Association of Prediabetes and Type 2 Diabetes With Cognitive Function After Stroke: A STROKOG Collaboration Study.

Background and Purpose- Type 2 diabetes mellitus (T2D) is associated with cognitive impairment and an increased risk of dementia, but the association between prediabetes and cognitive impairment is less clear, particularly in a setting of major cerebrovascular events. This article examines the impact of impaired fasting glucose and T2D on cognitive performance in a stroke population. Methods- Seven international observational studies from the STROKOG (Stroke and Cognition) consortium (n=1601; mean age, 66.0 years; 70% Asian, 26% white, and 2.6% African American) were included. Fasting glucose level (FGL) during hospitalization was used to define 3 groups, T2D (FGL ≥7.0 mmol/L), impaired fasting glucose (FGL 6.1-6.9 mmol/L), and normal (FGL <6.1 mmol/L), and a history of diabetes mellitus and the use of a diabetes mellitus medication were also used to support a diagnosis of T2D. Domain and global cognition Z scores were derived from standardized neuropsychological test scores. The cross-sectional association between glucose status and cognitive performance at 3 to 6 months poststroke was examined using linear mixed models, adjusting for age, sex, education, stroke type, ethnicity, and vascular risk factors. Results- Patients with T2D had significantly poorer performance in global cognition (SD, -0.59 [95% CI, -0.82 to -0.36]; P<0.001) and in all domains compared with patients with normal FGL. There was no significant difference between impaired fasting glucose patients and those with normal FGL in global cognition (SD, -0.10 [95% CI, -0.45 to 0.24]; P=0.55) or in any cognitive domain. Conclusions- Diabetes mellitus, but not prediabetes, is associated with poorer cognitive performance in patients 3 to 6 months after stroke.

Development of a short-form version of the Reading the Mind in the Eyes Test for assessing theory of mind in older adults.

BACKGROUND: The Reading the Mind in the Eyes test (RMET) is a 36-item assessment for theory of mind (ToM) performance. While this measure has been shown to be sensitive to age-related ToM difficulties, there are no established cutoffs or guidelines currently available that are specific to older adults. This article seeks to validate a short-form version of the RMET appropriate for use in such populations. METHODS: Cross-sectional data from 295 participants (mean age 86 years) from the Sydney Memory and Ageing Study, a longitudinal community observational cohort. Participants underwent an assessment battery that included the RMET. Individuals who scored >1SD below the RMET scores of cognitively normal participants were deemed to have below average RMET scores. Various model-building methods were used to generate short-form solutions of the RMET, which were compared with previously validated versions in their predictive power for below average full RMET performance. RESULTS: Individuals with below average RMET performance tended to be older and have poorer global cognition. Of the eight short-form solutions, the 21-item version generated using genetic algorithm exhibited the best classification performance with an area under the receiver operating curve (AUROC) of 0.98 and had 93.2% accuracy in classifying individuals with below average ToM. A shorter 10-item solution derived by ant colony optimization also had acceptable performance. CONCLUSION: We recommend the 21-item version of the RMET for use in older adult populations for identifying individuals with impaired ToM. Where an even shorter version is needed with a trade-off of slightly reduced performance, the 10-item version is acceptable.

An investigation into early-life stress and cognitive function in older age.

Early-life stress (ELS) has previously been identified as a risk factor for cognitive decline, but this work has predominantly focused on clinical groups and indexed traditional cognitive domains. It, therefore, remains unclear whether ELS is related to cognitive function in healthy community-dwelling older adults, as well as whether any effects of ELS also extend to social cognition. To test each of these questions, the Childhood Trauma Questionnaire (CTQ) was administered to 484 older adults along with a comprehensive neuropsychological test battery and a well-validated test of social cognitive function. The results revealed no differences in global cognition according to overall experiences of ELS. However, a closer examination into the different ELS subscales showed that global cognition was poorer in those who had experienced physical neglect (relative to those who had not). Social cognitive function did not differ according to experiences to ELS. These results indicate that the relationship between ELS and cognition in older age may be dependent on the nature of the trauma experienced.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Aging Is Associated With Multidirectional Changes in Social Cognition: Findings From an Adult Life-Span Sample Ranging From 18 to 101 Years.

OBJECTIVES: Normal adult aging is associated with changes in social cognition. Although 4 social cognitive domains have been identified (social perception, theory of mind [ToM], affective empathy, and social behavior), no study has tested all 4 domains concurrently in a life-span sample, limiting understanding of the relative magnitude of age-related changes across domains. This study addresses this gap by providing the first assessment of all 4 social cognitive domains in an adult life-span sample. METHODS: Three hundred and seventy-two participants ranging from 18 to 101 years of age took part in this study. Participants completed a testing battery that assessed social perception, ToM, affective empathy, and social behavior, as well as broader cognitive function and well-being. RESULTS: The results showed that adult aging is associated with multidirectional changes in social cognitive abilities, with ToM and social perception showing nonlinear decline across much of the life-span, and affective empathy and social behavior showing improvement. Age remained a significant predictor of all 4 social cognitive domains, even after accounting for broader cognitive function. Weak associations emerged between some of the social cognitive abilities and and indices of broader well-being. DISCUSSION: These findings provide novel and important evidence that normative aging is associated with both gains and losses in social cognition that occur at distinct points of the adult life-span, and that are at least partially independent of general age-related cognitive decline.

Measuring Empathy Across the Adult Lifespan: A Comparison of Three Assessment Types.

Empathy is a core component of social cognition that can be indexed via behavioral, informant-report, or self-report methods of assessment. However, concerns have been raised regarding the lack of convergence between these assessment approaches for cognitive empathy. Here, we provided the first comparison of all three measurement approaches for cognitive and affective empathy in a large adult sample (N = 371) aged 18 to 101 years. We found that poor convergence was more of a problem for cognitive empathy than affective empathy. While none of the cognitive empathy measures correlated with each other, for affective empathy, self-report was significantly associated with both behavioral and informant-report assessments. However, for both cognitive and affective empathy, there was evidence for poor discriminant validity within the measures. Out of the three assessment approaches, only the informant-report measures were consistently associated with indices of social functioning. Importantly, age did not moderate any of the tested relationships, indicating that both the strengths and the limitations of these different types of assessment do not appear to vary as a function of age. These findings highlight the variation that exists among empathy measures and are discussed in relation to their practical implications for the assessment of empathy.

The influence of rs53576 polymorphism in the oxytocin receptor (OXTR) gene on empathy in healthy adults by subtype and ethnicity: a systematic review and meta-analysis.

Empathy is essential for navigating complex social environments. Prior work has shown associations between rs53576, a single nucleotide polymorphism (SNP) located in the oxytocin receptor gene (OXTR), and generalized empathy. We undertook a systematic review and meta-analysis to assess the effects of rs53576 on subdomains of empathy, specifically cognitive empathy (CE) and affective empathy (AE), in healthy adults. Twenty cohorts of 8933 participants aged 18-98 were identified, including data from the Sydney Memory and Ageing Study, a cohort of older community adults. Meta-analyses found G homozygotes had greater generalized empathic abilities only in young to middle-aged adults. While meta-analyses of empathy subdomains yielded no significant overall effects, there were differential effects based on ethnicity. G homozygotes were associated with greater CE abilities in Asian cohorts (standardized mean difference; SMD: 0.09 [2.8·10-3-0.18]), and greater AE performance in European cohorts [SMD: 0.12 (0.04-0.21)]. The current literature highlights a need for further work that distinguishes between genetic and ethnocultural effects and explores effects of advanced age on this relationship.

Profile of and risk factors for poststroke cognitive impairment in diverse ethnoregional groups.

OBJECTIVE: To address the variability in prevalence estimates and inconsistencies in potential risk factors for poststroke cognitive impairment (PSCI) using a standardized approach and individual participant data (IPD) from international cohorts in the Stroke and Cognition Consortium (STROKOG) consortium. METHODS: We harmonized data from 13 studies based in 8 countries. Neuropsychological test scores 2 to 6 months after stroke or TIA and appropriate normative data were used to calculate standardized cognitive domain scores. Domain-specific impairment was based on percentile cutoffs from normative groups, and associations between domain scores and risk factors were examined with 1-stage IPD meta-analysis. RESULTS: In a combined sample of 3,146 participants admitted to hospital for stroke (97%) or TIA (3%), 44% were impaired in global cognition and 30% to 35% were impaired in individual domains 2 to 6 months after the index event. Diabetes mellitus and a history of stroke were strongly associated with poorer cognitive function after covariate adjustments; hypertension, smoking, and atrial fibrillation had weaker domain-specific associations. While there were no significant differences in domain impairment among ethnoracial groups, some interethnic differences were found in the effects of risk factors on cognition. CONCLUSIONS: This study confirms the high prevalence of PSCI in diverse populations, highlights common risk factors, in particular diabetes mellitus, and points to ethnoracial differences that warrant attention in the development of prevention strategies.

Development and validation of a risk score (CHANGE) for cognitive impairment after ischemic stroke.

Post-stroke cognitive impairment (PSCI) warrants early detection and management. We sought to develop a risk score for screening patients at bedside for risk of delayed PSCI. Ischemic stroke survivors with PSCI and no cognitive impairments (NCI) 3-6 months post-stroke were studied to identify candidate variables predictive of PSCI. These variables were used to develop a risk score using regression models. The score, and the best identified clinical cutoff point, underwent development, stability testing, and internal and external validation in three independent cohorts from Singapore and Hong Kong. Across 1,088 subjects, the risk score, dubbed CHANGE, had areas under the receiver operating characteristics curve (AUROC) from 0.74 to 0.82 in detecting significant risk for PSCI, and had predicted values following actual prevalence. In validation data 3-6 and 12-18 months post-stroke, subjects with low, medium, and high scores had PSCI prevalence of 7-23%, 25-58%, and 67-82%. CHANGE was effective in screening ischemic stroke survivors for significant risk of developing PSCI up to 18 months post-stroke. CHANGE used readily available and reliable clinical data, and may be useful in identifying at-risk patients for PSCI.

Higher Peripheral TREM2 mRNA Levels Relate to Cognitive Deficits and Hippocampal Atrophy in Alzheimer's Disease and Amnestic Mild Cognitive Impairment.

BACKGROUND: Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimer's disease (AD) risk. Recent studies have reported inconsistent peripheral TREM2 mRNA expression levels and relationship with cognitive scores in AD and mild cognitive impairment (MCI). Additionally, no study has examined the association of peripheral TREM2 levels with neuroimaging measures in AD and MCI. OBJECTIVE: To determine peripheral TREM2 mRNA levels in AD, amnestic MCI (aMCI) and healthy controls, and the association with cognitive performance and brain structural changes. METHODS: We measured peripheral TREM2 mRNA levels in 80 AD, 30 aMCI, and 86 healthy controls using real time polymerase chain reaction. TREM2 levels were correlated with various cognitive performance and brain volumes, correcting for APOE4 status. RESULTS: TREM2 mRNA levels were significantly higher in AD compared to controls and aMCI. Levels did not differ between aMCI and controls. Corrected for APOE4, higher TREM2 levels correlated with lower Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and episodic memory scores, and lower total grey matter and right hippocampal volumes. Whole-brain voxel-based morphometry analysis found negative association between TREM2 mRNA levels and grey matter volumes in temporal, parietal and frontal regions. AD subjects with MoCA scores ≤20 had higher TREM2 levels correlating with smaller total grey matter, left hippocampal and right hippocampal volumes. CONCLUSION: Peripheral TREM2 mRNA levels are higher in AD and are associated with AD-related cognitive deficits and hippocampal atrophy. Our findings suggest that TREM2 may be a potential non-invasive peripheral biomarker for AD diagnosis.

STROKOG (stroke and cognition consortium): An international consortium to examine the epidemiology, diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease.

INTRODUCTION: The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD). METHODS: Longitudinal studies with ≥75 participants who had suffered or were at risk of stroke or TIA and which evaluated cognitive function were invited to join STROKOG. The consortium will facilitate projects investigating rates and patterns of cognitive decline, risk factors for VCD, and biomarkers of vascular dementia. RESULTS: Currently, STROKOG includes 25 (21 published) studies, with 12,092 participants from five continents. The duration of follow-up ranges from 3 months to 21 years. DISCUSSION: Although data harmonization will be a key challenge, STROKOG is in a unique position to reuse and combine international cohort data and fully explore patient level characteristics and outcomes. STROKOG could potentially transform our understanding of VCD and have a worldwide impact on promoting better vascular cognitive outcomes.

Depression and anxiety are co-morbid but dissociable in mild Parkinson's disease: A prospective longitudinal study of patterns and predictors.

BACKGROUND: Depression and anxiety are common in Parkinson's disease (PD) and contribute significantly to a reduced quality of life in PD patients. Though they often co-exist, it is unclear whether depression and anxiety result from a shared pathological process. We studied the longitudinal course and determinants of depression and anxiety in PD in order to understand which factors contribute to the development of these symptoms. METHODS: We conducted a prospective longitudinal study of 89 mild PD patients over 18 months, measuring depressive and anxiety symptoms at 6 monthly intervals using the Geriatric Depression Scale and Hospital Anxiety and Depression Scale--'Anxiety' subscale. Univariate and multivariate Generalised Estimating Equations were used to investigate the course of depression and anxiety and their association with demographic factors, motor measures, non-motor symptoms, and pharmacological factors. RESULTS: Depression and anxiety were co-morbid in 13.5% of the sample. Depressive symptoms remained relatively stable while anxiety symptoms improved over the course of 18 months. Severity of depressive symptoms was associated with female gender, motor fluctuations, apathy, and anxiety, while severity of anxiety was associated with older age, higher educational attainment, shorter disease duration, younger age of disease onset, and excessive daytime sleepiness. CONCLUSIONS: Although depression and anxiety are frequently co-morbid in PD, they were dissociable from each other. They had distinct trajectories and different longitudinal relationships with demographic, motor, and non-motor factors that were unique to each disorder.

Baseline predictors of worsening apathy in Parkinson's disease: A prospective longitudinal study.

INTRODUCTION: Apathy is one of the most common behavioural disorders in Parkinson's disease (PD) and contributes significantly to a reduced quality of life in PD patients. METHODS: We conducted a prospective longitudinal study of 89 mild PD patients over 18 months, measuring apathy symptoms at 6-monthly intervals using the Starkstein Apathy Scale, as well as measures of motor and non-motor symptoms, cognitive function, and functional disability at baseline. Mixed-effects models were used to characterise the individual trajectories of apathy symptom severity, and linear regression with stepwise elimination procedure was used to select significant baseline predictors. RESULTS: Clinically significant levels of apathy were present in 42.7% of our sample at baseline, with symptom severity remaining relatively stable on average over the course of 18 months. Male gender, lower educational attainment, higher depression symptom severity, more severe functional disability, and the presence of dyskinesias at study entry predicted increasing apathy over the subsequent 18 months. CONCLUSIONS: Patients with these factors are at risk for progression of apathy, which may be prevented by treating depression and functional disability. Further studies are needed to address both the specific neurobiological pathways and psychosocial factors underpinning apathy in PD.

Neural correlates of anxiety symptoms in mild Parkinson's disease: A prospective longitudinal voxel-based morphometry study.

BACKGROUND: Anxiety is prevalent in patients with Parkinson's disease (PD) and may affect patients' quality of life. Yet, little is known about the neural basis of anxiety in PD, and none have used a longitudinal design. METHODS: 73 patients with mild PD were recruited and followed up for 18months. A whole-brain analysis was first used to identify brain regions associated with anxiety symptoms, followed by a regional analysis focusing on a priori hypothesised regions at baseline. A multivariate generalized estimating equations analysis was then conducted to determine the longitudinal association between grey matter (GM) volumetric changes of these significant regions and changes of anxiety symptoms. RESULTS: At baseline, anxiety symptom severity was associated with decreased GM volumes in the bilateral precuneus and anterior cingulate cortex (ACC). Over 18months, increased severity of anxiety symptoms was associated with decreased GM volume in the left precuneus and ACC, independent of age, gender, education, depressive symptom severity or use of psychiatric medication. CONCLUSIONS: These results mainly implicate the precuneus and ACC in the pathogenesis of anxiety in PD. We speculate that these structural changes could reflect the disrupted default mode network due to PD pathology, contributing to spontaneous anxiety-related self-focused thoughts.