ZOom Delivered Intervention Against Cognitive decline (ZODIAC) COVID-19 pandemic adaptations to the Post-Ischaemic Stroke Cardiovascular Exercise Study (PISCES): protocol for a randomised controlled trial of remotely delivered fitness training for brain health.

BACKGROUND: Stroke increases subsequent dementia risk yet there are no specific post-stroke therapies to protect cognition. Cardiorespiratory exercise is recommended for secondary prevention of stroke and may be neuroprotective. The Post Ischaemic Stroke Cardiovascular Exercise Study (PISCES) aims to reduce post-stroke secondary neurodegeneration and cognitive decline. During the pandemic, we pivoted to a ZOom Delivered Intervention Against Cognitive decline (ZODIAC) protocol, reducing pandemic-amplified barriers to exercise. METHODS: We present pandemic adaptions for a multicentre phase IIb assessor-blinded randomised controlled trial of ischaemic stroke survivors testing the efficacy and feasibility of an 8-week home-based exercise intervention delivered at 2 months post-stroke. We compare cardiorespiratory exercise (intervention arm) versus balance and stretching (active control arm). Participants are assessed with magnetic resonance imaging (MRI), fitness, blood, microbiome, and neuropsychological tests at three study visits: before and after the exercise intervention and at 12 months. Modifications to the original protocol include pre-exercise safety home visits, commercial delivery of exercise equipment to facilitate assessor blinding, and reconsideration of statistical plan to allow pooling of the studies. We have reduced in-person study visits from 27 to 3. Primary outcome remains between-group (intervention versus control) difference in brain volume change; secondary outcome is between-group difference in global cognitive ability to allow remote administration of a validated cognitive scale. DISCUSSION: Remotely delivered exercise interventions reduce participant burden and may reduce barriers to recruitment. A decrease in the number of in-person study visits can be supported by greater information capture via self-reported questionnaires and phone surveys. TRIAL REGISTRATION: Prospectively ACTRN12616000942459. Registered on July 2016.

Cortical thinning 3 years after ischaemic stroke is associated with cognitive impairment and APOE ε4.

Cortical thinning has been described in many neurodegenerative diseases and used for both diagnosis and disease monitoring. The imaging signatures of post-stroke vascular cognitive impairment have not been well described. We investigated the trajectory of cortical thickness over 3 years following ischaemic stroke compared to healthy stroke-free age- and sex-matched controls. We also compared cortical thickness between cognitively normal and impaired stroke survivors, and between APOE ɛ4 carriers and non-carriers. T1-weighted MRI and cognitive data for 90 stroke survivors and 36 controls from the Cognition And Neocortical Volume After Stroke (CANVAS) study were used. Cortical thickness was estimated using FreeSurfer volumetric reconstruction according to the Desikan-Killiany parcellation atlas. Segmentation inaccuracies were manually corrected and infarcted ipsilesional vertices in cortical thickness maps were identified and excluded using stroke lesion masks traced a-priori. Mixed-effects regression was used to compare cortical thickness cross-sectionally between groups and longitudinally between timepoints. Healthy control and stroke groups did not differ on demographics and most clinical characteristics, though controls were less likely to have atrial fibrillation. Age was negatively associated with global mean cortical thickness independent of sex or group, with women in both groups having significantly thicker cortex. Three months post-stroke, cortical thinning was limited and focal. From 3 months to 3 years, the rate of cortical thinning in stroke was faster compared to that in healthy controls. However, this difference in cortical thinning rate could not survive family-wise correction for multiple comparisons. Yet, cortical thinning at 3 years was found more spread especially in ipsilesional hemispheres in regions implicated in motor, sensory, and memory processing and recovery. The cognitively impaired stroke survivors showed greater cortical thinning, compared to controls, than those who were cognitively normal at 3 years. Also, carriers of the APOE ɛ4 allele in stroke exhibited greater cortical thinning independent of cognitive status. The temporal changes of cortical thickness in both healthy and stroke cohorts followed previously reported patterns of cortical thickness asymmetry loss across the human adult life. However, this loss of thickness asymmetry was amplified in stroke. The post-stroke trajectories of cortical thickness reported in this study may contribute to our understanding of imaging signatures of vascular cognitive impairment.

Poststroke White Matter Hyperintensities and Physical Activity: A CANVAS Study Exploratory Analysis.

PURPOSE: White matter hyperintensities (WMHs) are associated with poststroke cognitive decline and mortality. Physical activity (PA) may decrease WMH risk by reducing vascular risk factors and promoting cerebral perfusion. However, the association between poststroke PA and WMH progression remains unclear. We examined the association between PA and WMH volume 12 months after stroke, and between PA and change in WMH volume between 3 and 12 months after stroke. METHODS: We included ischemic stroke survivors from the Cognition And Neocortical Volume After Stroke cohort with available brain magnetic resonance imaging and objective PA data. Total, periventricular, and deep WMH volumes (in milliliters) were estimated with manually edited, automated segmentations (Wisconsin White Matter Hyperintensities Segmentation toolbox). Moderate-to-vigorous intensity PA (MVPA) was estimated using the SenseWear® Armband. Participants with MVPA ≥30 min·d -1 were classified as "meeting PA guidelines." We used quantile regression to estimate the associations between PA (MVPA and meeting PA guidelines) with WMH volume at 12 months and change in WMH volume between 3 and 12 months after stroke. RESULTS: A total of 100 participants were included (median National Institutes of Health Stroke Scale 2; interquartile range, 1-4). MVPA was not associated with WMH volume. In univariable analysis, meeting PA guidelines was associated with lower total, periventricular, and deep WMH volumes by 3.0 mL (95% confidence interval (CI), 0.5-9.7 mL), 2.8 mL (95% CI, 0.5-7.1 mL), and 0.9 mL (95% CI, 0.1-3.0 mL), respectively. However, in multivariable analysis, meeting PA guidelines was not associated with WMH volume, and older age was associated with greater WMH volume at 12 months. PA was not associated with change in WMH volume. CONCLUSIONS: Meeting PA guidelines was associated with lower WMH volume at 12 months in univariable analysis, but not in multivariable analysis. Age consistently predicted greater WMH volume.

Grey and white matter atrophy 1 year after stroke aphasia.

Dynamic whole-brain changes occur following stroke, and not just in association with recovery. We tested the hypothesis that the presence of a specific behavioural deficit after stroke would be associated with structural decline (atrophy) in the brain regions supporting the affected function, by examining language deficits post-stroke. We quantified whole-brain structural volume changes longitudinally (3-12 months) in stroke participants with (N = 32) and without aphasia (N = 59) as assessed by the Token Test at 3 months post-stroke, compared with a healthy control group (N = 29). While no significant difference in language decline rates (change in Token Test scores from 3 to 12 months) was observed between groups and some participants in the aphasic group improved their scores, stroke participants with aphasia symptoms at 3 months showed significant atrophy (>2%, P = 0.0001) of the left inferior frontal gyrus not observed in either healthy control or non-aphasic groups over the 3-12 months period. We found significant group differences in the inferior frontal gyrus volume, accounting for age, sex, stroke severity at baseline, education and total intracranial volume (Bonferroni-corrected P = 0.0003). In a subset of participants (aphasic N = 14, non-aphasic N = 36, and healthy control N = 25) with available diffusion-weighted imaging data, we found significant atrophy in the corpus callosum and the left superior longitudinal fasciculus in the aphasic compared with the healthy control group. Language deficits at 3 months post-stroke are associated with accelerated structural decline specific to the left inferior frontal gyrus, highlighting that known functional brain reorganization underlying behavioural improvement may occur in parallel with atrophy of brain regions supporting the language function.

Pre-stroke Physical Activity and Cerebral Collateral Circulation in Ischemic Stroke: A Potential Therapeutic Relationship?

Favorable cerebral collateral circulation contributes to hindering penumbral tissue from progressing to infarction and is associated with positive clinical outcomes after stroke. Given its clinical importance, improving cerebral collateral circulation is considered a therapeutic target to reduce burden after stroke. We provide a hypothesis-generating discussion on the potential association between pre-stroke physical activity and cerebral collateral circulation in ischemic stroke. The recruitment of cerebral collaterals in acute ischemic stroke may depend on anatomical variations, capacity of collateral vessels to vasodilate, and individual risk factors. Physical activity is associated with improved cerebral endothelial and vascular function related to vasodilation and angiogenic adaptations, and risk reduction in individual risk factors. More research is needed to understand association between cerebral collateral circulation and physical activity. A presentation of different methodological considerations for measuring cerebral collateral circulation and pre-stroke physical activity in the context of acute ischemic stroke is included. Opportunities for future research into cerebral collateral circulation, physical activity, and stroke recovery is presented.

Mood and Cognitive Trajectories Over the First Year after Mild Ischemic Stroke.

OBJECTIVES: Cognitive and mood dysfunction are major contributors to post-stroke disability. The longer-term trajectories of mood and cognition post-stroke remain unclear, as do which cognitive domains decline, improve, or remain stable after stroke, and in which patients. We aimed to characterize the cognitive trajectories of mild ischemic stroke survivors over one year compared to stroke-free controls, and to investigate whether symptoms of anxiety and depression were associated with cognitive function. MATERIALS AND METHODS: All participants were tested with a neuropsychological test battery at 3-months and 12-months post-stroke, assessing attention/processing speed, memory, visuospatial function, executive function, and language. Anxiety and depression symptomatology were also assessed at both timepoints. RESULTS: Stroke participants (N=126, mean age 68.44 years ±11.83, 87 males, median [Q1, Q3] admission NIHSS=2 [1, 4]) performed worse on cognitive tests and endorsed significantly higher depression and anxiety symptomatology than controls (N=40, mean age=68.82 years ±6.33, 25 males) at both timepoints. Mood scores were not correlated with cognitive performance. Stroke participants' scores trended higher across cognitive domains from 3- to 12-months but statistically significant improvement was only observed on executive function tasks. CONCLUSION: Stroke participants performed significantly worse than controls on all cognitive domains following mild ischemic stroke. Stroke participants only exhibited statistically significant improvement on executive function tasks between 3- and 12- months. Whilst anxiety and depression symptoms were higher in stroke participants, this was not correlated with cognitive performance. Further studies are needed to understand factors underlying cognitive recovery and decline after stroke.

Atrophy of Ipsilesional Hippocampal Subfields Vary Over First Year After Ischemic Stroke.

BACKGROUND: The structural integrity of hippocampal subfields has been investigated in many neurological disorders and was shown to be better associated with cognitive performance than whole hippocampus. In stroke, hippocampal atrophy is linked to cognitive impairment, but it is unknown whether the hippocampal subfields atrophy differently. PURPOSE: To evaluate longitudinal hippocampal subfield atrophy in first year poststroke, in comparison with atrophy in healthy individuals. STUDY TYPE: Cohort. SUBJECTS: A total of 92 ischemic stroke (age: 67 ± 12 years, 63 men) and 39 healthy participants (age: 69 ± 7 years, 24 men). FIELD STRENGTH/SEQUENCE: A3 T/T1-MPRAGE, T2-SPACE, and T2-FLAIR. ASSESSMENT: FreeSurfer (6.0) was used to delineate 12 hippocampal subfields. Whole hippocampal volume was computed as sum of subfield volumes excluding hippocampal fissure volume. Separate assessments were completed for contralesional and ipsilesional hippocampi. STATISTICAL TESTS: A mixed-effect regression model was used to compare subfield volumes cross-sectionally between healthy and stroke groups and longitudinally between 3-month and 12-month timepoints. False discovery rate at 0.05 significance level was used to correct for multiple comparisons. Also, a receiver operating characteristic (ROC) curve analysis was performed to assess differentiation between healthy and stroke participants based on subfield volumes. RESULTS: There were no volume differences between groups at 3 months, but there was a significant difference (P = 0.027) in whole hippocampal volume reduction over time between control and stroke ipsilesionally. Thus, the ipsilesional whole hippocampal volume in stroke became significantly smaller (P = 0.035) at 12 months. The hippocampal tail was the highest single-region contributor (22.7%) to ipsilesional hippocampal atrophy (1.19%) over 9 months. The cornu ammonis areas (CA1) subfield volume reduction was minimal in controls and stroke contralesionally but significant ipsilesionally (P = 0.007). CA1 volume significantly outperformed whole hippocampal volume (P < 0.01) in discriminating between stroke participants and healthy controls in ROC curve analysis. DATA CONCLUSION: Greater stroke-induced effects were observed in the ipsilesional hippocampus anteriorly in CA1 and posteriorly in the hippocampal tail. Atrophy of CA1 and hippocampal tail may provide a better link to cognitive impairment than whole hippocampal atrophy. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Neurodegeneration Over 3 Years Following Ischaemic Stroke: Findings From the Cognition and Neocortical Volume After Stroke Study.

Background: Stroke survivors are at high risk of dementia, associated with increasing age and vascular burden and with pre-existing cognitive impairment, older age. Brain atrophy patterns are recognised as signatures of neurodegenerative conditions, but the natural history of brain atrophy after stroke remains poorly described. We sought to determine whether stroke survivors who were cognitively normal at time of stroke had greater total brain (TBV) and hippocampal volume (HV) loss over 3 years than controls. We examined whether stroke survivors who were cognitively impaired (CI) at 3 months following their stroke had greater brain volume loss than cognitively normal (CN) stroke participants over the next 3 years. Methods: Cognition And Neocortical Volume After Stroke (CANVAS) study is a multi-centre cohort study of first-ever or recurrent adult ischaemic stroke participants compared to age- and sex-matched community controls. Participants were followed with MRI and cognitive assessments over 3 years and were free of a history of cognitive impairment or decline at inclusion. Our primary outcome measure was TBV change between 3 months and 3 years; secondary outcomes were TBV and HV change comparing CI and CN participants. We investigated associations between group status and brain volume change using a baseline-volume adjusted linear regression model with robust standard error. Results: Ninety-three stroke (26 women, 66.7 ± 12 years) and 39 control participants (15 women, 68.7 ± 7 years) were available at 3 years. TBV loss in stroke patients was greater than controls: stroke mean (M) = 20.3 cm3 ± SD 14.8 cm3; controls M = 14.2 cm3 ± SD 13.2 cm3; [adjusted mean difference 7.88 95%CI (2.84, 12.91) p-value = 0.002]. TBV decline was greater in those stroke participants who were cognitively impaired (M = 30.7 cm3; SD = 14.2 cm3) at 3 months (M = 19.6 cm3; SD = 13.8 cm3); [adjusted mean difference 10.42; 95%CI (3.04, 17.80), p-value = 0.006]. No statistically significant differences in HV change were observed. Conclusions: Ischaemic stroke survivors exhibit greater neurodegeneration compared to stroke-free controls. Brain atrophy is greater in stroke participants who were cognitively impaired early after their stroke. Early cognitive impairment was associated greater subsequent atrophy, reflecting the combined impacts of stroke and vascular brain burden. Atrophy rates could serve as a useful biomarker for trials testing interventions to reduce post-stroke secondary neurodegeneration. Clinical Trail Registration: http://www.clinicaltrials.gov, identifier: NCT02205424.

Hippocampal subfield volumes are associated with verbal memory after first-ever ischemic stroke.

INTRODUCTION: Hippocampal subfield volumes are more closely associated with cognitive impairment than whole hippocampal volume in many diseases. Both memory and whole hippocampal volume decline after stroke. Understanding the subfields' temporal evolution could reveal valuable information about post-stroke memory. METHODS: We sampled 120 participants (38 control, 82 stroke), with cognitive testing and 3T-MRI available at 3 months and 3 years, from the Cognition and Neocortical Volume after Stroke (CANVAS) study. Verbal memory was assessed using the Hopkins Verbal Learning Test-Revised. Subfields were delineated using FreeSurfer. We used partial Pearson's correlation to assess the associations between subfield volumes and verbal memory scores, adjusting for years of education, sex, and stroke side. RESULTS: The left cornu ammonis areas 2/3 and hippocampal tail volumes were significantly associated with verbal memory 3-month post-stroke. At 3 years, the associations became stronger and involved more subfields. DISCUSSION: Hippocampal subfield volumes may be a useful biomarker for post-stroke cognitive impairment.

Longitudinal hippocampal volumetric changes in mice following brain infarction.

Hippocampal atrophy is increasingly described in many neurodegenerative syndromes in humans, including stroke and vascular cognitive impairment. However, the progression of brain volume changes after stroke in rodent models is poorly characterized. We aimed to monitor hippocampal atrophy occurring in mice up to 48-weeks post-stroke. Male C57BL/6J mice were subjected to an intraluminal filament-induced middle cerebral artery occlusion (MCAO). At baseline, 3-days, and 1-, 4-, 12-, 24-, 36- and 48-weeks post-surgery, we measured sensorimotor behavior and hippocampal volumes from T2-weighted MRI scans. Hippocampal volume-both ipsilateral and contralateral-increased over the life-span of sham-operated mice. In MCAO-subjected mice, different trajectories of ipsilateral hippocampal volume change were observed dependent on whether the hippocampus contained direct infarction, with a decrease in directly infarcted tissue and an increase in non-infarcted tissue. To further investigate these volume changes, neuronal and glial cell densities were assessed in histological brain sections from the subset of MCAO mice lacking hippocampal infarction. Our findings demonstrate previously uncharacterized changes in hippocampal volume and potentially brain parenchymal cell density up to 48-weeks in both sham- and MCAO-operated mice.

Sleep architectural dysfunction and undiagnosed obstructive sleep apnea after chronic ischemic stroke.

OBJECTIVE/BACKGROUND: Sleep-wake dysfunction is bidirectionally associated with the incidence and evolution of acute stroke. It remains unclear whether sleep disturbances are transient post-stroke or are potentially enduring sequelae in chronic stroke. Here, we characterize sleep architectural dysfunction, sleep-respiratory parameters, and hemispheric sleep in ischemic stroke patients in the chronic recovery phase compared to healthy controls. PATIENTS/METHODS: Radiologically confirmed ischemic stroke patients (n = 28) and matched control participants (n = 16) were tested with ambulatory polysomnography, bi-hemispheric sleep EEG, and demographic, stroke-severity, mood, and sleep-circadian questionnaires. RESULTS: Twenty-eight stroke patients (22 men; mean age = 69.61 ± 7.4 years) were cross-sectionally evaluated 4.1 ± 0.9 years after mild-moderate ischemic stroke (baseline NIHSS: 3.0 ± 2.0). Fifty-seven percent of stroke patients (n = 16) exhibited undiagnosed moderate-to-severe obstructive sleep apnea (apnea-hypopnea index >15). Despite no difference in total sleep or wake after sleep onset, stroke patients had reduced slow-wave sleep time (66.25 min vs 99.26 min, p = 0.02), increased time in non-rapid-eye-movement (NREM) stages 1-2 (NREM-1: 48.43 vs 28.95, p = 0.03; NREM-2: 142.61 vs 115.87, p = 0.02), and a higher arousal index (21.46 vs 14.43, p = 0.03) when compared to controls. Controlling for sleep apnea severity did not attenuate the magnitude of sleep architectural differences between groups (NREM 1-3=ηp2 >0.07). We observed no differences in ipsilesionally versus contralesionally scored sleep architecture. CONCLUSIONS: Fifty-seven percent of chronic stroke patients had undiagnosed moderate-severe obstructive sleep apnea and reduced slow-wave sleep with potentially compensatory increases in NREM 1-2 sleep relative to controls. Formal sleep studies are warranted after stroke, even in the absence of self-reported history of sleep-wake pathology.

Pre-stroke physical activity and admission stroke severity: A systematic review.

BACKGROUND: Admission stroke severity is an important clinical predictor of stroke outcomes. Pre-stroke physical activity contributes to stroke prevention and may also be associated with reduced stroke severity. Summarizing the evidence to date will inform strategies to reduce burden after stroke. AIMS: To summarize the published evidence for the relationship between pre-stroke physical activity and admission stroke severity and to provide recommendations for future research. SUMMARY OF REVIEW: MEDLINE, Embase, Emcare, CENTRAL, and gray literature databases were searched on 14 February 2020 using search terms related to stroke and pre-stroke physical activity in adult stroke survivors. We screened 8,152 references and assessed 172 full-text references for eligibility. We included seven studies (n = 41,800 stroke survivors). All studies were observational, assessed pre-stroke physical activity using self-reported questionnaires, and assessed admission stroke severity using the National Institute of Health Stroke Scale. Analyses were categorized as the presence of pre-stroke physical activity (four studies) or dose-response (five studies). In three studies, presence of pre-stroke physical activity was associated with milder stroke severity, and no association in one study. Greater pre-stroke physical activity duration and intensity (two studies) or amount (three studies) were associated with milder stroke severity. Studies ranged between moderate to critical risk of bias, primarily due to confounding factors. Pre-stroke physical activity may be associated with reduced risk factors for severe stroke, distal occlusion, smaller infarcts, and shorter time-to-treatment delivery. CONCLUSION: Pre-stroke physical activity may be associated with reduced admission stroke severity. Lack of randomized controlled trials limited causality conclusions. Future research recommendations were provided.

Hippocampal Volume and Amyloid PET Status Three Years After Ischemic Stroke: A Pilot Study.

Hippocampal atrophy is seen in many neurodegenerative disorders and may be a cardinal feature of vascular neurodegeneration. We examined hippocampal volume (HV) in a group of ischemic stroke survivors with amyloid 18F-NAV4694 PET imaging three years after stroke. We compared HV between the amyloid-positive (n = 4) and amyloid-negative (n = 29) groups, and associations with co-morbidities using Charlson Comorbidity Indices and multi-way ANOVA. Amyloid status was not associated with verbal or visual delayed free recall memory indices or cognitive impairment. We found no association between amyloid status and HV in this group of ischemic stroke survivors.

Sleep-wake parameters can be detected in patients with chronic stroke using a multisensor accelerometer: a validation study.

STUDY OBJECTIVES: Sleep-wake dysfunction is bidirectionally associated with the pathogenesis and evolution of stroke. Longitudinal and prospective measurement of sleep after chronic stroke remains poorly characterized because of a lack of validated objective and ambulatory sleep measurement tools in neurological populations. This study aimed to validate a multisensor sleep monitor, the SenseWear Armband (SWA), in patients with ischemic stroke and control patients using at-home polysomnography. METHODS: Twenty-eight radiologically confirmed patients with ischemic stroke (aged 69.61 ± 7.35 years; mean = 4.1 years poststroke) and 16 control patients (aged 73.75 ± 7.10 years) underwent overnight at-home polysomnography in tandem with the SWA. Lin's concordance correlation coefficient and reduced major axis regressions were employed to assess concordance of SWA vs polysomnography-measured total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset. Subsequently, data were converted to 30-second epochs to match at-home polysomnography. Epoch-by-epoch agreement between SWA and at-home polysomnography was estimated using crude agreement, Cohen's kappa, sensitivity, and specificity. RESULTS: Total sleep time was the most robustly quantified sleep-wake variable (concordance correlation coefficient = 0.49). The SWA performed poorest for sleep measures requiring discrimination of wakefulness (sleep onset latency; concordance correlation coefficient = 0.16). The sensitivity of the SWA was high (95.90%) for patients with stroke and for control patients (95.70%). The specificity of the SWA was fair-moderate for patients with stroke (40.45%) and moderate for control patients (45.60%). Epoch-by-epoch agreement rate was fair (78%) in patients with stroke and fair (74%) in controls. CONCLUSIONS: The SWA shows promise as an ambulatory tool to estimate macro parameters of sleep-wake; however, agreement at an epoch level is only moderate-fair. Use of the SWA warrants caution when it is used as a diagnostic tool or in populations with significant sleep-wake fragmentation.

Degeneration of structural brain networks is associated with cognitive decline after ischaemic stroke.

Over one-third of stroke patients has long-term cognitive impairment. The likelihood of cognitive dysfunction is poorly predicted by the location or size of the infarct. The macro-scale damage caused by ischaemic stroke is relatively localized, but the effects of stroke occur across the brain. Structural covariance networks represent voxelwise correlations in cortical morphometry. Atrophy and topographical changes within such distributed brain structural networks may contribute to cognitive decline after ischaemic stroke, but this has not been thoroughly investigated. We examined longitudinal changes in structural covariance networks in stroke patients and their relationship to domain-specific cognitive decline. Seventy-three patients (mean age, 67.41 years; SD = 12.13) were scanned with high-resolution magnetic resonance imaging at sub-acute (3 months) and chronic (1 year) timepoints after ischaemic stroke. Patients underwent a number of neuropsychological tests, assessing five cognitive domains including attention, executive function, language, memory and visuospatial function at each timepoint. Individual-level structural covariance network scores were derived from the sub-acute grey-matter probabilistic maps or changes in grey-matter probability maps from sub-acute to chronic using data-driven partial least squares method seeding at major nodes in six canonical high-order cognitive brain networks (i.e. dorsal attention, executive control, salience, default mode, language-related and memory networks). We then investigated co-varying patterns between structural covariance network scores within canonical distributed brain networks and domain-specific cognitive performance after ischaemic stroke, both cross-sectionally and longitudinally, using multivariate behavioural partial least squares correlation approach. We tested our models in an independent validation data set with matched imaging and behavioural testing and using split-half validation. We found that distributed degeneration in higher-order cognitive networks was associated with attention, executive function, language, memory and visuospatial function impairment in sub-acute stroke. From the sub-acute to the chronic timepoint, longitudinal structural co-varying patterns mirrored the baseline structural covariance networks, suggesting synchronized grey-matter volume decline occurred within established networks over time. The greatest changes, in terms of extent of distributed spatial co-varying patterns, were in the default mode and dorsal attention networks, whereas the rest were more focal. Importantly, faster degradation in these major cognitive structural covariance networks was associated with greater decline in attention, memory and language domains frequently impaired after stroke. Our findings suggest that sub-acute ischaemic stroke is associated with widespread degeneration of higher-order structural brain networks and degradation of these structural brain networks may contribute to longitudinal domain-specific cognitive dysfunction.

Microstructural degeneration and cerebrovascular risk burden underlying executive dysfunction after stroke.

Executive dysfunction affects 40% of stroke patients, but is poorly predicted by characteristics of the stroke itself. Stroke typically occurs on a background of cerebrovascular burden, which impacts cognition and brain network structural integrity. We used structural equation modelling to investigate whether measures of white matter microstructural integrity (fractional anisotropy and mean diffusivity) and cerebrovascular risk factors better explain executive dysfunction than markers of stroke severity. 126 stroke patients (mean age 68.4 years) were scanned three months post-stroke and compared to 40 age- and sex-matched control participants on neuropsychological measures of executive function. Executive function was below what would be expected for age and education level in stroke patients as measured by the organizational components of the Rey Complex Figure Test, F(3,155) = 17, R2 = 0.25, p < 0.001 (group significant predictor at p < 0.001) and the Trail-Making Test (B), F(3,157) = 3.70, R2 = 0.07, p < 0.01 (group significant predictor at p < 0.001). A multivariate structural equation model illustrated the complex relationship between executive function, white matter integrity, stroke characteristics and cerebrovascular risk (root mean square error of approximation = 0.02). Pearson's correlations confirmed a stronger relationship between executive dysfunction and white matter integrity (r = - 0.74, p < 0.001), than executive dysfunction and stroke severity (r = 0.22, p < 0.01). The relationship between executive function and white matter integrity is mediated by cerebrovascular burden. White matter microstructural degeneration of the superior longitudinal fasciculus in the executive control network better explains executive dysfunction than markers of stroke severity. Executive dysfunction and incident stroke can be both considered manifestations of cerebrovascular risk factors.

Dynamic Regional Brain Atrophy Rates in the First Year After Ischemic Stroke.

BACKGROUND AND PURPOSE: Brain atrophy can be regarded as an end-organ effect of cumulative cardiovascular risk factors. Accelerated brain atrophy is described following ischemic stroke, but it is not known whether atrophy rates vary over the poststroke period. Examining rates of brain atrophy allows the identification of potential therapeutic windows for interventions to prevent poststroke brain atrophy. METHODS: We charted total and regional brain volume and cortical thickness trajectories, comparing atrophy rates over 2 time periods in the first year after ischemic stroke: within 3 months (early period) and between 3 and 12 months (later period). Patients with first-ever or recurrent ischemic stroke were recruited from 3 Melbourne hospitals at 1 of 2 poststroke time points: within 6 weeks (baseline) or 3 months. Whole-brain 3T magnetic resonance imaging was performed at 3 time points: baseline, 3 months, and 12 months. Eighty-six stroke participants completed testing at baseline; 125 at 3 months (76 baseline follow-up plus 49 delayed recruitment); and 113 participants at 12 months. Their data were compared with 40 healthy control participants with identical testing. We examined 5 brain measures: hippocampal volume, thalamic volume, total brain and hemispheric brain volume, and cortical thickness. We tested whether brain atrophy rates differed between time points and groups. A linear mixed-effect model was used to compare brain structural changes, including age, sex, years of education, a composite cerebrovascular risk factor score, and total intracranial volume as covariates. RESULTS: Atrophy rates were greater in stroke than control participants. Ipsilesional hemispheric, hippocampal, and thalamic atrophy rates were 2 to 4 times greater in the early versus later period. CONCLUSIONS: Regional atrophy rates vary over the first year after stroke. Rapid brain volume loss in the first 3 months after stroke may represent a potential window for intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02205424.

Pervasive White Matter Fiber Degeneration in Ischemic Stroke.

Background and Purpose- We examined if ischemic stroke is associated with white matter degeneration predominantly confined to the ipsi-lesional tracts or with widespread bilateral axonal loss independent of lesion laterality. Methods- We applied a novel fixel-based analysis, sensitive to fiber tract-specific differences within a voxel, to assess axonal loss in stroke (N=104, 32 women) compared to control participants (N=40, 15 women) across the whole brain. We studied microstructural differences in fiber density and macrostructural (morphological) changes in fiber cross-section. Results- In participants with stroke, we observed significantly lower fiber density and cross-section in areas adjacent, or connected, to the lesions (eg, ipsi-lesional corticospinal tract). In addition, the changes extended beyond directly connected tracts, independent of the lesion laterality (eg, corpus callosum, bilateral inferior fronto-occipital fasciculus, right superior longitudinal fasciculus). Conclusions- We conclude that ischemic stroke is associated with extensive neurodegeneration that significantly affects white matter integrity across the whole brain. These findings expand our understanding of the mechanisms of brain volume loss and delayed cognitive decline in stroke.

Regional neurodegeneration correlates with sleep-wake dysfunction after stroke.

Sleep-wake disruption is a key modifiable risk factor and sequela of stroke. The pathogenesis of poststroke sleep dysfunction is unclear. It is not known whether poststroke sleep pathology is due to focal infarction to sleep-wake hubs or to accelerated poststroke neurodegeneration in subcortical structures after stroke. We characterize the first prospective poststroke regional brain volumetric and whole-brain, fiber-specific, white matter markers of objectively measured sleep-wake dysfunction. We hypothesized that excessively long sleep (>8 h) duration and poor sleep efficiency (<80%) measured using the SenseWear Armband 3-months poststroke (n = 112) would be associated with reduced regional brain volumes of a priori-selected sleep-wake regions of interest when compared to healthy controls with optimal sleep characteristics (n = 35). We utilized a novel technique known as a whole-brain fixel-based analysis to investigate the fiber-specific white matter differences in participants with long sleep duration. Stroke participants with long sleep (n = 24) duration exhibited reduced regional volumes of the ipsilesional thalamus and contralesional amygdala when compared with controls. Poor sleep efficiency after stroke (n = 29) was associated with reduced ipsilesional thalamus, contralesional hippocampus, and contralesional amygdala volumes. Whole-brain fixel-based analyses revealed widespread macrostructural degeneration to the corticopontocerebellar tract in stroke participants with long sleep duration, with fiber reductions of up to 40%. Neurodegeneration to subcortical structures, which appear to be vulnerable to accelerated brain volume loss after stroke, may drive sleep-wake deficiencies poststroke, independent of lesion characteristics and confounding comorbidities. We discuss these findings in the context of the clinicopathological implications of sleep-related neurodegeneration and attempt to corroborate previous mechanistic-neuroanatomical findings.

The heterogeneous functional architecture of the posteromedial cortex is associated with selective functional connectivity differences in Alzheimer's disease.

The posteromedial cortex (PMC) is a key region involved in the development and progression of Alzheimer's disease (AD). Previous studies have demonstrated a heterogenous functional architecture of the region that is composed of discrete functional modules reflecting a complex pattern of functional connectivity. However, little is understood about the mechanisms underpinning this complex network architecture in neurodegenerative disease, and the differential vulnerability of connectivity-based subdivisions in the PMC to AD pathogenesis. Using a data-driven approach, we applied a constrained independent component analysis (ICA) on healthy adults from the Human Connectome Project to characterise the local functional connectivity patterns within the PMC, and its unique whole-brain functional connectivity. These distinct connectivity profiles were subsequently quantified in the Alzheimer's Disease Neuroimaging Initiative study, to examine functional connectivity differences in AD patients and cognitively normal (CN) participants, as well as the entire AD pathological spectrum. Our findings revealed decreased functional connectivity in the anterior precuneus, dorsal posterior cingulate cortex (PCC), and the central precuneus in AD patients compared to CN participants. Functional abnormalities in the dorsal PCC and central precuneus were also related to amyloid burden and volumetric hippocampal loss. Across the entire AD spectrum, functional connectivity of the central precuneus was associated with disease severity and specific deficits in memory and executive function. These findings provide new evidence showing that the PMC is selectively impacted in AD, with prominent network failures of the dorsal PCC and central precuneus underpinning the neurodegenerative and cognitive dysfunctions associated with the disease.