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.

Trends in Biochemical Parameters, Healthcare Resource and Medication Use in the 5 Years Preceding IBD Diagnosis: A Health Maintenance Organization Cohort Study.

BACKGROUND: Few data describing pre-diagnosis changes in patients with inflammatory bowel disease (IBD) exist. We aimed to determine if there is a pattern of change in use of health resources, medications and laboratory results in the years preceding diagnosis. METHODS: This retrospective study used electronic medical records of Maccabi Health Services (MHS). Patients with IBD ≥ 16 years of age and minimum of 5-years follow-up were identified by entry into the MHS IBD registry and included in the analysis. Demographic, clinical, medication and laboratory data were collected. Generalized estimating equation model was applied to study trends and compare between years. RESULTS: This study included 5643 patients with IBD. Of these, 3039 (53.8%) had Crohn's disease (CD), 2322 (41.1%) had ulcerative colitis (UC) and 282 (5%) had indeterminate colitis (IC). Laboratory parameters including white blood cells, platelets and C-reactive protein showed significant increases while haemoglobin and mean cell volume showed significant decreases in mean values in the 2 years prior to diagnosis with stable values prior to that (p < 0.0001). Parameters such as creatinine, total protein and albumin showed significant, progressive decreases in mean values starting 5 years prior to diagnosis (p < 0.0001). Patients with CD had distinct laboratory trends when compared with patients with UC. CONCLUSIONS: Changes in laboratory parameters, healthcare service and medication use occur during the 5-year period before IBD diagnosis. These data can have future clinical applicability by developing a composite score and referral algorithm introducing red flags into primary care visits and appropriate referral for specialist care.

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.

Cerebral Imaging Markers of GBA and LRRK2 Related Parkinson's Disease and Their First-Degree Unaffected Relatives.

Cerebral atrophy has been detected in patients with Parkinson's disease (PD) both with and without dementia, however differentiation based on genetic status has thus far not yielded robust findings. We assessed cortical thickness and subcortical volumes in a cohort of PD patients and healthy controls carriers of the G2019S mutation in the LRRK2 gene and the common GBA mutations, in an attempt to determine whether genetic status influences structural indexes. Cortical thickness and subcortical volumes were computed and compared between six groups of participants; idiopathic PD, GBA-PD, LRRK2-PD, non-manifesting non-carriers (NMNC), GBA-non-manifesting carriers (NMC) and LRRK2-NMC utilizing the FreeSurfer software program. All participants were cognitively intact based on a computerized cognitive assessment battery. Fifty-seven idiopathic PD patients, 9 LRRK2-PD, 12 GBA-PD, 49 NMNC, 41 LRRK2-NMC and 14 GBA-NMC participated in this study. Lower volumes among patients with PD compared to unaffected participants were detected in bilateral hippocampus, nucleus accumbens, caudate, thalamus, putamen and amygdala and the right pallidum (p = 0.016). PD patients demonstrated lower cortical thickness indexes in a majority of regions assessed compared with non-manifesting participants. No differences in cortical thickness and subcortical volumes were detected within each of the groups of participants based on genetic status. Mutations in the GBA and LRRK2 genes are not important determinants of cortical thickness and subcortical volumes in both patients with PD and non-manifesting participants. PD is associated with a general reduction in cortical thickness and sub-cortical atrophy even in cognitively intact patients.

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.

Post-stroke dementia - a comprehensive review.

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing.

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.

Cognitive decline after stroke: relation to inflammatory biomarkers and hippocampal volume.

BACKGROUND AND PURPOSE: Inflammation may contribute to cognitive impairment after stroke. Inflammatory markers are associated with hippocampal atrophy. We tested whether markers of inflammation, erythrocyte sedimentation rate (ESR), and serum levels of C-reactive protein are associated with reduced hippocampal volume and poor cognitive performance among stroke survivors. METHODS: We analyzed 368 consecutive cases from our prospective study of first-ever mild-moderate stroke patients. MRI, cognitive tests, and inflammatory markers were determined. Patients were reevaluated 6 and 12 months after the event. RESULTS: ESR remained unchanged in follow-up examinations, suggesting a chronic inflammation background in some patients. Higher levels of C-reactive protein and ESR were associated with worse performance in cognitive tests, particularly memory scores. This association was maintained for ESR (but not C-reactive protein) after adjustment for confounders (P=0.002). Patients with smaller hippocampi had inferior cognitive results. Moreover, in a multivariate regression model, higher ESR values (but not C-reactive protein) were related to reduced hippocampal volume (P=0.049). CONCLUSIONS: This report shows a strong relationship between ESR and hippocampal volume, as well as with cognitive performance among poststroke patients. This could plausibly relate to incipient cognitive decline via hippocampal pathways.

The obesity pattern of idiopathic intracranial hypertension in men.

BACKGROUND: Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a disorder of unknown etiology, predominantly affecting obese women of childbearing age. IIH is uncommon in men, with a reported female-to-male ratio of 8:1. The pathogenesis of IIH is poorly understood. Several mechanisms have been suggested, but no one mechanism has been able to account for all manifestations of the disease. This research aims to characterize the obesity phenotype(s) of men with IIH in order to find potential inducers for this disease. METHODS: This is a cross-sectional study based on subjects' medical records. It compared anthropometric parameters between 22 men with IIH, 60 healthy men, and 44 females with IIH. One-way analysis with age and body mass index included as covariates was applied for the assessment of the difference in fat distribution among the three groups. RESULTS: No significant differences were observed between the male IIH cohort and healthy males for age, BMI, and waist measurements, whereas hip circumference was significantly larger in the IIH cohort (114 ± 13 vs. 104 ± 16 cm; respectively, p < 0.001). Consequently, waist-to-hip ratio (WHR) was significantly lower in the male IIH cohort (0.88 ± 0.08 vs. 0.95 ± 0.12; p < 0.001). While no significant differences were observed for age and hip measurements between male IIH and female IIH cohorts, waist circumference and waist-to-hip ratio (WHR) were significantly larger in the male cohort (102 ± 19 cm vs. 95 ± 13 cm, p < 0.001; 0.88 ± 0.08 vs. 0.78 ± 0.06, p < 0.001, respectively). All these results maintained after adjustment for age and BMI. CONCLUSIONS: This is the first report of body fat distribution patterns in men with IIH. Whereas male IIH have larger central fat deposition than female IIH patients, abdominal fatness is less accentuated in IIH men compared to normal obese men. The later observation is in agreement with similar results regarding female IIH patients. We believe that these findings justify further investigation into the involvement of various fat depots in the pathogenesis of IIH in men and women alike.

Idiopathic intracranial hypertension is associated with lower body adiposity.

OBJECTIVE: To characterize the obesity phenotype(s) in patients with idiopathic intracranial hypertension (IIH). DESIGN: Database study. PARTICIPANTS: We studied 44 consecutive patients with IIH, in addition to 184 women attending the obesity clinic of the same medical center and 199 obese women participating in the first Israeli national survey on health and nutrition conducted in 1999 and 2000. METHODS: Anthropometric parameters were compared with those of 2 control groups of the same age range. MAIN OUTCOME MEASURES: Weight, height, and waist and hip circumference were measured. RESULTS: Forty subjects, comprising 91.0% of this cohort, were either overweight (body mass index, 25.0-29.9 kg/m(2)) or obese (body mass index > or = 30 kg/m2). Mean waist circumference was 95.3 cm for IIH, 99.8 cm for the national survey, and 114.5 cm for the obesity clinic cohort (P<0.001), whereas hip circumference was 121 cm for IIH, 118.4 cm for the national survey, and 125.8 cm (P = not significant) for the obesity clinic cohorts. Waist-to-hip ratio, a descriptive measure of body fat distribution approximately reflecting upper to lower body fat ratio, was 0.79 in the patients with IIH, 0.84 in the national survey group, and 0.91 in the obesity clinic cohort (P<0.001; all comparisons were adjusted for age and body mass index). CONCLUSIONS: In IIH, fat tends to preferentially accumulate in the lower body relative to other obese women of the same range. Whereas most complications of obesity, such as hypertension, diabetes, dyslipidemia, and the metabolic syndrome, are linked to upper body adiposity, IIH may represent a unique condition potentially induced by nonvisceral fat-related mechanisms. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

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.

The Price of Stress: High Bedtime Salivary Cortisol Levels Are Associated with Brain Atrophy and Cognitive Decline in Stroke Survivors. Results from the TABASCO Prospective Cohort Study.

BACKGROUND AND OBJECTIVE: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort. METHODS: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping. RESULTS: Higher bedtime cortisol levels immediately post-stroke were associated with larger neurological deficits (p < 0.001), brain atrophy (p = 0.025), worse white matter integrity (p = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p = 0.05, p = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores. CONCLUSIONS: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors.

Tracing the Neural Carryover Effects of Interpersonal Anger on Resting-State fMRI in Men and Their Relation to Traumatic Stress Symptoms in a Subsample of Soldiers.

Uncontrolled anger may lead to aggression and is common in various clinical conditions, including post traumatic stress disorder. Emotion regulation strategies may vary with some more adaptive and efficient than others in reducing angry feelings. However, such feelings tend to linger after anger provocation, extending the challenge of coping with anger beyond provocation. Task-independent resting-state (rs) fMRI may be a particularly useful paradigm to reveal neural processes of spontaneous recovery from a preceding negative emotional experience. We aimed to trace the carryover effects of anger on endogenous neural dynamics by applying a data-driven examination of changes in functional connectivity (FC) during rs-fMRI between before and after an interpersonal anger induction (N = 44 men). Anger was induced based on unfair monetary offers in a previously validated decision-making task. We calculated a common measure of global FC (gFC) which captures the level of FC between each region and all other regions in the brain, and examined which brain regions manifested changes in this measure following anger. We next examined the changes in all functional connections of each individuated brain region with all other brain regions to reveal which connections underlie the differences found in the gFC analysis of the previous step. We subsequently examined the relation of the identified neural modulations in the aftermath of anger with state- and trait- like measures associated with anger, including brain structure, and in a subsample of designated infantry soldiers (N = 21), with levels of traumatic stress symptoms (TSS) measured 1 year later following combat-training. The analysis pipeline revealed an increase in right amygdala gFC in the aftermath of anger and specifically with the right inferior frontal gyrus (IFG).We found that the increase in FC between the right amygdala and right IFG following anger was positively associated with smaller right IFG volume, higher trait-anger level and among soldiers with more TSS. Moreover, higher levels of right amygdala gFC at baseline predicted less reported anger during the subsequent anger provocation. The results suggest that increased amygdala-IFG connectivity following anger is associated with maladaptive recovery, and relates to long-term development of stress symptomatology in a subsample of soldiers.

Only White Matter Hyperintensities Predicts Post-Stroke Cognitive Performances Among Cerebral Small Vessel Disease Markers: Results from the TABASCO Study.

BACKGROUND: White matter hyperintensities (WMH) were shown to predict cognitive decline following stroke or transient ischemic attack (TIA). However, WMH are only one among other radiological markers of cerebral small vessel disease (SVD). OBJECTIVE: The aim of this study was to determine whether adding other SVD markers to WMH improves prediction of post-stroke cognitive performances. METHODS: Consecutive first-ever stroke or TIA patients (n = 266) from the Tel Aviv Acute Brain Stroke Cohort (TABASCO) study were enrolled. MRI scans were performed within seven days of stroke onset. We evaluated the relationship between cognitive performances one year following stroke, and previously suggested total SVD burden score including WMH, lacunes, cerebral microbleeds (CMB), and perivascular spaces (PVS). RESULTS: Significant negative associations were found between WMH and cognition (p < 0.05). Adding other SVD markers (lacunes, CMB, PVS) to WMH did not improve predication of post-stroke cognitive performances. Negative correlations between SVD burden score and cognitive scores were observed for global cognitive, memory, and visual spatial scores (all p < 0.05). However, following an adjustment for confounders, no associations remained significant. CONCLUSION: WMH score was associated with poor post-stroke cognitive performance. Adding other SVD markers or SVD burden score, however, did not improve prediction.

Subcortical Volumes Differ in Parkinson's Disease Motor Subtypes: New Insights into the Pathophysiology of Disparate Symptoms.

OBJECTIVES: Patients with Parkinson's disease (PD) can be classified, based on their motor symptoms into the Postural Instability Gait Difficulty (PIGD) subtype or the Tremor Dominant (TD) subtype. Gray matter changes between the subtypes have been reported using whole brain Voxel-Based Morphometry (VBM), however, the evaluation of subcortical gray matter volumetric differences between these subtypes using automated volumetric analysis has only been studied in relatively small sample sizes and needs further study to confirm that the negative findings were not due to the sample size. Therefore, we aimed to evaluate volumetric changes in subcortical regions and their association with PD motor subtypes. METHODS: Automated volumetric magnetic resonance imaging (MRI) analysis quantified the subcortical gray matter volumes of patients with PD in the PIGD subtype (n = 30), in the TD subtype (n = 30), and in 28 healthy controls (HCs). RESULTS: Significantly lower amygdala and globus pallidus gray matter volume was detected in the PIGD, as compared to the TD subtype, with a trend for an association between globus pallidus degeneration and higher (worse) PIGD scores. Furthermore, among all the patients with PD, higher hippocampal volumes were correlated with a higher (better) dual tasking gait speed (r = 0.30, p < 0.002) and with a higher global cognitive score (r = 0.36, p < 0.0001). Lower putamen volume was correlated with a higher (worse) freezing of gait score (r = -0.28, p < 0.004), an episodic symptom which is common among the PIGD subtype. As expected, differences detected between HCs and patients in the PD subgroups included regions within the amygdala and the dorsal striatum but not the ventral striatum, a brain region that is generally considered to be more preserved in PD. CONCLUSIONS: The disparate patterns of subcortical degeneration can explain some of the differences in symptoms between the PD subtypes such as gait disturbances and cognitive functions. These findings may, in the future, help to inform a personalized therapeutic approach.

Depressive symptoms following stroke and transient ischemic attack: is it time for a more intensive treatment approach? results from the TABASCO cohort study.

OBJECTIVE: To examine whether depressive symptoms after a stroke or a transient ischemic attack (TIA) increase the risk of cognitive impairment and functional deterioration at 2-year follow-up. METHODS: Participants were survivors of first-ever, mild-to-moderate ischemic stroke or TIA from the TABASCO prospective cohort study who underwent 3T magnetic resonance imaging and were examined by a multiprofessional team 6, 12, and 24 months after the event using direct interviews, depression scales, and neurologic, neuropsychological, and functional evaluations. The main outcome was the development of cognitive impairment, either mild cognitive impairment (MCI) or dementia. MCI was diagnosed by a decline on at least 1 cognitive domain (≥ 1.5 SD) of the Montreal Cognitive Assessment score and/or on the computerized neuropsychological battery, as compared with age- and education-matched published norms. Dementia was diagnosed by a consensus forum that included senior neurologists specializing in memory disorders and a neuropsychologist. RESULTS: Data were obtained from 306 consecutive eligible patients (mean age: 67.1 ± 10.0 years) who were admitted to the department of emergency medicine at the Tel Aviv Medical Center from April 1, 2008, to December 1, 2011, within 72 hours from onset of symptoms of TIA or stroke. Of these patients, 51 (16.7%) developed cognitive impairment during a 2-year follow-up. Multivariate regression analysis showed that a Geriatric Depression Scale (GDS) score ≥ 6 at admission and at 6 months after the event was a significant independent marker of cognitive impairment 2 years after the stroke/TIA (OR = 3.62, 95% CI, 1.01-13.00; OR = 3.68, 95% CI, 1.03-13.21, respectively). A higher GDS score at 6 months was also related to a worse functional outcome (P < .001). CONCLUSIONS: Our results support depression screening among stroke and TIA survivors as a tool to identify patients who are prone to have a worse cognitive and functional outcome. These patients may benefit from closer medical surveillance and a more intensive treatment approach. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01926691.

Impaired renal function is associated with brain atrophy and poststroke cognitive decline.

OBJECTIVE: To evaluate the interrelationship among impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. METHODS: The Tel Aviv Brain Acute Stroke Cohort study is a prospective cohort of mild-moderate ischemic stroke/TIA survivors without dementia who underwent a 3T MRI and were cognitively assessed at admission and for 24 months following stroke. Renal function was evaluated at admission by creatinine clearance (CCl) estimation. The volumes of ischemic lesions and preexisting white matter hyperintensities (WMH), brain atrophy, and microstructural changes of the normal-appearing white matter tissue were measured using previously validated methods. RESULTS: Baseline data were available for 431 participants. Participants with a CCl <60 mL/min at baseline performed significantly worse in all cognitive tests over time (p = 0.001) than those with a CCl ≥60 mL/min and had larger WMH volume and cortical atrophy and smaller hippocampal volume (all p < 0.001). After 2 years, 15.5% of the participants were diagnosed with cognitive impairment. Multiple logistic regression analysis, controlling for traditional risk factors, suggested CCl <60 mL/min at baseline as a significant predictor for the development of cognitive impairment 2 years after the index stroke (odds ratio 2.01 [95% confidence interval 1.03-3.92], p = 0.041). CONCLUSIONS: Impaired renal function is associated with increased WMH volume and cortical atrophy, known biomarkers of the aging brain, and is a predictor for cognitive decline 2 years after stroke/TIA. Decreased renal function may be associated with cerebral small vessel disease underlying poststroke cognitive decline, suggesting a new target for early intervention.

Cognitive state following stroke: the predominant role of preexisting white matter lesions.

BACKGROUND AND PURPOSE: Stroke is a major cause of cognitive impairment and dementia in adults, however the role of the ischemic lesions themselves, on top of other risk factors known in the elderly, remains controversial. This study used structural equation modeling to determine the respective impact of the new ischemic lesions' volume, preexisting white matter lesions and white matter integrity on post stroke cognitive state. METHODS: Consecutive first ever mild to moderate stroke or transient ischemic attack patients recruited into the ongoing prospective TABASCO study underwent magnetic resonance imaging scans within seven days of stroke onset and were cognitively assessed one year after the event using a computerized neuropsychological battery. The volumes of both ischemic lesions and preexisting white matter lesions and the integrity of the normal appearing white matter tissue were measured and their contribution to cognitive state was assessed using structural equation modeling path analysis taking into account demographic parameters. Two models were hypothesized, differing by the role of ischemic lesions' volume. RESULTS: Structural equation modeling analysis of 142 patients confirmed the predominant role of white matter lesion volume (standardized path coefficient ß =  -0.231) and normal appearing white matter integrity (ß =  -0.176) on the global cognitive score, while ischemic lesions' volume showed no such effect (ß = 0.038). The model excluding the ischemic lesion presented better fit to the data (comparative fit index 0.9 versus 0.092). CONCLUSIONS: Mild to moderate stroke patients with preexisting white matter lesions are more vulnerable to cognitive impairment regardless of their new ischemic lesions. Thus, these patients can serve as a target group for studies on cognitive rehabilitation and neuro-protective therapies which may, in turn, slow their cognitive deterioration.

Hyperandrogenism is associated with earlier age of onset of idiopathic intracranial hypertension in women.

PURPOSE: Previous reports have connected between Idiopathic intracranial hypertension (IIH), obesity and different hormonal states. The aim of this study was to characterize the endocrine profile in women with IIH. METHODS: This is a data-based study of 51 IIH patients. We measured anthropometric parameters and assessed hormonal profile including cortisol, testosterone, bioavailable testosterone (BT), prolactin, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, insulin, aldosterone, estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Pearson or Spearman rank correlation for non-normally distributed variables were calculated to evaluate the relation among the anthropometric measurements: age, body mass index (BMI), waist and hip circumference and waist to hip ratio (WHR) with hormones levels. RESULTS: Seventy-eight percent of the cohort had WHR < 0.85 and 21.6% had a WHR > 0.85. Increased levels of testosterone, BT and androstenedione were all positively related to younger age of diagnosis in patient who are diagnosed after the age of 25 (R = -1.066, -0.845, -0.735, p < 0.001, =0.024, 0.019, respectively). No correlation was found between any of the analyzed hormones and the duration of the disease, WHR or BMI, except insulin, which was positively related to BMI (R = 0.461, p = 0.001). CONCLUSIONS: Increased levels of circulating androgens are associated with earlier age of onset of IIH in women.