Publications by authors named "Amy Brodtmann"

92 Publications

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

Sleep Med 2021 Apr 15;83:45-53. Epub 2021 Apr 15.

The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia.

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.
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http://dx.doi.org/10.1016/j.sleep.2021.04.011DOI Listing
April 2021

Longitudinal hippocampal volumetric changes in mice following brain infarction.

Sci Rep 2021 May 13;11(1):10269. Epub 2021 May 13.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.

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 T-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.
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http://dx.doi.org/10.1038/s41598-021-88284-7DOI Listing
May 2021

Predicting Poststroke Cognitive Impairment: Sharpening the Diffuse?

Stroke 2021 May 10:STROKEAHA121035038. Epub 2021 May 10.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia. (A.B., M.V.).

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http://dx.doi.org/10.1161/STROKEAHA.121.035038DOI Listing
May 2021

Prognostic value of acute cerebrospinal fluid abnormalities in antibody-positive autoimmune encephalitis.

J Neuroimmunol 2021 Apr 30;353:577508. Epub 2021 Jan 30.

Department of Neuroscience, Monash University, Melbourne, Australia; Department of Neurology, Alfred Health, Melbourne, Australia; Department of Neurology, Melbourne Health, Melbourne, Australia; Department of Physiology, The University of Melbourne, Melbourne, Australia. Electronic address:

Objective: To examine the prognostic value of CSF abnormalities in seropositive autoimmune encephalitis (AE).

Methods: We retrospectively studied 57 cases of seropositive AE. Primary outcomes were mortality and modified Rankin Scale, while secondary outcomes were first line treatment failure, ICU admission and relapse. Regression analysis was performed.

Results: CSF white cell count (WCC) was higher in the NMDAR group, while elevated protein was more common amongst other subtypes. We found an association between WCC >5 cells/mm and treatment failure (OR 16.0, p = 0.006)), and between WCC >20 cells/mm and ICU admission (OR 19.3, p = 0.026).

Conclusions: Different subsets of AE have characteristic CSF abnormalities, which may aid recognition during early evaluation. CSF WCC had prognostic significance in our study.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577508DOI Listing
April 2021

Investigating the microstructural properties of normal-appearing white matter (NAWM) preceding conversion to white matter hyperintensities (WMHs) in stroke survivors.

Neuroimage 2021 05 9;232:117839. Epub 2021 Feb 9.

Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Melbourne Dementia Research Centre, University of Melbourne, Victoria, Australia. Electronic address:

Using advanced diffusion MRI, we aimed to assess the microstructural properties of normal-appearing white matter (NAWM) preceding conversion to white matter hyperintensities (WMHs) using 3-tissue diffusion signal compositions in ischemic stroke. Data were obtained from the Cognition and Neocortical Volume After Stroke (CANVAS) study. Diffusion-weighted MR and high-resolution structural brain images were acquired 3- (baseline) and 12-months (follow-up) post-stroke. WMHs were automatically segmented and longitudinal assessment at 12-months was used to retrospectively delineate NAWM voxels at baseline converting to WMHs. NAWM voxels converting to WMHs were further dichotomized into either: "growing" WMHs if NAWM adhered to existing WMH voxels, or "isolated de-novo" WMHs if NAWM was unconnected to WMH voxels identified at baseline. Microstructural properties were assessed using 3-tissue diffusion signal compositions consisting of white matter-like (WM-like: T), gray matter-like (GM-like: T), and cerebrospinal fluid-like (CSF-like: T) signal fractions. Our findings showed that NAWM converting to WMHs already exhibited similar changes in tissue compositions at baseline to WMHs with lower T and increased T (fluid-like, i.e. free-water) and T compared to persistent NAWM. We also found that microstructural properties of persistent NAWM were related to overall WMH burden with greater free-water content in patients with high WMH load. These findings suggest that NAWM preceding conversion to WMHs are accompanied by greater fluid-like properties indicating increased tissue water content. Increased GM-like properties may indicate a more isotropic microstructure of tissue reflecting a degree of hindered diffusion in NAWM regions vulnerable to WMH development. These results support the usefulness of microstructural compositions as a sensitive marker of NAWM vulnerability to WMH pathogenesis.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117839DOI Listing
May 2021

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

J Alzheimers Dis 2021 ;80(2):527-532

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.

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.
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http://dx.doi.org/10.3233/JAD-201525DOI Listing
January 2021

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

Int J Stroke 2021 Feb 23:1747493021995271. Epub 2021 Feb 23.

56369The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.

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 ( = 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.
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http://dx.doi.org/10.1177/1747493021995271DOI Listing
February 2021

Peripheral Immune Cell Ratios and Clinical Outcomes in Seropositive Autoimmune Encephalitis: A Study by the Australian Autoimmune Encephalitis Consortium.

Front Immunol 2020 14;11:597858. Epub 2021 Jan 14.

Department of Neuroscience, Monash University, Melbourne, VIC, Australia.

Objective: To examine the utility of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) as biomarkers of prognosis in seropositive autoimmune encephalitis (AE).

Methods: In this multicenter study, we retrospectively analyzed 57 cases of seropositive AE with hospital admissions between January 2008 and June 2019. The initial full blood examination was used to determine each patients' NLR and MLR. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability at 12 months and then at final follow-up. Primary outcomes were mortality and mRS, while secondary outcomes were failure of first line treatment, ICU admission, and clinical relapse. Univariate and multivariable regression analysis was performed.

Results: During initial hospital admission 44.7% of patients had unsuccessful first line treatment. After a median follow-up of 700 days, 82.7% had good functional outcome (mRS ≤2) while five patients had died. On multivariable analysis, high NLR was associated with higher odds of first line treatment failure (OR 1.32, 95% CI 1.03-1.69, p = 0.029). Increased MLR was not associated with any short or long-term outcome.

Conclusions: NLR on initial hospital admission blood tests may be provide important prognostic information for cases of seropositive AE. This study demonstrates the potential use of NLR as a prognostic marker in the clinical evaluation of patients with seropositive AE.
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http://dx.doi.org/10.3389/fimmu.2020.597858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840591PMC
January 2021

Imaging Markers of Brain Frailty and Outcome in Patients With Acute Ischemic Stroke.

Stroke 2021 Mar 28;52(3):1004-1011. Epub 2021 Jan 28.

Stroke Division (V.T.), The Florey Institute of Neuroscience and Mental Health.

Background And Purpose: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke.

Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial (AX200 in Ischemic Stroke Trial), a randomized controlled clinical trial of granulocyte colony-stimulating factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (ie, the brain parenchymal fraction) and total brain volumes from routine baseline magnetic resonance imaging data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces, white matter hyperintensities, lacunes, as well as a small vessel disease burden, were rated visually. Functional outcomes (modified Rankin Scale score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes.

Results: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased brain parenchymal fraction was associated with higher odds of excellent outcome (odds ratio per percent increase, 1.078 [95% CI, 1.008-1.153]). Total brain volumes and small vessel disease burden were not associated with functional outcome. An interaction between brain parenchymal fraction and large vessel occlusion on excellent outcome was not observed.

Conclusions: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00927836.
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http://dx.doi.org/10.1161/STROKEAHA.120.029841DOI Listing
March 2021

QSMART: Quantitative susceptibility mapping artifact reduction technique.

Neuroimage 2021 Jan 20;231:117701. Epub 2021 Jan 20.

Melbourne Brain Centre Imaging Unit, The University of Melbourne, Australia; Department of Biomedical Engineering, The University of Melbourne, Australia; Department of Medicine and Radiology, The University of Melbourne, Australia. Electronic address:

Purpose: Quantitative susceptibility mapping (QSM) is a novel MR technique that allows mapping of tissue susceptibility values from MR phase images. QSM is an ill-conditioned inverse problem, and although several methods have been proposed in the field, in the presence of a wide range of susceptibility sources, streaking artifacts appear around high susceptibility regions and contaminate the whole QSM map. QSMART is a post-processing pipeline that uses two-stage parallel inversion to reduce the streaking artifacts and remove banding artifact at the cortical surface and around the vasculature.

Method: Tissue and vein susceptibility values were separately estimated by generating a mask of vasculature driven from the magnitude data using a Frangi filter. Spatially dependent filtering was used for the background field removal step and the two susceptibility estimates were combined in the final QSM map. QSMART was compared to RESHARP/iLSQR and V-SHARP/iLSQR inversion in a numerical phantom, 7T in vivo single and multiple-orientation scans, 9.4T ex vivo mouse data, and 4.7T in vivo rat brain with induced focal ischemia.

Results: Spatially dependent filtering showed better suppression of phase artifacts near cortex compared to RESHARP and V-SHARP, while preserving voxels located within regions of interest without brain edge erosion. QSMART showed successful reduction of streaking artifacts as well as improved contrast between different brain tissues compared to the QSM maps obtained by RESHARP/iLSQR and V-SHARP/iLSQR.

Conclusion: QSMART can reduce QSM artifacts to enable more robust estimation of susceptibility values in vivo and ex vivo.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117701DOI Listing
January 2021

Advancing Stroke Recovery Through Improved Articulation of Nonpharmacological Intervention Dose.

Stroke 2021 Jan 12;52(2):761-769. Epub 2021 Jan 12.

Florey Institute of Neuroscience and Mental Health and NHMRC Centre of Research Excellence in Stroke Rehabilitation and Brain Recovery (J.B.), University of Melbourne, Heidelberg, Australia.

Dose articulation is a universal issue of intervention development and testing. In stroke recovery, dose of a nonpharmaceutical intervention appears to influence outcome but is often poorly reported. The challenges of articulating dose in nonpharmacological stroke recovery research include: (1) the absence of specific internationally agreed dose reporting guidelines; (2) inadequate conceptualization of dose, which is multidimensional; and (3) unclear and inconsistent terminology that incorporates the multiple dose dimensions. To address these challenges, we need a well-conceptualized and consistent approach to dose articulation that can be applied across stroke recovery domains to stimulate critical thinking about dose during intervention development, as well as promote reporting of planned intervention dose versus actually delivered dose. We followed the Design Research Paradigm to develop a framework that guides how to articulate dose, conceptualizes the multidimensional nature and systemic linkages between dose dimensions, and provides reference terminology for the field. Our framework recognizes that dose is multidimensional and comprised of a duration of days that contain individual sessions and episodes that can be active (time on task) or inactive (time off task), and each individual episode can be made up of information about length, intensity, and difficulty. Clinical utility of this framework was demonstrated via hypothetical application to preclinical and clinical domains of stroke recovery. The suitability of the framework to address dose articulation challenges was confirmed with an international expert advisory group. This novel framework provides a pathway for better articulation of nonpharmacological dose that will enable transparent and accurate description, implementation, monitoring, and reporting, in stroke recovery research.
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http://dx.doi.org/10.1161/STROKEAHA.120.032496DOI Listing
January 2021

Networking not working? Functional connectivity to predict post-stroke cognition.

Neurology 2021 Jan 6. Epub 2021 Jan 6.

Center of Excellence in Stroke Detection and Diagnosis, Johns Hopkins University, Baltimore, USA.

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http://dx.doi.org/10.1212/WNL.0000000000011501DOI Listing
January 2021

In vivo microstructural heterogeneity of white matter lesions in healthy elderly and Alzheimer's disease participants using tissue compositional analysis of diffusion MRI data.

Neuroimage Clin 2020 26;28:102479. Epub 2020 Oct 26.

Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.

White matter hyperintensities (WMH) are regions of high signal intensity typically identified on fluid attenuated inversion recovery (FLAIR). Although commonly observed in elderly individuals, they are more prevalent in Alzheimer's disease (AD) patients. Given that WMH appear relatively homogeneous on FLAIR, they are commonly partitioned into location- or distance-based classes when investigating their relevance to disease. Since pathology indicates that such lesions are often heterogeneous, probing their microstructure in vivo may provide greater insight than relying on such arbitrary classification schemes. In this study, we investigated WMH in vivo using an advanced diffusion MRI method known as single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD), which models white matter microstructure while accounting for grey matter and CSF compartments. Diffusion MRI data and FLAIR images were obtained from AD (n = 48) and healthy elderly control (n = 94) subjects. WMH were automatically segmented, and classified: (1) as either periventricular or deep; or (2) into three distance-based contours from the ventricles. The 3-tissue profile of WMH enabled their characterisation in terms of white matter-, grey matter-, and fluid-like characteristics of the diffusion signal. Our SS3T-CSD findings revealed substantial heterogeneity in the 3-tissue profile of WMH, both within lesions and across the various classes. Moreover, this heterogeneity information indicated that the use of different commonly used WMH classification schemes can result in different disease-based conclusions. We conclude that future studies of WMH in AD would benefit from inclusion of microstructural information when characterising lesions, which we demonstrate can be performed in vivo using SS3T-CSD.
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http://dx.doi.org/10.1016/j.nicl.2020.102479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652769PMC
October 2020

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

Brain Commun 2020 26;2(2):fcaa155. Epub 2020 Sep 26.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.

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.
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http://dx.doi.org/10.1093/braincomms/fcaa155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751023PMC
September 2020

A study protocol for a phase II randomised, double-blind, placebo-controlled trial of sodium selenate as a disease-modifying treatment for behavioural variant frontotemporal dementia.

BMJ Open 2020 11 16;10(11):e040100. Epub 2020 Nov 16.

Department of Neuroscience, Monash University, Melbourne, Victoria, Australia.

Introduction: Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder often neuropathologically associated with the accumulation of abnormally hyperphosphorylated tau, for which there is currently no disease-modifying treatment. Previous work by our group has shown sodium selenate upregulates the activity of protein phosphatase 2 in the brain, increasing the rate of tau dephosphorylation. The objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying treatment for bvFTD.

Methods And Analysis: This will be a multisite, phase IIb, double-blind placebo-controlled trial of sodium selenate. One hundred and twenty participants will be enrolled across 4 Australian academic hospitals. Following screening eligible participants will be randomised (1:1) to sodium selenate (15 mg three times a day) or placebo for 52 weeks. Participants will have regular safety and efficacy visits throughout the study period. The primary study outcome will be percentage brain volume change (PBVC) as measured on MRI over 52 weeks of treatment. This will be analysed with a general linear model (analysis of covariance (ANCOVA)) with the PBVC as an output, the treatment as an input and the baseline brain volume as covariate for adjustment purposes. Secondary outcomes include safety and tolerability measures, and efficacy measures; change in cerebrospinal fluid total-tau, Addenbrooke's Cognitive Examination-III and Cambridge Behavioural Inventory-Revised scores over the 52 weeks of treatment. These will also be analysed with ANCOVA where the corresponding baseline measure will be incorporated in the model. Additional exploratory outcomes will include other imaging, cognitive and biospecimen analyses.

Ethics And Dissemination: The study was approved by the Human Research and Ethics Committee of the lead site as part of the Australian Multisite Ethics approval system. The results of the study will be presented at national and international conferences and published in peer-reviewed journals.

Trial Registration Number: ACTRN12620000236998 .
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http://dx.doi.org/10.1136/bmjopen-2020-040100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670941PMC
November 2020

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

Sci Rep 2020 10 21;10(1):17911. Epub 2020 Oct 21.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.

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, R = 0.25, p < 0.001 (group significant predictor at p < 0.001) and the Trail-Making Test (B), F(3,157) = 3.70, R = 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.
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http://dx.doi.org/10.1038/s41598-020-75074-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578057PMC
October 2020

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

J Clin Sleep Med 2021 Feb;17(2):167-175

The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.5664/jcsm.8812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853221PMC
February 2021

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

Stroke 2020 09 10;51(9):e183-e192. Epub 2020 Aug 10.

The Florey Institute of Neuroscience and Mental Health (A.B., M.S.K., N.E., M.V., L.J.B., E.W.), University of Melbourne, Australia.

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.
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http://dx.doi.org/10.1161/STROKEAHA.120.030256DOI Listing
September 2020

Dementia is Associated With Poorer Quality of Care and Outcomes After Stroke: An Observational Study.

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):851-858

Stroke and Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.

Background: To determine whether preexisting dementia is associated with poorer quality of care and outcomes after stroke in the acute hospital phase.

Method: This was a retrospective analysis of pooled data from the Australian Stroke Foundation national audit conducted in 2015 and 2017. Dementia status was obtained from the medical records. Processes of care to assess quality included: stroke unit care, time-dependent therapy, nursing/allied health assessments, and preparation for discharge. Outcomes included in-hospital complications, independence on discharge, and destination. Logistic regression was used to examine associations between dementia status and processes of care. Multilevel random effects logistic regression, with level defined as hospital, was used to examine associations between dementia status and outcomes.

Results: There were 683/7,070 (9.7%) audited patients with dementia included. Patients with dementia were less likely to be treated in stroke units (58.3% vs 70.6%), receive thrombolysis if an ischemic stroke (5.8% vs 11.1%), have access within 48 hours to physiotherapy (56.4% vs 69.7%) or occupational therapy (46.8% vs 55.6%), see a dietitian if problems with nutrition (64.4% vs 75.9%), or have mood assessed (2.6% vs 12.3%). Patients with dementia were more likely to receive no rehabilitation (adjusted odds ratio 1.88, 95% confidence interval 1.25, 2.83) and be discharged to residential care (adjusted odds ratio 2.36, 95% confidence interval 1.50, 3.72).

Conclusion: People with dementia received poorer quality of care and had worse outcomes after stroke. Our findings raise questions regarding equity and the need for better understanding of why the quality of care differs after stroke for people with dementia.
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http://dx.doi.org/10.1093/gerona/glaa139DOI Listing
April 2021

Three-tissue compositional analysis reveals in-vivo microstructural heterogeneity of white matter hyperintensities following stroke.

Neuroimage 2020 09 22;218:116869. Epub 2020 Apr 22.

Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia; Melbourne Dementia Research Centre, University of Melbourne, Victoria, Australia.

White matter hyperintensities (WMHs) are frequently observed on brain scans of older individuals and are associated with cognitive impairment and vascular brain burden. Recent studies have shown that WMHs may only represent an extreme end of a diffuse pathological spectrum of white matter (WM) degeneration. The present study investigated the microstructural characteristics of WMHs using an advanced diffusion MRI modelling approach known as Single-Shell 3-Tissue Constrained Spherical Deconvolution (SS3T-CSD), which provides information on different tissue compartments within each voxel. The SS3T-CSD method may provide complementary information in the interpretation of pathological tissue through the tissue-specific microstructural compositions of WMHs. Data were obtained from stroke patients enrolled in the Cognition and Neocortical Volume After Stroke (CANVAS) study, a study examining brain volume and cognition after stroke. WMHs were segmented using an automated method, based on fluid attenuated inversion recovery (FLAIR) images. Automated tissue segmentation was used to identify normal-appearing white matter (NAWM). WMHs were classified into juxtaventricular, periventricular and deep lesions, based on their distance from the ventricles (3-10 ​mm). We aimed to compare in stroke participants the microstructural composition of the different lesion classes of WMHs and compositions of NAWM to assess the in-vivo heterogeneity of these lesions. Results showed that the 3-tissue composition significantly differed between WMHs classes and NAWM. Specifically, the 3-tissue compositions for juxtaventricular and periventricular WMHs both exhibited a relatively greater fluid-like (free water) content, which is compatible with a presence of interstitial fluid accumulation, when compared to deep WMHs. These findings provide evidence of microstructural heterogeneity of WMHs in-vivo and may support new insights for understanding the role of WMH development in vascular neurodegeneration.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116869DOI Listing
September 2020

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

Hum Brain Mapp 2020 Apr 20. Epub 2020 Apr 20.

Department of Health Sciences and Research, Medical University of South Carolina, Charleston, South Carolina, USA.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.
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http://dx.doi.org/10.1002/hbm.25015DOI Listing
April 2020

Pervasive White Matter Fiber Degeneration in Ischemic Stroke.

Stroke 2020 05 16;51(5):1507-1513. Epub 2020 Apr 16.

From the Dementia Research Theme, The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia (N.E., M.S.K., W.K., E.W., A.B.).

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.
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http://dx.doi.org/10.1161/STROKEAHA.119.028143DOI Listing
May 2020

Regional neurodegeneration correlates with sleep-wake dysfunction after stroke.

Sleep 2020 09;43(9)

The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1093/sleep/zsaa054DOI Listing
September 2020

Predicted Brain Age After Stroke.

Front Aging Neurosci 2019 10;11:348. Epub 2019 Dec 10.

Division of Behavioural Neuroscience, The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.

Aging is a known non-modifiable risk factor for stroke. Usually, this refers to chronological rather than biological age. Biological brain age can be estimated based on cortical and subcortical brain measures. For stroke patients, it could serve as a more sensitive marker of brain health than chronological age. In this study, we investigated whether there is a difference in brain age between stroke survivors and control participants matched on chronological age. We estimated brain age at 3 months after stroke, and then followed the longitudinal trajectory over three time-points: within 6 weeks (baseline), at 3 and at 12 months following their clinical event. We found that brain age in stroke participants was higher compared to controls, with the mean difference between the groups varying between 3.9 and 8.7 years depending on the brain measure used for prediction. This difference in brain age was observed at 6 weeks after stroke and maintained at 3 and 12 months after stroke. The presence of group differences already at baseline suggests that stroke might be an ultimate manifestation of gradual cerebrovascular burden accumulation and brain degeneration. Brain age prediction, therefore, has the potential to be a useful biomarker for quantifying stroke risk.
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http://dx.doi.org/10.3389/fnagi.2019.00348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914736PMC
December 2019

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

Hum Brain Mapp 2020 04 19;41(6):1557-1572. Epub 2019 Dec 19.

Austin Health, Heidelberg, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1002/hbm.24894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268042PMC
April 2020

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Lancet Neurol 2020 02 3;19(2):145-156. Epub 2019 Dec 3.

Institut du Cerveau et de la Moelle épinière & Centre de Référence des Démences Rares ou précoces, Institut de la Mémoire et de la Maladie d'Alzheimer, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France.

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.

Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.

Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.

Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.

Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.
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http://dx.doi.org/10.1016/S1474-4422(19)30394-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007771PMC
February 2020

Assessment of longitudinal hippocampal atrophy in the first year after ischemic stroke using automatic segmentation techniques.

Neuroimage Clin 2019 22;24:102008. Epub 2019 Oct 22.

The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia; Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.

We assessed first-year hippocampal atrophy in stroke patients and healthy controls using manual and automated segmentations: AdaBoost, FIRST (fsl/v5.0.8), FreeSurfer/v5.3 and v6.0, and Subfields (in FreeSurfer/v6.0). We estimated hippocampal volumes in 39 healthy controls and 124 stroke participants at three months, and 38 controls and 113 stroke participants at one year. We used intra-class correlation, concordance, and reduced major axis regression to assess agreement between automated and 'Manual' estimations. A linear mixed-effect model was used to characterize hippocampal atrophy. Overall, hippocampal volumes were reduced by 3.9% in first-ever stroke and 9.2% in recurrent stroke at three months post-stroke, with comparable ipsi-and contra-lesional reductions in first-ever stroke. Mean atrophy rates between time points were 0.5% for controls and 1.0% for stroke patients (0.6% contra-lesionally, 1.4% ipsi-lesionally). Atrophy rates in left and right-hemisphere strokes were comparable. All methods revealed significant volume change in first-ever and ipsi-lesional stroke (p < 0.001). Hippocampal volume estimation was not impacted by hemisphere, study group, or scan time point, but rather, by the interaction between the automated segmentation method and hippocampal size. Compared to Manual, Subfields and FIRST recorded the lowest bias. FreeSurfer/v5.3 overestimated volumes the most for large hippocampi, while FIRST was the most accurate in estimating small volumes. AdaBoost performance was average. Our findings suggest that first-year ipsi-lesional hippocampal atrophy rate especially in first-ever stroke, is greater than atrophy rates in healthy controls and contra-lesional stroke. Subfields and FIRST can complementarily be effective in characterizing the hippocampal atrophy in healthy and stroke cohorts.
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http://dx.doi.org/10.1016/j.nicl.2019.102008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849411PMC
September 2020

A Human Depression Circuit Derived From Focal Brain Lesions.

Biol Psychiatry 2019 11 2;86(10):749-758. Epub 2019 Aug 2.

Berenson-Allen Center for Non-Invasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Focal brain lesions can lend insight into the causal neuroanatomical substrate of depression in the human brain. However, studies of lesion location have led to inconsistent results.

Methods: Five independent datasets with different lesion etiologies and measures of postlesion depression were collated (N = 461). Each 3-dimensional lesion location was mapped to a common brain atlas. We used voxel lesion symptom mapping to test for associations between depression and lesion locations. Next, we computed the network of regions functionally connected to each lesion location using a large normative connectome dataset (N = 1000). We used these lesion network maps to test for associations between depression and connected brain circuits. Reproducibility was assessed using a rigorous leave-one-dataset-out validation. Finally, we tested whether lesion locations associated with depression fell within the same circuit as brain stimulation sites that were effective for improving poststroke depression.

Results: Lesion locations associated with depression were highly heterogeneous, and no single brain region was consistently implicated. However, these same lesion locations mapped to a connected brain circuit, centered on the left dorsolateral prefrontal cortex. Results were robust to leave-one-dataset-out cross-validation. Finally, our depression circuit derived from brain lesions aligned with brain stimulation sites that were effective for improving poststroke depression.

Conclusions: Lesion locations associated with depression fail to map to a specific brain region but do map to a specific brain circuit. This circuit may have prognostic utility in identifying patients at risk for poststroke depression and therapeutic utility in refining brain stimulation targets.
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http://dx.doi.org/10.1016/j.biopsych.2019.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531583PMC
November 2019

APOE ɛ4 Carriers Show Delayed Recovery of Verbal Memory and Smaller Entorhinal Volume in the First Year After Ischemic Stroke.

J Alzheimers Dis 2019 ;71(1):245-259

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.

Background: The apolipoprotein E (APOE) gene ɛ4 allele is a risk factor for Alzheimer's disease and cardiovascular disease. However, its relationship with cognition and brain volume after stroke is not clear.

Objective: We compared cognition and medial temporal lobe volumes in APOEɛ4 carriers and non-carriers in the first year after ischemic stroke.

Methods: We sampled 20 APOEɛ4 carriers and 20 non-carriers from a larger cohort of 135 ischemic stroke participants in the longitudinal CANVAS study. Participants were matched on a range of demographic and stroke characteristics. We used linear mixed-effect models to compare cognitive domain z-scores (attention, processing speed, executive function, verbal and visual memory, language, visuospatial function) and regional medial temporal lobe volumes (hippocampal, entorhinal cortex) between groups at each time-point (3, 12-months post-stroke), and within groups across time-points. APOE gene single nucleotide polymorphisms (SNPs; rs7412, rs429358) were genotyped on venous blood.

Results: APOEɛ4 carriers and non-carriers did not differ on any demographic, clinical, or stroke variable. Carriers performed worse than non-carriers in verbal memory at 3 months post-stroke (p = 0.046), but were better in executive function at 12 months (p = 0.035). Carriers demonstrated a significant improvement in verbal memory (p = 0.012) and executive function (p = 0.015) between time-points. Non-carriers demonstrated a significant improvement in visual memory (p = 0.0005). Carriers had smaller bilateral entorhinal cortex volumes (p < 0.05), and larger right sided and contralesional hippocampal volumes, at both time-points (p < 0.05).

Conclusion: APOE ɛ4 is associated with delayed recovery of verbal memory function and reduced entorhinal cortex volumes in the first year after ischemic stroke.
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http://dx.doi.org/10.3233/JAD-190566DOI Listing
October 2020

A systematic review protocol of timing, efficacy and cost effectiveness of upper limb therapy for motor recovery post-stroke.

Syst Rev 2019 07 25;8(1):187. Epub 2019 Jul 25.

Occupational Therapy Department, Alfred Health, Prahran, Melbourne, VIC, Australia.

Background: Improving upper limb (UL) motor recovery after stroke represents a major clinical and scientific goal. We aim to complete three systematic reviews to estimate the (1) association between time to start of UL therapy and motor recovery, (2) relative efficacy of different UL therapy approaches post-stroke and (3) cost-effectiveness of UL therapy interventions.

Methods: We have designed a systematic review protocol to address three systematic review questions that were each registered with PROSPERO. The search will be conducted in MEDLINE, EMBASE, and Cochrane Controlled Register of Trials. We will include randomised controlled trials, non-randomised clinical trials, before-after studies and observational studies of adult stroke survivors with an average stroke onset < 6 months, undergoing hospital-based therapy to improve UL function. Eligible interventions will aim to promote UL functional recovery. Two reviewers will independently screen, select and extract data. Study risk of bias will be appraised using appropriate tools. Clinical measures of motor recovery will be investigated (primary measure Fugl Meyer UL assessment), as well as measures of health-related quality of life (primary measure EQ-5D) and all cost-effectiveness analyses completed. Secondary outcomes include therapy dose (minutes, weeks, repetitions as available) and safety (i.e. adverse events, serious adverse events). A narrative synthesis will describe quality and content of the evidence. If feasible, we will conduct random effects meta-analyses where appropriate.

Discussion: We anticipate the findings of this review will increase our understanding of UL therapy and inform the generation of novel, data-driven hypotheses for future UL therapy research post-stroke.

Systematic Review Registration: PROSPERO, http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018019367, http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018111629, http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018111628.
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http://dx.doi.org/10.1186/s13643-019-1093-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657039PMC
July 2019