who progressed from MCI to dementia were excluded). Associations with reversion were investigated for (1) baseline factors that included diagnostic features, personality, neuroimaging, sociodemographics, lifestyle, and physical and mental health; (2) longitudinal change in potentially modifiable factors. RESULTS: There were 66 reverters to normal cognition and 157 non-reverters (stable MCI). Regression analyses identified diagnostic features as most predictive of prognosis, with reversion less likely in participants with multiple-domain MCI (p = 0.011), a moderately or severely impaired cognitive domain (p = 0.002 and p = 0.006), or an informant-based memory complaint (p = 0.031). Reversion was also less likely for participants with arthritis (p = 0.037), but more likely for participants with higher complex mental activity (p = 0.003), greater openness to experience (p = 0.041), better vision (p = 0.014), better smelling ability (p = 0.040), or larger combined volume of the left hippocampus and left amygdala (p<0.040). Reversion was also associated with a larger drop in diastolic blood pressure between baseline and follow-up (p = 0.026). DISCUSSION: Numerous factors are associated with reversion from MCI to normal cognition. Assessing these factors could facilitate more accurate prognosis of individuals with MCI. Participation in cognitively enriching activities and efforts to lower blood pressure might promote reversion.

The value of the metabolic syndrome concept in elderly adults: is it worth less than the sum of its parts?

OBJECTIVES: To determine whether the metabolic syndrome (MetS) or its components were more closely associated with disease states and inflammation in elderly adults. DESIGN: Sydney Memory and Ageing Study. Cross-sectional, observational cohort. SETTING: Population-derived, community-dwelling elderly adults. PARTICIPANTS: Nine hundred thirty individuals aged 70 to 90. MEASUREMENTS: Age- and sex-adjusted odds ratios (ORs) for disease states; fasting circulating inflammatory markers and oxidative metabolism byproducts. RESULTS: MetS was associated with diabetes mellitus (OR = 4.1, P < .001) and bowel cancer (OR = 9.1, P = .03) but not in analyses that controlled for component conditions. Models containing component conditions had the strongest associations with heart disease. Disease associations were improved after addition of component conditions to the MetS model. The reverse did not hold: disease associations were not improved when MetS was added to the components model. Low high-density lipoprotein cholesterol (HDL-C) was independently associated with myocardial infarction (OR = 2.32) and angina pectoris (OR = 2.59) (both P < .008). Waist circumference was independently associated with cancer (OR = 1.82, P = .008). Although MetS was associated with higher C-reactive protein, vascular cell adhesion molecule, interleukin-6, amyloid A, homocysteine, and malondialdehyde, it explained less than half of the variance of models containing its components. CONCLUSION: The observation that MetS is associated with disease states and markers of circulating inflammation in the elderly is explained mainly by abdominal obesity and low HDL-C. Longitudinal data will further clarify these cross-sectional findings that MetS appears to be less than the sum of its parts in elderly adults.

The association between systemic inflammation and cognitive performance in the elderly: the Sydney Memory and Ageing Study.

Inflammation may contribute to cognitive decline and dementia. This study examined the cross-sectional relationships between markers of systemic inflammation (C-reactive protein, interleukins-1ß, -6, -8, -10, -12, plasminogen activator inhibitor, serum amyloid A, tumour necrosis factor-α and vascular adhesion molecule-1) and cognitive function in 873 non-demented community-dwelling elderly participants aged 70-90 years. Regression analyses were performed to determine the relationships between cognitive domains and inflammatory markers, controlling for age, sex, education, cardiovascular risk factors, obesity and other metabolic factors, smoking, alcohol consumption, depression and presence of the apolipoprotein ε4 genotype. Regression analyses were repeated using four factors derived from a factor analysis of the cognitive tests. After Bonferroni correction for multiple testing, associations remained between raised levels of interleukin-12 and reduced performance in processing speed. Marked sex differences were noted in the abovementioned findings, with only females being significantly affected. Using the four factors derived from the factor analyses of cognitive test as dependent variables, interleukins-12 and -6 were both associated with the processing speed/executive function factor, even after controlling for relevant confounding factors. Thus, markers of systemic inflammation are related to cognitive deficits in a non-clinical community-dwelling elderly population, independent of depression, cardiovascular or metabolic risk factors, or presence of apolipoprotein ε4 genotype. Additional research is required to elucidate the pathophysiology and longitudinal development of these relationships.

Plasma apolipoprotein levels are associated with cognitive status and decline in a community cohort of older individuals.

OBJECTIVES: Apolipoproteins have recently been implicated in the etiology of Alzheimer's disease (AD). In particular, Apolipoprotein J (ApoJ or clusterin) has been proposed as a biomarker of the disease at the pre-dementia stage. We examined a group of apolipoproteins, including ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH and ApoJ, in the plasma of a longitudinal community based cohort. METHODS: 664 subjects (257 with Mild Cognitive Impairment [MCI] and 407 with normal cognition), mean age 78 years, from the Sydney Memory and Aging Study (MAS) were followed up over two years. Plasma apolipoprotein levels at baseline (Wave 1) were measured using a multiplex bead fluorescence immunoassay technique. RESULTS: At Wave 1, MCI subjects had lower levels of ApoA1, ApoA2 and ApoH, and higher levels of ApoE and ApoJ, and a higher ApoB/ApoA1 ratio. Carriers of the apolipoprotein E ε4 allele had significantly lower levels of plasma ApoE, ApoC3 and ApoH and a significantly higher level of ApoB. Global cognitive scores were correlated positively with ApoH and negatively with ApoJ levels. ApoJ and ApoE levels were correlated negatively with grey matter volume and positively with cerebrospinal fluid (CSF) volume on MRI. Lower ApoA1, ApoA2 and ApoH levels, and higher ApoB/ApoA1 ratio, increased the risk of cognitive decline over two years in cognitively normal individuals. ApoA1 was the most significant predictor of decline. These associations remained after statistically controlling for lipid profile. Higher ApoJ levels predicted white matter atrophy over two years. CONCLUSIONS: Elderly individuals with MCI have abnormal apolipoprotein levels, which are related to cognitive function and volumetric MRI measures cross-sectionally and are predictive of cognitive impairment in cognitively normal subjects. ApoA1, ApoH and ApoJ are potential plasma biomarkers of cognitive decline in non-demented elderly individuals.

Risk profiles of subtypes of mild cognitive impairment: the sydney memory and ageing study.

OBJECTIVES: To compare the risk profiles of mild cognitive impairment (MCI) subtypes in a population-based elderly sample. DESIGN: Cross-sectional study. SETTING: The population-based Sydney Memory and Ageing Study. PARTICIPANTS: Seven hundred fifty-seven English-speaking, community-dwelling individuals without dementia aged 70 to 90. MEASUREMENTS: Comprehensive neuropsychological assessments were used to diagnose MCI and its subtypes, categorized as amnestic (aMCI) or nonamnestic (naMCI) and as single- (sdMCI) or multiple- (mdMCI) domain. Risk profiles were derived from sociodemographic; lifestyle; and cardiac, physical, mental, and general health data. Whole-sample and sex-specific comparisons between aMCI and naMCI and between mdMCI and sdMCI were made using age- (and sex-) adjusted multiple regressions comprising initially significant univariate factors. RESULTS: Risk factors for MCI were presence of the apolipoprotein E (APOE) ε4 allele, heart disease, high homocysteine, poor odor identification ability, low visual acuity, and lower mental activity. The odds of having naMCI rather than aMCI were lower with greater levels of social activity and greater if taking antihypertensives, the latter particularly in men. The odds of naMCI were greater in men taking antidepressants or with a longer 6-meter walk time and in women with hypertension. The odds of having mdMCI rather than sdMCI were greater in participants with a history of depression or having the APOE ε4 allele. Greater odds of mdMCI were also associated with lower mental activity, particularly for women. For men, the odds of mdMCI were greater with the APOE ε4 allele and lower if diagnosed with high cholesterol. CONCLUSION: MCI subtypes exhibit distinctive, sex-dependent risk profiles. This is consistent with MCI subtypes having different etiologies and outcomes and supports the idea that subtyping MCI may offer predictive validity and clinical application.

Antioxidant levels in peripheral blood, disease activity and fibrotic stage in chronic hepatitis C.

BACKGROUND: This study addressed the suggested association between levels of the antioxidants glutathione (GSH), vitamin C and vitamin E in peripheral blood and the histological activity and fibrosis stage in chronic hepatitis C (CHC). We then determined whether regular antioxidant supplementation influenced these antioxidant levels or disease severity. METHODS: Clinical, biochemical, histological and demographic data were collected from 247 CHC patients at the time of liver biopsy. Whole blood total GSH, plasma vitamin C and E were assessed by high-performance liquid chromatography. Statistical analyses were performed to test for associations between the variables and to identify independent predictors for hepatic necroinflammatory and fibrosis scores. RESULTS: GSH and vitamin C, but not vitamin E correlated with both portal/periportal activity (r = -0.19, P = 0.004; r = -0.19, P = 0.009 respectively) and fibrosis stage (r = -0.18, P = 0.007; r = -0.18, P = 0.009 respectively). GSH was an independent negative predictor of portal/periportal inflammation (P = 0.02) and fibrosis (P = 0.01). Vitamin C was an independent negative predictor of fibrosis stage (P = 0.02). Antioxidant intake was associated with higher vitamin C (P < 0.0001) and vitamin E (P = 0.005) levels, but not GSH. CONCLUSIONS: Whole blood GSH and plasma vitamin C are negatively associated with hepatic portal/periportal inflammation and fibrosis stage in CHC. Controlled intervention studies with vitamin C and agents that boost endogenous GSH levels are warranted.

Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample.

BACKGROUND: Case control studies have supported a relationship between low folic acid and vitamin B112 and high homocysteine levels as possible predictors of depression. The results from epidemiological studies are mixed and largely from elderly populations. METHOD: A random subsample of 412 persons aged 60-64 years from a larger community sample underwent psychiatric and physical assessments, and brain MRI scans. Subjects were assessed using the PRIME-MD Patient Health Questionnaire for syndromal depression and severity of depressive symptoms. Blood measures included serum folic acid, vitamin B12, homocysteine and creatinine levels, and total antioxidant capacity. MRI scans were quantified for brain atrophy, subcortical atrophy, and periventricular and deep white-matter hyperintensity on T2-weighted imaging. RESULTS: Being in the lowest quartile of homocysteine was associated with fewer depressive symptoms, after adjusting for sex, physical health, smoking, creatinine, folic acid and B12 levels. Being in the lowest quartile of folic acid was associated with increased depressive symptoms, after adjusting for confounding factors, but adjustment for homocysteine reduced the incidence rate ratio for folic acid to a marginal level. Vitamin B12 levels did not have a significant association with depressive symptoms. While white-matter hyperintensities had significant correlations with both homocysteine and depressive symptoms, the brain measures and total antioxidant capacity did not emerge as significant mediating variables. CONCLUSIONS: Low folic acid and high homocysteine, but not low vitamin B12 levels, are correlates of depressive symptoms in community-dwelling middle-aged individuals. The effects of folic acid and homocysteine are overlapping but distinct.