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Executive dysfunction and white matter inflammation continue to be relatively understudied in rodent models of Alzheimer’s disease (AD). Behavioural inflexibility is an important component of executive dysfunction that can be further categorized as perseverative or regressive, which respectively specify whether maladaptive persistence occurs early or late during a behavioural change. Previous studies of the TgAPP21 rat model of AD (expressing pathogenic hAPP) suggested a potentially spontaneous increase of regressive behavioral inflexibility. In this study, 7–8-month-old male TgAPP21 rats were tested for behavioral flexibility, learning, and memory using an operant conditioning chamber and the Morris Water Maze (MWM). TgAPP21 rats demonstrated a regressive behavioral inflexibility during set shifting in an operant conditioning chamber (regressive errors η2 = 0.32 and number of errors after criterion η2 = 0.33). Regressive behavior was also demonstrated in the MWM probe test, wherein TgAPP21 rats significantly increased their swim time in the target quadrant during the last third of the probe test (43% vs 33% in the first 2 thirds of the probe test or the Wt rats’ 29%–32%); this behavioral phenotype has not been previously described in the MWM. TgAPP21 demonstrated further impairment of behavioural inflexibility as they committed a greater number of reversal errors in the operant conditioning chamber (η2 = 0.30). Diffuse microglia activation was increased in the white matter tracts of TgAPP21 (corpus callosum, cingulum, and internal capsule; η2 = 0.59–0.62), which was found to correlate with the number of reversal errors in the operant conditioning chamber (R2 = 0.42). As TgAPP21 rats do not spontaneously develop amyloid plaques but have been shown in previous studies to be vulnerable to the development of plaques, these rats demonstrate an important onset of cognitive change and inflammation in the pre-plaque phase of AD. TgAPP21 rats are also an instrumental model for studying the role and mechanism of white matter microglial activation in executive functioning. This is pertinent to clinical research of prodromal AD which has suggested that white matter inflammation may underlie impairment of executive functions such as behavioral flexibility.

Highlights •Age-related dementia is growing alarmingly worldwide and is estimated to affect 150 million people by 2050. •Cerebrovascular alterations are a major cause of dementia, but are also a culprit in AD. •New insights into pathobiology, prevention, and diagnosis have emerged, but therapies are not yet available. •Maintaining vascular health and preserving brain function may mitigate the public health impact of dementia.

Rationale Stroke etiology and risk factors vary by age, sex, setting (hospital or community-based) and by region. Identifying these differences would improve our understanding of stroke etiology, diagnosis, and treatment. Aim The Age, Sex and Setting in the Etiology of Stroke Study (ASSESS) is a multicenter cohort study to assess differences in stroke etiology. Methods and design Data from all centers will be categorized according to age, sex, setting, stroke subtypes. Centers with extensive hospital- or community-based data regarding stroke from Argentina, Australia, Canada, India, Iran, Italy, Ghana, Nigeria, Thailand, the United Kingdom and the United States have agreed to participate so far. Study outcomes The primary outcome includes differences in stroke etiology in study centers. The secondary outcomes include stroke incidence, risk factors, preventive strategies, and short- and long-term outcomes. Conclusion ASSESS will enable comparisons of data from different regions to determine the age and sex distribution of the most common causes of stroke in each setting. This will help clinicians to tailor the assessment and treatment of stroke patients on the basis of their specific local characteristics. It will also empower stroke epidemiologists to design preventive measures by targeting the specific characteristics of each population.

Fil: Torralva, Teresa. Instituto de Neurologia Cognitiva; Argentina. Universidad Diego Portales; Chile. Universidad Favaloro; Argentina. Australian Research Council; Australia

Background and objective A considerable number of patients with transient ischemic attack suffer from cognitive impairment, even after recovery of focal neurological deficits. In particular, executive functions such as working memory, abstraction, reasoning, verbal fluency and cognitive flexibility are impaired in these patients. The purpose of the present study was to explore the nature and prevalence of cognitive impairment in a series of patients with transient ischemic attack and minor stroke. Materials and methods We included 140 patients (61% women) who presented with a focal cerebral ischemic event lasting less than 24 h in the Urgent TIA outpatient clinic. All patients underwent a brief battery of neuropsychological tests, consisting of the Mini Mental State Examination (MMSE), Neurobehavioral Cognitive Status Examination–Judgment Subtest, Clock Drawing Test and Trail Making Test. Results A majority of patients (57%) were impaired on one or more of these neuropsychological tests. Nearly one-third of individuals were impaired on two or more tests. Cognitive impairment was most frequently observed on the Trail Making Test Part A (31% of patients) and Part B (40%). The Trail Making Test examines executive functions, as it requires cognitive flexibility, ability to maintain a complex response set and speed of processing. By contrast, only 5% of patients were impaired on the MMSE, a widely used neuropsychological test insensitive to executive dysfunction. Conclusions Our results highlight the limitations of the MMSE as an independent cognitive screening instrument for patients with TIAs and minor stroke and the high prevalence of executive dysfunction in these patients.

Background It remains unknown which brain regions are involved in the maintenance of gait dynamic stability in older adults, as characterized by a low stride time variability. Expansion of lateral cerebral ventricles is an indirect marker of adjacent brain tissue volume. The purpose of this study was to examine the association between stride time variability and the volume of sub-regions of the lateral cerebral ventricles among older community-dwellers. Methods One-hundred-fifteen participants free of hydrocephalus from the GAIT study (mean, 70.4 ± 4.4 years; 43.5% female) were included in this analysis. Stride time variability was measured at self-selected pace with a 10 m electronic portable walkway (GAITRite). Participants were separated into 3 groups based on tertiles of stride time variability (i.e., 2.8%). Brain ventricle sub-volumes were quantified from three-dimensional T 1 -weighted MRI using semi-automated software. Age, gender, Cumulative Illness Rating Scale for Geriatrics, Mini-Mental State Examination, Go-NoGo, brain vascular burden, 4-item Geriatric Depression Scale, psychoactive drugs, vision, proprioception, body mass index, muscular strength and gait velocity were used as covariates. Results Participants with the highest (i.e., worst) tertile of stride time variability exhibited larger temporal horns than those with the lowest (P = 0.030) and intermediate tertiles (P = 0.028). They also had larger middle portions of ventricular bodies than those with the intermediate tertile (P = 0.018). Larger temporal horns were associated with increase in stride time variability (adjusted β = 0.86, P = 0.005), specifically with the highest tertile of stride time variability (adjusted OR = 2.45, P = 0.044). Conclusions Higher stride time variability was associated with larger temporal horns in older community-dwellers. Addressing focal neuronal losses in temporal lobes may represent an important strategy to prevent gait instability.

Importance We describe a case of cramplike pain after a left thalamic ischemic stroke, a neglected type of central post-stroke pain and we describe its neuroanatomical correlates. Observations A 68-year-old right-handed man presented with right arm, leg, and flank cramplike pain noted upon awakening. Neurological examination was normal, with no evidence of objective sensory abnormalities. Because of the nature of the pain and the preserved sensory function, we first did not consider stroke as a potential cause, and suspected that pain was related to the combined effect of intense physical exercising on the right side and the use of statins. Diffusion-weighted magnetic resonance imaging showed an acute ischemic infarction within the left thalamus. By registering high-resolution 3 T T1-weighted and T2-weighted magnetic resonance images to the Talairach atlas, we showed the infarction is within the border between the pulvinar and the ventral posterior medial nuclei. Brodmann's areas 3, 1, 2, 4 and 6 were identified as the cortical correlates of the ischemic lesion by diffusion tensor tractography. Conclusions and relevance Thalamic cramplike pain should be recognized as a type of central post-stroke pain, probably produced by lesions localized to the border between the ventral posterior and pulvinar nuclei and connected to the ipsilateral primary somatosensory cortex and primary and secondary motor cortices.

Background Preventive electronic (e)-counselling has been shown to reduce cardiovascular risk factors. However, heterogeneity in outcomes is commonly reported due to differences in e-protocols. We incorporated key features of an established behavioural therapy, motivational interviewing, to help standardize e-counselling in order to reduce blood pressure in patients with hypertension. Methods Subjects (n = 387, mean age=56 years, 59% female, 72% taking ≥ 1 antihypertensive drug) were diagnosed with stage 1 or 2 hypertension. Subjects were randomized to a 4-month protocol of e-counselling (beta version of the "Blood Pressure Action Plan", Heart and Stroke Foundation of Canada) vs waitlist control (general e-information on heart-healthy living). Outcomes were systolic, diastolic, and pulse pressures, and total lipoprotein cholesterol after treatment. Results Intention to treat analysis did not find a significant group difference in outcomes due to contamination across the 2 arms of this trial. However, per protocol analysis indicated that subjects receiving ≥ 8 e-counselling messages (a priori therapeutic dose) vs 0 e-counselling messages (control) demonstrated greater reduction in systolic blood pressure (mean, −8.9 mm Hg; 95% confidence interval [CI], −11.5 to −6.4 vs −5.0 mm Hg; 95% CI, −6.7 to −3.3, P = 0.03), pulse pressure (−6.1 mm Hg; 95% CI, −8.1 to −4.1 vs −3.1 mm Hg; 95% CI, −4.3 to −1.8, P = 0.02) and total cholesterol (−0.24 mmol/L; 95% CI, −0.43 to −0.06 vs 0.05 mmol/L; 95% CI, −0.06 to 0.16, P = 0.03), but not diastolic blood pressure. Conclusions These findings support the merit of evaluating whether e-counselling can improve blood pressure control and reduce cardiovascular risk over the long-term.

Summary Sudden death is an important but widely under-recognised consequence of stroke. Acute stroke can disturb central autonomic control, resulting in myocardial injury, electrocardiographic abnormalities, cardiac arrhythmias, and ultimately sudden death. Experimental and clinical evidence suggests that autonomic imbalance is more frequent after infarcts involving the insular cortex, a crucial region for the control of sympathetic and parasympathetic autonomic functions. Cardiovascular comorbidities increase the risk of cardiac morbidity and mortality after stroke. Thus, many sudden deaths and serious non-fatal cardiac events after stroke are probably due to an interaction between cardiovascular and neurological causes. The exact mechanisms leading to sudden death remain incompletely understood. Further research is needed to investigate the autonomic consequences of acute stroke and to identify patients at high risk of sudden death.

Sporadic Alzheimer's disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors. Binding with the transporter associated with antigen processing (TAP) is thought to be the main way in which herpes simplex virus type 1 (HSV-1) evades immune surveillance. Several TAP gene polymorphisms were examined and a TAP2 SNP (rs241448) associated with AD found in two independent case-control samples, especially in carriers of the APOE4 allele. These findings are consistent with the hypothesis that human genetic variants facilitating the access of HSV-1 to the brain might result in susceptibility to AD.

It has been well established that neuroinflammation is involved in Alzheimer disease (AD) pathogenesis. Accumulation and aggregation of beta-amyloid (Abeta) peptide in the brains of patients with AD result in activation of glial cells which, in turn, initiates neuroinflammatory responses that involve reactive oxygen intermediates and release of inflammatory cytokines. In this study, bilateral intracerebroventricular (i.c.v.) injections of Abeta (25-35) in the rat resulted in impairment in learning and spatial memory and increased immunoreactive staining of AD-related neuropathological markers (Abeta, APP) and inflammatory mediators (OX-6, COX-2) in CA1 and dentate gyrus regions of the hippocampus. Pyrrolidine dithiocarbamate (PDTC) given intraperitoneally 30 min before Abeta injection and daily for 7 days postsurgery significantly prevented Abeta-induced neuropathological and neuroinflammatory responses, as well as the learning and spatial memory deficits. The potential of PDTC for reducing cognitive and neuropathological deficits may provide preliminary evidence for a new approach of AD treatment.

Summary Background Endarterectomy benefits certain patients with carotid stenosis, but benefits are lessened by perioperative surgical risk. Acetylsalicylic acid lowers the risk of stroke in patients who have experienced transient ischaemic attack and stroke. We investigated appropriate doses and the role of acetylsalicylic acid in patients undergoing carotid endarterectomy. Methods In a randomised, double-blind, controlled trial, 2849 patients scheduled for endarterectomy were randomly assigned 81 mg (n=709), 325 mg (n=708), 650 mg (n=715), or 1300 mg (n=717) acetylsalicylic acid daily, started before surgery and continued for 3 months. We recorded occurrences of stroke, myocardial infarction, and death. We compared patients on the two higher doses of acetylsalicylic acid with patients on the two lower doses. Findings Surgery was cancelled in 45 patients, none were lost to follow-up by 30 days, and two were lost by 3 months. The combined rate of stroke, myocardial infarction, and death was lower in the low-dose groups than in the high-dose groups at 30 days (5·4 vs 7·0%, p=0·07) and at 3 months (6·2 vs 8·4%, p=0·03). In an efficacy analysis, which excluded patients taking 650 mg or more acetylsalicylic acid before randomisation, and patients randomised within 1 day of surgery, combined rates were 3·7% and 8·2%, respectively, at 30 days (p=0·002) and 4·2% and 10·0% at 3 months (p=0·0002). Interpretation The risk of stroke, myocardial infarction, and death within 30 days and 3 months of endarterectomy is lower for patients taking 81 mg or 325 mg acetylsalicylic acid daily than for those taking 650 mg or 1300 mg.

Treatments for stroke have traditionally consisted of supportive care and the prevention of complications. The evidence that is accumulating justifies a more aggressive approach. Experimental and clinical data show that there is a variable therapeutic window that may exceed 6-8 h ; 1 that stroke units spare lives and reduce disability; 2 and that thrombolysis with recombinant tissue plasminogen activator (rtPA) makes a difference in acute stroke) This article focuses on the ideal treatment of acute ischaemic stroke in the first 24 h.

Stroke, whether ischemic or hemorrhagic, induces cardiac damage by nonischemic mechanisms. The evidence derives from autopsy studies and investigation of ECG, cardiac enzyme changes, and plasma catecholamine changes after stroke. Increased sympathoadrenal tone, resulting from damage to cortical areas involved in cardiac and autonomic control is the likely cause. Recent experimental evidence indicates that the insular cortex plays a principal role in stroke-related cardiac damage.

The Canadian American Ticlopidine Study (CATS) is a randomised, double-blind, placebo-controlled trial to assess the effect of ticlopidine (250 mg twice daily) in reducing the rate of subsequent occurrence of stroke, myocardial infarction, or vascular death in patients who have had a recent thromboembolic stroke. Twenty-five centres entered 1072 patients into the study between 1 week and 4 months after their qualifying stroke. The patients were treated and followed for up to 3 years (mean 24 months). In the efficacy analysis, the event rate per year for stroke, myocardial infarction or vascular death, considered together, was 15·3% in the placebo group and 10·8% in the ticlopidine group, representing a relative risk reduction with ticlopidine of 30·2% (95% confidence interval 7·5-48·3%; p=0·006). Ticlopidine was beneficial for both men and women (relative risk reductions 28·1%, p=0·037, and 34·2%, p=0·045, respectively). Analysis by intention-to-treat gave a smaller estimate of risk reduction (23·3%, p=0·020) for stroke, myocardial infarction, or vascular death. Adverse experiences associated with ticlopidine included neutropenia (severe in about 1% of cases) and skin rash and diarrhoea (severe in 2% of cases each); all were reversible. This study provides evidence of a beneficial effect of ticlopidine in both men and women with a recent thromboembolic stroke.