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Purpose: We examined whether differences in findings of studies examining mild cognitive impairment (MCI) were associated with recruitment methods by comparing sample characteristics in two contemporaneous Australian studies, using population-based and convenience sampling., Method: The Sydney Memory and Aging Study invited participants randomly from the electoral roll in defined geographic areas in Sydney. The Australian Imaging, Biomarkers and Lifestyle Study of Ageing recruited cognitively normal (CN) individuals via media appeals and MCI participants via referrals from clinicians in Melbourne and Perth. Demographic and cognitive variables were harmonized, and similar diagnostic criteria were applied to both samples retrospectively., Results: CN participants recruited via convenience sampling were younger, better educated, more likely to be married and have a family history of dementia, and performed better cognitively than those recruited via population-based sampling. MCI participants recruited via population-based sampling had better memory performance and were less likely to carry the apolipoprotein E ε4 allele than clinically referred participants but did not differ on other demographic variables., Conclusion: A convenience sample of normal controls is likely to be younger and better functioning and that of an MCI group likely to perform worse than a purportedly random sample. Sampling bias should be considered when interpreting findings., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Non-demented community-dwelling older adults aged 70-90 years (n = 1,037) randomly recruited from the electoral roll completed neuropsychological and medical assessments over six years. The overall prevalence of mild cognitive impairment (MCI) at baseline was 36.7%. Risk factors for MCI include APOE ε4 allele carrier status, high homocysteine, heart disease, poor odour identification, low visual acuity and low mental activity, but notable age and sex differences were observed. Neuropsychiatric symptoms were rare; depression was the most common and was associated with cognitive impairment in at least one domain as well as subsequent dementia 2 years later. Poorer cognitively demanding functional abilities were associated with cognitive impairment. Biomarkers for cognitive impairment and decline were identified. Inflammatory markers and plasma apolipoprotein levels were associated with poorer performance in the attention/processing speed domain. Measures of white matter lesions, white matter integrity, sulcal morphology and tractography were identified as novel biomarkers of early cognitive decline. Stronger deactivation in the posteromedial cortex with increasing memory load on functional MRI predicted future decline. Compared to previous reports, our prevalence rates of MCI were higher but rates of progression to dementia and reversion to normal were similar, as were risk factors for progression to dementia.

Measuring the geometry or morphology of sulcal folds has recently become an important approach to investigating neuroanatomy. However, relationships between cortical sulci and other brain structures are poorly understood. The present study investigates how age-related changes in sulcal width are associated with age-related changes in traditional indices of brain structure such as cortical thickness, and cortical gray matter (GM), white matter (WM), subcortical, and white matter hyperintensity (WMH) volumes. These indices and sulcal width were measured at baseline and at two-year follow up in 185 community-dwelling individuals (91 men) aged 70-89 years. There were significant increases in sulcal width and WMH volume, and significant decreases in all other indices between baseline and follow-up. Sulcal widening was associated with decreases in cortical GM, subcortical and WM volumes. A further association between sulcal width and cortical thickness became non-significant when cortical GM volume was controlled for. Our findings give insights into the mechanisms responsible for cortical sulcal morphology. The relationships between sulcal morphology and other common measures suggest that it could be a more comprehensive measure for clinical classifications than traditional neuroimaging metrics, such as cortical thickness., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders., Methods/design: Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress., Discussion: The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.

Language has been extensively investigated by functional neuroimaging studies. However, only a limited number of structural neuroimaging studies have examined the relationship between language performance and brain structure in healthy adults, and the number is even less in older adults. The present study sought to investigate correlations between grey matter volumes and three standardized language tests in late life. The participants were 344 non-demented, community-dwelling adults aged 70-90 years, who were drawn from the population-based Sydney Memory and Ageing Study. The three language tests included the Controlled Oral Word Association Task (COWAT), Category Fluency (CF), and Boston Naming Test (BNT). Correlation analyses between voxel-wise GM volumes and language tests showed distinctive GM correlation patterns for each language test. The GM correlates were located in the right frontal and left temporal lobes for COWAT, in the left frontal and temporal lobes for CF, and in bilateral temporal lobes for BNT. Our findings largely corresponded to the neural substrates of language tasks revealed in fMRI studies, and we also observed a less hemispheric asymmetry in the GM correlates of the language tests. Furthermore, we divided the participants into two age groups (70-79 and 80-90 years old), and then examined the correlations between structural laterality indices and language performance for each group. A trend toward significant difference in the correlations was found between the two age groups, with stronger correlations in the group of 70-79 years old than those in the group of 80-90 years old. This difference might suggest a further decline of language lateralization in different stages of late life.

The present study investigated changes in sulcal morphology associated with late-life aging and mild cognitive impairment (MCI). Participants were 219 community-dwelling 70-90 year-olds from the Sydney Memory and Ageing Study; all had MRI scans and were classified as having normal cognition (NC) or MCI at each of waves 1 and 2, two years apart. Automated methods were used to calculate a global sulcal index (g-SI), widths of five prominent sulci, and regional cortical thickness. There were significant longitudinal declines in g-SI and increases in sulcal width among the entire sample, but the rate of change differed among cognitive subgroups. Participants with MCI at both waves (persisting MCI) showed accelerated sulcal widening, particularly for the superior frontal and superior temporal sulci. The sulcal morphology of participants who reverted from MCI to NC was more consistent with stable NC than persisting MCI. Overall cortical thickness decreased between waves similarly across the subgroups. While changes in sulcal morphology are characteristic of normal late-life aging, they are accelerated in individuals with MCI (in contrast to changes in cortical thickness). Sulcal measures also differentiate between persistent MCI and MCI that reverts to NC, and may thus help in predicting the prognosis of MCI patients., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

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.

Background: Dementia caregiving is strongly linked to depression, anxiety, and burden in caregivers. Little is known about whether the same holds for people supporting an older person with mild cognitive impairment (MCI). We aim to systematically review the current evidence for negative caregiver outcomes in MCI using Pearlin and colleagues' stress process model as a theoretical framework., Methods: Widely used scientific literature databases were searched using MCI- and caregiver-related terms with "AND" relations. Results were limited to quantitative English language articles published in peer-reviewed journals between 1980 and November 2010., Results: Of the 266 identified articles, six reported relevant depression data on 988 MCI caregivers (73% spouses). The pooled Center for Epidemiologic Studies Depression scale (CES-D) mean score was 12.95 (standard deviation = 6.16). The pooled depression prevalence (i.e., CES-D score ≥ 16 or equivalent) was 23%. Two studies compared depression in MCI and dementia caregivers, indicating higher levels in dementia caregivers. Other outcomes, such as burden, stress, or anxiety, were only investigated by individual studies precluding pooling of data. Similarly, pooling of the data on the predictors of caregiver outcomes was impossible because of data heterogeneity. However, descriptive analysis of predictors revealed that Pearlin and colleagues' caregiver stress process model at least partially applies to the MCI context., Conclusions: The studies reviewed were all cross sectional in design, involving clinical samples, thus limiting generalizability. Depression and psychological comorbidity, although not as pronounced as in dementia caregivers, are common complications in MCI caregivers. The long-term course of outcomes in MCI caregivers requires further investigation., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Mild cognitive impairment (MCI) is associated with an increased dementia risk. This study reports incidence of MCI subtypes, rates of progression to dementia, and stability of MCI classification., Methods: We examined 873 community-dwelling adults aged 70 to 90 years over 2 years as part of an ongoing population-based longitudinal study, the Sydney Memory and Ageing Study. Neuropsychological testing assessed five cognitive domains, and a diagnosis of no cognitive impairment, MCI, or dementia (follow-up only) was made according to published criteria., Results: The incidence of MCI was 104.6 (95% confidence interval: 81.6-127.7) per 1000 person-years, with higher incidence in men (men, 156.8; women, 70.3). Incidence rates for single-domain amnestic, multiple-domain amnestic, single-domain nonamnestic, and multiple-domain nonamnestic MCI were 47.7, 7.9, 45.0, and 3.9 per 1000 person-years, respectively. The 2-year rate of progression from MCI at baseline to dementia was 4.8%, being highest for multidomain amnestic MCI (9.1%). Of those with MCI at baseline, 28.2% reverted to no cognitive impairment at follow-up. Sensitivity analyses by redefining criteria for cognitive impairment did not affect stability of diagnosis, although changing the threshold of domain impairment reduced baseline MCI prevalence from 36.7% to 5.7% and incidence to 23.5, and increased 2-year progression rate from MCI to dementia to 14.3%., Conclusions: Incidence rates for MCI are higher than previously reported, particularly in men and for single-domain MCI; rates for amnestic and nonamnestic MCI were comparable. Multidomain amnestic MCI was the most likely subtype to progress to dementia, but overall, the diagnosis of MCI, particularly single-domain MCI, shows considerable instability., (Copyright © 2012 The Alzheimer's Association. All rights reserved.)

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.

Background: Alzheimer's disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD., Methods: We studied 155 cognitively normal (CN) and 27 'late' aMCI individuals with stable diagnosis over 2 years, and 39 'early' aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts., Results: Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes., Conclusions: Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.

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.

Objectives: : The aim of this article was to examine the prevalence and incidence over 2 years of mild cognitive impairment (MCI) in English speakers from linguistic minorities., Design: : Cross-sectional and longitudinal with 2-year follow-up., Setting: : Eastern suburbs of Sydney, New South Wales, Australia., Participants: : Eight hundred twenty-seven community-dwelling participants from English-speaking backgrounds (ESB) and 160 participants from non-English-speaking backgrounds (NESB) recruited through the electoral roll., Measurements: : Participants were assessed using 11 neuropsychological tests measuring memory, language, attention/processing speed, and executive function. Questionnaires measuring functional impairment and subjective cognitive complaints were completed by participants or informants., Results: : We found a two- to threefold higher prevalence of MCI in NESB participants than ESB participants depending on the impairment criterion applied. This difference was because of higher rates of objective cognitive impairment in NESB participants; rates of functional impairment and subjective cognitive complaints did not differ between the groups. This association between MCI prevalence and NESB status was accounted for by the proportion of time the participant spoke English and the proportion of life they had lived in Australia, but not by age, gender, and education. There were no differences between NESB and ESB groups in MCI incidence, dementia incidence, or rates of conversion from MCI to dementia. NESB participants had lower rates of reversion from MCI to normal., Conclusions: : It is difficult to accurately diagnose MCI in persons from linguistic minority groups, even when proficient in English as neuropsychological test scores may not be valid for these groups. English language ability and level of acculturation should be considered when assessing older persons from ethnic minority groups.

Background: Previous studies using diffusion tensor imaging (DTI) have observed microstructural abnormalities in white matter regions in both Alzheimer's disease and mild cognitive impairment (MCI). The aim of this work was to examine the abnormalities in white matter and subcortical regions of MCI and its subtypes in a large, community-dwelling older aged cohort., Methods: A community-based sample of 396 individuals without dementia underwent medical assessment, neuropsychiatric testing, and neuroimaging. Of these, 158 subjects were classified as MCI and 238 as cognitively normal (controls) based on international MCI consensus criteria. Regional fractional anisotropy (FA) and mean diffusivity (MD) measures were calculated from the DTI and compared between groups. The false discovery rate correction was applied for multiple testing., Results: Subjects with MCI did not have significant differences in FA compared with controls after correction for multiple testing, but had increased MD in the right putamen, right anterior limb of the internal capsule, genu and splenium of the corpus callosum, right posterior cingulate gyrus, left superior frontal gyrus, and right and left corona radiata. When compared with controls, changes in left anterior cingulate, left superior frontal gyrus, and right corona radiata were associated with amnestic MCI (aMCI), whereas changes in the right putamen, right anterior limb of the internal capsule, and the right corona radiata were associated with non-amnestic MCI (naMCI). On logistic regression, the FA values in the left superior gyrus and MD values in the anterior cingulate distinguished aMCI from naMCI., Conclusions: MCI is associated with changes in white matter and subcortical regions as seen on DTI. Changes in some anterior brain regions distinguish aMCI from naMCI.

Mild cognitive impairment (MCI) is a heterogeneous neurocognitive disorder that can be classified into various subtypes. The present study aims to examine the gray matter (GM) atrophy patterns of MCI subtypes in comparison with a cognitively healthy group. Participants, including 135 MCI subjects and 120 cognitively healthy controls, were drawn from the Sydney Memory and Ageing Study. The MCI subjects were first categorized into amnestic (aMCI) and non-amnestic (naMCI) subtypes, which were then divided into single-domain (aMCI-SD and naMCI-SD) and multiple-domain subtypes (aMCI-MD and naMCI-MD). Furthermore, naMCI-SD was divided into three subgroups (language, processing speed, and executive function) according to individual cognitive impairment. Voxel-wise GM volumes were then compared between MCI subtypes and controls. The aMCI group had significantly lower GM volumes in the bilateral hippocampi and temporal cortices than the controls. This was mainly due to GM reduction of aMCI-MD but not aMCI-SD, as the latter did not show any significant GM reduction. GM reduction of naMCI and its two subdivisions was shown in widespread brain regions compared to controls. GM volumes of the multiple-domain subtypes (aMCI-MD and naMCI-MD) were lower than their single-domain counterparts (aMCI-SD and naMCI-SD) in the frontal and temporal lobes, respectively. Moreover, the language subgroup of naMCI-SD showed GM reduction in the frontal and temporal lobes compared to controls. MCI subtypes displayed specific patterns of GM atrophy that appear to be related to their various clinical presentations, which implies that underlying mechanisms of MCI subtypes are different., (Copyright © 2012 Elsevier B.V. All rights reserved.)

While the conversion from mild cognitive impairment to Alzheimer's disease has received much recent attention, the transition from normal cognition to mild cognitive impairment is largely unexplored. The present pattern recognition study addressed this by using neuropsychological test scores and neuroimaging morphological measures to predict the later development of mild cognitive impairment in cognitively normal community-dwelling individuals aged 70-90years. A feature selection algorithm chose a subset of neuropsychological and FreeSurfer-derived morphometric features that optimally differentiated between individuals who developed mild cognitive impairment and individuals who remained cognitively normal. Support vector machines were used to train classifiers and test prediction performance, which was evaluated via 10-fold cross-validation to reduce variability. Prediction performance was greater when using a combination of neuropsychological scores and morphological measures than when using either of these alone. Results for the combined method were: accuracy 78.51%, sensitivity 73.33%, specificity 79.75%, and an area under the receiver operating characteristic curve of 0.841. Of all the features investigated, memory performance and measures of the prefrontal cortex and parietal lobe were the most discriminative. Our prediction method offers the potential to detect elderly individuals with apparently normal cognition at risk of imminent cognitive decline. Identification at this stage will facilitate the early start of interventions designed to prevent or slow the development of Alzheimer's disease and other dementias., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Amnestic mild cognitive impairment (aMCI) is a syndrome widely considered to be prodromal Alzheimer's disease. Accurate diagnosis of aMCI would enable earlier treatment, and could thus help minimize the prevalence of Alzheimer's disease. The aim of the present study was to evaluate a magnetic resonance imaging-based automated classification schema for identifying aMCI. This was carried out in a sample of community-dwelling adults aged 70-90 years old: 79 with a clinical diagnosis of aMCI and 204 who were cognitively normal. Our schema was novel in using measures of both spatial atrophy, derived from T1-weighted images, and white matter alterations, assessed with diffusion tensor imaging (DTI) tract-based spatial statistics (TBSS). Subcortical volumetric features were extracted using a FreeSurfer-initialized Large Deformation Diffeomorphic Metric Mapping (FS+LDDMM) segmentation approach, and fractional anisotropy (FA) values obtained for white matter regions of interest. Features were ranked by their ability to discriminate between aMCI and normal cognition, and a support vector machine (SVM) selected an optimal feature subset that was used to train SVM classifiers. As evaluated via 10-fold cross-validation, the classification performance characteristics achieved by our schema were: accuracy, 71.09%; sensitivity, 51.96%; specificity, 78.40%; and area under the curve, 0.7003. Additionally, we identified numerous socio-demographic, lifestyle, health and other factors potentially implicated in the misclassification of individuals by our schema and those previously used by others. Given its high level of performance, our classification schema could facilitate the early detection of aMCI in community-dwelling elderly adults., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (© 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.)

Objective and Background: Previous studies exploring cognitive functioning in RLS have either relied on medication free subjects sampled within a clinical context or on subjects with RLS symptoms identified within population samples. However, in contrast to clinical samples, population studies so far have not excluded the use of antidepressants, hypnotics, or RLS relevant medication, and study subjects were exclusively older in age. We therefore report on cognitive functioning in predominantly middle-aged individuals with RLS symptoms sampled from the general population and free of mental disorders and of hypnotic, psychopharmacological, or RLS relevant medication., Methods: Participants with RLS symptoms and individually matched controls were identified within the MARS control study, a non-clinical control group study of 550 participants between 18 and 75 years. Cognitive functioning was assessed with the Trail Making Test A and B and a computerized German version of the Wisconsin Card Sorting Test (WCST). Performance was compared between 41 participants with RLS and 133 controls, and between a subgroup of 10 participants with frequent RLS symptoms (≥ 2/week) and 36 matched controls., Results: There was no difference in cognitive functioning for the complete group of participants with RLS and controls. However, participants with frequent RLS symptoms showed impaired performance in the WCST., Conclusion: The results of this study add to the evidence that executive functioning is impaired in individuals with frequent RLS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: While activities of daily living are by definition preserved in mild cognitive impairment (MCI), there is evidence of poorer instrumental activities of daily living (IADL) functioning in MCI compared to normal ageing. The aims of the present study were to examine differences in IADL between individuals with MCI and cognitively normal elderly, and to examine the relationships of IADL with cognitive functions., Methods: The sample of 762 community-living participants aged 70-90 were assessed with a comprehensive neuropsychological test battery and with the informant-completed Bayer-Activities of Daily Living Scale (B-ADL)., Results: Compared to cognitively normal individuals, the MCI group was rated as having more difficulties on the B-ADL and performed worse on cognitive tests. Factor analysis of the B-ADL items yielded two factors, which were labelled 'high cognitive demand' (HCD) and 'low cognitive demand' (LCD). Individuals with MCI scored worse than cognitively normal participants on the HCD factor but similarly on the LCD factor. Men were rated as having more difficulties on the HCD, but not the LCD, factor compared to women. The HCD factor score correlated significantly with all five cognitive domains measured, but the LCD factor correlated significantly only with attention/processing speed and to a lesser extent with executive function., Conclusions: Having more difficulties in IADL, especially those with higher demand on cognitive capacities, was found to be associated with MCI and overall cognitive functioning. This has implications for the definition of MCI, as lack of functional impairment is generally used as a criterion for diagnosis., (Copyright © 2010 John Wiley & Sons, Ltd.)

The relationship between cognitive functions and brain structure has been of long-standing research interest. Most previous research has attempted to relate cognition to volumes of specific brain structures or thickness of cortical regions, with relatively few studies examining other features such as cortical surface anatomy. In this study, we examine the relationship between cortical sulcal features and cognitive function in a sample (N=316) of community-dwelling subjects aged between 70 and 90 years (mean=78.06±4.75; male/female=130/186) who had detailed neuropsychological assessments and brain MRI scans. Using automated methods on 3D T1-weighted brain scans, we computed global sulcal indices (g-SIs) of the whole brain and average sulcal spans of five prominent sulci. The g-SI, which reflects the complexity of sulcal folds across the cerebral hemispheres, showed a significant positive correlation with performance in most cognitive domains including attention/processing speed, memory, language and executive function. Regionally, a negative correlation was found between some cognitive functions and sulcal spans, i.e. poorer cognitive performance was associated with a wider sulcal span. Of the five cognitive domains examined, the performance of processing speed was found to be correlated with the spans of most sulci, with the strongest correlation being with the superior temporal sulcus. Memory did not show a significant correlation with any individual sulcal index, after correcting for age and sex. Of the five sulci measured, the left superior temporal sulcus showed the highest sensitivity, with significant correlations with performances in all cognitive domains except memory, after controlling for age, sex, years of education and brain size. The results suggest that regionally specific sulcal morphology is associated with cognitive function in elderly individuals., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The basal forebrain area (BFA) is closely connected to the hippocampus by virtue of cholinergic neuronal projections. Structural neuroimaging studies have shown reduced volumes of both structures in Alzheimer's disease and its prodromal stage mild cognitive impairment (MCI), but generally not in the same investigation. By combining voxel based morphometry and region of interest methods, we measured the grey matter (GM) volumes of the two brain regions with the goal of elucidating their contributions to MCI and its two subtypes (amnestic MCI and non-amnestic MCI) in an elderly epidemiological sample. The results replicated previous findings that the atrophies of both brain regions were associated with an increased likelihood of MCI and its two subtypes. However, in a regression model for the prediction of MCI with GM volumes for both regions used as predictors, only hippocampal atrophy remained significant. Two possible interpretations for this pattern of results were discussed. One is that the observed correlation between BFA atrophy and MCI is spurious and due to the hippocampal atrophy correlated with both. Alternatively, our observation is consistent with the possibility that BFA atrophy has a causal effect on MCI, which is mediated via its influence on hippocampal atrophy. Furthermore, we found that the left hippocampal atrophy had a stronger effect than the right hippocampus and bilateral BFA in the prediction of amnestic MCI occurrence when the four unilateral areas were entered into one regression model. In addition, a slight but statistically significant difference was found in the left hippocampal volume between APOE ε4 allele carriers and non-carriers, consistent with prior studies.

Background/aim: While a number of studies examined the neuroanatomical correlates of cognitive function in older adults, the results have been inconsistent. Examination of a large epidemiologically acquired sample with high-resolution magnetic resonance imaging has the potential to enhance the evidence in this field., Methods: The participants were 326 non-demented elderly adults undergoing a battery of neuropsychological tests and brain magnetic resonance imaging scans. Regression analyses were performed to examine the correlation between voxel-based grey matter (GM) volume and four cognitive domain scores., Results: Positive correlations were observed between specific GM volumes and cognitive domains, i.e. bilateral temporal lobes and hippocampi with language; bilateral temporal, parietal, and occipital lobes with processing speed; and bilateral frontal, temporal, parietal, and occipital lobes with executive function. The positive correlation between verbal memory performance and GM volume in the bilateral medial temporal lobes was not significant after correction for age., Conclusion: Our findings suggest that the location of GM correlates of cognitive tests is largely consistent with the conventional understanding of the neuroanatomical basis of cognition. However, the lack of hemispheric predominance in these GM correlates, and the extensively positive correlation between GM volume and cognitive performance, perhaps reflects the characteristics of the ageing brain., (Copyright © 2011 S. Karger AG, Basel.)

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.

Restless legs syndrome (RLS) is a frequent sleep-related movement disorder with disturbed sleep and quality of life. RLS patients complain about increased daytime sleepiness, but there are only few and inconsistent reports about cognitive functioning in this group. We compared cognitive performance of 23 unmedicated RLS patients to that of 23 healthy controls matched individually for age, gender, and educational level. Cognitive tasks were chosen to assess short-term attention, working memory, learning and memory, verbal fluency, and executive functioning. RLS patients performed worse than controls in the area of attention and verbal fluency, and performance in these tasks was associated with RLS severity, sleep quality, depression scores, and memory. There was no difference for working memory, memory, learning, cognitive flexibility, and abstract reasoning. We conclude that there is evidence for deficits in short-term attention and verbal fluency in RLS patients., (© 2010 Movement Disorder Society.)

Mild cognitive impairment (MCI) as a clinical diagnosis has limited specificity, and identifying imaging biomarkers may improve its predictive validity as a pre-dementia syndrome. This study used diffusion tensor imaging (DTI) to detect white matter (WM) structural alterations in MCI and its subtypes, and aimed to examine if DTI can serve as a potential imaging marker of MCI. We studied 96 amnestic MCI (aMCI), 69 non-amnestic MCI (naMCI), and 252 cognitively normal (CN) controls. DTI was performed to measure fractional anisotropy (FA), and tract-based spatial statistics (TBSS) were applied to investigate the characteristics of WM changes in aMCI and naMCI. The diagnostic utility of DTI in distinguishing MCI from CN was further evaluated by using a binary logistic regression model. We found that FA was significantly reduced in aMCI and naMCI when compared with CN. For aMCI subjects, decreased FA was seen in the frontal, temporal, parietal, and occipital WM, together with several commissural, association, and projection fibres. The best discrimination between aMCI and controls was achieved by combining FA measures of the splenium of corpus callosum and crus of fornix, with accuracy of 74.8% (sensitivity 71.0%, specificity 76.2%). For naMCI subjects, WM abnormality was more anatomically widespread, but the temporal lobe WM was relatively spared. These results suggest that aMCI is best characterized by pathology consistent with early Alzheimer's disease, whereas underlying pathology in naMCI is more heterogeneous, and DTI analysis of white matter structural integrity can serve as a potential biomarker of MCI and its subtypes., (Copyright 2010 Elsevier Inc. All rights reserved.)

The concept of "mild cognitive impairment" (MCI) refers to alterations in cognition in the transition between normal aging and dementia. However, from a neuropsychological point of view the conventional diagnostic criteria appear not sufficiently valid. In particular, it is still difficult to differentiate between subjects with MCI and subjects with depression plus cognitive deficits on the basis of their neuropsychological profiles. The aim of this study is to compare cognitive deficit patterns of subjects with MCI and with depression. 24 subjects with MCI, 50 subjects with depression (DEP) and 20 healthy control subjects were included (age: 55-74years). The neuropsychological assessment consisted of standardized tests to assess attention, memory, and executive functions. Compared to healthy controls both subject groups showed significantly lower performance in all cognitive domains. However, we did not find significant differences in cognitive performance between MCI and DEP subjects, neither at baseline nor at follow-up. In addition, preliminary results of follow-up assessments after 2 (DEP) and 6months (MCI), respectively, revealed no significant changes in cognition in subjects with depression, regardless of whether depressive symptoms had improved. Subjects with MCI also showed no changes in cognition at follow-up. The comparable neuropsychological patterns identified in the two subject groups may be understood as a consequence of similar alterations in cognitive systems, supporting the idea of a final common pathway disorder. Thus, the cognitive deficits present in a subgroup of subjects with depression may possibly better be understood in the context of MCI., (Copyright 2009 Elsevier Ltd. All rights reserved.)

A large number of structural brain studies using magnetic resonance imaging (MRI) have reported age-related cortical changes and sex difference in brain morphology. Most studies have focused on cortical thickness or density, with relatively few studies of cortical sulcal features, especially in the elderly. In this paper, we report global sulcal indices (g-SIs) of both cerebral hemispheres and the average sulcal span in six prominent sulci, as observed in T1-weighted scans obtained from a large community cohort of 319 non-demented individuals aged between 70 and 90 years (mean=78.06+/-4.75; male/female=149/170), using automated methods. Our results showed that for both hemispheres, g-SIs had significant negative correlations with age in both men and women. Using an interactive effect analysis, we found that g-SIs for men declined faster with age than that for women. The widths of all six sulcal spans increased significantly with age, with largest span increase occurring in the superior frontal sulcus. Compared to women, men had significantly wider sulcal spans for all sulci that were examined. Our findings suggest that both age and sex contribute to significant cortical gyrification differences and variations in the elderly. This study establishes a reference for future studies of age-related brain changes and neurodegenerative diseases in the elderly., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system and cognitive impairment are consistent findings in depression. This study examines the associations between HPA system regulation, cognitive functioning, and psychopathology in depressed inpatients on admission and at discharge., Methods: The HPA system dysregulation was evaluated with the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. Cognitive assessment included speed of information processing, divided and selective attention, as well as short-term and working memory. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Data from 75 depressed inpatients are reported, 51 (68%) of them achieved remission., Results: Despite a significant reduction of depressive symptoms between admission and discharge, a high rate of patients remained cognitively impaired. Selective attention improved significantly in remitters and nonremitters, while speed of information processing increased only in remitters. The cortisol response to the DEX/CRH test decreased significantly only in remitters, which was uncorrelated with cognitive performance. In nonremitters, severity of depression was significantly correlated with information processing time while improvement in short-term memory was negatively associated with the cortisol response at discharge., Conclusions: Our data support the assumption that psychopathological symptoms and the HPA system dysregulation can be dissociated in their impact on cognitive functioning in depressed patients.

Background: Epidemiologic and clinical studies suggest comorbidity between major depressive disorder (MDD) and obesity. To elucidate the impact of weight on the course of depression beyond comorbidity, we investigated psychopathology, attention, neuroendocrinology, weight change, and treatment response in MDD patients, depending on their weight., Methods: Four hundred eight inpatients with MDD participated in the Munich Antidepressant Response Signature Study, designed to discover biomarkers and genotypes that are predictive for clinical outcome. Psychopathology and anthropometric parameters were monitored weekly in 230 patients. In subsamples, combined dexamethasone-corticotropin-releasing hormone and attention tests were conducted at admission and discharge. One thousand twenty-nine diagnosed matched controls served for morphometric comparisons., Results: Patients with MDD had a significantly higher body mass index (BMI) compared with healthy controls. Patients with high BMI (> or =25) showed a significantly slower clinical response, less improvement in neuroendocrinology and attention, and less weight gain than did patients with normal BMI (18.5 < or = BMI < 25) during antidepressant treatment., Conclusions: Our findings suggest that overweight and obesity characterize a subgroup of MDD patients with unfavorable treatment outcome.