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Increased efforts in neuroscience seek to understand how macro-anatomical and physiological connectomes cooperatively work to generate cognitive behaviors. However, the structure-function coupling characteristics in normal aging individuals remain unclear. Here, we developed an index, the Coupling in Brain Structural connectome and Functional connectome (C-BSF) index, to quantify regional structure-function coupling in a large community-based cohort. C-BSF used diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (fMRI) data from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study (PRECISE) cohort (2007 individuals, age: 61.15 ± 6.49 years) and the Sydney Memory and Ageing Study (MAS) cohort (254 individuals, age: 83.45 ± 4.33 years). We observed that structure-function coupling was the strongest in the visual network and the weakest in the ventral attention network. We also observed that the weaker structure-function coupling was associated with increased age and worse cognitive level of the participant. Meanwhile, the structure-function coupling in the visual network was associated with the visuospatial performance and partially mediated the connections between age and the visuospatial function. This work contributes to our understanding of the underlying brain mechanisms by which aging affects cognition and also help establish early diagnosis and treatment approaches for neurological diseases in the elderly.

Introduction: Poststroke cognitive impairment is common, but the trajectory and magnitude of cognitive change after stroke are unclear. We aimed to measure changes in the trajectory of cognitive function following a first stroke, controlling for pre-stroke cognitive performance using diverse population-based studies from the Cohort Studies of Memory in an International Consortium (COSMIC). Methods: Fourteen longitudinal cohorts from 11 countries from Asia, Africa, North America, South America, Europe, and Australia contributed data. Cognitive domain scores were formed by selecting the most common test administered amongst studies in each domain (memory, processing speed, language, and executive function) and the scores standardised; global cognition was the standardised average of the 4 domains and the primary outcome. One-stage IPD meta- analysis with linear mixed model and regression discontinuity design was used to model the change in cognitive function. Time-dependent incident stroke, age, time in study, and time since stroke were included in the basic model. In the full model we adjusted for sex, education, ethno- racial group, study period and potential confounders significant in the basic model at p

Introduction: Several sets of diagnostic criteria have been published for vascular dementia (VaD) since the 1960s. The last 15 years have seen a re-evaluation of the criteria and proposals for new sets of criteria. Methods: A narrative review of the diagnosis of vascular dementia was performed and the development and performance of various sets of criteria examined. Results: Cognitive disorders of vascular aetiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular dementia (VaD), vascular cognitive impairment (VCI), vascular cognitive disorders (VCD) or vascular cognitive impairment and dementia (VCID). The most used criteria in the 1990s were the NINDS-AIREN and ADDTC criteria. The DSM-5 criteria were published in 2013, followed by the VASCOG criteria in 2014 [1], and VICCCS criteria in 2018. A comparison of the criteria suggested good correspondence between the recent criteria (DSM-5, VASCOG and VICCCS) but not with the older criteria (table 1) [2]. However, several challenges remain in relation to the heterogeneity of the disorder and the lack of established biomarkers. Recent developments in neuropsychology and neuroimaging of vascular cognitive disorders warrant a re-examination of the criteria to improve consistency in diagnosis to aid both clinical practice and research. Discussion: Criteria for vascular disorders have achieved a certain level of consistency but need continuing examination with advances in the field. While neuroimaging biomarkers have improved greatly, fluid and retinal biomarkers need further development.

Abstract Deep brain stimulation (DBS) is a promising treatment for severe, treatment-resistant obsessive-compulsive disorder (OCD). Here, nine participants (four females, mean age 47.9 ± 10.7 years) were implanted with DBS electrodes bilaterally in the bed nucleus of the stria terminalis (BNST). Following a one-month postoperative recovery phase, participants entered a three-month randomised, double-blind, sham-controlled phase before a twelve-month period of open-label stimulation incorporating a course of cognitive behavioural therapy (CBT). The primary outcome measure was OCD symptoms as rated with the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the blinded phase, there was a significant benefit of active stimulation over sham (p = 0.025, mean difference 4.9 points). After the open phase, the mean reduction in YBOCS was 16.6 ± 1.9 points (χ 2 (11) = 39.8, p = 3.8 × 10−5), with seven participants classified as responders. CBT resulted in an additive YBOCS reduction of 4.8 ± 3.9 points (p = 0.011). There were two serious adverse events related to the DBS device, the most severe of which was an infection during the open phase necessitating device explantation. There were no serious psychiatric adverse events related to stimulation. An analysis of the structural connectivity of each participant’s individualised stimulation field isolated right-hemispheric fibres associated with YBOCS reduction. These included subcortical tracts incorporating the amygdala, hippocampus and stria terminalis, in addition to cortical regions in the ventrolateral and ventromedial prefrontal cortex, parahippocampal, parietal and extrastriate visual cortex. In conclusion, this study provides further evidence supporting the efficacy and tolerability of DBS in the region of the BNST for individuals with otherwise treatment-refractory OCD and identifies a connectivity fingerprint associated with clinical benefit.

Introduction: The Iranian Brain Imaging Database (IBID) was initiated in 2017, with 5 major goals: provide researchers easy access to a neuroimaging database, provide normative quantitative measures of the brain for clinical research purposes, study the aging profile of the brain, examine the association of brain structure and function, and join the ENIGMA consortium. Many prestigious databases with similar goals are available. However, they were not done on an Iranian population, and the battery of their tests (e.g. cognitive tests) is selected based on their specific questions and needs. Methods: The IBID will include 300 participants (50% female) in the age range of 20 to 70 years old, with an equal number of participants (#60) in each age decade. It comprises a battery of cognitive, lifestyle, medical, and mental health tests, in addition to several Magnetic Resonance Imaging (MRI) protocols. Each participant completes the assessments on two referral days. Results: The study currently has a cross-sectional design, but longitudinal assessments are considered for the future phases of the study. Here, details of the methodology and the initial results of assessing the first 152 participants of the study are provided. Conclusion: IBID is established to enable research into human brain function, to aid clinicians in disease diagnosis research, and also to unite the Iranian researchers with interests in the brain.

ObjectiveBulimia nervosa (BN) and binge eating disorder (BED) are eating disorders (EDs) characterized by recurrent binge eating (BE) episodes. Overlap exists between ED diagnostic groups, with BE episodes presenting one clinical feature that occurs transdiagnostically. Neuroimaging of the responses of those with BN and BED to disorder-specific stimuli, such as food, is not extensively investigated. Furthermore, to our knowledge, there have been no previous published studies examining the neural response of individuals currently experiencing binge eating, to low energy foods. Our objective was to examine the neural responses to both low energy and high energy food images in three emotive categories (disgust; fear; and happy) in BN and BED participants.MethodsNineteen females with BN (n = 14) or BED (n = 5), comprising the binge eating group (BEG; N = 19), and 19 age-matched healthy control (HC)’s completed thorough clinical assessment prior to functional MRI (fMRI). Neural response to low energy and high energy foods and non-food images was compared between groups using whole-brain exploratory analyses, from which six regions of interest (ROI) were then selected: frontal, occipital, temporal, and parietal lobes; insula and cingulate.ResultsIn response to low energy food images, the BEG demonstrated differential neural responses to all three low energy foods categories (disgust; fear; and happy) compared to HCs. Correlational analyses found a significant association between frequency of binge episodes and diminished temporal lobe and greater occipital lobe response. In response to high energy food images, compared to HC’s, the BEG demonstrated significantly decreased neural activity in response to all high energy food images. The HC’s had significantly greater neural activity in the limbic system, occipital lobe, temporal lobe, frontal lobe, and limbic system in response to high energy food images.ConclusionResults in the low energy food condition indicate that binge frequency may be related to increased aberrant neural responding. Furthermore, differences were found between groups in all ROI’s except the insula. The neural response seen in the BEG to disgust food images may indicate disengagement with this particular stimuli. In the high energy food condition, results demonstrate that neural activity in BN and BED patients may decrease in response to high energy foods, suggesting disengagement with foods that may be more consistent with those consumed during a binge eating episode.

Abstract Data collected from clinical trials and cohort studies, such as dementia studies, are often high-dimensional, censored, heterogeneous and contain missing information, presenting challenges to traditional statistical analysis. There is an urgent need for methods that can overcome these challenges to model this complex data. At present there is no cure for dementia and no treatment that can successfully change the course of the disease. Machine learning models that can predict the time until a patient develops dementia are important tools in helping understand dementia risks and can give more accurate results than traditional statistical methods when modelling high-dimensional, heterogeneous, clinical data. This work compares the performance and stability of ten machine learning algorithms, combined with eight feature selection methods, capable of performing survival analysis of high-dimensional, heterogeneous, clinical data. We developed models that predict survival to dementia using baseline data from two different studies. The Sydney Memory and Ageing Study (MAS) is a longitudinal cohort study of 1037 participants, aged 70–90 years, that aims to determine the effects of ageing on cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal study aimed at identifying biomarkers for the early detection and tracking of Alzheimer's disease. Using the concordance index as a measure of performance, our models achieve maximum performance values of 0.82 for MAS and 0.93 For ADNI.

Abstract Background Peripheral blood microRNAs (miRNA) have been identified as potential biomarkers for Alzheimer’s disease (AD). Study results have generally been inconsistent and limited by sample heterogeneity. The aim of this study is to establish candidate blood miRNA biomarkers for AD by comparing differences in miRNA expression between participants with brain amyloid imaging-defined AD and normal cognition. Methods Blood RNA was extracted from a subset of participants from the Australian Imaging Biomarkers Lifestyle Study of Ageing cohort (AIBL) with brain amyloid imaging results. MiRNA profiling was performed using small RNA sequencing on 71 participants, comprising 40 AD with high brain amyloid burden on imaging (amyloid positive) and 31 cognitively normal controls with low brain amyloid burden (amyloid negative). Cross-sectional comparisons were made between groups to examine differential miRNA expression levels using Fisher’s exact tests. Replication of results was undertaken using a publicly available dataset of blood miRNA data of AD and controls. In silico analysis of downstream messenger RNA targets of candidate miRNAs was performed to elucidate potential biological function. Results After quality control, 816 miRNAs were available for analysis. There were 71 significantly differentially expressed miRNAs between the AD and control groups (p

Abstract Introduction Coronavirus disease 2019 (COVID‐19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID‐19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID‐19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID‐19 to neurologic illness, both short and long term. Methods This article describes what is known so far in terms of links among COVID‐19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long‐term neurocognitive sequelae of SARS‐CoV‐2 infection. Key Points The following review describes what is known so far in terms of molecular and epidemiological links among COVID‐19, the brain, neurological symptoms, and AD and related dementias (ADRD) The primary objective of this large‐scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long‐term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS‐CoV‐2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS‐CoV‐2 triggers ADRD‐like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility. The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under‐represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long‐term consequences, and trends in cognitive aging, ADRD, and vascular disease. We provide a framework for current and future studies to be carried out within the Consortium. and offers a “green paper” to the research community with a very broad, global base of support, on tools suitable for low‐ and middle‐income countries aimed to compare and combine future longitudinal data on the topic. The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID‐19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high‐quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.

To examine the relationships of retinal structural (optical coherence tomography) and visual functional (multifocal visual evoked potentials, mfVEP) indices with neuropsychological and brain structural measurements in healthy older subjects. 95 participants (mean (SD) age 68.1 (9.0)) years were recruited in the Optic Nerve Decline and Cognitive Change (ONDCC) study in this observational clinical investigation. OCT was conducted for retinal nerve fibre layer (RNFL) and mfVEP for amplitude and latency measurements. Participants undertook neuropsychological tests for cognitive performance and MRI for volumetric evaluation of various brain regions. Generalised estimating equation models were used for association analysis (p

Abstract Background There is limited understanding of the underlying mechanisms explaining the role of concern about falling on fall risk in older people. Anxiety is known to interact with cognitive resources and, as people get older, they require more cognitive resources to maintain balance. This might affect an individual’s ability to perform cognitive-motor tasks concurrently. The aim of this study was to investigate the effect of a visuospatial dual-task on stepping performance in older people with and without concern about falling and the impact of repeating this task in those with high concern about falling. Methods Three-hundred-eight community-dwelling older people, aged 70 to 90 years old, participated in the study. Participants were asked to perform a Choice Stepping Reaction Time (CSRT) task in two conditions; once without any other tasks (single task condition), and once while simultaneously performing a visuospatial task (dual-task condition). Participants were asked to rate their levels of concern and confidence specifically related to each of the 25 stepping trials (before/after). We also measured general concern about falling, affect, and sensorimotor and cognitive functioning. Results Total stepping reaction times increased when participants also performed the visuospatial task. The relation between general concern about falling and stepping reaction time, was affected by sensorimotor and executive functioning. Generalised linear mixed models showed that the group with moderate to high levels of general concern about falling had slower total stepping reaction times than those with lower levels of concern about falling, especially during the dual-task condition. Individuals with greater general concern about falling showed reduced confidence levels about whether they could do the stepping tasks under both conditions. Repeatedly performing the stepping task reduced the immediate task-specific concern about falling levels and increased confidence in all participants. Conclusions These findings reveal that people with higher general concern about falling experienced more difficulties during a dual-task condition than people with lower levels of concern. Of further interest, better sensorimotor and cognitive functioning reduced this effect. Graded exposure has potential to reduce concern about falling during fear-evoking activities, especially in conjunction with therapies that improve balance, mood and cognitive function.

The relationships between aging and brain morphology have been reported in many previous structural brain studies. However, the trajectories of successful brain aging in the extremely old remain underexplored. In the limited research on the oldest old, covering individuals aged 85 years and older, there are very few studies that have focused on the cortical morphology, especially cortical sulcal features. In this paper, we measured sulcal width and depth as well as cortical thickness from T1-weighted scans of 290 nondemented community-dwelling participants aged between 76 and 103 years. We divided the participants into young old (between 76 and 84; mean = 80.35±2.44; male/female = 76/88) and oldest old (between 85 and 103; mean = 91.74±5.11; male/female = 60/66) groups. The results showed that most of the examined sulci significantly widened with increased age and that the rates of sulcal widening were lower in the oldest old. The spatial pattern of the cortical thinning partly corresponded with that of sulcal widening. Compared to females, males had significantly wider sulci, especially in the oldest old. This study builds a foundation for future investigations of neurocognitive disorders and neurodegenerative diseases in the oldest old, including centenarians.

We investigated the association between poststroke cognitive impairment and a specific effective network connectivity in the prefrontal–basal ganglia circuit. The resting-state effective connectivity of this circuit was modeled by employing spectral dynamic causal modeling in 11 poststroke patients with cognitive impairment (PSCI), 8 poststroke patients without cognitive impairment (non-PSCI) at baseline and 3-month follow-up, and 28 healthy controls. Our results showed that different neuronal models of effective connectivity in the prefrontal–basal ganglia circuit were observed among healthy controls, non-PSCI, and PSCI patients. Additional connected paths (extra paths) appeared in the neuronal models of stroke patients compared with healthy controls. Moreover, changes were detected in the extra paths of non-PSCI between baseline and 3-month follow-up poststroke, indicating reorganization in the ipsilesional hemisphere and suggesting potential compensatory changes in the contralesional hemisphere. Furthermore, the connectivity strengths of the extra paths from the contralesional ventral anterior nucleus of thalamus to caudate correlated significantly with cognitive scores in non-PSCI and PSCI patients. These suggest that the neuronal model of effective connectivity of the prefrontal–basal ganglia circuit may be sensitive to stroke-induced cognitive decline, and it could be a biomarker for poststroke cognitive impairment 3 months poststroke. Importantly, contralesional brain regions may play an important role in functional compensation of cognitive decline.

Peripheral dermal fibroblasts (DF) from a healthy 56 year old female were obtained from the Centre for Healthy Brain Ageing (CHeBA) Biobank, University of New South Wales, under the material transfer agreement with the University of Wollongong. DFs were reprogrammed via mRNA-delivered transcription factors into induced pluripotent stem cells (iPSCs). The generated iPSCs were confirmed to be pluripotent, capable of three germ layer differentiation and are thus a useful resource for creating iPSC-derived healthy human cells of any lineage.Resource tableUnlabelled TableUnique stem cell line identifierUOWi001-AAlternative name(s) of stem cell lineiPSC RB 9–8InstitutionIllawarra Health and Medical Research Institute, University of WollongongContact information of distributorLezanne Ooi, lezanne@uow.edu.auType of cell lineiPSCOriginHumanAdditional origin infoAge: 56Sex: femaleCell SourceDermal fibroblastClonalityClonalMethod of reprogrammingTransgene-freeGenetic ModificationNoType of ModificationN/AAssociated diseaseN/AGene/locusN/AMethod of modificationN/AName of transgene or resistanceN/AInducible/constitutive systemN/ADate archived/stock date21/12/17Cell line repository/bankN/AEthical approvalHE 13/299 University of Wollongong Human Ethics Committee

目的 利用半自动化分析软件对脑白质疏松患者不同区域白质损伤进行定量，并对其与认知功能评 分进行偏相关分析。 方法 2011年1月-2017年1月在北京天坛医院进行健康体检的50～85岁社区“健康”人群63例，对 其进行认知功能评价[简易精神状态量表（mi ni -mental state examination，MMSE）、蒙特利尔认知量表 （Montreal cognitive assessment，MoCA）]及影像学数据采集，基于液体衰减反转恢复序列定量计算全脑、 侧脑室旁及深部皮层下脑白质受损体积，将认知功能评分与以上白质受损体积进行偏相关分析，探 索白质受损在认知障碍发生发展过程中所起的作用。 结果 控制年龄、性别、文化程度后，全脑白质体积与MMSE评分、MoCA评分有偏相关性（R’=-0.428， P =0.001）（R’=-0.539，P＜0.001），尤其是侧脑室旁白质体积（R’=-0.427，P =0.001）（R’=-0.559，P ＜0.001），与深部皮层下白质也存在偏相关性（R’=-0.365，P =0.004）（R’=-0.447，P＜0.001）。 结论 全脑、侧脑室旁、深部皮层下脑白质损伤体积增大，认知功能评分随之下降；MMSE评分、 MoCA评分与侧脑室旁白质损伤之间的相关性较深部皮层下白质损伤更大。 Abstract: Objective To analyze white matter hyperintensity (WMH) in different brain regions in patients with cerebral leukoaraiosis using semi-automatic quantitative analysis software, and analyze the partial correlation of WMH and cognitive impairment. Methods A total of 63 ‘healthy’ community subjects (50-85 years) who had a physical examination in Beijing Tiantan hospital from January 2011 to January 2017 were included in this study. The cognitive function of all subjects were assessed using mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). We quantitatively analyzed the WMH in the whole brain, periventricular and deep cortex on fluid attenuated inversion recovery (FLAIR) sequence, which represented white matter lesion, and made a partial correlation analysis of the volume of white matter lesion and cognitive function score, to investigate the role of white matter lesion in the development of cognitive impairment. Results After adjusting for age, gender and education level, the volume of whole brain white matter lesion still had a partial correlation with MMSE and MoCA scores (R’=-0.428, P =0.001; R’=-0.539, P

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.

Summary: Repopulation of brain circuits by neural precursors is a potential therapeutic strategy for neurodegenerative disorders; however, choice of cell is critical. Previously, we introduced a two-step culture system that generates a high yield of neural precursors from small samples of adult canine skin. Here, we probe their gene and protein expression profiles in comparison with dermal fibroblasts and brain-derived neural stem cells and characterize their neuronal potential. To date, we have produced >50 skin-derived neural precursor (SKN) lines. SKNs can be cultured in a highly replicable fashion and uniformly express a panel of identifying markers. Upon differentiation, they self-upregulate neural specification genes, generating neurons with basic electrophysiological functionality. This unique population of neural precursors, derived from mature skin, overcomes many of the practical issues that have limited clinical translation of alternative cell types. Easily accessible, neuronally committed, and patient specific, SKNs may have potential for the treatment of brain disorders. : In this article, the authors characterize a unique population of neurogenic cells derived from small samples of adult canine skin. These cells are shown to be highly homogeneous and capable of generating high yields of neurons that display basic synaptic and electrophysiological functionality. Accordingly, they propose that these cells may have applications in autologous neuroreplacement therapies. Keywords: skin, adult stem cells, SKN, neural precursors, neurogenic, differentiation, neurons

Glutathione (GSH) is one of the most abundant thiol antioxidants in cells. Many chronic and age-related diseases are associated with a decline in cellular GSH levels or impairment in the catalytic activity of the GSH biosynthetic enzyme glutamate cysteine ligase (GCL). γ-glutamylcysteine (GGC), a precursor to glutathione (GSH), can replenish depleted GSH levels under oxidative stress conditions, by circumventing the regulation of GSH biosynthesis and providing the limiting substrate. Soluble amyloid-β (Aβ) oligomers have been shown to induce oxidative stress, synaptic dysfunction and memory deficits which have been reported in Alzheimer’s disease (AD). Calcium ions, which are increased with age and in AD, have been previously reported to enhance the formation of Aβ40 oligomers, which have been casually associated with the pathogenesis of the underlying neurodegenerative condition. In this study, we examined the potential beneficial effects of GGC against exogenous Aβ40 oligomers on biomarkers of apoptosis and cell death, oxidative stress, and neuroinflammation, in human astrocytes. Treatment with Aβ40 oligomers significantly reduced the cell viability and apoptosis of astrocyte brain cultures and increased oxidative modifications of DNA, lipids, and protein, enhanced pro-inflammatory cytokine release and increased the activity of the proteolytic matrix metalloproteinase enzyme, matric metalloproteinase (MMP)-2 and reduced the activity of MMP-9 after 24 h. Co-treatment of Aβ40 oligomers with GGC at 200 μM increased the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) and led to significant increases in the levels of the total antioxidant capacity (TAC) and GSH and reduced the GSSG/GSH ratio. GGC also upregulated the level of the anti-inflammatory cytokine IL-10 and reduced the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and attenuated the changes in metalloproteinase activity in oligomeric Aβ40-treated astrocytes. Our data provides renewed insight on the beneficial effects of increased GSH levels by GGC in human astrocytes, and identifies yet another potential therapeutic strategy to attenuate the cytotoxic effects of Aβ oligomers in AD.

Recent advances in mass spectrometry-based techniques have inspired research into lipidomics, a subfield of '-omics', which aims to identify and quantify large numbers of lipids in biological extracts. Although lipidomics is becoming increasingly popular as a screening tool for understanding disease mechanisms, it is largely unknown how the lipidome naturally varies by age and sex in healthy individuals. We aimed to identify cross-sectional associations of the human lipidome with 'physiological' ageing, using plasma from 100 subjects with an apolipoprotein E (APOE) E3/E3 genotype, and aged between 56 to 100 years. Untargeted analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS) and data processing using LipidSearch software. Regression analyses confirmed a strong negative association of age with the levels of various lipid, which was stronger in males than females. Sex-related differences include higher LDL-C, HDL-C, total cholesterol, particular sphingomyelins (SM), and docosahexaenoic acid (DHA)-containing phospholipid levels in females. Surprisingly, we found a minimal relationship between lipid levels and body mass index (BMI). In conclusion, our results suggest substantial age and sex-related variation in the plasma lipidome of healthy individuals during the second half of the human lifespan. In particular, globally low levels of blood lipids in the 'oldest old' subjects over 95 years could signify a unique lipidome associated with extreme longevity.

Objectives: In this cross-sectional study, we aimed to explore the mechanisms of early cognitive impairment in a post stroke non-dementia cerebral small vessel disease (SVD) cohort by comparing the SVD score with the structural brain network measures. Method: 127 SVD patients were recruited consecutively from a stroke clinic, comprising 76 individuals with mild cognitive impairment (MCI) and 51 with no cognitive impairment (NCI). Detailed neuropsychological assessments and multimodal MRI were performed. SVD scores were calculated on a standard scale, and structural brain network measures were analyzed by diffusion tensor imaging (DTI). Between-group differences were analyzed, and logistic regression was applied to determine the predictive value of SVD and network measures for cognitive status. Mediation analysis with structural equation modeling (SEM) was used to better understand the interactions of SVD burden, brain networks and cognitive deficits. Results: Group difference was found on all global brain network measures. After adjustment for age, gender, education and depression, significant correlations were found between global brain network measures and diverse neuropsychological tests, including TMT-B (r = −0.209, p

This study aimed to determine whether sulcal morphology differs between middle age (MA) and older healthy individuals. Furthermore, we sought to determine whether age-related differences in sulcal characteristics were more strongly associated with differences in local or global cortical volumes. Participants (age 44–50, N = 403; age 64–70, N = 390) from the Personality and Total Health Through Life (PATH) study were included. Sulci were 17.3% wider, on average, in old age (OA) compared to MA participants, with the largest difference in the left superior frontal sulcus. Differences in sulcal width were generally higher in males than females. Differences in the width of the superior frontal and central sulci were significantly associated with differences in the volume of adjacent local gyri, while age-related differences in the width of lateral and superior temporal sulci were associated with differences in whole brain cortical volume. These findings suggest that sulcal characteristics provide unique information about changes in local and global brain structure in aging.

Introduction Data-linkage studies using administrative hospital data have shown that people with dementia have double the rate of injury-related hospitalisations and poorer health outcomes than those without. No previous research has explored whether people with mild cognitive impairment are also at increased risk of serious injury requiring hospitalisation. Objectives and Approach A major barrier to the use of administrative hospital data for undertaking research focusing on people with MCI is that MCI cannot be reliably identified from ICD-10 coded administrative data. To overcome this limitation, hospitalisation and death data was linked to data from participants (community-dwelling 70-90 year olds) enrolled in the population-based longitudinal Sydney Memory and Ageing Study (MAS). MAS participants underwent comprehensive neuropsychological assessments at baseline, then 2, 4 and 6 years’ follow-up to accurately determine cognitive status at each time-period. Linkage to hospital records allowed identification of injury-related hospitalisations and outcomes for the 2-year period following each assessment. Results There were 335 injury-related hospitalisations for the 867 participants; 222 (25.6%) participants had at least one injury-related hospitalisation. After adjusting for age-and-sex, participants in a state of MCI had 1.7 (95%CI 1.2-2.4) times higher odds of an injury-related hospitalisation than participants in a state of normal cognition, whilst participants with dementia had 2.3 (95%CI 1.2-4.4) times higher odds. There was no difference in odds between participants with MCI and dementia. Of the 116 hospitalisations for people with MCI, the majority (79.3%) were due to falls. Non-fracture head injuries (25.9%), upper limb and trunk fractures (13.8% respectively) were the most common injury type. There were no differences in injury type, mean length of stay, or 30-day mortality between people with normal cognition, MCI and dementia. Conclusion/Implications Older people with objectively defined MCI are at higher risk of injury, predominantly as a result of falls, than their cognitively intact peers. Falls-risk screening and fall prevention initiatives may be indicated for people with MCI. Further research is required to determine which cognitive domains contribute to this increased risk.

Amnestic MCI (aMCI) and non-amnestic MCI (naMCI) are considered to differ in etiology and outcome. Accurately classifying MCI into meaningful subtypes would enable early intervention with targeted treatment. In this study, we employed structural magnetic resonance imaging (MRI) for MCI subtype classification. This was carried out in a sample of 184 community-dwelling individuals (aged 73–85 years). Cortical surface based measurements were computed from longitudinal and cross-sectional scans. By introducing a feature selection algorithm, we identified a set of discriminative features, and further investigated the temporal patterns of these features. A voting classifier was trained and evaluated via 10 iterations of cross-validation. The best classification accuracies achieved were: 77% (naMCI vs. aMCI), 81% (aMCI vs. cognitively normal (CN)) and 70% (naMCI vs. CN). The best results for differentiating aMCI from naMCI were achieved with baseline features. Hippocampus, amygdala and frontal pole were found to be most discriminative for classifying MCI subtypes. Additionally, we observed the dynamics of classification of several MRI biomarkers. Learning the dynamics of atrophy may aid in the development of better biomarkers, as it may track the progression of cognitive impairment.

BACKGROUND/AIMS:Despite reporting high levels of burden, supporters of people with young onset dementia (YOD) underuse formal community services. Previous quantitative studies in YOD are of limited utility in guiding service design because they did not consider important contextual barriers to service use. The aim of this study was to identify all relevant barriers and describe the service features considered most important to improving uptake by people with YOD and their supporters. METHODS:Eighty-six people with consensus-confirmed YOD (mean onset age 55.3 years) and/or their primary supporter participated in quantitative interviews, and 50 also participated in one of seven qualitative focus groups. Interview participants reported levels of community service use and reasons for non-use, functional impairment, behavioural and psychological symptoms, supporter burden, social network, and informal care provision. Focus group participants expanded on reasons for non-use and aspects of an ideal service. RESULTS:Although at least one community service was recommended to most participants (96.8%), 66.7% chose not to use one or more of these. Few of the clinical or demographic factors included here were related to service use. Qualitative analyses identified that lack of perceived need, availability, and YOD-specific barriers (including ineligibility, unaffordability, lack of security, lack of childcare) were commonly reported. Five aspects of an ideal service were noted: unique, flexibile, affordable, tailored, and promoting meaningful engagement. CONCLUSION:People with YOD and their families report that formal community services do not meet their personal and psychological needs. Researchers can provide ongoing assessment of program feasibility, suitability, and generalisability.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with increased oxidative stress and neuroinflammation. Markers of increased protein, lipid and nucleic acid oxidation and reduced activities of antioxidant enzymes have been reported in AD plasma. Amyloid plaques in the AD brain elicit a range of reactive inflammatory responses including complement activation and acute phase reactions, which may also be reflected in plasma. Previous studies have shown that human AD plasma may be cytotoxic to cultured cells. We investigated the effect of pooled plasma (n = 20 each) from healthy controls, individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) on cultured microglial cells. AD plasma and was found to significantly decrease cell viability and increase glycolytic flux in microglia compared to plasma from healthy controls. This effect was prevented by the heat inactivation of complement. Proteomic methods and isobaric tags (iTRAQ) found the expression level of complement and other acute phase proteins to be altered in MCI and AD plasma and an upregulation of key enzymes involved in the glycolysis pathway in cells exposed to AD plasma. Altered expression levels of acute phase reactants in AD plasma may alter the energy metabolism of glia.

O autor apresenta uma visão geral da literatura atual sobre homocisteína como um fator de risco para os transtornos neuropsiquiátricos. Foram pesquisados os bancos de dados MEDLINE, Current Contents e EMBASE (entre 1966 e 2002) para publicações em língua inglesa utilizando as palavras-chave ''Homocisteína'' e ''AVC''; ''Doença de Alzheimer''; ''Déficit Cognitivo'', ''Epilepsia'', ''Depressão'' ou ''Doença de Parkinson''. Artigos individuais foram pesquisados para referências cruzadas relevantes. É biologicamente plausível que altos níveis de homocisteína possam causar lesão cerebral e transtornos neuropsiquiátricos. A homocisteína é pró-aterogênica e pró-trombótica. Dessa forma, aumenta o risco de acidente vascular cerebral, podendo ter um efeito neurotóxico direto. Evidências de que a homocisteína seja um fator de risco para doença microvascular cerebral são conflitantes, mas justificam maiores estudos. Estudos transversais e alguns longitudinais suportam a crescente prevalência de acidente vascular cerebral e demência vascular em indivíduos com hiper-homocisteinemia. As evidências de crescente neurodegeneração estão se acumulando. A relação com a depressão ainda é experimental, da mesma forma como com a epilepsia. Atualmente, estudos sobre tratamentos são necessários para colocar as evidências sobre bases mais sólidas. Os pacientes de alto risco também devem ser pesquisados para hiper-homocisteínemia, cujo tratamento deve ser feito com ácido fólico. Mais evidências são necessárias antes que pesquisas populacionais possam ser recomendadas.The author presents an overview of the current literature on homocysteine as a risk factor for neuropsychiatric disorders. The databases MEDLINE, Current Contents and EMBASE were searched (between 1966 and 2002) for English language publications with the key words 'Homocysteine' and 'Stroke'; 'Alzheimer Disease'; 'Cognitive Impairment'; 'Epilepsy'; 'Depression'; or 'Parkinson's disease'. Individual articles were hand searched for relevant cross-references. It is biologically plausible that high homocysteine levels may cause brain injury and neuropsychiatric disorders. Homocysteine is proatherogenic and prothrombotic, thereby increasing the risk of cerebrovascular disease, and may have a direct neurotoxic effect. Evidence for homocysteine as a risk factor for cerebral microvascular disease is conflicting but warrants further study. Cross-sectional and some longitudinal studies support increased prevalence of stroke and vascular dementia in hyperhomocysteinemic individuals. The evidence of increased neurodegeneration is accumulating. The relationship with depression is still tentative, as it is with epilepsy. Currently, treatment studies are necessary to place the evidence on a stronger footing, and maybe high-risk patients should be screened for hyperhomocysteinemia and this should be treated with folic acid. More research evidence is necessary before population screening can be recommended.

Background and Purpose: Defining how brain structures differ in pre-clinical dementia is important to better understand the pathological processes involved and to inform clinical practice. The aim of this study was to identify significant brain correlates (volume and asymmetry in volume) of mild cognitive disorders when compared to normal controls in a large community-based sample of young-old individuals who were assessed for cognitive impairment. Methods: Cortical and sub-cortical volumes were measured using a semi-automated method in 398 participants aged 65-70 years who were selected from a larger randomly sampled cohort and who agreed to undergo an MRI scan. Diagnoses were reached based on established protocols for MCI and a more inclusive category of any Mild Cognitive Disorder (any-MCD: which includes AAMI, AACD, OCD, MNC, CDR, MCI). Logistic regression analyses were used to assess the relationship between volume and asymmetry of theoretically relevant cerebral structures (predictors) and MCI or any-MCD while controlling for age, sex, and intra-cranial volume. Results: The main correlates of cognitive impairment assessed in multivariate analyses were hippocampal asymmetry (more to left, MCI: OR 0.83, 95%CI 0.71-0.96, p = .013; MCD: OR 0.86, 95%CI 0.77-0.97, p = .011), lateral ventricle asymmetry (more to left, MCI: OR 0.95, 95%CI 0.91-0.99, p = .009; MCD: OR 0.95, 95%CI 0.92-0.98, p = .004), and cerebellar cortex asymmetry (more to left, MCI: OR 1.51, 95%CI 1.13-2.01, p = .005). Conclusions: In this population-based cohort stronger associations were found between asymmetry measures, rather than raw volumes in cerebral structures, and mild cognitive disorders.

ObjectiveEpidemiological studies suggest that complex mental activity may reduce the risk for dementia, however an underlying mechanism remains unclear. Our objective was to determine whether individual differences in lifespan complex mental activity are linked to altered rates of hippocampal atrophy independent of global measures of neurodegeneration.MethodsThirty seven healthy older individuals had their complex mental activity levels estimated using the Lifetime of Experiences Questionnaire (LEQ) and completed serial MRI investigations at baseline and three years follow-up. Hippocampal volume and semi-automatic quantitation of whole brain volume (WBV) and white matter hyperintensities (WMHs) were compared at both time points.ResultsHigher LEQ scores were correlated with hippocampal volume independent of covariates at the three year follow-up stage (r = 0.43, p = 0.012). Moreover, those with higher LEQ scores experienced less hippocampal atrophy over the follow-up period (r = 0.41, p = 0.02). High LEQ individuals had less than half the hippocampal volume decline of low LEQ individuals in a multivariate analysis (F = 4.47, p = 0.042). No parallel changes were found in measures of WBV and WMHs.ConclusionsHigh level of complex mental activity across the lifespan was correlated with a reduced rate of hippocampal atrophy. This finding could not be explained by general differences in intracranial volume, larger hippocampi at baseline, presence of hypertensive disease, gender or low mood. Our results suggest that neuroprotection in medial temporal lobe may be one mechanism underlying the link between mental activity and lower rates of dementia observed in population-based studies. Additional studies are required to further explore this novel finding.