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.

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.

Symptoms of depression and cognitive impairment in young adults after stroke/transient ischemic attack.

Depression and cognitive complaints are common after stroke; these issues have been studied in older populations, but not in the young. Two hundred and seventy four eligible stroke and TIA patients consented to participate and complete the Center for Epidemiologic Studies Depression Scale, and National Institute of Neurological Disorders and Stroke - Canadian Stroke Network 30-min neuropsychological battery; 57 (21%) were ≤ 50 years of age. Younger patients reported greater symptoms of depression and less executive dysfunction than older patients. This study highlights age differences in post-stroke depression symptoms and cognitive impairment, and emphasizes the need for screening across ages.

The Role of Apathy and Depression on Verbal Learning and Memory Performance After Stroke.

OBJECTIVE: Psychiatric symptoms, including depression and apathy, may significantly impede functional and cognitive capabilities following a cerebrovascular event. This study examined the role of apathy and depression on learning and memory performance in stroke patients. METHOD: Stroke patients (n = 140 [119 ischemic, 21 hemorrhagic], mean age = 60.6 [SD = 15.1]) completed the Apathy Evaluation Scale (AES), the Center for Epidemiologic Studies Depression Scale (CES-D), and the California Verbal Learning Test-Second Edition (CVLT-II). RESULTS: Using a 2 × 2 MANOVA with depression (CESD ≥ 16) and apathy (AES ≥ 34) as the independent variables and cognitive performance (i.e., verbal acquisition, short-term free recall, and long-term free recall) as the dependent variables, we found a main effect for apathy (F[3,134] = 2.98, p = .034), such that apathetic stroke patients (n = 24) performed significantly worse on verbal acquisition (F[1,136] = 6.44; p = .012), short-term free recall (F[1,136] = 7.86; p = .006), and long-term free recall (F[1,136] = 8.37; p = .004) than nonapathetic stroke patients (n = 116). There was no main effect of depression on cognitive performance (F[1,136] = 1.72, p = .155). CONCLUSIONS: These results suggest that apathy, not depression, is related to verbal memory performance in stroke patients. Future research should explore whether treatment of apathy (e.g., improving motivation) could be a novel target for improving cognition after stroke. Researchers should also examine whether this model can be applied to other aspects of cognition, including executive function and other areas of memory including autobiographical and working memory.

Apathy, not depressive symptoms, as a predictor of semantic and phonemic fluency task performance in stroke and transient ischemic attack.

OBJECTIVES: This study examined the relationship between apathy and cognition in patients with cerebrovascular disease. Apathy may result from damage to frontal subcortical circuits causing dysexecutive syndromes, but apathy is also related to depression. We assessed the ability of apathy to predict phonemic fluency and semantic fluency performance after controlling for depressive symptoms in 282 individuals with stroke and/or transient ischemic attack. METHOD: Participants (N = 282) completed the Phonemic Fluency Test, Semantic Fluency Test, Center for Epidemiologic Studies Depression Scale, and Apathy Evaluation Scale. A cross-sectional correlational design was utilized. RESULTS: Using hierarchical linear regressions, apathy scores significantly predicted semantic fluency performance (ß = -.159, p = .020), but not phonemic fluency performance (ß = -.112, p = .129) after scaling scores by age and years of education and controlling for depressive symptoms. Depressive symptoms entered into the first step of both hierarchical linear regressions did not predict semantic fluency (ß = -.035, p = .554) or phonemic fluency (ß = -.081, p = .173). Apathy and depressive symptoms were moderately correlated, r(280) = .58, p < .001. CONCLUSIONS: The results of this study are consistent with research supporting a differentiation between phonemic and semantic fluency tasks, whereby phonemic fluency tasks primarily involve frontal regions, and semantic fluency tasks involve recruitment of more extended networks. The results also highlight a distinction between apathy and depressive symptoms and suggest that apathy may be a more reliable predictor of cognitive deficits than measures of mood in individuals with cerebrovascular disease. Apathy may also be more related to cognition due to overlapping motivational and cognitive frontal subcortical circuitry. Future research should explore whether treatments for apathy could be a novel target for improving cognitive outcomes after stroke.

The "DOC" screen: Feasible and valid screening for depression, Obstructive Sleep Apnea (OSA) and cognitive impairment in stroke prevention clinics.

BACKGROUND: Post-stroke Depression, Obstructive sleep apnea (OSA) and Cognitive impairment ("DOC") are associated with greater mortality, worse recovery and poorer quality of life. Best practice recommendations endorse routine screening for each condition; yet, all are under-assessed, diagnosed and treated. We seek to determine the feasibility and validity of an integrated tool ("DOC" screen) to identify stroke clinic patients at high-risk of depression, OSA, and cognitive impairment. METHODS: All consecutive new referrals to a regional Stroke Prevention Clinic who were English-speaking and non-aphasic were eligible to be screened. Time for screen completion was logged. DOC screen results were compared to the neuropsychological battery and polysomnogram assessments using a modified receiver operator characteristic and area under the curve analysis. Data is reported to conform to STARD guidelines. FINDINGS: 1503 people were screened over 2 years. 89% of eligible patients completed the screen in 5 minutes or less (mean 4.2 minutes), less than half the time it takes to complete the Montreal Cognitive Assessment (MoCA). 437 people consented to detailed testing. Of those, 421 completed the Structured Clinical Interview for Depression within 3 months of screening, 387 completed detailed neuropsychological testing within 3 months, and 88 had overnight polysomnograms. Screening scores combined with demographic variables (age, sex, education, body mass index), had excellent validity compared to gold standard diagnoses: DOC-Mood AUC 0.90; DOC-Apnea AUC 0.80; DOC-Cog AUC 0.81. DOC screen scores can reliably categorize patients in to low-, intermediate- or high-risk groups for further action and can do so with comparable accuracy to more time-consuming screens. CONCLUSIONS: Systematic screening of depression, obstructive sleep apnea, and cognitive impairment in 5 minutes or less is feasible and valid in a high volume stroke clinic using the DOC screen. The DOC screen may facilitate improved identification and treatment of these comorbidities to improve function in patients after stroke and in those with other neurological diseases that share these comorbid conditions (e.g. Alzheimer's disease/mild cognitive impairment, Parkinson's disease, Traumatic Brain Injury, multiple sclerosis).

Post-stroke depression, obstructive sleep apnea, and cognitive impairment: Rationale for, and barriers to, routine screening.

Stroke can cause neurological impairment ranging from mild to severe, but the impact of stroke extends beyond the initial brain injury to include a complex interplay of devastating comorbidities including: post-stroke depression, obstructive sleep apnea, and cognitive impairment ("DOC"). We reviewed the frequency, impact, and treatment options for each DOC condition. We then used the Ottawa Model of Research Use to examine gaps in care, understand the barriers to knowledge translation, identification, and addressing these important post-stroke comorbidities. Each of the DOC conditions is common and result in poorer recovery, greater functional impairment, increased stroke recurrence and mortality, even after accounting for traditional vascular risk factors. Despite the strong relationships between DOC comorbidities and these negative outcomes as well as recommendations for screening based on best practice recommendations from several countries, they are frequently not assessed. Barriers related to the nature of the screening tools (e.g., time consuming in high-volume clinics), practice environment (e.g., lack of human resources or space), as well as potential adopters (e.g., equipoise surrounding the benefits of treatment for these conditions) pose challenges to routine screening implementation. Simple, feasible approaches to routine screening coupled with appropriate, evidence-based treatment protocols are required to better identify and manage depression, obstructive sleep apnea, and cognitive impairment symptoms in stroke prevention clinic patients to reduce the impact of these important post-stroke comorbidities. These tools may in turn facilitate large-scale randomized controlled treatment trials of interventions for DOC conditions that may help to improve cardiovascular outcomes after stroke or TIA.

Investigation of melanocortin system gene variants in antipsychotic-induced weight gain.

OBJECTIVES: The use of second-generation antipsychotic medications may result in substantial weight gain in a subset of schizophrenia patients. Distinct populations of neurons expressed in the hypothalamus, including the cocaine- and amphetamine-regulated transcript (CART), the polypeptide pro-opiomelanocortin (POMC) and the agouti-related protein (AGRP), have regulatory roles in weight control and energy homeostasis. Thus, we investigated the potential role of CART, POMC and AGRP genetic variants in antipsychotic-induced weight gain (AIWG). METHODS: Five CART single nucleotide polymorphisms (SNPs) (rs10515115, rs3763153, rs3857384, rs11575893, rs16871471), three POMC SNPs (rs6713532, rs1047521, rs3754860) and one AGRP SNP (rs1338993), were genotyped in 218 patients treated with antipsychotics for chronic schizophrenia and evaluated for AIWG. We compared weight change (%) across genotypic groups using analysis of covariance. RESULTS: None of the SNPs in POMC, CART, AGRP were significantly associated with AIWG in the refined samples stratified by ethnicity and medication treatment. CONCLUSIONS: In this exploratory study, we observed that POMC, CART and AGRP gene variants are not a major contributor to AIWG. However larger samples are required to completely rule out their effect on AIWG.

The CLOQS trial protocol: a cluster-randomized trial evaluating a simple, low-cost intervention to reduce treatment times in acute stroke.

RATIONALE: In acute stroke, time is brain: faster tissue plasminogen activator treatment improves patient outcomes. Published guidelines for door-to-scanner time are <25 minutes, and for door-to-needle time <60 minutes. These benchmarks are rarely met. Paradoxically, the earlier a stroke patient arrives to hospital, the longer treatment takes. There is an urgent need to shift focus away from the 4.5 hour time window, towards treatment times <60 minutes. AIMS: The objective of the Countdown Lights to Optimize Quality in acute Stroke (CLOQS) trial is to determine whether a simple, low-cost organizational behavior intervention, a large, red stopwatch timer attached to the stretcher upon arrival, will decrease door-to-scanner and door-to-needle treatment times for tissue plasminogen activator-treated patients. DESIGN: A multicenter, time-clustered randomized control trial. The stopwatch timers will be used in Emergency Departments for all acute stroke patients across the University of Toronto Stroke Program. The order of intervention (ON) and control (OFF) blocks will be randomly assigned in a 1:1 ratio over an 18 month period. Blocks will be weighted in a 2:1 ratio of ON/OFF using a permuted block design (ON blocks last two weeks; OFF blocks last one week). STUDY OUTCOMES: The primary end-point is percentage of patients achieving best-practice guidelines (door-to-needle treatment time <60 minutes). Secondary end-points are median time intervals for 1) door-to-scanner and 2) door-to-needle times during ON versus OFF blocks. Tertiary end-points are in-hospital mortality and time series analysis to determine change in treatment times from prior to study onset through study completion.

Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis.

AIMS: This study aims to test for possible associations between the gene coding for the 5-HT2C receptor and antipsychotic-induced weight gain. MATERIALS & METHODS: Four HTR2C polymorphisms (rs498207, C-759T, G-697C and Ser23Cys) were investigated in our sample of 205 chronic schizophrenia patients. RESULTS: Significant over-representation of the C-G-Cys23 haplotype in patients with weight gain (OR: 1.93; 95% CI: 1.04-3.56; p = 0.0015) was found. Similarly, haplotype analyses of percentage weight change were also significant (p = 0.029) for the C-G-Cys23 haplotype associated with the highest average percent weight gain. Observations in the polymorphisms are consistent with previous studies. An updated meta-analysis of nine previous studies plus our current sample suggest that the -759C allele is associated with antipsychotic-induced weight gain. CONCLUSION: Additional studies, including the resequencing of the region surrounding the HTR2C promoter, and functional studies of the promoter polymorphisms, may elucidate the mechanism underlying this genetic association.

Association study of polymorphisms in cholecystokinin gene and its receptors with antipsychotic induced weight gain in schizophrenia patients.

Cholecystokinin (CCK) gene and its receptors play an important role in several biological processes including satiety signaling. Administration of exogenous or endogenously secreted CCK leads to decreased food intake in both rats and humans. Similarly, in rats pretreated with intraperitoneal CCK, antagonists of the CCKA receptor prevent decrease in food intake. The CCKB receptor plays an important role in anxiety and gastric acid secretion. We investigated the role of polymorphisms in the CCK gene (2 SNPs) and its receptors CCKA (4 SNPs) and CCKB (4SNPs, 1 microsatellite, CTn) in antipsychotic induced weight gain (n=215). Weight change (%) from baseline was compared across genotypic groups using analysis of covariance. In the European ancestry patients treated with clozapine or olanzapine a trend of association was observed with the SNP rs2929183 (p=0.10) in CCKBR gene. Carriers of the genotype AA (3.23%±4.8) gained less weight than the AG and GG genotypes (6.50%±6.5; p=0.035). A similar trend was observed for the CTn repeat, where carriers of the LL genotype gained less weight (3.73%±5.41) than the S allele carrying genotypes (6.29%±6.2, p=0.05). In the subjects of African ancestry we observed similar marginal association although with the opposite allele. However, none of these observations would survive corrections for multiple testing. None of the other polymorphisms in either CCK or CCKA receptor genes was associated with weight change (%). In conclusion, CCKB receptor gene may play a role in antipsychotic induced weight gain. However, these observations need to be replicated in a larger and independent sample set.