Robust reference group normative data for neuropsychological tests accounting for primary language use in Asian American older adults.

OBJECTIVE: The present study aimed to develop neuropsychological norms for older Asian Americans with English as a primary or secondary language, using data from the National Alzheimer's Coordinating Center (NACC). METHOD: A normative sample of Asian American participants was derived from the NACC database using robust criteria: participants were cognitively unimpaired at baseline (i.e., no MCI or dementia) and remained cognitively unimpaired at 1-year follow-up. Clinical and demographic characteristics were compared between Primary and Secondary English speakers using analyses of variance for continuous measures and chi-square tests for categorical variables. Linear regression models compared neuropsychological performance between the groups, adjusting for demographics (age, sex, and education). Regression models were developed for clinical application to compute demographically adjusted z-scores. RESULTS: Secondary English speakers were younger than Primary English speakers (p < .001). There were significant differences between the groups on measures of mental status (Mini-Mental State Examination, p = .002), attention (Trail Making Test A, Digit Span Forward Total Score, p <.001), language (Boston Naming Test, Animal Fluency, Vegetable Fluency, p < .001), and executive function (Trail Making Test B, p = .02). CONCLUSIONS: Separate normative data are needed for Primary vs. Secondary English speakers from Asian American backgrounds. We provide normative data on older Asian Americans to enable clinicians to account for English use in the interpretation of neuropsychological assessment scores.

Role of Notch signaling in neurovascular aging and Alzheimer's disease.

The Notch signaling pathway is an evolutionarily conserved cell signaling system known to be involved in vascular development and function. Recent evidence suggests that dysfunctional Notch signaling could play a critical role in the pathophysiology of neurodegenerative diseases. We reviewed current literature on the role of Notch signaling pathway, and specifically Notch receptor genes and proteins, in aging, cerebrovascular disease and Alzheimer's disease. We hypothesize that Notch signaling may represent a key point of overlap between age-related vascular and Alzheimer's pathophysiology contributing to their comorbidity and combined influence on cognitive decline and dementia. Numerous findings from studies of genetics, neuropathology and cell culture models all suggest a link between altered Notch signaling and Alzheimer's pathophysiology. Age-related changes in Notch signaling may also trigger neurovascular dysfunction, contributing to the development of neurodegenerative diseases; however, additional studies are warranted. Future research directly exploring the influence of aberrant Notch signaling in the development of Alzheimer's disease is needed to better understand this mechanism.

Older adults with perivascular spaces exhibit cerebrovascular reactivity deficits.

BACKGROUND: Perivascular spaces on brain magnetic resonance imaging (MRI) may indicate poor fluid drainage in the brain and have been associated with numerous neurological conditions. Cerebrovascular reactivity (CVR) is a marker of cerebrovascular function and represents the ability of cerebral blood vessels to regulate cerebral blood flow in response to vasodilatory or vasoconstrictive stimuli. We aimed to examine whether pathological widening of the perivascular space in older adults may be associated with deficits in CVR. METHODS: Independently living older adults free of dementia or clinical stroke were recruited from the community and underwent brain MRI. Pseudo-continuous arterial spin labeling MRI quantified whole brain cerebral perfusion at rest and during CVR to hypercapnia and hypocapnia induced by visually guided breathing exercises. Perivascular spaces were visually scored using existing scales. RESULTS: Thirty-seven independently living older adults (mean age = 66.3 years; SD = 6.8; age range 55-84 years; 29.7% male) were included in the current analysis. Multiple linear regression analysis revealed a significant negative association between burden of perivascular spaces and global CVR to hypercapnia (B = -2.0, 95% CI (-3.6, -0.4), p = .015), adjusting for age and sex. Perivascular spaces were not related to CVR to hypocapnia. DISCUSSION: Perivascular spaces are associated with deficits in cerebrovascular vasodilatory response, but not vasoconstrictive response. Enlargement of perivascular spaces could contribute to, or be influenced by, deficits in CVR. Additional longitudinal studies are warranted to improve our understanding of the relationship between cerebrovascular function and perivascular space enlargement.

Reduction in Stroke After Transient Ischemic Attack in a Province-Wide Cohort Between 2003 and 2015.

BACKGROUND: Improvements in management of transient ischemic attack (TIA) have decreased stroke and mortality post-TIA. Studies examining trends over time on a provincial level are limited. We analyzed whether efforts to improve management have decreased the rate of stroke and mortality after TIA from 2003 to 2015 across an entire province. METHODS: Using administrative data from the Canadian Institute for Health Information's (CIHI) databases from 2003 to 2015, we identified a cohort of patients with a diagnosis of TIA upon discharge from the emergency department (ED). We examined stroke rates at Day 1, 2, 7, 30, 90, 180, and 365 post-TIA and 1-year mortality rates and compared trends over time between 2003 and 2015. RESULTS: From 2003 to 2015 in Ontario, there were 61,710 patients with an ED diagnosis of TIA. Linear regressions of stroke after the index TIA showed a significant decline between 2003 and 2015, decreasing by 25% at Day 180 and 32% at 1 year (p < 0.01). The 1-year stroke rate decreased from 6.0% in 2003 to 3.4% in 2015. Early (within 48 h) stroke after TIA continued to represent approximately half of the 1-year event rates. The 1-year mortality rate after ED discharge following a TIA decreased from 1.3% in 2003 to 0.3% in 2015 (p < 0.001). INTERPRETATION: At a province-wide level, 1-year rates of stroke and mortality after TIA have declined significantly between 2003 and 2015, suggesting that efforts to improve management may have contributed toward the decline in long-term risk of stroke and mortality. Continued efforts are needed to further reduce the immediate risk of stroke following a TIA.

Call 911: Lower Ambulance Utilization Among Young Adults, Especially Women, with Stroke.

BACKGROUND: Delayed presentation to the emergency department influences acute stroke care and can result in worse outcomes. Despite public health messaging, many young adults consider stroke as a disease of older people. We determined the differences in ambulance utilization and delays to hospital presentation between women and men as well as younger (18-44 years) versus older (≥45 years) patients with stroke. METHODS: We conducted a population-based retrospective study using national administrative health data from the Canadian Institute of Health Information databases and examined data between 2003 and 2016 to compare ambulance utilization and time to hospital presentation across sex and age. RESULTS: Young adults account for 3.9% of 463,310 stroke/transient ischemic attack/hemorrhage admissions. They have a higher proportion of hemorrhage (37% vs. 15%) and fewer ischemic events (50% vs. 68%) compared with older patients. Younger patients are less likely to arrive by ambulance (62% vs. 66%, p < 0.001), with younger women least likely to use ambulance services (61%) and older women most likely (68%). Median stroke onset to hospital arrival times were 7 h for older patients and younger men, but 9 h in younger women. There has been no improvement among young women in ambulance utilization since 2003, whereas ambulance use increased in all other groups. CONCLUSIONS: Younger adults, especially younger women, are less likely to use ambulance services, take longer to get to hospital, and have not improved in utilization of emergency services for stroke over 13 years. Targeted public health messaging is required to ensure younger adults seek emergency stroke care.

Younger Age and Depressive Symptoms Predict High Risk of Generalized Anxiety After Stroke and Transient Ischemic Attack.

Background and Purpose- Depression and anxiety are common after stroke/transient ischemic attack (TIA). These conditions are associated with poor functional outcome and worse quality of life. However, few studies have explored predictors of poststroke risk of generalized anxiety, especially in patients without comorbid depressive symptoms. We aimed to explore predictors of high risk of generalized anxiety after stroke/TIA. Methods- Consecutive stroke and TIA referrals to the Sunnybrook Stroke Prevention Clinic over a 2-year period (April 2012-April 2014) who spoke English, were not severely aphasic, and who consented to complete neuropsychological testing were included in this analysis. Generalized anxiety and depressive symptoms were assessed using the Generalized Anxiety Disorder 7-item scale and Center for Epidemiological Studies Depression Scale, respectively. Results- Two hundred and fifty-eight patients completed the Generalized Anxiety Disorder 7-item scale, of whom 56 (22%) were at high risk for generalized anxiety (scores ≥10). Younger age (odds ratio=0.96; 95% CI, 0.93-0.99; P=0.004) and greater depressive symptoms (odds ratio=1.20; 95% CI, 1.14-1.26; P≤0.001) were significant predictors of being at high risk for generalized anxiety after stroke/TIA. Younger patients (≤50 years) were significantly more likely to be at high risk for both depression and generalized anxiety than older patients (30% versus 12%, χ2 [1, N=258]=10.98, P=0.001). Our model explained 56% of the variance in risk of generalized anxiety after stroke. In patients without severe depressive symptoms (n=193, 75%), age and severity of depressive symptoms remained the only factors associated with risk of generalized anxiety. Conclusions- Anxiety is common after stroke/TIA and is highly correlated with poststroke depressive symptoms and age, even among those without severe depressive symptoms. Given the greater frequency of both generalized anxiety and depressive symptoms in young survivors, routine screening for depression and further evaluation of anxiety after stroke/TIA is warranted.

Screening for Post-Stroke Depression and Cognitive Impairment at Baseline Predicts Long-Term Patient-Centered Outcomes After Stroke.

BACKGROUND: Independence and reintegration into community roles are important patient-centered outcomes after stroke. Depression and cognitive impairment are common post-stroke conditions that may impair long-term function even years after a stroke. However, screening for these post-stroke comorbidities remains infrequent in stroke prevention clinics and the utility of this screening for predicting long-term higher-level function has not been evaluated. AIMS: To evaluate the ability of a validated brief Depression, Obstructive sleep apnea, and Cognitive impairment screen (DOC screen) to predict long-term (2-3 years after stroke) community participation and independence in instrumental activities of daily living post stroke. METHODS: One hundred twenty-four patients (mean age, 66.3 [standard deviation = 15.7], 52.4% male) completed baseline depression and cognitive impairment screening at first stroke clinic visit, and telephone interviews 2 to 3 years post stroke to assess community independence (Frenchay Activities Index [FAI]) and participation (Reintegration to Normal Living Index [RNLI]). A subset of these patients also consented to complete detailed neuropsychological testing at baseline. Univariate and multivariate linear (FAI) and logistic (RNLI) regression analyses were used to determine the individual relationship between baseline data (predictors) and follow-up scores. RESULTS: Older age (ß = -0.17, P = .001), greater stroke severity (ß = 1.84, P = .015), more depressive (ß = -2.41, P = .023), and cognitive (ß = -2.15, P = .046) symptoms independently predicted poor instrumental activity ( R2 = .27; P < .001). Measures of executive dysfunction were the strongest correlates of poor instrumental activity. Higher depression risk was the only significant predictor of participation on the RNLI in regression modeling (odds ratio = 0.46, P = .028). CONCLUSIONS: Baseline DOC screening in stroke prevention clinics shows that symptoms of depression and cognitive impairment are independent predictors of impaired higher-level functioning and community reintegration 2 to 3 years after stroke. Novel rehabilitation and psychological interventions targeting people with these conditions are needed to improve long-term patient-centered outcomes.

"Good Outcome" Isn't Good Enough: Cognitive Impairment, Depressive Symptoms, and Social Restrictions in Physically Recovered Stroke Patients.

BACKGROUND AND PURPOSE: Functional outcome after stroke is often only evaluated using the modified Rankin Scale, which primarily assesses activities of daily living. Stroke patients may experience difficulties with social reintegration and mental functions, feel isolated, and experience poor quality of life, even after physical recovery is complete. Functional assessments based solely on activity limitations may not be able to capture the full range of problems experienced by stroke survivors. METHODS: Telephone interviews were conducted 2 to 3 years poststroke to assess outcome on multiple levels of functioning as stated in the WHO International Classification of Functioning: body function (Montreal Cognitive Assessment and Patient Health Questionnaire-2), activity (modified Rankin Scale), and participation (Reintegration to Normal Living Index). RESULTS: Ninety-six (68%) patients had a favorable functional outcome (modified Rankin Scale <2). Of these, 79, 91, and 93 patients completed the Montreal Cognitive Assessment, Reintegration to Normal Living Index, and Patient Health Questionnaire-2, respectively. Forty-three (54%) patients were cognitively impaired, 47 (52%) had restrictions in reintegration, and 30 (32%) endorsed symptoms of depression. There was no difference in Montreal Cognitive Assessment or Patient Health Questionnaire-2 scores between those who had activity limitations and those who had not. CONCLUSIONS: More than half of stroke patients with excellent functional recovery measured by the modified Rankin Scale continue to have cognitive impairment and participation restrictions, and one third of patients continue to have depression 2 to 3 years later. Current definitions of good functional outcome used in the majority of stroke acute trials focus on activity limitations, but greater attention to multiple levels of recovery is required.

Reliability of beat-to-beat blood pressure variability in older adults.

Blood pressure variability (BPV) is emerging as an important risk factor across numerous disease states, including cerebrovascular and neurodegenerative disease in older adults. However, there is no current consensus regarding specific use cases for the numerous available BPV metrics. There is also little published data supporting the ability to reliably measure BPV across metrics in older adults. BPV metrics were derived from continuous beat-to-beat blood pressure monitoring data. Two sequential 7-minute waveforms were analyzed. Absolute and relative reliability testing was performed. Differences between antihypertensive medication users and non-users on BPV metric reliability was also assessed. All sequence and dispersion based BPV metrics displayed good test-retest reliability. A measure of BP instability displayed only moderate reliability. Systolic and diastolic average real variability displayed the highest levels of reliability at ICC= .87 and .82 respectively. Additionally, systolic average real variability was the most reliable metric in both the antihypertensive use group, and the no antihypertensive use group. Beat-to-beat dispersion and sequence-based metrics of BPV can be reliably obtained from older adults using noninvasive continuous blood pressure monitoring. Average real variability may be the most reliable and specific beat-to-beat blood pressure variability metric due to its decreased susceptibility to outliers and low frequency blood pressure oscillations.

The interactive effect of intra-beat and inter-beat blood pressure variability on neurodegeneration in older adults.

Blood pressure variability (BPV) and arterial stiffness are age-related hemodynamic risk factors for neurodegenerative disease, but it remains unclear whether they exert independent or interactive effects on brain health. When combined with high inter-beat BPV, increased intra-beat BPV indicative of arterial stiffness could convey greater pressure wave fluctuations deeper into the cerebrovasculature, exacerbating neurodegeneration. This interactive effect was studied in older adults using multiple markers of neurodegeneration, including medial temporal lobe (MTL) volume, plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Older adults (N=105) without major neurological or systemic disease were recruited and underwent brain MRI and continuous BP monitoring to quantify inter-beat BPV through systolic average real variability (ARV) and intra-beat variability through arterial stiffness index (ASI). Plasma NfL and GFAP were assessed. The interactive effect of ARV and ASI on MTL atrophy, plasma NfL, and GFAP was studied using hierarchical linear regression. Voxel-based morphometry (VBM) was used to confirm region-of-interest analysis findings. The interaction between higher ARV and higher ASI was significantly associated with left-sided MTL atrophy in both the region-of-interest and false discovery rate-corrected VBM analysis. The interactive effect was also significantly associated with increased plasma NfL, but not GFAP. The interaction between higher ARV and higher ASI is independently associated with increased neurodegenerative markers, including MTL atrophy and plasma NfL, in independently living older adults. Findings could suggest the increased risk for neurodegeneration associated with higher inter-beat BPV may be compounded by increased intra-beat variability due to arterial stiffness.

Central autonomic network dysfunction and plasma Alzheimer's disease biomarkers in older adults.

BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden.

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer's disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = -.02, 95% CI (-.04, -.008), p =.003] and in APOE4 carriers [B = -.03, 95% CI (-.06, -.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

Short-term blood pressure variability and brain functional network connectivity in older adults.

Background: Blood pressure variability is increasingly linked with cerebrovascular disease and Alzheimer's disease, independent of mean blood pressure levels. Elevated blood pressure variability is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. It remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat-to-beat blood pressure variability and functional connectivity in brain networks vulnerable to aging and Alzheimer's disease. Methods: 53 community-dwelling older adults (mean [SD] age = 69.9 [7.5] years, 62.3% female) without history of dementia or clinical stroke underwent continuous blood pressure monitoring and resting state fMRI scan. Blood pressure variability was calculated as variability independent of mean. Functional connectivity was determined by resting state fMRI for several brain networks: default, salience, dorsal attention, fronto-parietal, and language. Multiple linear regression examined relationships between short-term blood pressure variability and functional network connectivity. Results: Elevated short-term blood pressure variability was associated with lower functional connectivity in the default network (systolic: standardized ß = -0.30 [95% CI -0.59, -0.01], p = .04). There were no significant associations between blood pressure variability and connectivity in other functional networks or between mean blood pressure and functional connectivity in any network. Discussion: Older adults with elevated short-term blood pressure variability exhibit lower resting state functional connectivity in the default network. Findings support the role of blood pressure variability in neurovascular dysfunction and Alzheimer's disease. Blood pressure variability may represent an understudied early vascular risk factor for neurovascular dysfunction relevant to Alzheimer's disease, with potential therapeutic implications.

Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.

Blood-Derived Progenitor Cells Are Depleted in Older Adults with Cognitive Impairment: A Role for Vascular Resilience?

BACKGROUND: Depletion of blood-derived progenitor cells, including so called "early endothelial progenitor cells", has been observed in individuals with early stage Alzheimer's disease relative to matched older control subjects. These findings could implicate the loss of angiogenic support from hematopoietic progenitors or endothelial progenitors in cognitive dysfunction. OBJECTIVE: To investigate links between progenitor cell proliferation and mild levels of cognitive dysfunction. METHODS: We conducted in vitro studies of blood-derived progenitor cells using blood samples from sixty-five older adults who were free of stroke or dementia. Peripheral blood mononuclear cells from venous blood samples were cultured in CFU-Hill media and the number of colony forming units were counted after 5 days in vitro. Neuropsychological testing was administered to all participants. RESULTS: Fewer colony forming units were observed in samples from older adults with a Clinical Dementia Rating global score of 0.5 versus 0. Older adults whose samples developed fewer colony forming units exhibited worse performance on neuropsychological measures of memory, executive functioning, and language ability. CONCLUSION: These data suggest blood progenitors may represent a vascular resilience marker related to cognitive dysfunction in older adults.

Blood pressure variability, central autonomic network dysfunction and cerebral small vessel disease in APOE4 carriers.

Background: Increased blood pressure variability (BPV) is a risk factor for cerebral small vessel disease (CSVD) and neurodegeneration, independent of age and average blood pressure, particularly in apolipoprotein E4 (APOE4) carriers. However, it remains uncertain whether BPV elevation is a cause or a consequence of vascular brain injury, or to what degree injury to the central autonomic network (CAN) may contribute to BPV-associated risk in APOE4 carriers. Methods: Independently living older adults (n=70) with no history of stroke or dementia were recruited from the community and underwent 5 minutes of resting beat-to-beat blood pressure monitoring, genetic testing, and brain MRI. Resting BPV, APOE genotype, CSVD burden on brain MRI, and resting state CAN connectivity by fMRI were analyzed. Causal mediation and moderation analysis evaluated BPV and CAN effects on CSVD in APOE4 carriers (n=37) and non-carriers (n=33). Results: Higher BPV was associated with the presence and extent of CSVD in APOE4 carriers, but not non-carriers, independent of CAN connectivity (B= 18.92, P= .02), and CAN connectivity did not mediate the relationship between BPV and CSVD. In APOE4 carriers, CAN connectivity moderated the relationship between BPV and CSVD, whereby BPV effects on CSVD were greater in those with lower CAN connectivity (B= 36.43, P= .02). Conclusions: Older APOE4 carriers with higher beat-to-beat BPV exhibit more extensive CSVD, independent of average blood pressure, and the strength of CAN connectivity does not mediate these effects. Findings suggest increased BPV is more likely a cause, not a consequence, of CSVD. BPV is more strongly associated with CSVD in APOE4 carriers with lower rsCAN connectivity, suggesting CAN dysfunction and BPV elevation may have synergistic effects on CSVD. Further studies are warranted to understand the interplay between BPV and CAN function in APOE4 carriers.

Older Adults With Higher Blood Pressure Variability Exhibit Cerebrovascular Reactivity Deficits.

BACKGROUND: Elevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury. METHODS: The present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.6 [SD 8.7] years) without a history of dementia or stroke. Short-term BP variability was determined from BP measurements collected continuously during a 5-minute resting period followed by cerebrovascular reactivity during 5-minute hypocapnia and hypercapnia challenge induced by visually guided breathing conditions. Cerebrovascular reactivity was quantified as percent change in cerebral perfusion by pseudo-continuous arterial spin labeling (pCASL)-MRI per unit change in end-tidal CO2. RESULTS: Elevated systolic BP variability was related to lower whole brain cerebrovascular reactivity during hypocapnia (ß = -0.43 [95% CI -0.73, -0.12]; P = 0.008; adjusted R2 =.11) and hypercapnia (ß = -0.42 [95% CI -0.77, -0.06]; P = 0.02; adjusted R2 = 0.19). CONCLUSIONS: Findings add to prior work linking BP variability and cerebrovascular disease burden and suggest BP variability may also be related to prodromal markers of cerebrovascular dysfunction and disease, with potential therapeutic implications.

Men Are at Higher Risk of Screening Positive for Vascular Cognitive Impairment Compared to Women after Stroke and Transient Ischemic Attack.

While women have greater incidence of dementia, men have higher prevalence of vascular risk factors. This study examined sex differences in risk of screening positive for cognitive impairment after stroke. Ischemic stroke/TIA patients (N = 5969) participated in this prospective, multi-centered study, which screened for cognitive impairment using a validated brief screen. Men showed a higher risk of screening positive for cognitive impairment after adjusting for age, education, stroke severity, and vascular risk factors, suggesting that other factors may be contributing to increased risk among men (OR = 1.34, CI 95% [1.16, 1.55], p < 0.001). The effect of sex on cognitive impairment after stroke warrants further attention.

Enlarged perivascular spaces and plasma Aß42/Aß40 ratio in older adults without dementia.

Dilation of perivascular spaces (PVS) in the brain may indicate poor fluid drainage due to the accumulation of perivascular cell debris, waste, and proteins, including amyloid-beta (Aß). No prior study has assessed whether plasma Aß levels are related to PVS in older adults without dementia. Independently living older adults (N = 56, mean age = 68.2 years; Standard deviation (SD) = 6.5; 30.4% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. PVS were qualitatively scored and dichotomized to low PVS burden (scores 0-1,) or high PVS burden (score>1). Plasma was assayed using a Quanterix Simoa Kit to quantify Aß42 and Aß40 levels. A significant difference was observed in plasma Aß42/Aß40 ratio between low and high PVS burden, controlling for age (F[1, 53] = 5.59, p = 0.022, η2 = 0.10), with lower Aß42/Aß40 ratio in the high PVS burden group. Dilation of PVS is associated with a lower plasma Aß42/Aß40 ratio, which may indicate higher cortical amyloid deposition. Future longitudinal studies examining PVS changes, and the pathogenesis of AD are warranted.

Language discordance as a marker of disparities in cerebrovascular risk and stroke outcomes: A multi-center Canadian study.

Background: Differences in ischemic stroke outcomes occur in those with limited English proficiency. These health disparities might arise when a patient's spoken language is discordant from the primary language utilized by the health system. Language concordance is an understudied concept. We examined whether language concordance is associated with differences in vascular risk or post-stroke functional outcomes, depression, obstructive sleep apnea and cognitive impairment. Methods: This was a multi-center observational cross-sectional cohort study. Patients with ischemic stroke/transient ischemic attack (TIA) were consecutively recruited across eight regional stroke centers in Ontario, Canada (2012 - 2018). Participants were language concordant (LC) if they spoke English as their native language, ESL if they used English as a second language, or language discordant (LD) if non-English speaking and requiring translation. Results: 8156 screened patients. 6,556 met inclusion criteria: 5067 LC, 1207 ESL and 282 LD. Compared to LC patients: (i) ESL had increased odds of diabetes (OR = 1.28, p = 0.002), dyslipidemia (OR = 1.20, p = 0.007), and hypertension (OR = 1.37, p<0.001) (ii) LD speaking patients had an increased odds of having dyslipidemia (OR = 1.35, p = 0.034), hypertension (OR = 1.37, p<0.001), and worse functional outcome (OR = 1.66, p<0.0001). ESL (OR = 1.88, p<0.0001) and LD (OR = 1.71, p<0.0001) patients were more likely to have lower cognitive scores. No associations were noted with obstructive sleep apnea (OSA) or depression. Conclusions: Measuring language concordance in stroke/TIA reveals differences in neurovascular risk and functional outcome among patients with limited proficiency in the primary language of their health system. Lower cognitive scores must be interpreted with caution as they may be influenced by translation and/or greater vascular risk. Language concordance is a simple, readily available marker to identify those at risk of worse functional outcome. Stroke systems and practitioners must now study why these differences exist and devise adaptive care models, treatments and education strategies to mitigate barriers influenced by language discordance.