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

Probably the best way to prevent this is for your doctor to have EXACT 100% RECOVERY PROTOCOLS

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

Amy Brodtmann^1,2,3*, Emilio Werden¹, Mohamed Salah Khlif¹, Laura J. Bird¹, Natalia Egorova^1,2,4, Michele Veldsman^1,5, Heath Pardoe⁶, Graeme Jackson^1,3, Jennifer Bradshaw⁷, David Darby^1,2, Toby Cumming¹, Leonid Churilov^1,3† and Geoffrey Donnan^1,3†

• ¹The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
• ²Melbourne Dementia Research Centre, Florey Institute and University of Melbourne, Parkville, VIC, Australia
• ³Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia
• ⁴Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia
• ⁵Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
• ⁶Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States
• ⁷Department of Clinical Neuropsychology, Austin Health, Heidelberg, VIC, Australia

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.

Introduction

Stroke care has been transformed in the last three decades by improved reperfusion treatments and rehabilitation therapies. Despite this, the global burden of stroke remains high, in part due to long-term cognitive impairments and increased risk of dementia (1). Cumulative vascular risk factors increase dementia risk (2, 3); conversely, good cardiovascular health reduces this risk (4). Risk of stroke and of cognitive decline are also conflated: cognitive impairment can anticipate the development of incident stroke (5) and be a manifestation of this risk (6). One of the strongest risk factors for post-stroke cognitive impairment is a history of pre-stroke cognitive or functional decline (7).

Brain atrophy precedes and predicts cognitive decline in many neurodegenerative syndromes, but the trajectories of brain volume loss and cognitive impairment in stroke survivors are poorly understood. These have been difficult to disentangle given relatively few post-stroke longitudinal cohort studies with high-quality serial imaging and cognitive data. Prior studies also often included people with pre-stroke cognitive impairment and dementia, further complicating associations. Structural brain changes are already present at the time of stroke, including smaller hippocampal volumes and increased white matter hyperintensity (WMH) volumes (8). It has been demonstrated that both greater brain atrophy and increased WMH are associated with risk of future stroke (9). We have demonstrated that stroke survivors have greater predicted brain age (10), extensive white matter degeneration at 3 months after stroke (11), and hippocampal, thalamic and ipsilesional hemispheric atrophy that continues over the first post-stroke year (12).

Brain atrophy rates are now being used as biomarkers for clinical trials in a number of neurological disorders (13, 14), including dementia (15). Regional atrophy rates have been shown to correlate with other markers of neurodegeneration, including CSF and blood biomarkers (16). Annualised hippocampal and total brain atrophy rates have been described in normal ageing and dementia syndromes (17–20), as well as being used as outcome measures for treatment response in clinical trials (15, 21). While the neuroimaging signatures of AD and other neurodegenerative diseases are now well-described (22–25), there are few data in ischaemic stroke survivors.

Understanding the trajectories of brain volume loss in people with vascular contributions to their cognitive profile has important clinical implications. Mixed neuropathologies are ubiquitous in late-life dementias (26), and a greater understanding of vascular neurodegenerative imaging signatures would assist in diagnostic assignment and clinical treatment. Total and regional brain atrophy rates may serve as useful tools to assess treatment response for interventions to reduce post-stroke secondary degeneration and vascular cognitive impairment, especially as most recent multimodal intervention trials for dementia prevention largely targeted cardiovascular risk (27, 28). An imaging biomarker has several advantages over more traditionally used cognitive assessments, as atrophy rates are not as dependent on language, educational attainment, culture, or socio-economic status as canonical cognitive tests (29, 30).

We aimed to determine whether ischaemic stroke was associated with progressive neurodegeneration via a prospective, 3-year cohort study comparing participants with ischaemic stroke to their age- and sex-matched healthy controls. Our aim in this study was to test for associations between group status: total brain volume in stroke vs. control participants for our primary hypothesis, brain volume change in those stroke participants with cognitive impairment vs. normal cognition at 3 months in our secondary hypothesis. We included participants with no history of cognitive impairment or decline, cross-checked via interview with family members and treating health practitioners. In addition, we aimed to determine whether stroke survivors with cognitive impairment at 3 months exhibited greater brain atrophy over the subsequent 3 years compared to those who were cognitively normal. We hypothesised that stroke survivors would exhibit greater total brain volume loss than controls, and that those who were cognitively impaired at 3 months after stroke would exhibit greater brain volume loss than those who were cognitively normal.