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.

Distinct network topology in Alzheimer's disease and behavioral variant frontotemporal dementia.

BACKGROUND: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social-emotional functional deficits. METHODS: In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. RESULTS: Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. CONCLUSIONS: Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

Interactions Between Acute Infarcts and Cerebrovascular Pathology Predict Poststroke Dementia.

BACKGROUND: Chronic cerebrovascular pathology accelerates the incidence of poststroke dementia (PSD). Whether the risk of PSD varies according to different types of chronic cerebrovascular pathology remains unclear. OBJECTIVES: We investigated whether PSD is associated with a unique pattern of interactions between chronic cerebrovascular pathologies and acute stroke lesions. MATERIALS AND METHOD: In this case-control study of acute mild stroke patients (n=185), cases included patients who developed PSD at a 6-month poststroke follow-up, and controls included patients who remained nondemented at 6 months, matched on prestroke cognitive status. Magnetic resonance imaging was performed at initial stroke presentation; neuropsychological assessments were performed 6 months after the stroke. RESULTS: White matter hyperintensities (WMH), chronic lacunes, microbleeds, and acute infarcts were not associated with PSD after controlling for demographics, cardiovascular risk, and global cortical atrophy. The risk of PSD was largest for patients with acute large subcortical infarcts (>15 mm) and concomitant periventricular WMH compared with patients with large subcortical infarcts and punctate/absent periventricular WMH [odds ratio (OR)=5.85, 95% confidence interval (CI)=1.85-40.04]. A moderate risk of PSD was observed for patients with acute multiple small infarcts (3 to 15 mm) and concomitant lacunes (OR=2.48, 95% CI=0.94-6.51) or concomitant lobar microbleeds (OR=2.20, 95% CI=0.89-5.41), compared with patients with acute multiple small infarcts and absent lacunes or microbleeds. Single small infarcts did not interact with cerebrovascular pathology to affect PSD. CONCLUSIONS: The risk of PSD varies depending on the presence of chronic cerebrovascular pathologies and type of acute infarcts. Clinical implications support a precision medicine approach for stratifying those at highest risk of PSD.

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.

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.

Age Moderates Associations of Hypertension, White Matter Hyperintensities, and Cognition.

BACKGROUND: Hypertension and white matter hyperintensities (WMH) are mutually associated risk factors for cognitive impairment. However, age may modify the associations between hypertension and WMH, and their links to cognitive impairment. OBJECTIVE: We evaluated the interaction between age and hypertension on WMH, and the age-stratified associations of hypertension and WMH with cognition. METHODS: Key measures include systolic blood pressure (SBP), WMH (modified Fazekas visual ratings of cranial MRI), and the Montreal Cognitive Assessment (MoCA). Participants (N = 488) with prodromal and mild dementia were age-stratified (≤49, 50-59, 60-69,≥70), and considered hypertensive if their SBP≥140 mmHg. The interaction between age strata and hypertension on WMH, and age-stratified associations of hypertension and WMH with cognition, were evaluated using multiple linear regression analyses. Analyses controlled for other risk factors for WMH and cognitive impairment. RESULTS: Age moderated the association between SBP and WMH. Hypertension was associated with higher WMH only in those aged 60-69, and WMH trends across age bands differed between those with and without hypertension. Finally, WMH and SBP≥140 were independently associated with lower MoCA scores within the 50-59 age band, while WMH alone was associated with poorer MoCA scores in the≥70 age band. CONCLUSION: In adults with prodromal or mild dementia, hypertension was associated with WMH specifically in the 60-69 age strata. Associations between hypertension and WMH with poorer cognition also differed across age bands. Future studies will be needed to investigate whether blood pressure management to slow cognitive decline by targeting WMH may be age dependent.

The role of cerebral microbleeds in the incidence of post-stroke dementia.

Microbleeds are a marker of cerebrovascular disease however its role in incident post-stroke dementia (PSD) remains unclear. We investigated whether microbleeds are associated with incident PSD, domain-specific cognitive impairment and cognitive decline over a 2-year follow-up; and whether microbleeds interact with acute stroke-related infarcts to synergistically affect cognitive outcomes. In a cohort of patients with first-episode mild ischemic stroke and no pre-stroke dementia, we found patients with 3 or more mixed microbleeds (presence of both lobar and deep) were 4 times more at risk of developing PSD compared to patients with no microbleeds. Patients with strictly lobar microbleeds were 10 times more at risk of developing memory impairment while patients with possible CAA-related microbleeds were 8 times more at risk of developing memory impairment compared to patients with no microbleeds. Microbleeds did not predict cognitive decline at the 2-year follow-up. Acute stroke infarcts were not related to any cognitive outcomes. Microbleeds did not interact with stroke infracts to synergistically affect cognitive outcomes. Our findings suggest that the combined effect of possible CAA and hypertension-related microbleeds play a large and direct role in incident PSD. Management of vasculopathy and amyloid deposition may positively impact cognitive outcomes after stroke.

The Longitudinal Impact of Excessive Daytime Somnolence on Motor and Nonmotor Symptoms of Parkinson's Disease in a Southeast Asian Cohort.

OBJECTIVE: Sleep-wake disturbances, such as excessive daytime somnolence (EDS), are nonmotor symptoms of Parkinson's disease (PD) and significantly affect the quality of life. This study aimed to examine the relationship between EDS and motor and nonmotor symptoms of PD. METHODS: Eighty-two patients with idiopathic mild PD were followed up twice a year for 2 years and assessed on sleep, mood, anxiety, cognition, function, and disease severity. Data were analyzed retrospectively, comparing motor and nonmotor outcomes between those with EDS and those without. RESULTS: At baseline, 27.9% had EDS and were similar in demographic and clinical characteristics to those without; 10% had persistent EDS during the first year of follow-up. Excessive daytime somnolence had a significant main effect on mood and anxiety as shown by consistently higher scores on the Geriatric Depression Scale (P = .022) and Hospital Anxiety and Depression Scale-Anxiety subscale scores (P = .011) throughout duration of follow-up. The group with persistent EDS showed greater rate of worsening Frontal Assessment Battery scores by the end of first-year follow-up (P = .025) and greater rate of worsening Apathy Scale scores by the end of 2-year follow-up (P = .002). No significant effects of EDS on motor symptoms and disease severity were found. CONCLUSIONS: In a Southeast Asian cohort of patients with PD, EDS had a negative longitudinal impact on mood, anxiety, apathy, and cognitive function but no impact on motor symptoms and disease severity. Excessive daytime somnolence is thus a potential therapeutic target to improve nonmotor outcomes.

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.

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.

Association of Asymmetrical White Matter Hyperintensities and Apolipoprotein E4 on Cognitive Impairment.

BACKGROUND: Asymmetrical patterns of cerebral damage have been widely observed in a range of neurodegenerative diseases, including Alzheimer's disease (AD). OBJECTIVE: To elucidate the clinical associations of asymmetrical white matter hyperintensities (WMH) in mild cognitive impairment (MCI) and AD. METHODS: Regional WMH asymmetry of 340 participants (90 healthy controls, 132 MCI, 118 AD) was calculated as the difference in normalized hemispheric WMH volume (WMH/ICV) adjusted for structural brain asymmetry of respective lobar regions and total WMH. WMH asymmetry was analyzed in relation to disease classification, cognition, and APOE4 status using ANCOVA and multiple regression analysis, controlling for gender, age, ethnicity, and correcting for multiple comparisons using Bonferroni correction. Moderation analysis examined interaction effects of APOE4 on associations between cognition and WMH asymmetry. RESULTS: Greater left-dominant occipital WMH asymmetry was observed in AD, compared to healthy controls and MCI, and was associated with poorer global cognition, memory, language, and executive functions among cognitively impaired participants (MCI and AD). Cognitively impaired APOE4 carriers displayed greater left-dominant WMH asymmetry in the whole brain and frontal lobe, compared to non-carriers. Importantly, effects were independent of structural brain asymmetry, global cerebral atrophy, and overall WMH burden. Moderation analysis demonstrated associations between left-dominant WMH asymmetry and cognition in cognitively impaired APOE4 non-carriers, but not APOE4 carriers. CONCLUSION: Leftward asymmetry of WMH may be more pathological in nature, compared to symmetrical WMH. Furthermore, the detrimental effects of WMH asymmetry was more relevant in APOE4-negative cognitive impairment, compared to APOE4-positive which may be driven primarily by AD pathology.

Mechanisms Linking White Matter Lesions, Tract Integrity, and Depression in Alzheimer Disease.

OBJECTIVE: Late-life depression involves the disconnection of white matter tracts that regulate mood. A pathogenic link between poor tract integrity and depressive symptoms is believed to be white matter lesions (WML), however the mechanisms linking tract integrity, WML, and depression remains unexplored. The authors sought to identify whether the association between reduced tract integrity and depressive symptoms is mediated by WML in patients with Alzheimer disease (AD), and whether individual characteristics moderate this effect. METHODS: This was a cross-sectional study in a tertiary memory clinic. A total of 91 patients with mild AD and 79 healthy elderly, comparable in depressive symptoms, white matter hyperintensities (WMH) volume, cardiovascular risk, age, and sex were chosen. Tract integrity was assessed using diffusion tensor imaging, WML were indexed as WMH, measured using fluid-attenuation inversion recovery imaging, and depressive symptoms were measured with the informant-based Geriatric Depression Scale. RESULTS: In patients with mild AD, reduced tract integrity in right hemispheric cortical-subcortical tracts and the genu of the corpus callosum was moderately associated with depressive symptoms. This association was fully mediated by WML. Moderation analysis indicated that old age strengthened the association between all tracts and depressive symptoms, as mediated by WML. In cognitively healthy elderly, neither tracts nor WML were related to depressive symptoms. CONCLUSION: Reduced tract integrity may be important but not sufficient for the manifestation of depressive symptoms in mild AD. Instead, WML may drive the pathogenic link between reduced tract integrity and depressive symptoms.

Cerebrovascular Disease Is a Risk for Getting Lost Behavior in Prodromal Dementia.

Cerebrovascular disease (CVD) contributes to spatial navigation deficits; however, the everyday outcomes of this association remain unexplored. We investigated whether CVD was a risk for getting lost behavior (GLB) in elderly with mild cognitive impairment (MCI) and mild Alzheimer disease (AD). Getting lost behavior was assessed using a semistructured clinical interview and was associated with white matter lesions (WMLs) in patients with MCI. Specifically, right occipital WMLs increased the odds of GLB by 12 times (P = .03) and right temporal WMLs increased the odds of GLB by 4 times (P = .01), regardless of age, gender, global cognitive impairment, and occipital or medial temporal gray matter atrophy. Hypertension increased the risk of GLB in MCI by contributing to the burden of WMLs. White matter lesions were not associated with GLB in mild AD. Our findings suggest that interventions aimed at reducing GLB in prodromal dementia may involve preventing WMLs by optimizing hypertension control.

Serial position effects differ between Alzheimer's and vascular features in mild cognitive impairment.

Individuals with mild cognitive impairment (MCI) exhibit varying serial position effect (SPE) performances. The relationship between SPE performance in word list recall and clinical, genetic, and neuroimaging features of MCI requires elucidation. 119 MCI and 68 cognitively normal (CN) participants underwent cognitive assessment, apolipoprotein E (ApoE) genotyping, and volumetric MRI brain scans processed via voxel-based morphometry. A 10-word recall task was used to assess SPE performance in relation to recency and primacy recall. MCI participants were classified as having Good SPE performance (high primacy and recency, Good SPE) or Poor SPE performance (low primacy only, LP-SPE; low recency only, LR-SPE; or both low, Low SPE). Poor SPE participants had reduced grey matter (GM) volumes and increased white matter hyperintensities (WMH) volumes. Participants with LP-SPE demonstrated reduced hippocampal GM volumes and were more likely to be ApoE ε4 carriers. LR-SPE was associated with higher WMH volumes. Presence of both greater WMH volumes and ApoE ε4 resulted in Low SPE. LP-SPE MCI participants had features typical of Alzheimer's disease. LR-SPE MCI was associated with increased WMH volumes, likely representing vascular pathology. SPE profiles are associated with distinct clinical patterns of MCI pathophysiology and could have potential as a clinical marker.

Regional White Matter Hyperintensity Influences Grey Matter Atrophy in Mild Cognitive Impairment.

The association between cerebrovascular disease pathology (measured by white matter hyperintensities, WMH) and brain atrophy in early Alzheimer's disease (AD) remain to be elucidated. Thus, we investigated how WMH influence neurodegeneration and cognition in prodromal and clinical AD. We examined 51 healthy controls, 35 subjects with mild cognitive impairment (MCI), and 30 AD patients. We tested how total and regional WMH is related to specific grey matter volume (GMV) reductions in MCI and AD compared to controls. Stepwise regression analysis was further performed to investigate the association of GMV and regional WMH volume with global cognition. We found that total WMH volume was highest in AD but showed the strongest association with lower GMV in MCI. Frontal and parietal WMH had the most extensive influence on GMV loss in MCI. Additionally, parietal lobe WMH volume (but not hippocampal atrophy) was significantly associated with global cognition in MCI while smaller hippocampal volume (but not WMH volume) was associated with lower global cognition in AD. Thus, although WMH volume was highest in AD subjects, it had a more pervasive influence on brain structure and cognitive impairment in MCI. Our study thus highlights the importance of early detection of cerebrovascular disease, as its intervention at the MCI stage might potentially slow down neurodegeneration.

Associations between lesions and domain-specific cognitive decline in poststroke dementia.

OBJECTIVE: To investigate whether the effect of prestroke and stroke-related lesions on incident poststroke dementia (PSD) is mediated by a unique pattern of domain-specific cognitive impairment, and the relative strength of these anatomical-cognitive associations in predicting incident PSD. METHODS: In this incident case-control study (n = 150), we defined incident cases as acute stroke patients who developed PSD and controls as acute stroke patients who remained free from dementia at a 6 month follow-up, matched on age, prestroke cognitive status, and number of stroke-related lesions. MRI was performed at initial clinical presentation; neuropsychological assessments and clinical diagnosis of PSD was performed 6 months poststroke. Moderated mediation analysis evaluated the interactions among PSD, anatomical lesions, cognitive domains, and individual demographic and medical characteristics. RESULTS: Compared to stroke-related lesions, prestroke lesions were associated with the widest range of cognitive domain impairments and had stronger clinical utility in predicting incident PSD. Specifically, global cortical atrophy (GCA) and deep white matter hyperintensities (WMH) were indirectly associated with PSD by disrupting executive functions, memory, and language. Acute infarcts were indirectly associated with PSD by disrupting executive functions and language. The strongest mediator was executive dysfunction, increasing risk of PSD in patients with deep WMH, GCA, and large infarcts by more than 9 times, with sex and educational attainment moderating the magnitude of association. Periventricular WMH were directly associated with incident PSD but not mediated by deficits in cognitive domains. CONCLUSION: We provide an anatomical-cognitive framework that can be applied to stratify patients at highest risk of PSD and to guide personalized interventions.