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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.)

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: 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.)

Objective: Depression might be a risk factor for dementia. However, little is known about the prevalence of depressive symptoms in mild cognitive impairment (MCI) and whether mood or motivation-related symptoms are predominant., Method: A total of 767 non-demented community-dwelling adults aged 70-90 years completed a comprehensive assessment, including neuropsychological testing, and a past psychiatric/medical history interview. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS) and Kessler Psychological Distress Scale (K10). Exploratory factor analysis was performed on the GDS and K10 to derive 'mood' and 'motivation' subscales., Results: A total of 290 participants were classified as having MCI and 468 as cognitively normal (CN). Participants with MCI reported more depressive symptoms, and more MCI participants met the cut-off for clinically significant symptoms, relative to CN participants. Those with amnestic MCI (aMCI), but not non-amnestic MCI, had more depressive symptoms and were more likely to meet the cut-off for clinically significant depressive symptoms, relative to CN participants. Participants with MCI reported more mood-related symptoms than CN participants, while there were no differences between groups on motivation-related symptoms., Conclusion: Individuals with MCI, especially aMCI, endorse more depressive symptoms when compared with cognitively intact individuals. These findings highlight the importance of assessing and treating depressive symptoms in MCI., (© 2012 John Wiley & Sons A/S.)

Objectives: To investigate relationships between the use of cardiovascular medications, including angiotensin system-blocking medications (ASBMs), orthostatic hypotension (OH), fall risk, and falls in community-dwelling older people., Design: Prospective cohort study., Setting: Sydney, Australia., Participants: Five hundred twenty community-dwelling older adults., Measurements: Medical, medication and falls history were obtained from a standardized questionnaire in all participants. Blood pressure was measured in supine, seated, and tilted positions. Fall risk was assessed using the Physiological Profile Assessment (PPA). Falls data were collected prospectively for 12 months using monthly fall calendars. Participants were defined as nonfallers (no falls) and fallers (≥ 1 falls) at the end of the 12-month follow-up., Results: Participants taking medications affecting the angiotensin system had greater quadriceps strength, but after adjusting for sex, this difference became insignificant. People taking ASBMs were less likely to fall (odds ratio = 0.68, 95% confidence interval = 0.48-0.97), and the association between ASBMs and falls remained significant after adjusting for sex, body mass index, PPA score, and psychotropic medication and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) use. OH was more frequently observed in participants taking alpha adrenergic receptor blockers (α-blockers), but the presence of OH did not increase fall risk., Conclusion: The use of cardiovascular medications in older people did not increase the risk of falls, and the use of ASBMs was associated with lower fall risk. The mechanisms for this apparent protective effect are unclear and appear not to be directly related to muscle strength. More research is required to elucidate the possible protective effects of certain cardiovascular medications in relation to falls in older people., (© 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.)

Objectives: Pulse wave velocity (PWV) is a measure of arterial stiffness and its increase with ageing has been associated with damage to cerebral microvessels and cognitive impairment. This study examined the relationship between carotid-femoral PWV and specific domains of cognitive function in a non-demented elderly sample., Method: Data were drawn from the Sydney Memory and Ageing Study, a cohort study of non-demented community-dwelling individuals aged 70-90 years, assessed in successive waves two years apart. In Wave 2, PWV and cognitive function were measured in 319 participants. Linear regression was used to analyse the cross-sectional relationship between arterial stiffness and cognitive function in the whole sample, and separately for men and women. Analysis of covariance was used to assess potential differences in cognition between subjects with PWV measurements in the top and bottom tertiles of the cohort. Covariates were age, education, body mass index, pulse rate, systolic blood pressure, cholesterol, depression, alcohol, smoking, hormone replacement therapy, apolipoprotein E ε4 genotype, use of anti-hypertensive medications, history of stroke, transient ischemic attack, myocardial infarction, angina, diabetes, and also sex for the whole sample analyses., Results: There was no association between PWV and cognition after Bonferroni correction for multiple testing. When examining this association for males and females separately, an association was found in males, with higher PWV being associated with lower global cognition and memory, however, a significant difference between PWV and cognition between males and females was not found., Conclusion: A higher level of PWV was not associated with lower cognitive function in the whole sample.

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.

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.

Objective: Age differences in episodic memory (memory) have been attributed to a general reduction in processing speed (the "speed mediation hypothesis"), but also to declines in the efficiency of executive functions operations ("executive decline hypothesis"). To test predictions from these competing models, we examined the mediating effects of processing speed (speed) and executive functions (executive) on age and episodic memory in three older adult cohorts., Method: The first sample comprised 842 individuals from the Sydney Memory and Aging Study (MAS). The second and third samples included 476 individuals from the Older Australian Twins Study (OATS), with each twin from a pair randomly assigned to form two samples. A series of regression analyses was performed on each of the three samples independently, so as to obtain the sizes and statistical significances of the indirect effects of age on each of the memory variables, mediated by each of the Executive and Speed composites. Sex was a control variable for all analyses. Analyses were repeated with current depression as an additional control variable., Results: Data from the MAS sample suggested that both Speed and Executive composites were significant mediators, with the former having a stronger mediation effect. A similar pattern was found in the two OATS samples., Conclusions: These findings are consistent with those of previous studies in which speed had a stronger mediating effect than executive on age-related variation in memory. They provide further support for the speed mediation hypothesis, although not negating the executive decline hypothesis., ((c) 2012 APA, all rights reserved.)

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.

Inflammation may contribute to cognitive decline and dementia. This study examined the cross-sectional relationships between markers of systemic inflammation (C-reactive protein, interleukins-1β, -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.

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., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

This study addresses the paucity of research on the prospective relationship between a range of inflammatory markers and symptoms of depression and anxiety during aging. In the Sydney Memory and Aging Study, the relationships between remitted depression, current and first onset of symptoms of depression or anxiety (Geriatric Depression Scale and Goldberg Anxiety Scale (GDS, GAS), and markers of systemic inflammation (C-reactive protein (CRP), interleukins-1β, -6, -8, -10, -12, plasminogen activator inhibitor-1 (PAI-1), serum amyloid A, tumor necrosis factor-α, and vascular adhesion molecule-1) were investigated. The sample consists of N=1037 non-demented community-dwelling elderly participants aged 70-90 years assessed at baseline and after 2-years. All analyses were adjusted for gender, age, years of education, total number of medical disorders diagnosed by a doctor, cardiovascular disorders, endocrine disorders, smoking, body mass index, currently using anti-depressants, NSAIDS or statins and diabetes mellitus. The results show a significant linear relationship between increasing levels of IL-6 and depressive symptoms at baseline only, whereas IL-8 was associated with depressed symptoms at baseline and at 2 years follow-up. In addition, IL-8 was associated with first onset of mild to moderate depressive symptoms over 2 years. Logistic regression analyses showed that PAI-1 (OR=1.37, 95% CI=1.10-1.71, p=0.005) was associated with remitted depression. Results for anxiety symptoms were negative. The findings are suggestive of IL-6 and IL-8 being associated with current symptoms and IL-8 being associated with first onset of depressive symptoms, whereas PAI-1 could be regarded as a marker of remitted depression., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Twin studies have shown that many aspects of brain structure are heritable, suggesting a strong genetic contribution to brain structure. Less is known about functional aspects of the brain, in particular biologically relevant metabolites in the brain such as those measured by proton magnetic resonance spectroscopy (((1))H MRS), N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myoinositol (ml), which have been suggested as possible markers of brain aging and early dementia. We examined 296 (56 male/108 female monozygotic and 43 male/89 female dizygotic) older twins (mean age 72.2 ± 5.5 years, range 65-88), for the levels of these metabolites relative to the H(2)O signal in the posterior cingulate cortex using ((1))H MRS. All metabolites showed substantial heritability, which was greatest for the neuronal integrity marker NAA (72%), and less so for the others - Cr (51%), Cho (33%) and ml (55%). The heritability of these markers did not change significantly with age or sex. The genetic determination of NAA, along with the evidence that NAA levels change in aging and neurodegenerative diseases suggest that it is a potential endophenotype of brain aging and dementia., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Background: Reports of neuroleptic malignant syndrome (NMS) induced by second-generation antipsychotic drugs highlight a propensity for atypical clinical presentations., Aims: To systematically compare the clinical profile of NMS induced by first- (1G-NMS) and second-generation antipsychotic drugs (2G-NMS)., Method: The Australian Adverse Drug Reaction Advisory Committee (ADRAC) database was searched to identify individuals with NMS reported between April 1994 and September 2010. The clinical characteristics of 208 people with NMS induced by monotherapy with first- or second-generation antipsychotic drugs, as well as presenting features of NMS, were compared., Results: The individuals with 2G-NMS were younger and more likely to have a psychotic disorder diagnosis. The features of NMS in the two groups were very similar, except that people with 2G-NMS were less likely to present with rigidity or extrapyramidal signs compared with those with 1G-NMS. This difference was due to the lower rates of rigidity in those with clozapine-induced NMS. Mortality was considerably lower for those with 2G-NMS (3.0%) compared with 1G-NMS (16.3%), and the former were more likely to have received supportive treatment., Conclusions: The clinical profile of 2G-NMS is largely similar to 1G-NMS, with clozapine-induced NMS being differentiated by the relative lack of rigidity as a feature. Mortality is lower for 2G-NMS.

"Executive functions" (EF) is a multidimensional construct which encompasses many higher-order cognitive control operations, and is considered a potential mediator of age-associated changes in other cognitive domains. Here we examine the heritability of four measures of EF, and the genetic influences on their covariation with general cognitive abilities (GCA) from the Older Australian Twins Study. Participants included 117 pairs of monozygotic twins, 98 pairs of dizygotic twins, and 42 single twins, with a mean age of 71. Genetic modeling showed that additive genetic factors contributed to 59, 63,29, and 31% of the variance in the four measures: working memory, verbal fluency, response inhibition and cognitive flexibility, respectively. The phenotypic associations among the four EF measures were modest, which is in line with other evidence that EF is a multi-dimensional construct.All of the covariation between the EF measures was attributable to a common genetic factor. Similarly, all of the covariation between EF and General Cognitive Ability was explained by a common genetic factor, with no significant covariance due to environmental (E) factors. The genetic correlations between the measures were moderately high, suggesting that they may have common biological underpinnings. The genetic influence in the covariation of the EF measures and GCA also suggests that some aspects of EF and GCA share the same genes or same set of genes.

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.)

The fornix is a major efferent tract of the hippocampus, a structure critical for normal memory function. However, the role of structural degradation of the fornix in memory dysfunction in mild cognitive impairment (MCI) has remained unclear. We used diffusion tensor tractography to measure microstructural properties of the fornix and the corticospinal tract (CST), as a control tract, in 206 cognitively normal subjects, 76 amnestic MCI (aMCI) and 51 non-amnestic MCI (naMCI) subjects. Hippocampal volumes were measured using deformation-based morphometry. We found significant fractional anisotropy reductions in the left fornix and radial diffusivity (RD) increases in bilateral fornices in aMCI, but not in naMCI, compared with controls. No significant changes in the CST were found in aMCI subjects, but naMCI subjects showed significantly increased RD and axial diffusivity of the right CST, compared with controls. Increased left fornical RD measure was correlated with poor verbal memory performance in aMCI subjects. In addition, reduced microstructural integrity of the fornix was associated with hippocampal atrophy in aMCI. This study suggests that microstructural alteration of the fornix is a contributor to early episodic memory dysfunction in non-demented individuals.

Neuropsychiatric symptoms (NPS) are non-cognitive disturbances such as depression. Rates of NPS have been shown to increase as cognitive ability declines and may be useful in predicting transition from mild cognitive impairment (MCI) to dementia. This community-based study reports the association between NPS and cognitive decline over two years. Participants included 873 community dwelling adults aged 70-90 years enrolled in the Sydney Memory and Ageing Study. NPS were assessed by the Neuropsychiatric Inventory (NPI). Cognitive impairment was defined by diagnosis (MCI or incident dementia) or neuropsychological test performance across five cognitive domains. Cognitive decline was defined by progression to dementia or worse neuropsychological performance. Total NPS at baseline did not differ between those without cognitive impairment (26.2%) and those with MCI (28.8%), but agitation and apathy were associated with MCI. Only baseline depression was associated with dementia at follow-up. Total NPS at baseline was cross-sectionally associated with cognitive impairment in executive function, attention, and global cognition, but did not predict cognitive decline. Depression, anxiety, agitation, anxiety, and apathy were all associated with impairment in at least one cognitive domain, but only anxiety and agitation were significantly associated with cognitive decline. Sensitivity analyses applied more stringent criteria for NPS and cognitive impairment in MCI but did not alter interpretation of results from the main analysis. Overall rates of NPS at baseline were not associated with MCI, dementia, or cognitive decline over two years. Additional follow-up is needed to further examine this association over a longer time course.

Processing speed (PS) is one of the basic elements of cognitive functions and has been regarded as a "common mechanism" which mediates general cognitive decline in aging. The present study of Australian twins (117 monozygotic pairs, 98 dizygotic pairs, and 42 single twins aged 65 years and over), estimated the genetic influences in five measures of PS: Digit Symbol Coding (DS), Trail Making Test A (TMTA), Stroop color naming and word reading (Stroop), Simple Reaction Time (SRT) and Complex Reaction Time (CRT); and their covariation with general cognitive ability (GCA): reasoning, problem-solving, and memory. Additive genetic factors explained 62% of the variance in DS, 42% in TMTA, 57% in Stroop, and 48% and 35% in SRT and CRT, respectively. Quantitative genetic modeling showed that all of the covariation between the five PS measures and GCA could be explained by one common genetic factor, while the covariation between the PS measures was partly explained by non-shared environmental as well as genetic influences. The genetic correlation among the PS measures was strongest for DS and TMTA, and between the PS measures and GCA was strongest for DS. These findings suggest that the different PS measures, as well as GCA were to a large extent influenced by the same set of genes and that the relationship between PS and GCA is entirely due to shared-genetic influences.

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.)

Depressive symptoms are common in the elderly and they have been associated with cognitive and functional impairment. However, relatively less is known about the relationship of a lifetime history of depression to cognitive impairment and functional status. The aim of this cross-sectional study was to assess whether current depressive symptoms and past depression are associated with cognitive or functional impairment in a community-based sample representative of east Sydney, Australia. We also examined whether there was an interaction between current and past depression in their effects on cognitive performance. Eight hundred non-demented aged participants received a neuropsychological assessment, a past psychiatric history interview and the 15-item Geriatric Depression Scale. The Bayer-Activities of Daily Living scale was completed by an informant to determine functional ability. Clinically relevant depressive symptoms were present in 6.1% of the sample and 16.6% reported a history of depression. Participants with current depression had significantly higher levels of psychological distress and anxiety, and lower life satisfaction and performed worse on memory and executive function compared to participants without current depression. After controlling for anxiety the effect on executive function was no longer significant while the effect on memory remained significant. A history of depression was associated with worse executive function, higher levels of psychological distress and anxiety, and lower life satisfaction. After controlling for psychological distress the effect of past depression on executive function was no longer significant. There were no significant interactions between current and past depression in their effects on cognitive performance. There were no differences between participants with or without current depression and with or without past depression on functional abilities. These results support the view that current and past depressive episodes are associated with poorer cognitive performance but not with functional abilities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Aim: To examine the concordance rates of common medical conditions and neurocognitive performance in monozygotic (MZ) and dizygotic (DZ) older twins., Methods: Twins aged ≥ 65 years and living in the three Eastern states of Australia were recruited through the Australian Twin Registry and underwent detailed neuropsychological and medical assessment., Results: Assessments were conducted on 113 MZ and 96 DZ twin pairs, with a mean age of 70.5 years. MZ twins were more concordant than DZ twins for hypertension and asthma. MZ twins had higher correlations than DZ twins on most neuropsychological tests, with the exception of some tests related to processing speed. The concordance rate for mild cognitive impairment or dementia was 76.2% in MZ twins and 42.9% in DZ twins, a non-significant difference., Conclusions: Except for some aspects of processing speed, most cognitive functions in older individuals show significant heritability. The heritability of neurocognitive disorders is, however, low., (© 2011 The Authors. Australasian Journal on Ageing © 2011 ACOTA.)

Objective: The lack of generally accepted diagnostic criteria for neuroleptic malignant syndrome (NMS) impedes research and clinical management of patients receiving antipsychotic medications. The purpose of this study was to develop NMS diagnostic criteria reflecting a broad consensus among clinical knowledge experts, represented by an international multispecialty physician panel., Participants: Eleven psychiatrists, 2 neurologists, 2 anesthesiologists, and 2 emergency medicine specialists participated in a formal Delphi consensus procedure., Evidence: A core bibliography consisting of 12 prominent, current reviews of the NMS literature was identified by an objective, comprehensive electronic search strategy. Each panel member was given a copy of these references and asked to examine them before commencing the survey process., Consensus Process: After reviewing the core bibliography, panel members were asked to list any clinical signs or symptoms or diagnostic studies that they believed, on the basis of their knowledge and clinical experience, were useful in making a diagnosis of NMS. In subsequent survey rounds, panel members assigned priority points to these items, and items that failed to receive a minimum priority score were eliminated from the next round. Information about individual panel member responses was fed back to the group anonymously in the form of the group median or mean and the number of members who had ranked or scored each survey item. The a priori consensus endpoint was defined operationally as a change of 10% or less in the mean priority score for any individual item, and an average absolute value change of 5% or less across all items, between consecutive rounds. The survey was conducted from January 2009 through September 2009., Results: Consensus was reached on the fifth round regarding the following criteria: recent dopamine antagonist exposure, or dopamine agonist withdrawal; hyperthermia; rigidity; mental status alteration; creatine kinase elevation; sympathetic nervous system lability; tachycardia plus tachypnea; and a negative work-up for other causes. The panel also reached a consensus on the relative importance of these criteria and on the following critical values for quantitative criteria: hyperthermia, > 100.4°F or > 38.0°C on at least 2 occasions; creatine kinase elevation, at least 4 times the upper limit of normal; blood pressure elevation, ≥ 25% above baseline; blood pressure fluctuation, ≥ 20 mm Hg (diastolic) or ≥ 25 mm Hg (systolic) change within 24 hours; tachycardia, ≥ 25% above baseline; and tachypnea, ≥ 50% above baseline., Conclusions: These diagnostic criteria significantly advance the field because they represent the consensus of an international multispecialty expert panel, include critical values, provide guidance regarding the relative importance of individual elements, and are less influenced by particular theoretical biases than most previously published criteria. They require validation before being applied in clinical settings., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

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.)

Background: Early detection of progressive cognitive decline offers an opportunity for preventative interventions with enormous public health implications. Functional neuroimaging during cognitive activity in individuals at risk of dementia has the potential to advance this objective. In a prior study, we evaluated the utility of a novel functional magnetic resonance imaging paradigm that incorporated a graded working memory (WM) task to detect changes associated with mild cognitive impairment (MCI). We observed greater deactivation of posteromedial cortex (PMC) under conditions of increased WM load in MCI compared with control subjects. Our objective here is to test whether this paradigm can predict ensuing functional decline., Methods: Thirty individuals with MCI who underwent baseline functional magnetic resonance image scanning were followed clinically for 2 years. Multiple linear regression analyses were used to determine whether deactivation in PMC under increased load at baseline independently predicted decline in instrumental activities of daily living (IADL)., Results: Greater deactivation in PMC to increased load predicted greater decline in IADL after controlling for baseline clinical severity, MCI subtype, apolipoprotein ε4 carrier status, gray matter, PMC and hippocampal volumes, and task performance., Conclusions: Increased deactivation observed at baseline was a harbinger of subsequent functional decline as measured by IADL in a cohort with MCI. This graded WM challenge may operate like a memory stress test by producing a threshold effect beyond which abnormal deactivation is elicited in MCI subjects who are at greatest risk of functional decline., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

In this review, we examined the published reports on the heritability of cognitive functioning in old age. Twenty-four papers from five study centers, comprising of participants with a mean age of 65 years and above were examined. The comparability of findings from different studies was compromised by the use of different measures for the same cognitive domain, and with large scale twin studies in cognitive aging limited to a few Scandinavian countries. While the results from cross-sectional samples appear to lend support for the notion that heritability of cognitive functions decreases in the elderly, the findings are best considered inconclusive. Longitudinal reports show little evidence for genetic effects, but an increase in unique environmental influences on the rate of cognitive change as age increases. In relation to the two prominent theories of cognitive aging, the genetic influence on processing speed as a major contributor to cognitive aging has been indicated in three reports, whereas the genetic relationship between executive functions and other cognitive functions has not been explored. Only two studies have focused on sex difference and did not find sex-specific genetic influence in cognitive abilities. This review indicates that there are complex relationships between heritability, environmental influence, and cognitive functions in the elderly. It highlights the need for more research, with consistent and appropriate cognitive measures, with data obtained from larger and more geographically and culturally diverse twin samples.

Objectives: Objective cognitive impairment determined by neuropsychological test performance is a core criterion for the diagnosis of mild cognitive impairment (MCI), yet no consensus has been reached on how this criterion should be operationalized. The aims of this study were to investigate the effect of varying the criteria used to determine cognitive impairment (CI) on prevalence and case definition and to examine comparability of different criteria., Design: Cross-sectional study., Setting: Sydney Memory and Ageing Study, Australia., Participants: Nine hundred eighty-seven nondemented community-dwelling adults aged 70-90 years were enrolled in this study., Measurements: Participants received a comprehensive neuropsychological test battery measuring four cognitive domains. They were classified as normal or cognitively impaired by applying two types of “impairment” rule that varied the statistical threshold for impairment and the criteria used to determine impairment for each cognitive domain. Prevalence of four MCI cognitive subtypes was determined according to nine different criteria and two types of normative data. Rates of CI were compared in persons of English-speaking and non-English-speaking backgrounds (NESB)., Results: Prevalence of CI ranged from 4 to 70% depending on the impairment criteria used. Agreement between different criteria was poor to moderate. This lack of consistency had greatest impact on MCI subtype classifications with many being reclassified as “normal” or into a different subtype when stringency of the criteria was increased or decreased. Higher rates of impairment were found in persons of NESB across all cognitive domains., Conclusions: The prevalence of CI was strongly affected by the choice of neuropsychological assessment parameters. Guidelines for operationalizing CI are required.

Objectives: To document the prevalence of self- and informant report of cognitive problems, usually referred to as "subjective cognitive complaints" (SCCs), in a community-dwelling sample of older adults and to examine the relationship between SCCs and objective impairment, mood, and personality measures., Participants: Eight hundred twenty-seven nondemented community-dwelling adults aged 70-90 years., Measurements: Participants were asked 24 SCC questions, including the Memory Complaint Questionnaire (MAC-Q), and completed neuropsychological testing in the domains of memory, language, executive function, visuospatial skills, and psychomotor speed. The Geriatric Depression Scale, Goldberg Anxiety Scale, and Neuroticism, Openness, and Conscientiousness from the NEO-Five Factor Inventory were used as measures of participants' psychological status. Informants completed 19 SCC questions, including a modified short Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)., Results: Overall, 95.5% of participants or their informants endorsed at least one SCC. Although participants were more likely to endorse a memory complaint, informants seemed more accurate in endorsing a complaint when cognitive impairment was objectively present. SCC correlated with participants' scores on measures of depression, anxiety, neuroticism, and inversely with measures of openness and conscientiousness. Age, education, and sex had little impact on these effects. Regression analysis showed that psychological factors explained the number of complaints more than cognitive performance., Conclusions: The usefulness of SCCs as a criterion for mild cognitive impairment is questioned because of their high prevalence and their relationship to psychological factors. This may be helpful for clinicians to bear in mind when presented with patients with cognitive complaints.

Background: A 48 year-old woman presented with an 18 month history of bizarre and complex delusions on a background of social, behavioral and cognitive decline over several years. Her psychosis progressed despite receiving high doses of antipsychotics. The patient's father also had a psychotic episode in his 40s. He subsequently developed motor neuron disease, which caused his death at 68 years of age., Investigations: Physical examination, neuropsychological testing, nerve conduction studies, brain MRI and transcranial magnetic stimulation., Diagnosis: On the basis of the patient's age at onset of the delusions, imaging findings and family history, a diagnosis of frontotemporal dementia (FTD) was favored over a primary psychotic disorder. The ubiquitin-positive and TAR DNA binding protein 43-positive inclusions that were found at autopsy confirmed the diagnosis of FTD., Management: The patient was treated with various antipsychotics at high doses; however, her delusions continued to progress. No disease-specific treatments for FTD currently exist.

Background/aims: Raised low-grade systemic inflammation has been associated with dementia, and preliminary studies suggest an association with mild cognitive impairment (MCI). This study examines the relationship between systemic inflammation and MCI subtypes., Methods: We measured the inflammatory markers C-reactive protein, interleukins (IL)-1β, -6, -8, -10 and -12, plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), tumor necrosis factor-α (TNF-α) and vascular adhesion molecule-1 (VCAM-1) in the Sydney Memory and Ageing Study (MAS) cohort, a longitudinal study of 1,037 Australians aged 70-90 years., Results: After adjusting for possible confounding variables, levels of TNF-α and SAA were higher in participants with MCI compared to cognitively normal individuals, and some sex differences were apparent. Nonamnestic multiple domain MCI was associated with higher levels of IL-1β and IL-12, TNF-α and SAA compared to cognitively normal, amnestic MCI (single and multiple domain) and nonamnestic single domain MCI. PAI-1 levels were higher in cognitively normal and nonamnestic multiple domain MCI than in amnestic multiple domain MCI., Conclusion: Our findings suggest an association between specific inflammatory markers and MCI subtypes, highlight sex differences in the association with MCI, and point to a discrete impact of systemic inflammation on cognition., (Copyright © 2011 S. Karger AG, Basel.)

The Older Australian Twins Study (OATS) was recently initiated to investigate genetic and environmental factors and their associations and interactions in healthy brain ageing and ageing-related neurocognitive disorders. The study extends the classic MZ-DZ design to include one or two equivalently aged siblings for each twin pair and utilizes the rich resources of the Australian Twin Registry. The study has a number of distinguishing features including comprehensive psychiatric, neuropsychological, cardiovascular, metabolic, and neuroimaging assessments, a longitudinal design and links with a brain donor program. The study measures many behavioral and environmental factors, but in particular lifetime physical and mental activity, physical and psychological trauma, loss of parent early in life, later losses and life events, early-life socioeconomic environment, alcohol and drug use, occupational exposure, and nutrition. It also includes comprehensive cardiovascular assessment, blood biochemistry, genetics and proteomics. The socio-demographic and health data on the first 172 pairs of twins participating in this study are presented. Prevalence of mild cognitive impairment is 12.8% and of dementia 1.5% in the sample. The target sample size is 1000, with at least 400 pairs of twins aged 65-90 years. The cohort will be assessed every two years, with in-depth assessments being repeated. OATS offers an excellent opportunity for collaboration with other similar studies as well as researchers who share the same interests.

Objectives: Mild cognitive impairment (MCI) is recognized as a predementia state, but its definition is inconsistent and only 20%-30% develop dementia after 2 years. Biomarkers may help identify individuals at greatest risk of progressive decline. The authors examine a novel neuroimaging technique, diffusion tensor imaging (DTI) as a potential biomarker of MCI., Design: Cross-sectional prospective study., Setting: Subjects were recruited randomly using the electoral roll from two electorates in East Sydney, Australia., Participants: A community-dwelling sample (N = 249) and age 70-90 years., Measurements: Screening to exclude dementia, comprehensive neuropsychiatric assessment, cognitive test battery, structural magnetic resonance imaging and DTI to obtain measures of fractional anisotropy (FA) and mean diffusivity (MD). MCI was diagnosed by standard criteria., Results: After controlling for age, sex, and years of education, the amnestic MCI (aMCI) group demonstrated microstructural pathology in the parahippocampal white matter, frontal white matter, splenium of corpus callosum, and posterior cingulate region. The nonamnestic MCI (naMCI) group demonstrated microstructural pathology in the frontal white matter, internal capsule, occipital white matter, and the posterior cingulate region. A binary logistic regression model showed that DTI of the left posterior cingulate was significant in identifying persons with aMCI to an accuracy of 85.1%. Receiver operating characteristics curve analysis yielded a sensitivity of 80% and specificity of 60.3% in distinguishing aMCI from naMCI and the normal comparison group., Conclusion: DTI of the posterior cingulate region discriminates MCI from cognitively normal individuals with accuracy and has the potential to be used as a biomarker of MCI, in particular aMCI.

Neuroleptic malignant syndrome (NMS) is a rare but potentially severe idiosyncratic adverse reaction usually seen in the context of treatment with antipsychotic drugs. Although NMS is historically associated with the classic or 'typical' antipsychotic drugs, it is also a potential adverse effect of atypical antipsychotic drugs. The widespread use of atypical antipsychotic drugs highlights the need to examine the data relating to the symptomatology, diagnosis, classification and management of NMS with these newer agents. We used MEDLINE and EMBASE to identify NMS case reports and systematic reviews published to June 2008 related to the atypical antipsychotic drugs clozapine, olanzapine, risperidone, paliperidone, aripiprazole, ziprasidone, amisulpride and quetiapine. Case reports and reviews were systematically examined. Our review suggests that, in general, NMS associated with atypical antipsychotic drugs manifests in a typical manner. One notable exception is clozapine-induced NMS, which appears less likely to manifest with extrapyramidal features, including rigidity and tremor. The available literature highlights the divergence of opinion relating to the core diagnostic features of NMS and its conceptualization as a categorical versus dimensional disorder. Both these issues have relevance for the identification of atypical or milder forms of NMS, which are sometimes seen with atypical antipsychotic drugs.

Objective: The prevalence of mental disorders in the elderly is disputed. The debate in this area can be informed by data from large population surveys that contain sufficient elderly participants. The aim of the present paper was to provide the first direct comparison of the prevalence and demographic correlates of ICD-10 anxiety and affective disorders in the middle-aged and the elderly., Method: The 12 month prevalence and demographic correlates of affective and anxiety disorders were compared in a community sample of middle-aged and elderly Australian residents who took part in the Australian National Mental Health and Well-being Survey (NMHWS)., Results: One in seven middle-aged participants and one in 16 elderly participants experienced symptoms consistent with any anxiety or affective disorder in the preceding 12 months. Compared to the middle-aged participants, the elderly had lower rates for most affective and anxiety disorders, and for the combined presence of any disorder. Demographic correlates of mental disorder, especially marital status, were different for the two groups., Conclusions: Community-dwelling elderly in Australia have lower rates of mental disorder compared to the middle-aged. Differences in demographic correlates between groups support the notion that the determinants of mental disorder in the elderly differ substantially from those in middle age.

Objective: To describe the 1- and 12-month prevalence of mental disorders, their demographic correlates, and their impact on service utilization and disability in individuals 65 years of age and over in a comprehensive epidemiological survey of mental health in Australia., Methods: A noninstitutionalized national probability sample of elderly Australian residents was interviewed as part of the Australian National Mental Health and Well-being Survey (NMHWS). The prevalence of International Classification of Diseases, Tenth Revision and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition mental disorders was estimated from the Composite International Diagnostic Interview and other screening instruments., Results: Of 1,792 elderly NMHWS respondents, 13% reported symptoms consistent with a mental disorder in the past 1 month, and 16% reported symptoms consistent with a mental disorder in the past 12 months. Women experienced higher rates of affective disorders and generalized anxiety disorder and had lower rates of substance abuse compared with men. After excluding cognitive disorder, increasing age was associated with less likelihood of having symptoms of any mental disorder. Older age and never having been married were associated with less likelihood of having symptoms of an affective disorder. Those with cognitive impairment were more likely to have had symptoms consistent with an affective disorder. Comorbidity was predictive of increasing disability on the 12-item Short Form but rates of mental health consultation were low, even for those with multiple disorders., Conclusion: Community-dwelling elderly Australians experience substantial rates of mental disorders. Demographic correlates of mental disorder in this elderly population appear to differ from those established in younger populations. Mental disorder in elderly Australians is associated with significant disability, but rates of specialist mental health consultation is low, even for those with multiple comorbidities. The reasons for this must be examined.

Objective: This article examines the influence of sociodemographic, biological, and health variables on Mini-Mental State Exam (MMSE) performance, and assesses how the diversity of the population should be reflected in the MMSE cutoff scores used for screening., Methods: The sociodemographic profiles and MMSE scores of adults aged 65-years and over who participated in the Australian National Mental Health and Well-being Survey were assessed (N = 1,792)., Results: The regression models showed that older age, education levels, language spoken at home and in country of birth, socioeconomic status (SES), occupation, sex, and presence of a mood disorder made significant and unique contributions to performance on the MMSE. The individual (univariate) influence of each factor ranged from -2.61 to 0.09 points, with non-English speaking background (NESB) making the biggest impact. Based on a MMSE score of < or =23 points, 7.7% of the Australian elderly population screened positive for cognitive impairment that may be indicative of dementia. In those scoring < or =23 points, the multivariate model accounted for 24.61% of the variance., Conclusion: Many sociodemographic variables and the presence of a mood disorder influence MMSE performance. Using conventional cutoff scores for screening will lead to a high rate of false positives in older adults (75+ years), those with NESB, and those with low SES, and is insensitive for those with high education. The authors suggest simple rules for the correction of the impact of these variables.

RU 35926/CI-979 (milameline) is a partial muscarinic agonist with promnestic effects in animal models. Preliminary animal studies suggest that this agent has the capacity to reverse cholinergic dysfunction and that it may impact on regional cerebral blood flow (rCBF). A total of 10 subjects with Alzheimer's disease (AD) of mild severity underwent high resolution split-dose single photon emission computed tomography (SPECT) during performance of a verbal recognition and control task, both before and after 18 weeks treatment with melameline or placebo. SPECT images were coregistered with individual's magnetic resonance imaging scans allowing extraction of rCBF values from multiple anatomical regions of interest (ROI). The effect of milameline was examined in eight individuals who were found after unblinding to be taking active drug. Effects of milameline were most apparent in the frontal regions, basal ganglia and thalamus. In the group as a whole, the greatest increase in rCBF due to milameline treatment was observed in the left globus pallidus. Response to milameline treatment was associated with increases in rCBF in the cingulate gyrus bilaterally, and less so for the left thalamus. Milameline-related increases in rCBF values were exaggerated by the verbal recognition task. Milameline has a demonstrable effect on cerebral blood flow in mild AD. Consistent with emerging animal data, the effects on rCBF appear most prominent in frontal and subcortical regions in AD subjects. The effects on rCBF appear to be augmented by the performance of a cognitively demanding task, raising the possibility that such tasks could assist in building an awareness of the functional neuropsychopharmacology of drugs designed for cognitive enhancement.

Background: In view of the recent technological advances and its ease of availability, we used single photon emission computed tomography (SPECT) to examine the performance of early Alzheimer's disease (AD) subjects on a verbal recognition memory task., Methods: Eighteen early AD and 10 matched healthy control subjects underwent split-dose (99m)Tc-HMPAO (Ceretec) SPECT using a verbal recognition memory and control task. SPECT images co-registered with MRI scans were used to determine relative regional cerebral blood flow (rCBF) changes in regions of interest., Results: In healthy control subjects, verbal recognition increased rCBF in the right occipital region, thalamus, left prefrontal pole, posterior parietal region and cerebellum, and decreased rCBF in the right hippocampus. AD subjects showed bilateral prefrontal, posterior parietal and occipital increases, unilateral increase in the left posterior temporal region, and bilateral reductions in the hippocampus. Although activation was significantly different between the two groups in the right thalamus and left medial prefrontal region, the verbal recognition task did not enhance discrimination between groups., Conclusions: Compared with controls, AD subjects activate a similar but more extensive bilateral network during verbal recognition, possibly reflecting an attempt to compensate for impaired processing., (Copyright 2006 S. Karger AG, Basel.)

In spite of its wide availability, single photon emission computerized tomography (SPECT) scanning is uncommonly used in the assessment of Alzheimer's disease (AD) and related dementias. In light of recent advances in scanning protocols and image analysis, SPECT needs to be re-examined as a tool in the diagnosis of dementia. A total of 18 subjects with early AD and 10 healthy elderly control subjects were examined with high resolution SPECT during the performance of a simple word discrimination task. SPECT images were coregistered with individual magnetic resonance imaging scans, allowing delineation of predetermined neuroanatomical Regions of Interest (ROI). There was a gradation of regional cerebral blood flow (rCBF) values in both groups, with the lowest values being in the hippocampus and the highest in the striatum, thalamus and cerebellum. Compared to healthy controls, AD subjects demonstrated lower relative rCBF in parietal and prefrontal cortices. Analysis of individual ROI demonstrated bilateral reduction of rCBF in prefrontal poles, posterior temporal and anterior parietal cortex, and unilateral reduction of rCBF in left dorsolateral prefrontal cortex, right posterior parietal cortex and the left cingulate body. There were no significant differences for hippocampal, occipital or basal ganglia rCBF. Discriminant function analysis indicated that rCBF in the prefrontal polar regions achieved the best classification of cases. SPECT has utility in the diagnostic assessment of AD if standardized and semiquantitative techniques are used.

Objective: This paper examines the current literature pertaining to brain ageing. The objective of this review is to provide an overview of the effects of ageing on brain structure and function and to examine possible mediators of these changes., Methods: A MEDLINE search was conducted for each area of interest. A selective review was undertaken of relevant articles., Results: Although fundamental changes in fluid intellectual abilities occur with age, global cognitive decline is not a hallmark of the ageing process. Decline in fluid intellectual ability is paralleled by regionally specific age related changes apparent from both structural and functional neuroimaging studies. The histopathological mediators of these changes do not appear to be reduction in neuronal number, which, with the exception of selected hippocampal regions, remain relatively stable across age. At the molecular level, several mechanisms of age related change have been postulated. Such theoretical models await refinement and may eventually provide a basis for therapy designed to reduce effects of the ageing process. The role of possible protective factors such as 'brain reserve', neuroprotective agents and hormonal factors in modifying individual vulnerability to the ageing process has been the focus of a limited number of studies., Conclusion: Our understanding of the functional and structural changes associated with both healthy and pathological ageing is rapidly gaining in sophistication and complexity. An awareness of the fundamental biological substrates underpinning the ageing process will allow improved insights into vulnerability to neuropsychiatric disease associated with advancing age.