White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta-analysis, systematic review, and recommendations for future study harmonization.

INTRODUCTION: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps. METHODS: A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke. RESULTS: Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier. DISCUSSION: Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.

Characterization of Behaviour and Remote Degeneration Following Thalamic Stroke in the Rat.

Subcortical ischemic strokes are among the leading causes of cognitive impairment. Selective atrophy of remote brain regions connected to the infarct is thought to contribute to deterioration of cognitive functions. The mechanisms underlying this secondary degenerative process are incompletely understood, but are thought to include inflammation. We induce ischemia by unilateral injection of endothelin-I into the rat dorsomedial thalamic nucleus, which has defined reciprocal connections to the frontal cortex. We use a comprehensive test battery to probe for changes in behaviour, including executive functions. After a four-week recovery period, brain sections are stained with markers for degeneration, microglia, astrocytes and myelin. Degenerative processes are localized within the stroke core and along the full thalamocortical projection, which does not translate into measurable behavioural deficits. Significant microglia recruitment, astrogliosis or myelin loss along the axonal projection or within the frontal cortex cannot be detected. These findings indicate that critical effects of stroke-induced axonal degeneration may only be measurable beyond a threshold of stroke severity and/or follow a different time course. Further investigations are needed to clarify the impact of inflammation accompanying axonal degeneration on delayed remote atrophy after stroke.

Prevalence of dementia, heart disease and stroke in community-dwelling adults in Canada, 2016-2021: opportunities for joint prevention.

INTRODUCTION: This aim of this study is to provide updated estimates on the prevalence of dementia, heart disease, and stroke in Canadian communities. Targeting all three conditions together, at the community level, may be key to disease prevention and health aging in the Canadian population. METHODS: Using nationwide health survey data, we calculated the age-standardized prevalence of self-reported dementia, heart disease and stroke in adults aged 18 years and over residing in Canadian communities from 2016 to 2021. Poisson regression models were used to detect statistically significant changes in the prevalence of all three conditions from 2016 to 2021. RESULTS: Less than 1% (~ 175,000 individuals) of adults residing in Canadian communities reported dementia, 5% (~ 1.5 million individuals) reported heart disease, and more than 1% (~ 370,000 individuals) reported stroke annually from 2016 to 2021. Overall, the age-standardized prevalence for stroke decreased minimally from 2016 to 2021 (p = 0.0004). Although the age-standardized prevalence of heart disease and dementia decreased from 2016 to 2018, subsequent increases in prevalence from 2018 to 2021 led to a lack of overall statistically significant changes from 2016 to 2021 (p = 0.10 for heart disease and p = 0.37 for dementia). CONCLUSION: Recent increases in the prevalence of dementia, heart disease and stroke in Canadian communities threaten to reverse any gains in vascular disease prevention over the past six years. Findings reveal the urgent need for intensified prevention efforts that are community-based with a focus on joint reduction in the shared risk factors contributing to all three diseases.

Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid.

BACKGROUND AND PURPOSE: In the elderly, cerebral ischemia (CI) occurs in the presence of high levels of amyloid. Neuroinflammation plays a critical role in the pathophysiology of Alzheimer's disease and CI. This study examined infarct size, neuroinflammation, and cognitive deficits over time in rat models of Alzheimer's disease and CI. METHODS: beta-amyloid toxicity was modeled using bilateral intracerebroventricular injections of beta-amyloid 25 to 35 peptides. CI was modeled using unilateral injections of the potent vasoconstrictor, endothelin-1, into the striatum. RESULTS: Infarct volumes were higher in the presence of amyloid and compared with the CI model alone. In the CI model alone, the infarct volume was significantly smaller 28 days after surgery compared with 7 days after surgery. However, when Alzheimer's disease and CI models were combined, the infarct volume was significantly larger 28 days after surgery compared with 7 days after surgery. The neuroinflammation in the region of the infarct was also significantly increased. The Barnes circular platform test showed time-dependent increases in memory and learning deficits in the beta-amyloid-treated rats that were even greater when beta-amyloid treatment was combined with CI. CONCLUSIONS: CI in the presence of high levels of amyloid results in progressive increases in infarct size, neuroinflammation, and cognitive deficits.

Effects of triflusal and aspirin in a rat model of cerebral ischemia.

BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury.

Association of Dual-Task Gait With Incident Dementia in Mild Cognitive Impairment: Results From the Gait and Brain Study.

Importance: Gait performance is affected by neurodegeneration in aging and has the potential to be used as a clinical marker for progression from mild cognitive impairment (MCI) to dementia. A dual-task gait test evaluating the cognitive-motor interface may predict dementia progression in older adults with MCI. Objective: To determine whether a dual-task gait test is associated with incident dementia in MCI. Design, Setting, and Participants: The Gait and Brain Study is an ongoing prospective cohort study of community-dwelling older adults that enrolled 112 older adults with MCI. Participants were followed up for 6 years, with biannual visits including neurologic, cognitive, and gait assessments. Data were collected from July 2007 to March 2016. Main Outcomes and Measures: Incident all-cause dementia was the main outcome measure, and single- and dual-task gait velocity and dual-task gait costs were the independent variables. A neuropsychological test battery was used to assess cognition. Gait velocity was recorded under single-task and 3 separate dual-task conditions using an electronic walkway. Dual-task gait cost was defined as the percentage change between single- and dual-task gait velocities: ([single-task gait velocity - dual-task gait velocity]/ single-task gait velocity) × 100. Cox proportional hazard models were used to estimate the association between risk of progression to dementia and the independent variables, adjusted for age, sex, education, comorbidities, and cognition. Results: Among 112 study participants with MCI, mean (SD) age was 76.6 (6.9) years, 55 were women (49.1%), and 27 progressed to dementia (24.1%), with an incidence rate of 121 per 1000 person-years. Slow single-task gait velocity (<0.8 m/second) was not associated with progression to dementia (hazard ratio [HR], 3.41; 95% CI, 0.99-11.71; P = .05)while high dual-task gait cost while counting backward (HR, 3.79; 95% CI, 1.57-9.15; P = .003) and naming animals (HR, 2.41; 95% CI, 1.04-5.59; P = .04) were associated with dementia progression (incidence rate, 155 per 1000 person-years). The models remained robust after adjusting by baseline cognition except for dual-task gait cost when dichotomized. Conclusions and Relevance: Dual-task gait is associated with progression to dementia in patients with MCI. Dual-task gait testing is easy to administer and may be used by clinicians to decide further biomarker testing, preventive strategies, and follow-up planning in patients with MCI. Trial Registration: clinicaltrials.gov: NCT03020381.

Effect of blinded peer review on abstract acceptance.

CONTEXT: Peer review should evaluate the merit and quality of abstracts but may be biased by geographic location or institutional prestige. The effectiveness of blinded peer review at reducing bias is unknown. OBJECTIVE: To evaluate the effect of blinded review on the association between abstract characteristics and likelihood of abstract acceptance at a national research meeting. DESIGN AND SETTING: All abstracts submitted to the American Heart Association's annual Scientific Sessions research meeting from 2000-2004. Abstract review included the author's name and institution (open review) from 2000-2001, and this information was concealed (blinded review) from 2002-2004. Abstracts were categorized by country, primary language, institution prestige, author sex, and government and industry status. MAIN OUTCOME MEASURE: Likelihood of abstract acceptance during open and blinded review, by abstract characteristics. RESULTS: The mean number of abstracts submitted each year for evaluation was 13,455 and 28.5% were accepted. During open review, 40.8% of US and 22.6% of non-US abstracts were accepted (relative risk [RR], 1.81; 95% confidence interval [CI], 1.75-1.88), whereas during blinded review, 33.4% of US and 23.7% of non-US abstracts were accepted (RR, 1.41; 95% CI, 1.37-1.45; P<.001 for comparison between peer review periods). Among non-US abstracts, during open review, 31.1% from English- speaking countries and 20.9% from non-English-speaking countries were accepted (RR, 1.49; 95% CI, 1.39-1.59), whereas during blinded review, 28.8% and 22.8% of abstracts were accepted, respectively (RR, 1.26; 95% CI, 1.19-1.34; P<.001). Among abstracts from US academic institutions, during open review, 51.3% from highly prestigious and 32.6% from nonprestigious institutions were accepted (RR, 1.57; 95% CI, 1.48-1.67), whereas during blinded review, 38.8% and 29.0% of abstracts were accepted, respectively (RR, 1.34; 95% CI, 1.26-1.41; P<.001). CONCLUSIONS: This study provides evidence of bias in the open review of abstracts, favoring authors from the United States, English-speaking countries outside the United States, and prestigious academic institutions. Moreover, blinded review at least partially reduced reviewer bias.

Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: inflammatory responses.

BACKGROUND AND PURPOSE: Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Inflammatory mechanisms are involved in AD pathology and stroke and may be the mediator between AD and stroke toxicity. METHODS: AD was modeled by cerebroventricular injections of beta-amyloid (Abeta[25-35]) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined using immunohistochemical analysis. Memory and motor tasks were assessed using the Montoya staircase test. RESULTS: Abeta injections elicited increases in pathological and inflammatory correlates of AD in multiple forebrain sites. Increases in astrocytosis and reactive microglia in the hippocampus were enhanced with the combination of endothelin and Abeta(25-35). Abeta(25-35) treatment decreased performance in the Montoya staircase behavioral test. CONCLUSIONS: The enhanced inflammatory response with Abeta toxicity and ischemia may mediate the inability to improve behavioral performance caused by the stroke. Anti-inflammatory treatment may ameliorate the pathological and behavioral deficits associated with the combination of AD and stroke.

Prognostic importance of leukoaraiosis in patients with symptomatic internal carotid artery stenosis.

BACKGROUND AND PURPOSE: Leukoaraiosis (LA) is a frequent finding on brain CT scans. This study examined patients with LA and symptomatic internal carotid artery disease. METHODS: Patients in the North American Symptomatic Carotid Endarterectomy Trial were evaluated for the extent of LA. Long-term prognosis and perioperative risk associated with carotid endarterectomy were assessed. RESULTS: Among 2618 patients, 493 had LA: 354 restricted and 139 widespread. Patients with LA were older, had a history of hypertension, had more hemispheric ischemic events (particularly stroke), and had small, deep brain infarcts. The 3-year risks of stroke for medically treated patients were 20.2% (no LA), 27.3% (restricted LA), and 37.2% (widespread LA) (P=0.01). For surgically treated patients, the risks were 14.2%, 25.4%, and 33.6%, respectively (P<0.001). With widespread LA, occurrence of disabling strokes doubled in medical patients and tripled in surgical patients. The 30-day perioperative risks of any stroke or death for surgical patients with 50% to 99% internal carotid artery stenosis were 5.3% (no LA), 10.6% (restricted LA), and 13.9% (widespread LA). Despite higher perioperative risk, endarterectomy reduced the absolute 3-year risk of stroke ipsilateral to the symptomatic 50% to 99% stenosed artery by 11.6% (P=0.46) for patients with widespread LA, 7.6% (P=0.39) with those with restricted LA, and 10.9% (P<0.001) for those with no LA. CONCLUSIONS: In patients with a transient ischemic attack or nondisabling stroke associated with internal carotid artery disease, presence of LA was associated with an increased risk of any stroke and of disabling or fatal stroke. Patients with widespread LA had the worst prognosis. Despite the higher perioperative risk, endarterectomy reduced the risk of stroke.

Triflusal reduces cerebral ischemia induced inflammation in a combined mouse model of Alzheimer's disease and stroke.

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP(23) transgenic mice receiving strokes. Six month-old APP(23) mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP(23) mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.

Rates of cognitive decline in Alzheimer's disease and dementia with Lewy bodies.

Increased interest in types of dementia has developed as more cases are identified in aging populations. Here we compare the rates of cognitive decline over time in three groups with dementia from the University of Western Ontario Dementia Study: Alzheimer's disease (AD), dementia with Lewy bodies and a group with both AD and Lewy bodies. All diagnoses were verified by autopsy using standard diagnostic methods. Cognitive impairment was measured with the Extended Scale for Dementia (ESD). Members of each group with dementia were age and sex matched with individuals without dementia as controls. The 15 cases of AD, 7 cases with Lewy bodies and 8 cases with both conditions were all free of significant vascular disease. Linear regression was used to determine the rate of changes in ESD scores over time in months. All three control groups showed no change in cognitive status over time. As expected, all groups with dementia showed progressive cognitive impairment. Analysis of the slope parameter showed that all groups deteriorated at the same rate of approximately 2 ESD points per month. Quadratic models fit better than simple linear models in all groups. Results suggest that the final rate of cognitive decline in dementia may not necessarily reflect the underlying cause.