CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury.

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.

CCR5-Δ32 polymorphism-a possible protective factor from gait impairment amongst post-stroke patients.

BACKGROUND AND PURPOSE: Stroke and small vessel disease cause gait disturbances and falls. The naturally occurring loss-of-function mutation in the C-C chemokine receptor 5 gene (CCR5-Δ32) has recently been reported as a protective factor in post-stroke motor and cognitive recovery. We sought to examine whether it also influences gait and balance measures up to 2 years after stroke. METHOD: Participants were 575 survivors of first-ever, mild-moderate ischaemic stroke or transient ischaemic attack from the TABASCO prospective study, who underwent a 3 T magnetic resonance imaging at baseline and were examined by a multi-professional team 6, 12 and 24 months after the event, using neurological, neuropsychological and mobility examinations. Gait rhythm and the timing of the gait cycle were measured by force-sensitive insoles. CCR5-Δ32 status and gait measures were available for 335 patients. RESULTS: CCR5-Δ32 carriers (16.4%) had higher gait speed and decreased (better) stride and swing time variability 6 and 12 months after the index event compared to non-carriers (p < 0.01 for all). The association remained significant after adjustment for age, gender, education, ethnicity and stroke severity. CONCLUSIONS: Significant associations were found between gait measurements and CCR5-Δ32 loss-of-function mutation amongst stroke survivors. This is the first study showing that genetic predisposition may predict long-term gait function after ischaemic stroke.

Posttraumatic Stress Symptoms After Stroke: The Effects of Anatomy and Coping Style.

BACKGROUND: Posttraumatic stress disorder (PTSD) can be triggered by life-threatening medical emergencies, such as stroke. Data suggest that up to 25% of stroke survivors will develop PTSD symptomatology, but little is known about predisposing factors. We sought to examine whether neuroimaging measures and coping styles are related to PTSD symptoms after stroke. METHODS: Participants were survivors of first-ever, mild-moderate ischemic stroke, or transient ischemic attack from the TABASCO study (Tel Aviv Brain Acute Stroke Cohort). All participants underwent a 3T magnetic resonance imaging at baseline and were examined 6, 12, and 24 months thereafter, using neurological, neuropsychological, and functional evaluations. At baseline, coping styles were evaluated by a self-reported questionnaire. PTSD symptoms were assessed using the PTSD checklist. Data were available for 436 patients. RESULTS: Forty-eight participants (11%) developed probable PTSD (PTSD checklist ≥44) during the first year after the stroke/transient ischemic attack. Stroke was more likely to cause PTSD than transient ischemic attack. Stroke severity, larger white matter lesion volume, and worse hippocampal connectivity were associated with PTSD severity, while infarct volume or location was not. In a multivariate analysis, high-anxious and defensive coping styles were associated with a 6.66-fold higher risk of developing poststroke PTSD ([95% CI, 2.08-21.34]; P<0.01) compared with low-anxious and repressive coping styles, after adjusting for age, education, stroke severity, brain atrophy, and depression. CONCLUSIONS: In our cohort, PTSD was a common sequela among stroke survivors. We suggest that risk factors for PTSD development include stroke severity, white matter damage, and premorbid coping styles. Early identification of at-risk patients is key to effective treatment.

Endovascular thrombectomy is beneficial for functional nonagenarians - a multicenter cohort analysis.

INTRODUCTION: The use of endovascular thrombectomy (EVT) has dramatically increased in recent years. However, most existing studies used an upper age limit of 80 and data regarding the safety and efficacy of EVT among nonagenarians is still lacking. METHODS: 767 consecutive patients undergoing EVT for large vessel occlusion (LVO) in three participating centers were recruited into a prospective ongoing database. Demographic, clinical and imaging characteristics were documented. Statistical analysis was done to evaluate EVT outcome among nonagenarians compared to younger patients. RESULTS: The current analysis included 41 (5.4%) patients older than 90 years. Compared to younger patients, nonagenarians were more often female (78% versus 50.3%, p ≤ 0.001), had worse baseline mRS scores (2 [0-3] versus 0 [0-2], p < 0.001), higher rates of hypertension and hyperlipidemia and a higher admission NIHSS (20 [14-23] versus 16 [11-20], p < 0.001). No differences were found between groups regarding the involved vessel, stroke etiology, time from symptoms to door or symptoms to EVT, successful recanalization rates and hemorrhagic transformation rates. Nonagenarians had worse mRS at 90 days (5 [3-6] versus 3 [2-5], p = 0.001), similar discharge NIHSS (5 [1-11] versus 4 [1-11], p = 0.78) and higher mortality rates (36.6% versus 15.8%, p < 0.001). All nonagenarians with baseline mRS 4 have died within 90 days. 36.4% of nonagenarian patients with baseline MRS of 3 or less had favorable outcome. DISCUSSION: This study demonstrates that nonagenarian stroke patients with baseline mRS of 3 or less benefit from EVT with no significant difference in the rate of favorable outcome compared to octogenarians.

CCR5-Δ32 polymorphism: a possible protective factor for post-stroke depressive symptoms.

Background: A naturally occurring loss-of-function mutation in the gene for C-C chemokine receptor type 5 (CCR5-Δ32) has recently been reported as a protective factor in post-stroke motor and cognitive recovery. We sought to examine whether this mutation also prevented the development of depressive symptoms up to 2 years after a stroke. Methods: Participants were survivors of a first-ever mild to moderate ischemic stroke or transient ischemic attack from the TABASCO prospective study who underwent a 3 T MRI at baseline and were examined by a multiprofessional team 6, 12 and 24 months after the event, including an evaluation of depressive symptoms using the Geriatric Depression Scale. Results: CCR5-Δ32 status and a baseline depression evaluation were available for 435 patients. Compared with noncarriers, CCR5-Δ32 carriers (16.1%) had fewer depressive symptoms at admission (p = 0.035) and at 6 months (p < 0.001), 12 months (p < 0.001) and 24 months (p = 0.006) after the index event. This association remained significant at 6 and 12 months after adjustment for age, sex, education, antidepressant use, ethnicity and the presence of cortical infarcts. These findings were more robust in women. Compared to baseline, depressive symptoms in CCR5-Δ32 noncarriers tended to remain stable or grow worse over time, but in CCR5-Δ32 carriers, symptoms tended to improve. Limitations: A limitation of this study was the exclusion of patients who had a severe stroke or who had pre-stroke depression. Conclusion: Carriers of the CCR5-Δ32 allele had a lower tendency to develop depressive symptoms post-stroke, and this phenomenon was more prominent in women. These findings could have clinical implications; they suggest a mechanism-based treatment target for post-stroke depression. Drugs mimicking this loss-of-function mutation exist and could serve as a novel antidepressant therapy.

Working status is related to post stroke/TIA cognitive decline: data from the TABASCO study.

BACKGROUND AND AIMS: Occupational status may influence physical and mental post-stroke outcomes. We aimed to evaluate the association between occupational status and type, or engagement in social and family activities, neuroimaging measures and cognitive decline (CD) in a prospective cohort of stroke patients. METHODS: We included 273 first-ever stroke survivors at working age. All patients underwent 3T MRI at admission, as well as clinical and cognitive assessments at admission, 6, 12 and 24 months thereafter. RESULTS: Ninty nine (36.3%) of the participants were unemployed prior to the stroke. Age, sex, work type, other comorbidities, stroke severity or location were not associated with return to work. Patients who returned to work (87.4%) had better cognitive results and less depressive symptoms than those who retired after the event. Pre-stroke unemployment was associated with diabetes mellitus, hypertension, dyslipidemia, depression, poorer cognitive scores and brain atrophy. During the follow-up, 11% developed CD. CD was more common among previously unemployed than employed participants (19.2% vs. 6.3%, p = 0.001). Multiple regression adjusted for risk factors, revealed that pre-stroke unemployment was an independent predictor of CD (HR, 3.0; 95% CI: 1.06-8.44). Furthermore, engagement in mentally stimulating jobs decreased the risk for CD. CONCLUSIONS: Pre-stroke unemployment and post-stroke work disruption were each associated with depression and poorer cognitive performance up to two years post-stroke, as well as with brain atrophy at admission. Retirement after the stroke may increase the risk of developing CD. These results highlight the importance of continued employment in preserving cognitive abilities among stroke survivors.

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

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01926691.

Cognitive state following mild stroke: A matter of hippocampal mean diffusivity.

The hippocampus is known to play a vital role in learning and memory and was demonstrated as an early imaging marker for Alzheimer's disease (AD). However, its role as a predictor for mild cognitive impairment and dementia following stroke is unclear. The main purpose of this study was to examine the associations between hippocampal volume, mean diffusivity (MD) and connectivity and cognitive state following stroke. Eighty three consecutive first ever mild to moderate stroke or transient ischemic attack (TIA) survivors from our ongoing prospective TABASCO (Tel Aviv Brain Acute Stroke Cohort) study underwent magnetic resonance imaging scans within 7 days of stroke onset. Hippocampal volume was measured from T1 weighted images, hippocampal mean diffusivity was calculated from diffusion tensor imaging and connectivity was calculated from resting state fMRI. Global cognitive assessments were evaluated during hospitalization and 6 and 12 months later using a computerized neuropsychological battery. Multiple linear regression analysis was used to test which of the hippocampi measurements best predict cognitive state. All three imaging parameters were significantly correlated to each other (|r's| >0.3, P's < 0.005), and with cognitive state 6 and 12 months after the event. Multiple regression analyses demonstrated the predictive role of hippocampal mean diffusivity (ß = -0.382, P = 0.026) on cognitive state, above and beyond that of volume and connectivity of this structure. To our knowledge, the combination of hippocampal volume, mean diffusivity and connectivity in first ever post stroke or TIA patients has not yet been considered in relation to cognitive state. The results demonstrate the predictive role of hippocampal mean diffusivity, suggesting that these changes may precede and contribute to volumetric and connectivity changes in the hippocampi, potentially serving as a marker for early identification of patients at risk of developing cognitive impairment or dementia.

Gait measures as predictors of poststroke cognitive function: evidence from the TABASCO study.

BACKGROUND AND PURPOSE: Patients with stroke are at risk for developing cognitive impairment. We tested whether the assessment of balance and gait can enhance the prediction of long-term cognitive outcome in stroke survivors. METHODS: Participants were patients with first-ever, mild-moderate ischemic stroke or transient ischemic attack from the Tel Aviv Brain Acute Stroke Cohort (TABASCO) study, a large prospective cohort study, who underwent 3-T MRI and were followed for ≥2 years using neurological, neuropsychological, and mobility examinations 6, 12, and 24 months after the index event. RESULTS: Data were available for 298 patients (age: 66.7±9.6 years). Forty-six participants (15.4%) developed cognitive decline (CD) over the 2 years of follow-up. The CD group and cognitively intact group did not differ in their neurological deficits or in their infarct volume or location. Nonetheless, 6 months after stroke, the Timed Up and Go test took longer in those who later developed CD (P<0.001). Additionally, the CD group also had lower Berg Balance Scale scores (P<0.001), slower gait (P<0.001), and fewer correct answers during dual-task walking (P=0.006). Separate analyses of the patients with transient ischemic attack revealed similar results. Multivariate regression analysis showed that Timed Up and Go times >12 s at 6 months after stroke/transient ischemic attack was a significant independent risk marker of CD 24 months after stroke (odds ratio=6.07, 95% confidence interval: 1.36-27.15). CONCLUSIONS: These results suggest that measures of balance and gait are significant risk markers of cognitive status 2 years after stroke. Relatively simple, performance-based tests of mobility may enhance the identification of stroke/transient ischemic attack survivors who have an increased risk of developing CD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01926691.

Circle of Willis integrity in acute middle cerebral artery occlusion: does the posterior communicating artery matter?

BACKGROUND: Collateral circulation is an important determinant of outcome in people with acute ischemic stroke due to large vessel occlusion (LVO). OBJECTIVE: To explore the impact of the circle of Willis (CW) anatomical characteristics ipsilateral to the occlusion site, particularly the posterior communicating artery (PComA) and the A1-portion of the anterior cerebral artery (A1-ACA), on stroke outcomes in a cohort of patients with LVO and middle cerebral artery (MCA) occlusion, undergoing endovascular thrombectomy (EVT). METHODS: This is a retrospective cohort study performed in a comprehensive tertiary stroke center. The study population consisted of consecutive patients with LVO with proximal MCA occlusion (M1) between June 2016 and April 2021, undergoing EVT. Demographic, clinical, and imaging information was extracted from patient files. Patency and diameters of ipsilateral A1-ACA and PComA were manually measured on admission CT angiography images in the core laboratory. RESULTS: One hundred and five patients with LVO comprised the study cohort, mean age 72.3 years, 43.8% were male, mean National Institutes of Health Stroke Scale score at admission 15.2. The cohort was grouped according to CW vessel characteristics. On univariate analysis, a well-developed PComA was associated with lower rates of hemorrhagic transformation (1.8% vs 14.3%, P=0.01) and a trend towards lower mortality rates (8.9% vs 20.4%, P=0.08).On multivariable regression analysis a well-developed PComA emerged as an independent predictor for survival (aOR=0.09, 95% CI 0.01 to 0.4 for survival at discharge, P=0.009, aOR=0.22, 95% CI 0.05 to 0.8 for survival at 90 days, P=0.02). CONCLUSIONS: In a cohort of patients with LVO due to M1 occlusion undergoing EVT, a well-developed PComA was associated with significantly lower hemorrhagic transformation rates, a trend towards better functional outcomes, and independently predicted survival. Larger studies are needed to understand the differential effect of CW collateral conduits on stroke outcome and evaluate the practicality of incorporating such factors in the clinical decision-making process prior to EVT.

Association between intracranial vessel calcifications, structural brain damage, and cognitive impairment after minor strokes: a prospective study.

Background: Vascular calcifications are a hallmark of atherosclerosis, and in the coronary arteries are routinely used as a prognostic marker. Calcifications of intracranial vessels (ICC) are frequently observed on non-contrast CT (NCCT) and their effect on post-stroke cognitive impairment (PSCI) remains unclear. Our aim was to explore the association of ICC with prospective long-term cognitive function and advanced MRI-measures in a large prospective cohort of cognitively intact mild stroke survivors. Methods: Data from the Tel-Aviv brain acute stroke cohort (TABASCO) study [ClinicalTrials.gov #NCT01926691] were analyzed. This prospective cohort study (n = 575) aimed to identify predictors of PSCI, in cognitively intact mild stroke survivors. A quantitative assessment of the intracranial calcium content - The ICC score (ICCS) was calculated semi-automatically on NCCT using a validated calcium quantification application. Participants underwent a 3 T-MRI and prospective comprehensive cognitive clinical and laboratory assessments at enrollment, 6, 12, and 24-months. Results: Data were available for 531 participants (67.4 years, 59.5% males). The incidence of PSCI at two-years doubled in the high ICCS group (26% vs. 13.7%, p < 0.001). The high ICCS group had significantly greater small-vessel-disease (SVD) tissue changes and reduced microstructural-integrity assessed by Diffusion-Tensor-Imaging (DTI) maps (p < 0.05 for all). In multivariate analysis, a higher ICCS was independently associated with brain atrophy manifested by lower normalized white and gray matter, hippocampal and thalamic volumes (ß = -0.178, ß = -0.2, ß = -0.137, ß = -0.157; p < 0.05) and independently predicted PSCI (OR 1.83, 95%CI 1.01-3.35). Conclusion: Our findings suggest that the ICCS, which is a simple and readily available imaging marker on NCCT, is associated with brain atrophy, microstructural damage, the extent of SVD, and may predict PSCI. This finding has implications for identifying individuals at risk for PSCI and implementing targeted interventions to mitigate this risk.

The pivotal role of timing of intravenous thrombolysis bridging treatment prior to endovascular thrombectomy.

Background: The role of intravenous thrombolysis (IVT) as bridging treatment prior to endovascular thrombectomy (EVT) is under debate and better patient selection is needed. Objectives: As the efficacy and safety of IVT diminish with time, we aimed to examine the impact of bridging treatment within different time frames from symptom onset. Design: A retrospective registry study. Methods: Data were extracted from ongoing prospective EVT registries in two large tertiary centers. The current study included IVT-eligible patients with onset to door (OTD) < 4 h. We examined the efficacy and safety of bridging treatment through a comparison of the IVT + EVT group with the direct-EVT group by different time frames. Results: In all, 408 patients (age 71.1 ± 14.6, 50.6% males) were included, among them 195 received IVT + EVT and 213 underwent direct EVT. Both groups had similar characteristics. In the IVT + EVT group only, longer OTD was associated with lower rates of favorable outcome (p = 0.021) and higher rates of hemorrhagic transformation (HT; p = 0.001). In patients with OTD ⩽ 2 h, IVT + EVT compared to direct EVT had higher rates of TICI 2b-3 (86.2% versus 80.7%, p = 0.038). In patients with OTD > 2 h, IVT + EVT had lower rates of favorable outcome (33.3% versus 56.9%, p = 0.021), worse discharge National Institutes of Health Stroke Scale [7 (2-13) versus 3 (1-8), p = 0.024], and higher rates of HT (34.0% versus 8.5%, p < 0.001). Discussion: In this study, we found OTD times to have a significant effect on the impact of IVT bridging treatment. Our study shows that among patients with OTD < 2 h bridging treatment may be associated with higher rates of successful recanalization. By contrast, in patients with OTD > 2 h, bridging treatment was associated with worse outcomes. Further time-sensitive randomized trials are needed.

Stroke Risk and Antithrombotic Treatment During Follow-up of Patients With Ischemic Stroke and Cortical Superficial Siderosis.

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke (IS) or transient ischemic attack (TIA) and cortical superficial siderosis (cSS), there are few data regarding the risk of future cerebrovascular events and also about the benefits and safety of antithrombotic drugs for secondary prevention. We investigated the associations of cSS and stroke risk in patients with recent IS or TIA. METHODS: We retrospectively analyzed the Microbleeds International Collaborative Network (MICON) database. We selected patients with IS or TIA from cohorts who had MRI-assessed cSS, available data on antithrombotic treatments, recurrent cerebrovascular events (intracranial hemorrhage [ICrH], IS, or any stroke [ICrH or IS]), and mortality. We calculated incidence rates (IRs) and performed univariable and multivariable Cox regression analyses. RESULTS: Of 12,669 patients (mean age 70.4 ± 12.3 years, 57.3% men), cSS was detected in 273 (2.2%) patients. During a mean follow-up of 24 ± 17 months, IS was more frequent than ICrH in both cSS (IR 57.1 vs 14.6 per 1,000 patient-years) and non-cSS (33.7 vs 6.3 per 1,000 patient-years) groups. Compared with the non-cSS group, cSS was associated with any stroke on multivariable analysis {IR 83 vs 42 per 1,000 patient-years, adjusted hazard ratio [HR] for cSS 1.62 (95% CI: 1.14-2.28; p = 0.006)}. This association was not significant in subgroups of patients treated with antiplatelet drugs (n = 6,554) or with anticoagulants (n = 4,044). Patients with cSS who were treated with both antiplatelet drugs and anticoagulants (n = 1,569) had a higher incidence of ICrH (IR 107.5 vs 4.9 per 1,000 patient-years, adjusted HR 13.26; 95% CI: 2.90-60.63; p = 0.001) and of any stroke (IR 198.8 vs 34.7 per 1,000 patient-years, adjusted HR 5.03; 95% CI: 2.03-12.44; p < 0.001) compared with the non-cSS group. DISCUSSION: Patients with IS or TIA with cSS are at increased risk of stroke (ICrH or IS) during follow-up; the risk of IS exceeds that of ICrH for patients receiving antiplatelet or anticoagulant treatment alone, but the risk of ICrH exceeds that of IS in patients receiving both treatments. The findings suggest that either antiplatelet or anticoagulant treatment alone should not be avoided in patients with cSS, but combined antithrombotic therapy might be hazardous. Our findings need to be confirmed by randomized clinical trials.

Leukoaraiosis is a chronic atherosclerotic disease.

BACKGROUND AND PURPOSE: White matter changes (WMCs), or leukoaraiosis (LA), are associated with increased age, hypertension, diabetes mellitus, and history of stroke. Although several lines of evidence suggest a role of atherosclerosis in atherothrombotic vascular events, their involvement in LA remains to be determined. Our study examines this association in ischemic stroke patients. METHODS: One hundred and seventy consecutive ischemic stroke or transient ischemic attack (TIA) patients were included. All patients underwent brain computed tomography (CT) with assessment of the extension and severity of WMCs, carotid arteries duplex scan with measurements of intima-media thickness (IMT) and plaques. RESULTS: Seventy-two patients (42.4%) were found to have white matter lesions, of whom 28.8% had advanced LA. Mean IMT was significantly higher in patients with LA and with advanced LA (P = 0.002, P = 0.003, resp.). In addition, LA and LA severity were associated with existence of carotid plaque (P = 0.007, P = 0.004, resp.). In multivariate logistic regression analysis, including all vascular risk factors, LA was found to be associated with age and IMT. CONCLUSION: This study reinforces the tight association between LA and carotid atherosclerosis in ischemic stroke patients. We conclude that a chronic atherosclerotic disease underlies the pathophysiology of leukoaraiosis and its progression.

The Usefulness of the Erythrocyte Sedimentation Rate and C-reactive Protein for the Differential Diagnosis of Non-Arteritic Anterior Ischemic Optic Neuropathy in the Era of Microinflammation.

PURPOSE: The presence of a microinflammatory response is one of the possible pathological mechanisms related to the development of nonarteritic anterior ischemic optic neuropathy (NAAION), a common cause of optic neuropathy in old age.We tested whether individuals with NAAION harbor a heightened microinflammatory response compared to controls. METHODS: We measured the erythrocyte sedimentation rate (ESR) and high sensitivity C-reactive protein (hs-CRP) in NAAION patients during hospital admission and in four matched controls for each patient, retrieved from a large cohort of 20,000 apparently healthy individuals. RESULTS: We included 128 NAAION patients and 512 controls. No significant differences were found between patients and controls regarding the inflammatory biomarkers. CONCLUSIONS: This is the first report showing a lack of difference in ESR and hs-CRP levels between NAAION patients and matched controls, suggesting NAAION is not associated with a heightened inflammatory response, such as the one associated with multiple atherothrombotic risk factors.

The Interrelation Between Chronic Headache, Cognitive Scores, and MRI Markers Among Stroke Survivors.

BACKGROUND: Migraine is known to mildly increase the risk for ischemic stroke and is associated with vascular MRI markers. However, the potential effect of chronic headache (CH) on stroke outcomes has not been studied. OBJECTIVE: We aimed to assess the interrelation between CH and post-stroke cognitive impairment. METHODS: Data from 455 patients with a first ever stroke from the TABASCO study was available. All patients underwent 3T brain MRI, blood analysis, and a serial cognitive assessment at baseline and 6, 12, and 24 months after. RESULTS: Eighty-five (18.7%) patients reported suffering from CH, of whom 53 (62.4%) reported symptoms of photophobia or nausea, and 34 (40%) reported an aura. CH was associated with female sex, lower prevalence of T2DM (p < 0.001), and lower HbA1C levels (p < 0.001). Multiple regression analysis, controlling for age, sex, education, vascular risk factors, and the presence of acute lesions in MRI, revealed that CH was an independent predictor of better cognitive scores 6, 12, and 24 months post-stroke (p = 0.015, p = 0.01, and p = 0.012, respectively). Stroke patients suffering from CH had also higher normalized gray, white matter, and thalamus volumes, and better white matter microstructural integrity (p < 0.001, p = 0.037, p < 0.001, p = 0.008, respectively)Conclusion:In this study, CH was consistently associated with better long term cognitive scores among post stroke subjects. These surprising findings may partially arise from the higher prevalence of T2DM among subjects without CH, that may represent the existence of chronic cerebrovascular disease, and may reflect mechanisms involving glucose metabolism.

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology.

The K variant of butyrylcholinesterase (BChE-K, 20% incidence) is a long debated risk factor for Alzheimer disease (AD). The A539T substitution in BChE-K is located at the C terminus, which is essential both for BChE tetramerization and for its capacity to attenuate beta-amyloid (Abeta) fibril formation. Here, we report that BChE-K is inherently unstable as compared with the "usual" BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD. A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Abeta oligomerization than its BSP-U counterpart. Correspondingly, highly purified recombinant human rBChE-U monomers suppressed beta-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Abeta neurotoxicity. Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes.

Serum cholinesterase activities distinguish between stroke patients and controls and predict 12-month mortality.

To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholine suppresses inflammation. Therefore, carriers of polymorphisms that modify cholinergic activity should be particularly susceptible to inflammatory damage. Our study sought diagnostic values of AChE and Cholinergic Status (CS, the total capacity for acetylcholine hydrolysis) in suspected stroke patients. For this purpose, serum cholinesterase activities, butyrylcholinesterase-K genotype and inflammatory biomarkers were determined in 264 ischemic stroke patients and matched controls during the acute phase. AChE activities were lower (P<0.001), and butyrylcholinesterase activities were higher in patients than in controls (P=0.004). When normalized to sampling time from stroke occurrence, both cholinergic parameters were correlated with multiple inflammatory biomarkers, including fibrinogen, interleukin-6 and C-reactive protein (r=0.713, r=0.607; r=0.421, r=0.341; r=0.276, r=0.255; respectively; all P values<0.001). Furthermore, very low AChE activities predicted subsequent nonsurvival (P=0.036). Also, carriers of the unstable butyrylcholinesterase-K variant were more abundant among patients than controls, and showed reduced activity (P<0.001). Importantly, a cholinergic score combining the two cholinesterase activities discriminated between 94.3% matched pairs of patients and controls, compared with only 75% for inflammatory measures. Our findings present the power of circulation cholinesterase measurements as useful early diagnostic tools for the occurrence of stroke. Importantly, these were considerably more distinctive than the inflammatory biomarkers, albeit closely associated with them, which may open new venues for stroke diagnosis and treatment.

Vascular and Neurodegenerative Markers for the Prediction of Post-Stroke Cognitive Impairment: Results from the TABASCO Study.

BACKGROUND: Stroke is a major cause of cognitive impairment and dementia. However, the underlying mechanisms beyond post-stroke cognitive impairment (PSCI) are not fully explained to date. OBJECTIVE: We studied the contribution of vascular pathology measures to PSCI, separate from and in conjunction with pathologic markers associated with Alzheimer's disease (AD). METHODS: Data from 397 cognitively intact ischemic stroke patients were available. All patients underwent 3T MRI and evaluated for white matter hyperintensity volume (WMHV) and integrity, ischemic lesions, small vessel disease (SVD) markers and grey matter (GM), hippocampal and cerebrospinal fluid (CSF) volumes. Comprehensive cognitive tests were performed on admission and after two years. We used multiple regression to evaluate the contributions of vascular pathology measures (Framingham risk score, WMHV, and existence of SVD) and AD-associated markers (apolipoprotein E4 status and hippocampal volume). RESULTS: During two years follow-up, 80 participants (20.2%) developed PSCI. Low GM and cortex volume and high WMHV and CSF volume, but not the new lesion volume, predicted the development of PSCI in a dose-dependent relationship (p = 0.001). Vascular related imaging markers and risk factors predicted PSCI better than AD related markers (p < 0.001). CONCLUSIONS: Brain structural measures, including total GM volume, WMHV, and CSF volume were independently associated with PSCI and may serve as early biomarkers for risk prediction. In our sample, vascular pathology measures contributed significantly better to PSCI prediction than markers associated with AD. The newly detected ischemic lesion has not emerged as biomarker for PSCI risk, thus maybe a part of the ongoing vascular pathology.