Post-stroke Cognitive Decline Research Articles

A longitudinal study of the post-stroke immune response and cognitive functioning: the StrokeCog study protocol

BackgroundStroke increases the risk of cognitive impairment even several years after the stroke event. The exact mechanisms of post-stroke cognitive decline are unclear, but the immunological response to stroke might play a role. The aims of the StrokeCog study are to examine the associations between immunological responses and long-term post-stroke cognitive trajectories in individuals with ischemic stroke.MethodsStrokeCog is a single-center, prospective, observational, cohort study. Starting 6–12 months after stroke, comprehensive neuropsychological assessment, plasma and serum, and psychosocial variables will be collected at up to 4 annual visits. Single cell sequencing of peripheral blood monocytes and plasma proteomics will be conducted. The primary outcome will be the change in global and domain-specific neuropsychological performance across annual evaluations. To explain the differences in cognitive change amongst participants, we will examine the relationships between comprehensive immunological measures and these cognitive trajectories. It is anticipated that 210 participants will be enrolled during the first 3 years of this 4-year study. Accounting for attrition, an anticipated final sample size of 158 participants with an average of 3 annual study visits will be available at the completion of the study. Power analyses indicate that this sample size will provide 90% power to detect an average cognitive change of at least 0.23 standard deviations in either direction.DiscussionStrokeCog will provide novel insight into the relationships between immune events and cognitive change late after stroke.

Different Cognitive and Functional Outcomes in Attenuated and Full Delirium Syndromes Among Recent Stroke Survivors

BackgroundVery little is known about the outcomes of poststroke delirium in relation to its symptom spectrum. We investigated the 3-months cognitive and functional outcomes of attenuated (ADS) and full delirium syndromes in Nigerian survivors of first ever stroke. MethodsA prospective observational study with repeated assessments conducted in the first week of stroke using the confusion assessment method. Full delirium was diagnosed according to criteria in the fifth edition of the diagnostic and statistical manual of mental disorders (DSM-V). ADS was characterised in survivors who were free of full, but had ≥two core features of, delirium. Baseline and follow-up assessments were conducted using the Mini-Mental state examination (MMSE), 10-words list learning and delayed recall test, Animal naming test and Barthel index. ResultsAmong 150 participants, ADS was present in 32 (21.3%), full delirium in 29 (19.3%). In linear regression analyses adjusting for age, economic status and systemic hypertension, ADS [(Mean difference (MD) = -3.8, 95% C.I = -7.0, -0.7)] and full delirium (MD = -5.6, 95% C.I = -9.0, -2.1) independently predicted poorer global cognitive functioning at follow-up. Significant declines in memory (MD = -1.9, 95% C.I = -2.8, 0.9), executive (MD = -2.2, 95% C.I = -4.1, -0.3) and physical functioning (MD = -2.8, 95% C.I = -5.5, -0.2), as well as a 4-fold increase in the independent odds (O.R) for dementia (O.R = 4.1, 95% C.I = 1.0,16.1) were also recorded in full, but not attenuated, delirium. ConclusionAttenuated and full delirium are associated with graded risk of poststroke cognitive decline. Reconsideration of poststroke delirium as a spectrum, rather than threshold-based categorical diagnosis will improve detection and prioritization of stroke survivors at increased risk of cognitive decline.

Cognitive, Functional, and Mortality Outcomes of Attenuated Delirium Syndrome in Stroke Survivors.

There is a knowledge gap on the prognostic significance of subsyndromes of delirium. We describe the association of poststroke attenuated delirium syndrome (ADS) with cognitive, functional, and mortality outcomes at 3 months. A longitudinal observational study in which repeated assessments for delirium symptoms were conducted in the first week of stroke using the confusion assessment method. Attenuated delirium syndrome was characterized in survivors who were free of the full delirium syndrome but had ≥2 core features of delirium. Baseline and follow-up assessments were conducted using the Mini-Mental State Examination (MMSE), 10-word list learning and delayed recall test, Animal naming test, and Barthel index. Among 150 participants recruited consecutively over 2 years, ADS was present in 32 (21.3%). Of 121 who were free of the full delirium syndrome, 21 (17.4%) had died by 3 months. Those who survived were more likely to be receiving treatment for systemic hypertension (88.5%, P = .007). In analyses adjusting for the effect of age, economic status, and systemic hypertension, ADS in the first week of stroke predicted cognitive decline at 3 months ([mean difference (MD) in MMSE scores = -3.8, 95% CI = -7.0 to -0.7, P = .019]). However, ADS was not associated with greater decline in activities of daily life (MD = -0.4, 95% CI = -2.8 to 2.0) or significant odds ratio (OR) of mortality (OR = 2.3, 95% CI = 0.8-6.3). Attenuated delirium syndrome may be an important marker of cognitive impairment at 3 months poststroke. Its detection may lead to identification of stroke survivors who are likely to benefit from evidence-based preventive interventions for poststroke cognitive decline.

Abstract TMP28: Serotonin Transporter Polymorphism Impact on Cortisol Level and Outcome After Stroke

Background: The short (s) allele of a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is related to reduced serotonin transporter efficiency and an increased vulnerability to stress and mental disorders. The 5-HTTLPR s allele was reported as associate with hypothalamic-pituitary-adrenal (HPA)-axis reactivity to stress, depression and negatively impact on memory. Acute stroke is associated with elevated cortisol levels as part of the body’s reaction to a stress provoking event. We investigated whether 5-HTT genotype interacts with physiological stress to impact on outcome after stroke. Methods: Data from 485 non-depressed cognitively intact first-ever mild to moderate stroke patients from the TABASCO study were available. Patients underwent 3T MRI scans, saliva cortisol measure and comprehensive neuropsychological assessments at admission, 6, and 12 and 24 months thereafter. Results: Carriers of the 5-HTT-s allele (23.2%) had significantly higher admission bedtime salivary cortisol (p=0.042) and more depressive symptoms 12 and 24 months after the index event (p=0.043, p=0.05, respectively) than non-carriers. Higher admission salivary cortisol levels negatively correlated with hippocampal and amigdalar volume at admission (r=-0.257, p=0.004; r=-0.177, p=0.048, respectively) as well as with lower cognitive and higher depression scores 24 months post-stroke (r=-0.2, p=0.032, r=0.245, p=0.007, respectively). The association between salivary cortisol levels, depressive and cognitive scores was stronger in 5-HTT-s carriers than non-carriers. Conclusions: We report that carriers of the 5-HTT-s allele may be at risk to develop depressive symptoms post-stroke. The interactive effects of the s allele and cortisol levels on hippocampal volume and post-stroke depressive symptoms, as well as cognitive performance, suggest that the negative effect of the serotonin polymorphism on the development of post-stroke depression and cognitive decline is mediated by the HPA axis. Since genetic factors may influence vulnerability to the adverse effects of stress, serotonin receptors may provide a novel target for therapeutics to prevent depression and cognitive deterioration in stroke patients.

Validation of a New Cognitive Screening Method for Stroke Patients.

Objective Two million adults under fifty years of age have a cerebral stroke every year worldwide. Neuropsychological assessment is the best way to identify poststroke cognitive dysfunction, but it is often time-consuming and can be tiring for the patient, and hospitals vary in their availability of neuropsychological expertise. A valid and reliable cognitive screening method could be advantageous in identifying patients who need comprehensive neuropsychological examination. Our purpose in this study was to validate a newly developed cognitive screening method as an identifier of cognitive dysfunction after stroke in working-aged patients. Methods We analyzed new cognitive screening method concurrent validity by comparing it in two groups formed on the basis of a comprehensive neuropsychological examination for 77 stroke patients. We identified the best balance of sensitivity and specificity by using receiver operating characteristic curve analysis and investigated the impact of the sociodemographic variables to the screening method total score variation. Results We found a significant correlation between the method's total score and performance in neuropsychological examination. The cognitive method's internal consistency was strong; Cronbach's alpha for all items was .818. The best balance of sensitivity (88%) and specificity (50%) was found at a total score cut point of 138. Subjects' age and length of education were each responsible for 10% of total score variation. Conclusions This study shows promising results for this new cognitive screening tool's ability to identify poststroke cognitive decline and patients' need for further detailed neuropsychological examination.

Quantitative and Qualitative EEG as a Prediction Tool for Outcome and Complications in Acute Stroke Patients.

Currently, the relevance of EEG measurements in acute stroke patients is considered low in clinical practice. However, recent studies on the predictive value of EEG measurements after stroke for various outcomes may increase the role of EEG in patients with stroke. We aimed to review the current literature on the utility of EEG measurements after stroke as a tool to predict outcome and complications, focusing on studies in which the EEG measurement was performed in the acute phase after the event and in which long-term outcome measures were reported. In our literature review, we identified 4 different outcome measures (functional outcome, mortality, development of post-stroke cognitive decline, and development of post-stroke epilepsy) where studies on the utility of acute EEG measurements exist. There is a large body of evidence for the prediction of functional outcome, in which a multitude of associated quantitative and qualitative EEG parameters are described. In contrast, only few studies focus on mortality as outcome parameter. We found studies of high methodical quality on the prediction of post-stroke cognitive decline, though the number of patients in these studies often was small. The role of EEG as a prediction tool for seizures and epilepsy after stroke could increase after a recently published study, especially if its result can be incorporated into already existing post-stroke epilepsy prediction tools. In summary, EEG is useful for the prediction of functional outcome, mortality, development of post-stroke cognitive decline and epilepsy, even though there is a discrepancy between the large amount of studies on EEG in acute stroke patients and its underuse in clinical practice.

Cerebral Small Vessel Disease Burden Is Associated With Accelerated Poststroke Cognitive Decline: A 1-Year Follow-Up Study.

This study investigated the association between small vessel disease (SVD) burden, a combination of multiple SVD markers and cognitive dysfunction after stroke. The study sample comprised 451 patients with first-ever acute ischemic stroke. Cognitive functions were assessed with the Mini-Mental State Examination (MMSE) at 3, 9, and 15 months after the index stroke. Cognitive impairment was defined as an MMSE score of ≤26. A total SVD score, indicating SVD burden, was constructed by summing the scores of the 4 SVD markers (white matter hyperintensities [WMHs], lacunes, cerebral microbleeds, and perivascular spaces) ascertained by magnetic resonance imaging (range: 0-4). The association between SVD burden and cognitive dysfunction was assessed with linear mixed models or generalized estimating equation models, as appropriate. The majority of patients had mild-to-moderate stroke and at least one identifiable SVD marker. Cognitive impairment was found in about one-third of patients. After adjusting for confounding factors, the SVD burden was associated with MMSE scores (β = -0.37, P = .003) and cognitive impairment (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.02-1.42). SVD burden was specifically associated with the performance of MMSE subscores including orientation to place and time, calculation, and word recall. Of the SVD markers, WMHs was the most robust predictor of decrease in MMSE scores (β = -0.25, P = .01) and cognitive impairment (OR = 1.14, 95% CI = 1.01-1.29). Cerebral SVD burden is associated with decreased MMSE scores, suggesting cognitive dysfunction during the first year after mild-to-moderate acute ischemic stroke.

Poststroke Cognitive Decline: A Longitudinal Study from a Tertiary Care Center.

Objectives Poststroke cognitive decline (PSCD) is a serious disabling consequence of stroke. The purpose of this study is to find the prevalence of PSCD and sociodemographic and clinical determinants of risk factors of PSCD. Materials and Methods This study was a prospective, hospital-based study conducted on 200 stroke patients from stroke registry during October 2015 to April 2017. Detailed clinical evaluation was done. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were used to determine PSCD after 3 and 6 months as per the Diagnostic and Statistical Manual of Mental Disorders V . Chi-squared test was used to find the association between two variables. The Wilcoxon signed-rank test was used to compare the difference in cognitive impairment between two follow-ups at 3 and 6 months, respectively. A p-value < 0.05 was considered statistically significant. Results The prevalence of PSCD measured by MoCA scale at 3 and 6 months was 67 and 31.6%, respectively. By MMSE scale, cognitive decline prevalence at 3 months was found to be 87 (46.3%), which reduced to 22 (17.1%) at 6 months. The association between MMSE scale and type of stroke was significant at 3 months. Conclusion One-third of the stroke patients developed PSCD within 3 months of onset of stroke, with different levels of severity. The major predictors of new-onset poststroke cognitive impairment were diabetes and hypertension. The prevalence of PSCD reduced significantly at 6 months of stroke on follow-up.

Progression of cognitive decline before and after incident stroke.

To determine the trajectory of cognitive decline before and after incident stroke. By using data from the English Longitudinal Study of Ageing, we studied 9,278 participants without dementia with no history of stroke who underwent cognitive assessment at baseline (wave 1) and at least 1 other time point (waves 2-7). We used linear mixed models to analyze repeated measures and longitudinal data. Among the 9,278 participants (56.8% women, mean age 63.1 ± 10.3 years), 471 (5.1%) incident stroke events were identified. Compared with stroke-free participants, multivariable-adjusted rates of prestroke cognitive decline in global cognition, memory, semantic fluency, and temporal orientation of participants who later experienced an incident stroke were increased by -0.029 , -0.016, -0.022, and -0.024 SD/y, respectively. Among the 471 stroke survivors, the multivariable-adjusted acute changes in the 4 cognitive domains were -0.257, -0.150, -0.121, and -0.272 SD, respectively. In the years after stroke, global cognition declined over time and was steeper than its prestroke slope, that is, by -0.064 SD/y after multivariable adjustment. The rates of memory, semantic fluency, and temporal orientation decline were -0.046, -0.033, and -0.037 SD/y, respectively. Accelerated prestroke cognitive decline and poststroke cognitive decline were associated with incident stroke over a follow-up period of 12 years. Attention should be paid to the long-term cognitive problems of stroke survivors, and intervention and management of major vascular risk factors should start from early life or midlife to reduce the risk of cerebrovascular disease and the associated cognitive impairment.

Cerebral microbleeds are associated with cognitive decline early after ischemic stroke

The present study aimed to investigate whether cerebral microbleeds (CMB) are associated with vascular cognitive decline (VCD) already in the early course after ischemic stroke, and-if so-whether distinct cognitive domains are affected more preferentially by CMB. In a prospective cohort study, cognitive performance was examined in 33 stroke patients showing ≥ 1 CMB on MRI. Matched for age, gender, clinical and radiological characteristics, 33 stroke survivors without CMB served as a control group. Neuropsychological testing was performed in both groups six months after the index event using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-plus test battery. CMB-positive stroke patients showed more severe cognitive decline in mini mental state test compared to the control group (p = 0.024). Regarding the episodic memory, CMB-positive patients reached lower scores in Word-List-Learning- (p = 0.009) and the Word-List-Recognition-test (p = 0.006), whereas the findings in Word-List-Recall-test were similar in both groups. While semantic fluency is not more affected in CMB-positive than in CMB-negative patients, those with CMB reveal a significantly impaired phonemic fluency (p = 0.007). Concerning the visuospatial abilities, stroke patients with CMB showed restricted recall of recently learned visual information. Only slight differences between both groups were found in any test investigating the participants' executive functions. Cognitive abilities are more severely impaired in CMB-positive stroke patients compared to CMB-free controls, whereby memory-associated functions are most affected. CMB might be associated with post-stroke cognitive decline, particularly with impaired memory and phonemic fluency.

Abstract WP564: Deep Immune Profiling of the Post-Stroke Peripheral Immune Response Reveals Tri-phasic Response and Correlations With Long-Term Cognitive Outcomes

Introduction: Stroke produces profound local and systemic immune responses that engage all major innate and adaptive immune compartments. The aim of this study was to characterize the systemic immune response to stroke and to determine if it contributes to long-term cognitive disability. Methods: We included 24 consecutive subjects with ischemic stroke and excluded patients for autoimmune disorders, use of immunosuppressant drugs, or life expectancy &lt;90 days. Blood samples were collected for up to 9 timepoints after stroke (days 1, 2, 3, 5, 7, 14, 30, 90, and 365). Change in cognitive function between days 90 and 365 was assessed using the Montreal Cognitive Assessment (MoCA). Control samples were from a cohort of 24 sex- and age-matched patients prior to hip replacement surgery. We used mass cytometry to acquire 240 immune features from each sample, representing 20 immune cell subtypes, their frequency, cell surface markers, and activation states. Elastic Net (EN) regularized regression modeling was used to characterize phases of the immune response and to correlate stages of the immune response with change in cognitive function. Results: The EN model identified three distinct phases of the systemic immune response to ischemic stroke: The acute phase (day 2) was characterized by increased STAT3 (signal transducer and activator of transcription 3) signaling responses in innate immune cell types. The intermediate phase (day 5) was characterized by increased CREB (cAMP response element-binding protein) signaling responses in adaptive immune cell types. The late phase (day 90) was characterized by persistent elevation of neutrophils and IgM+ B cells. By day 365 there was a return to baseline immune responses, comparable to the controls. A decline in MoCA scores between day 90 and day 365 after stroke correlated with a stronger inflammatory response in the acute phase (r = -0.692, Bonferroni-corrected p = 0.04). Conclusions: The results demonstrate three distinct phases of the peripheral immune response that occur after stroke, spanning from days 2 to day 90. The acute phase immune response predicts post-stroke cognitive decline, suggesting that therapies aimed at optimizing this response could lead to preservation of cognitive functioning post-stroke.

Matrix metalloproteinase-9 blood level as a predictor of post-stroke cognitive impairment

Ischemic stroke is one of the leading causes of disability of the population. Among the consequences of stroke besides motor, speech disorders, the most important cause of cognitive impairments, it’s frequency is variable between 25-40%. Post-stroke cognitive disorders are pathogenetically heterogeneous conditions. The nature, modality and severity are determined by the clinical subtype of it’s development. So, cognitive impairment most often can be a consequence of a strategic infarcts, multi-infarct damage, decompensation of chronic cerebrovascular pathology against the background of an acute condition or neurodegenerative process that existed earlier and diagnosed before the appearance of any signs of stroke. In addition, the subtype of ischemic stroke also matters. In stroke, a family of zinc-binding proteolytic enzymes, in particular matrix metalloproteinase-9, plays a significant role in the development of damage of the brain tissue, which is of great importance in the reconstruction of the extracellular matrix. A high serum concentration of metalloproteinase-9 increases the severity of ischemic damage, the severity of the stroke and worsens the functional outcome of the disease. In addition, metalloproteinase-9 is also considered as a biomarker for Alzheimer’s disease, since it acts as a proteolytic enzyme, which, along with neprilizine, cleaves the amyloid protein. The results of a survey of 135 patients in the acute and early recovery period of ischemic stroke are presented. The level of metalloproteinase-9 and cognitive impairment have been studied on 1-2 and 21-22 days of the disease. It was found that a higher level of metalloproteinase-9 in blood plasma reflects a high probability of post-stroke cognitive impairment at the end of an acute period of ischemic stroke. The increase in metalloproteinase-9 did not depend on the localization of the focus of the stroke and its volume. Thus, metalloproteinase-9 investigation in the acute period of the ischemic stroke can predict the development of post-stroke cognitive decline.

Racial and ethnic differences in post-stroke subjective cognitive decline exist

BackgroundRacial and ethnic minorities consistently demonstrate disparate post-stroke outcomes. However, there is a paucity of literature related to whether this disparity exists specifically in post-stroke cognitive decline. ObjectiveTo determine if racial and ethnic disparities exist in post-stroke subjective cognitive decline (SCD) among non-Hispanic Blacks (Blacks), American Indians or Alaska Natives (AI/ANs), Hispanics, and non-Hispanic Whites (Whites) in the United States using data from the Behavioral Risk Factor Surveillance System (BRFSS). MethodsA retrospective analysis was completed using the 2016 BRFSS data in adults who self-reported stroke and SCD. Descriptive statistics were completed for baseline comparisons using chi squared tests for categorical variables. A binary logistic regression controlling for baseline differences was completed to examine racial and ethnic differences in SCD. ResultsSignificant differences in SCD were identified across all racial and ethnic groups. When compared to Whites, Blacks, AI/ANs, and Hispanics more frequently reported worsening confusion or memory loss that interfered with day-to-day activities and the ability to work, volunteer, and engage in social activities outside of the home. AI/ANs who reported SCD were more likely than Whites to have help available. Hispanic persons with SCD or their family members were most likely to discuss SCD with a healthcare provider. ConclusionAlthough persons from all racial and ethnic groups in this study experienced some degree of SCD, Blacks, AI/ANs, and Hispanics most frequently reported worsening confusion or memory loss impacting engagement in day-to-day activities and the ability to work, volunteer, and engage in social activities outside of the home.

A pilot study on the immediate and long-term effects of hybrid therapy of computer-based cognitive training and aerobic exercise in stroke patients with cognitive decline

While the salient physical disability after stroke has long been emphasized, post-stroke cognitive decline hindering motor and functional recovery is often ignored. This study evaluated the immediate and long-term effects of hybrid therapies of computer-based cognitive training and aerobic exercise in stroke patients with cognitive decline. Stroke survivors with cognitive decline were separated into sequential (SEQ) and control groups (CON). Participants in the SEQ group ( n = 15) received 30-minute aerobic exercise followed by 30-minute computerized cognitive training; participants in the CON group ( n = 12) received 30-minute non-aerobic exercise (e.g., stretching and muscle strengthening) and 30-minute unstructured cognitive training (e.g., reading newspapers and playing board games). All participants received trainings for three days per week for 12 weeks. The cognitive function outcomes included Montreal Cognitive Assessment (MoCA) and Verbal Paired Associates and Word Lists subtests from the Wechsler Memory Scale-III (WMS-III). Health-related quality of life was measured by EQ5D. Outcome measures were administered at baseline, immediately after training (3rd month), and at 6-month follow-up (9th month). Preliminary results showed that the SEQ group showed greater improvement in MoCA, WMS-Verbal Pair and Word Lists at post-training than the CON group, but not the EQ5D. These effects remained or had less decrements 6 months post-training compared to the CON group. Hybrid therapy of computer-based cognitive training and aerobic exercise training is favored to facilitate cognitive function in stroke survivors with cognitive decline. Our study demonstrates the potential benefit of this hybrid approach for long-term enhancement of cognition following stroke.

Huatuo Zaizao pill ameliorates cognitive impairment of APP/PS1 transgenic mice by improving synaptic plasticity and reducing A\u03b2 deposition

BackgroundIt is well known that Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Amyloid-β (Aβ) deposition and synaptic dysfunction play important roles in the pathophysiology of Alzheimer’s disease (AD). The Huatuo Zaizao pill (HT) is a Traditional Chinese Medicine (TCM) that has been used clinically for many years in China, mainly for post-stroke rehabilitation and cognitive decline; however, the mechanism of cognitive function is not clear. In this study, we investigated the effect of HT on hippocampal synaptic function, Amyloid-β (Aβ) deposition in APP/PS1 AD transgenic mice.MethodSix-month-old APP/PS1 transgenic (Tg) mice were randomly divided into control, HT-treated, and memantine (MEM)-treated groups. Then, these groups were orally administered vehicle (for the control), HT (0.25 g/kg) and MEM (5 mg/kg) respectively for 4 weeks. The Morris water maze, Novel Object Recognition, and Open field tests were used to assess cognitive behavioral changes. We evaluated the effects of HT on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular tests. Synaptic morphology in the hippocampus was investigated by electron microscopy. Western blotting was used to assess synaptic-associated protein and Aβ production and degrading levels. Immunofluorescence staining was used to determine the relative integrated density.ResultsHT can ameliorate hippocampus-dependent memory deficits and improve synaptic dysfunction by reversing LTP impairment in APP/PS1 transgenic mice. Moreover, HT reduces amyloid plaque deposition by regulating α-secretase and γ-secretase levels.ConclusionHT can improve the learning and memory function of APP/PS1 transgenic mice by improving synaptic function and reducing amyloid plaque deposition.

Risk Factors for Poststroke Cognitive Decline: The REGARDS Study (Reasons for Geographic and Racial Differences in Stroke).

Poststroke cognitive decline causes disability. Risk factors for poststroke cognitive decline independent of survivors' prestroke cognitive trajectories are uncertain. Among 22 875 participants aged ≥45 years without baseline cognitive impairment from the REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke), enrolled from 2003 to 2007 and followed through September 2015, we measured the effect of incident stroke (n=694) on changes in cognitive functions and cognitive impairment (Six-Item Screener score <5) and tested whether patient factors modified the effect. Median follow-up was 8.2 years. Incident stroke was associated with acute declines in global cognition, new learning, verbal memory, and executive function. Acute declines in global cognition after stroke were greater in survivors who were black (P=0.04), men (P=0.04), and had cardioembolic (P=0.001) or large artery stroke (P=0.001). Acute declines in executive function after stroke were greater in survivors who had <high school education versus college graduates (P=0.01). Incident stroke was associated with faster declines in global cognition and executive function but not new learning or verbal memory compared with prestroke slopes. Faster declines in global cognition over years after stroke were greater in survivors who were older (P<0.01), resided outside the Stroke Belt (P=0.005), or had cardioembolic stroke (P=0.01). Faster declines in executive function over years after stroke were greater in survivors who were older (P<0.01) or lacked hypertension (P=0.03). Incident stroke alters a patient's cognitive trajectory, and this effect is greater with increasing age and cardioembolic stroke. Race, sex, geography, and hypertension status may modify the risk of poststroke cognitive decline.

Abstract WP106: Acetazolamide Stabilizes Stroke Induced Respiratory Dysfunction and Improves Longterm Cognitive Outcome

Background: Respiratory dysfunction is a common complication of stroke, with an incidence more than 60% in first time stroke patients, leading to poorer recovery and increased mortality. We developed a mouse model of stroke induced respiratory dysfunction (SIRD) characterized by hypoventilation and apnea. Mice that had the highest incidence of post-stroke apneas developed progressive cognitive decline. Acetazolamide (Act), a carbonic anhydrase inhibitor, promotes metabolic acidosis increasing respiratory activity. Hypothesis: Acetazolamide will stimulate basal respiratory activity, eliminating apneas and hypoxic events, and will enhance post stroke cognitive outcomes. Methods: Whole body plethysmography was performed on WT C57/B6 young (2-3 month) male mice to establish baseline breathing frequency, tidal volume, minute ventilation and number of apneas. Mice were subjected to 60 MCAO or sham surgery. Plethysmography was performed on day 3, 7 and weekly thereafter. Act (40mg/kg) continuous administration via SQ implanted Alzet pump or vehicle (n=11/group) was initiated on day 14. Cognitive tests were conducted over six weeks. Results: Act treatment improved respiratory frequency (152.6±6.49 vs. 318.4±61.9, p&lt;0.05) and decreased the number of apneas (5.4±0.7 vs. 1±0.5, p&lt;0.001) in stroke mice (Fig. 1). Spatial learning/memory assessed on day 42 with Barnes Maze found Act-treated mice had a shorter escape time than vehicle (median escape time 160.48 vs. 14.16s, survival curve for time to escape p=0.0001, Mantel-Cox test). Summary: Apnea and hypoxia are seen in a murine model of SIRD, the severity of which correlated with post-stroke cognitive decline. These deficits were reversed with chronic Acetazolamide treatment. Research supported by the NCATS Award Number TL1TR000369.

Abstract TP140: The Beneficial Effects of Sequential Combination of Cognitive Training and Aerobic Exercise in Stroke Patients With Cognitive Decline

Introduction: Post-stroke cognitive decline is a major problem that affects up to 70% of stroke survivors. Combination of aerobic exercise and cognitive training has been found to be effective for improving cognitive functions in individuals with dementia and community-dwelling elderly. However, the training effects of combined training on stroke survivors with cognitive decline require further investigation. Hypothesis: A sequential combination of aerobic exercise and cognitive training would be effective than control training on cognitive function, physical activity, and quality of life in stroke survivors with cognitive decline. Methods: Stroke survivors with cognitive decline were recruited and separated into sequential (SEQ) and control groups (CON). Participants in the SEQ group (N=15) first received 30-minute aerobic exercise followed by 30-minute computerized cognitive training; participants in the CON group (N=15) received non-aerobic exercise and unstructured cognitive training for 60 minutes. All participants received trainings for three days per week for 12 weeks. The cognitive function outcomes included Montreal Cognitive Assessment (MoCA) and double decision (i.e., visual spatial processing). Six-minute walk test (6MWT) and International Physical Activity Questionnaire (IPAQ) were used to evaluate physical activity. Quality of life was assessed by Stroke Impact Scale (SIS). We used paired sample t-test to examine the within group training effect and analysis of covariance to determine the between groups training effect. Results: From pre to post training, the SEQ group improved cognitive function (MoCA, p &lt;0.001; double decision, p =0.006), physical function (6MWT, p =0.038; IPAQ, p =0.052) but not quality of life (SIS, p =0.47). The CON group, however, had no significant changes across all variables (all p ’s&gt;0.05). Compared to the CON group, the SEQ group improved cognitive function (MoCA, p =0.03) and physical activity (6MWT, p =0.025), but no group difference was found in double decision, IPAQ and SIS. (all p ’s&gt;0.05). Conclusions: A sequential combination of aerobic exercise and cognitive training approach is favored to facilitate cognitive function and physical activity in stroke survivors with cognitive decline.

Type 2 Diabetes Mellitus and Impaired Renal Function Are Associated With Brain Alterations and Poststroke Cognitive Decline

Type 2 diabetes mellitus (T2DM) is associated with diseases of the brain, kidney, and vasculature. However, the relationship between T2DM, chronic kidney disease, brain alterations, and cognitive function after stroke is unknown. We aimed to evaluate the inter-relationship between T2DM, impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. The TABASCO (Tel Aviv brain acute stroke cohort) is a prospective cohort of stroke/transient ischemic attack survivors. The volume and white matter integrity, ischemic lesions, and brain and hippocampal volumes were measured at baseline using 3-T MRI. Cognitive tests were performed on 507 patients, who were diagnosed as having mild cognitive impairment, dementia, or being cognitively intact after 24 months. At baseline, T2DM and impaired renal function (estimated creatinine clearance [eCCl] <60 mL/min) were associated with smaller brain and hippocampal volumes, reduced cortical thickness, and worse white matter microstructural integrity. Two years later, both T2DM and eCCl <60 mL/min were associated with poorer cognitive scores, and 19.7% of the participants developed cognitive decline (mild cognitive impairment or dementia). Multiple analysis, controlling for age, sex, education, and apolipoprotein E4, showed a significant association of both T2DM and eCCl <60 mL/min with cognitive decline. Having both conditions doubled the risk compared with patients with T2DM or eCCl <60 mL/min alone and almost quadrupled the risk compared with patients without either abnormality. T2DM and impaired renal function are independently associated with abnormal brain structure, as well as poorer performance in cognitive tests, 2 years after stroke. The presence of both conditions quadruples the risk for cognitive decline. T2DM and lower eCCl have an independent and additive effect on brain atrophy and the risk of cognitive decline. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01926691.

Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults.

Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke. In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (≥5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations). Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only. Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.