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Cerebral microinfarcts (CMIs) are small ischemic lesions invisible to the naked eye at brain autopsy, while the larger ones (0.5–4 mm in diameter) have been visualized in-vivo on magnetic resonance imaging (MRI). CMIs can be detected on diffusion-weighted imaging (DWI) as incidental small DWI-positive lesions (ISDPLs) and on structural MRI for those confined to the cortex and in the chronic phase. ISDPLs may evolve into old cortical-CMIs, white matter hyperintensities or disappear depending on their location and size. Novel techniques in neuropathology and neuroimaging facilitate the detection of CMIs, which promotes understanding of these lesions. CMIs have heterogeneous causes, involving both cerebral small- and large-vessel disease as well as heart diseases such as atrial fibrillation and congestive heart failure. The underlying mechanisms incorporate vascular remodeling, inflammation, blood–brain barrier leakage, penetrating venule congestion, cerebral hypoperfusion, and microembolism. CMIs lead to clinical outcomes, including cognitive decline, a higher risk of stroke and mortality, and accelerated neurobehavioral disturbances. It has been suggested that CMIs can impair brain function and connectivity beyond the microinfarct core and are also associated with perilesional and global cortical atrophy. This review aims to summarize recent progress in studies involving both cortical-CMIs and ISDPLs since 2017, including their detection, etiology, risk factors, MRI correlates, and clinical consequences. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of dementia. Comprehensive characterization of the time course of disease progression will result in better understanding of aetiology and clinical consequences of SVD. SVD progression has been studied extensively over the years, usually describing change in SVD markers over time using neuroimaging at two time points. As a consequence, SVD is usually seen as a rather linear, continuously progressive process. This assumption of continuous progression of SVD markers was recently challenged by several studies that showed regression of SVD markers. Here, we provide a review on disease progression in sporadic SVD, thereby taking into account both progression and regression of SVD markers with emphasis on white matter hyperintensities (WMH), lacunes and microbleeds. We will elaborate on temporal dynamics of SVD progression and discuss the view of SVD progression as a dynamic process, rather than the traditional view of SVD as a continuous progressive process, that might better fit evidence from longitudinal neuroimaging studies. We will discuss possible mechanisms and clinical implications of a dynamic time course of SVD, with both progression and regression of SVD markers. [ABSTRACT FROM AUTHOR]

Background: Information about cognitive functioning is vital in the management of stroke, but the literature is mostly based on data from individuals older than 50 years of age who make up the majority of the stroke population. As cognitive functioning is subject to change due to aging, it is unclear whether such cognitive impairment patterns from the general stroke literature apply to the growing population of younger people with a stroke. Aim: The aim of the study was to conduct a systematic review and meta-analysis of the proportion and severity of cognitive impairment in young-stroke patients. Summary of review: MEDLINE, Embase, PsycINFO, and Web of Science were systematically searched up to 11 October 2022. Studies were included if they reported on a population of young-stroke patients, evaluated cognitive functioning as an outcome measure, and reported original data. We estimated the pooled prevalence rates for cognitive impairment and for aphasia. In addition, we calculated the pooled estimates for the severity of impairment per cognitive domain in the chronic phase (defined as >6 months post-stroke). Six hundred thirty-five articles were identified, of which 29 were eligible for inclusion. The pooled prevalence of cognitive impairment was 44% (k = 10; 95% confidence interval (CI): 34–54%) and of aphasia 22% (k = 13; 95% CI: 12–39%). Young-stroke patients in the chronic phase performed worse than stroke-free healthy age-appropriate controls across all cognitive domains examined, with Hedges' g effect sizes ranging from −0.49 to −1.64. Conclusion: Around half of all young-stroke patients present with cognitive impairment and around a quarter with aphasia. Our data suggest that patterns of impairment in young-stroke patients follow those in the general stroke literature. [ABSTRACT FROM AUTHOR]

The article presents author's views on increased risk of cerebrovascular events among young survivors of cancer. Topics discussed include long life expectancy and adequacy of information, long-term cerebrovascular complications, hospitalization of cancer survivors, complications of radiotherapy, and accelerated atherosclerosis.

The article analyzes brain imaging studies in patients with diabetes. Based on the studies, there is convincing evidence for an association between diabetes and cerebral atrophy and lacunar infarcts, but the risk factors for these brain imaging abnormalities have not been identified and the relation with impaired cognition has not been addressed.

Objectives:. (a) To determine the prevalence of unexplained symptoms among newly referred patients in a Dutch academic outpatient clinic for general neurology; (b) To identify factors that can serve as characteristics and possibly as screening instruments for unexplained symptoms in this population. Methods:. Observational study, consisting of self-assessment questionnaires. Patients and resident neurologists completed self-designed questionnaires, which included questions about possible features of unexplained symptoms. Patients also completed the Hospital Anxiety and Depression Scale (HADS), evaluating the existence of anxiety and depressive symptoms. Diagnosis of unexplained symptoms was based on the final classification of the patient’s symptoms as non-organic, after assessment by a senior neurologist. In the analysis, separate predicting factors and groups of factors were adjusted for age, sex and HADS-score, and analysed as possible characteristics of unexplained symptoms. Results:. 35% of the patients (208 total, 174 completed questionnaires) were considered to suffer from unexplained symptoms.Young age (p < 0.001) and female sex (p = 0.007) were significantly associated with unexplained symptoms, high HADS-scores were not (p = 0.10). Characteristics associated with unexplained symptoms were the resident’s preliminary impression of symptoms being non-organic, after reading of the referral letter [OR 96.8, 95% confidence interval (95 %-CI) 29.7–315, PPV 82%, NPV 96%] and after the first encounter (OR 305, 95 %-CI 37.3–2494.6, PPV 83%, NPV 98%), but before the actual history taking and neurological examination. The only other non-demographic characteristic of unexplained symptoms was a visit in order to obtain a second opinion (OR 2.43, 95 %-CI 1.15–5.10). Clustering of these factors, however, did not have sufficient predictive power to result in an accurate screening instrument. Conclusions:. Unexplained symptoms are common in the neurology outpatient clinic and are to some extent predicted by the physician’s preliminary judgement of symptoms. However, history taking and neurological examination remain indispensable for the detection of less obvious organic disorders. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months. Methods: CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders. Results: 125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07–8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%). Conclusion: Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization. [ABSTRACT FROM AUTHOR]

The major vascular cause of dementia is cerebral small vessel disease (SVD). Its diagnosis relies on imaging hallmarks, such as white matter hyperintensities (WMH). WMH present a heterogenous pathology, including myelin and axonal loss. Yet, these might be only the “tip of the iceberg.” Imaging modalities imply that microstructural alterations underlie still normal‐appearing white matter (NAWM), preceding the conversion to WMH. Unfortunately, direct pathological characterization of these microstructural alterations affecting myelinated axonal fibers in WMH, and especially NAWM, is still missing. Given that there are no treatments to significantly reduce WMH progression, it is important to extend our knowledge on pathological processes that might already be occurring within NAWM. Staining of myelin with Luxol Fast Blue, while valuable, fails to assess subtle alterations in white matter microstructure. Therefore, we aimed to quantify myelin surrounding axonal fibers and axonal‐ and microstructural damage in detail by combining (immuno)histochemistry with polarized light imaging (PLI). To study the extent (of early) microstructural damage from periventricular NAWM to the center of WMH, we refined current analysis techniques by using deep learning to define smaller segments of white matter, capturing increasing fluid‐attenuated inversion recovery signal. Integration of (immuno)histochemistry and PLI with post‐mortem imaging of the brains of individuals with hypertension and normotensive controls enables voxel‐wise assessment of the pathology throughout periventricular WMH and NAWM. Myelin loss, axonal integrity, and white matter microstructural damage are not limited to WMH but already occur within NAWM. Notably, we found that axonal damage is higher in individuals with hypertension, particularly in NAWM. These findings highlight the added value of advanced segmentation techniques to visualize subtle changes occurring already in NAWM preceding WMH. By using quantitative MRI and advanced diffusion MRI, future studies may elucidate these very early mechanisms leading to neurodegeneration, which ultimately contribute to the conversion of NAWM to WMH. [ABSTRACT FROM AUTHOR]

Stroke affects up to one in five people during their lifetime in some high-income countries, and up to almost one in two in low-income countries. Globally, it is the second leading cause of death. Clinically, the disease is characterised by sudden neurological deficits. Vascular aetiologies contribute to the most common causes of ischaemic stroke, including large artery disease, cardioembolism, and small vessel disease. Small vessel disease is also the most frequent cause of intracerebral haemorrhage, followed by macrovascular causes. For acute ischaemic stroke, multimodal CT or MRI reveal infarct core, ischaemic penumbra, and site of vascular occlusion. For intracerebral haemorrhage, neuroimaging identifies early radiological markers of haematoma expansion and probable underlying cause. For intravenous thrombolysis in ischaemic stroke, tenecteplase is now a safe and effective alternative to alteplase. In patients with strokes caused by large vessel occlusion, the indications for endovascular thrombectomy have been extended to include larger core infarcts and basilar artery occlusion, and the treatment time window has increased to up to 24 h from stroke onset. Regarding intracerebral haemorrhage, prompt delivery of bundled care consisting of immediate anticoagulation reversal, simultaneous blood pressure lowering, and prespecified stroke unit protocols can improve clinical outcomes. Guided by underlying stroke mechanisms, secondary prevention encompasses pharmacological, vascular, or endovascular interventions and lifestyle modifications. [ABSTRACT FROM AUTHOR]

Cognitive and affective sequelae of cerebellar disease are receiving increased attention, but their actual rate of occurrence remains unclear. Complaints may have a significant impact on patients, affecting social behavior and psychological well-being. This study aims to explore the extent of subjective cognitive and affective symptoms in patients with degenerative ataxias in the Netherlands. An explorative study was set up in a heterogeneous group of degenerative ataxia patients. Self-reported cognition was evaluated in terms of executive functioning and affect (Dysexecutive Questionnaire/DEX), and memory/attention (Cognitive Failures Questionnaire/CFQ). The Daily Living Questionnaire (DLQ) was administered to quantify the impact on daily life. Furthermore, informants completed questionnaires to obtain insight into patients' self-awareness and social cognition (Observable Social Cognition Rating Scale/OSCARS). This study shows that subjective complaints in the domains of (1) executive functioning and/or (2) memory and attention were reported by 29% of all patients (n = 24/84). In addition, more difficulties in daily life in terms of language/comprehension and community/participation were reported, and this was more common for patients with cognitive complaints than those without. Discrepancies between patients and informants about executive functioning were present in both directions. Deficits in social cognition were not identified at the group level, but more social-cognitive problems were observed in patients with more executive problems rated by informants. Taken together, our findings indicate that cognitive complaints are common in patients with degenerative cerebellar disorders and have an impact on daily life functioning. These results may help to increase awareness of cognitive symptoms and their impact in patients with cerebellar ataxia, their significant others, and professional caregivers. [ABSTRACT FROM AUTHOR]

Working memory and episodic memory are two different processes, although the nature of their interrelationship is debated. As these processes are predominantly studied in isolation, it is unclear whether they crucially rely on different neural substrates. To obtain more insight in this, 81 adults with sub-acute ischemic stroke and 29 elderly controls were assessed on a visual working memory task, followed by a surprise subsequent memory test for the same stimuli. Multivariate, atlas- and track-based lesion-symptom mapping (LSM) analyses were performed to identify anatomical correlates of visual memory. Behavioral results gave moderate evidence for independence between discriminability in working memory and subsequent memory, and strong evidence for a correlation in response bias on the two tasks in stroke patients. LSM analyses suggested there might be independent regions associated with working memory and episodic memory. Lesions in the right arcuate fasciculus were more strongly associated with discriminability in working memory than in subsequent memory, while lesions in the frontal operculum in the right hemisphere were more strongly associated with criterion setting in subsequent memory. These findings support the view that some processes involved in working memory and episodic memory rely on separate mechanisms, while acknowledging that there might also be shared processes. [ABSTRACT FROM AUTHOR]

Clinical populations with basal ganglia pathologies may present with language production impairments, which are often described in combination with comprehension measures or attributed to motor, memory, or processing-speed problems. In this systematic review and meta-analysis, we studied word production in four (vascular and non-vascular) pathologies of the basal ganglia: stroke affecting the basal ganglia, small vessel disease, Parkinson's disease, and Huntington's disease. We compared scores of these clinical populations with those of matched cognitively unimpaired adults on four well-established production tasks, namely picture naming, category fluency, letter fluency, and past-tense verb inflection. We conducted a systematic search in PubMed and PsycINFO with terms for basal ganglia structures, basal ganglia disorders and language production tasks. A total of 114 studies were included, containing results for one or more of the tasks of interest. For each pathology and task combination, effect sizes (Hedges' g) were extracted comparing patient versus control groups. For all four populations, performance was consistently worse than that of cognitively unimpaired adults across the four language production tasks (p-values < 0.010). Given that performance in picture naming and verb inflection across all pathologies was quantified in terms of accuracy, our results suggest that production impairments cannot be fully explained by motor or processing-speed deficits. Our review shows that while language production difficulties in these clinical populations are not negligible, more evidence is necessary to determine the exact mechanism that leads to these deficits and whether this mechanism is the same across different pathologies. [ABSTRACT FROM AUTHOR]

Background In case of carotid artery occlusion, the risk and extent of ischemic cerebral damage are highly dependent on the pathways of collateral flow including the anatomy of the circle of Willis. In this report, cases are presented to illustrate that 4-dimensional computed tomography angiography (4D-CTA) can be considered as a noninvasive alternative to digital subtraction angiography for the evaluation of circle of Willis collateral flow. Case Description Five patients with unilateral internal carotid artery (ICA) occlusion underwent 4D-CTA for the evaluation of intracranial hemodynamics. Next to a visual evaluation of 4D-CTA, temporal information was visualized using a normalized color scale on the cerebral vasculature, which enabled quantification of the contrast bolus arrival time. In these patients, 4D-CTA demonstrated dominant middle cerebral artery blood supply on the side of ICA occlusion originating from either the contralateral ICA or posterior circulation via the communicating arteries. Conclusions Temporal dynamics of collateral flow in the circle of Willis can be depicted with 4D-CTA in patients with a unilateral carotid artery occlusion. [ABSTRACT FROM AUTHOR]

The article discusses research being done on the prevalence, incidence and risk factors associated with prestroke and poststroke dementia. It references a study by S. T. Pendlebury and P. M. Rothwell published in "The Lancet Neurology" periodical in 2009. Based on the findings, several of the risk factors for dementia that was developed before the onset of stroke, including medial temporal lobe atrophy, were similar to those for Alzheimer disease (AD). Also noted is the significance of accurate differentiation between poststroke dementia subtypes.

Background and objectives: It has been suggested that white matter hyperintensity lesions (WMHs), which typically progress over time, can also regress, and that this might be associated with favorable cognitive performance. We determined the prevalence of WMH regression in patients with cerebral small vessel disease (SVD) and examined which demographic, clinical, and radiological markers were associated with this regression. Methods: We used semi-automated lesion marking methods to quantify WMH volume at multiple timepoints in three cohorts with symptomatic SVD; two with moderate-to-severe symptomatic SVD (the SCANS observational cohort and the control arm of the PRESERVE interventional trial) and one with mild-to-moderate SVD (the RUN DMC observational cohort). Mixed-effects ordered logistic regression models were used to test which factors predicted participants to show WMH regression. Results: No participants (0/98) in SCANS, 6/42 (14.3%) participants in PRESERVE, and 6/276 (2.2%) in RUN DMC showed WMH regression. On multivariate analysis, only lower WMH volume (OR: 0.36, 95% CI: 0.23–0.56) and better white matter microstructural integrity assessed by fractional anisotropy using diffusion tensor imaging (OR: 1.55, 95% CI: 1.07–2.24) predicted participant classification as regressor versus stable or progressor. Discussion: Only a small proportion of participants demonstrated WMH regression across the three cohorts, when a blinded standardized assessment method was used. Subjects who showed regression had less severe imaging markers of disease at baseline. Our results show that lesion regression is uncommon in SVD and unlikely to be a major factor affecting the use of WMH quantification as an outcome for clinical trials. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2. [ABSTRACT FROM AUTHOR]

Objective: Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross‐sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow‐up of 14 years. Methods: This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow‐up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed‐effect models were constructed to estimate individual rate changes of MRI‐characteristics. Results: Follow‐up for incident parkinsonism was near‐complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR] = 1.46 per 1‐SD increase, 95% confidence interval [CI] = 1.21–1.78), peak width of skeletonized mean diffusivity (HR = 1.66 per 1‐SD increase, 95% CI = 1.34–2.05), and presence of lacunes (HR = 1.84, 95% CI = 0.99–3.42) were associated with increased risk of all‐cause parkinsonism. Incident lacunes were associated with incident VaP (HR = 4.64, 95% CI = 1.32–16.32). Interpretation: Both baseline SVD severity and SVD progression are independently associated with long‐term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130–1141 [ABSTRACT FROM AUTHOR]

The major vascular cause of dementia is cerebral small vessel disease (SVD), including white matter hyperintensities (WMH) amongst others. While the underlying pathology of SVD remains unclear, chronic hypertension and neuroinflammation are recognized as important risk factors for SVD and for the conversion of normal-appearing white matter (NAWM) to WMH. Unfortunately, most studies investigating the role of neuroinflammation in WMH relied on peripheral blood markers, e.g., markers for systemic or vascular inflammation, as a proxy for inflammation in the brain itself. However, it is unknown whether such markers accurately capture inflammatory changes within the cerebral white matter. Therefore, we aimed to comprehensively investigate the impact of hypertension on perivascular- and neuroinflammation in both WMH and NAWM. We conducted high field brain magnetic resonance imaging (MRI), followed by (immuno-)histopathological staining of neuroinflammatory markers on human post-mortem brains of elderly people with a history of hypertension (n = 17) and age-matched normotensive individuals (n = 5). MRI images were co-registered to (immuno-)histopathological data including stainings for microglia and astroglia to assess changes in MRI-based WMH at microscopic resolution. Perivascular inflammation was carefully assessed based on the severity of perivascular astrogliosis of the smallest vessels throughout white matter regions. Hypertension was associated with a larger inflammatory response in both WMH and NAWM. Notably, the presence of close-range perivascular inflammation was twice as common among those with hypertension than in controls both in WMH and NAWM, suggesting that neurovascular inflammation is critical in the etiology of WMH. Moreover, a higher degree of microglial activation was related to a higher burden of WMH. Our results indicate that neuro(vascular)inflammation at the level of the brain itself is involved in the etiology of WMH. Future therapeutic strategies focusing on multitarget interventions including antihypertensive treatment as well as neuroinflammation may ameliorate WMH progression. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. Previous studies on the prevalence of cSVD are mostly based on single geographically defined cohorts in high-income countries. Studies investigating the prevalence of cSVD in low- and middle-income countries (LMICs) are expanding but have not been systematically assessed. Aim: This study aims to systematically review the prevalence of cSVD in LMICs. Results: Articles were searched from the Ovid MEDLINE and EMBASE databases from 1 January 2000 to 31 March 2022, without language restrictions. Title/abstract screening, full-text review, and data extraction were performed by two to seven independent reviewers. The prevalence of cSVD and study sample size were extracted by pre-defined world regions and health status. The Risk of Bias for Non-randomized Studies tool was used. The protocol was registered on PROSPERO (CRD42022311133). A meta-analysis of proportion was performed to assess the prevalence of different magnetic resonance imaging markers of cSVD, and a meta-regression was performed to investigate associations between cSVD prevalence and type of study, age, and male: female ratio. Of 2743 studies identified, 42 studies spanning 12 global regions were included in the systematic review. Most of the identified studies were from China (n = 23). The median prevalence of moderate-to-severe white matter hyperintensities (WMHs) was 20.5%, 40.5%, and 58.4% in the community, stroke, and dementia groups, respectively. The median prevalence of lacunes was 0.8% and 33.5% in the community and stroke groups. The median prevalence of cerebral microbleeds (CMBs) was 10.7% and 22.4% in the community and stroke groups. The median prevalence of moderate-to-severe perivascular spaces was 25.0% in the community. Meta-regression analyses showed that the weighted median age (51.4 ± 0.0 years old; range: 36.3–80.2) was a significant predictor of the prevalence of moderate-to-severe WMH and lacunes, while the type of study was a significant predictor of the prevalence of CMB. The heterogeneity of studies was high (>95%). Male participants were overrepresented. Conclusions: This systematic review and meta-analysis provide data on cSVD prevalence in LMICs and demonstrated the high prevalence of the condition. cSVD research in LMICs is being published at an increasing rate, especially between 2010 and 2022. More data are particularly needed from Sub-Saharan Africa and Central Europe, Eastern Europe, and Central Asia. [ABSTRACT FROM AUTHOR]

Background: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset.Methods: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308.Findings: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17]).Interpretation: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting.Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors to better understand pathogenesis and to predict disease progression and severity. We analysed data from 624 patients with symptomatic cerebral small vessel disease from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54 764 unannotated features and examined their association with respect to disease severity, assessed using MRI small vessel disease markers, cognition and future risk of all-cause dementia. Our analysis identified 28 metabolites that were significantly associated with small vessel disease imaging markers and cognition. Decreased levels of multiple glycerophospholipids and sphingolipids were associated with increased small vessel disease load as evidenced by higher white matter hyperintensity volume, lower mean diffusivity normalized peak height, greater brain atrophy and impaired cognition. Higher levels of creatine, FA(18:2(OH)) and SM(d18:2/24:1) were associated with increased lacune count, higher white matter hyperintensity volume and impaired cognition. Lower baseline levels of carnitines and creatinine were associated with higher annualized change in peak width of skeletonized mean diffusivity, and 25 metabolites, including lipoprotein subclasses, amino acids and xenobiotics, were associated with future dementia incidence. Our results show multiple distinct metabolic signatures that are associated with imaging markers of small vessel disease, cognition and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in small vessel disease. The metabolomic profiles may also provide novel insights into disease pathogenesis and help identify novel treatment approaches. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (SVD) is considered a disconnection syndrome, which can be quantified using structural brain network analysis obtained from diffusion MRI. Network analysis is a demanding analysis approach and the added benefit over simpler diffusion MRI analysis is largely unexplored in SVD. In this pre-registered study, we assessed the clinical and technical validity of network analysis in two non-overlapping samples of SVD patients from the RUN DMC study (n = 52 for exploration and longitudinal analysis and n = 105 for validation). We compared two connectome pipelines utilizing single-shell or multi-shell diffusion MRI, while also systematically comparing different node and edge definitions. For clinical validation, we assessed the added benefit of network analysis in explaining processing speed and in detecting short-term disease progression. For technical validation, we determined test-retest repeatability. Our findings in clinical validation show that structural brain networks provide only a small added benefit over simpler global white matter diffusion metrics and do not capture short-term disease progression. Test-retest reliability was excellent for most brain networks. Our findings question the added value of brain network analysis in clinical applications in SVD and highlight the utility of simpler diffusion MRI based markers. [ABSTRACT FROM AUTHOR]

Objectives: Given the strong association between systemic inflammation and cognitive decline, we aimed to determine whether nonneurologic infections are associated with accelerated cognitive decline and structural changes in the brain using pre- and post-infection neuropsychologic assessments and repeated brain MR images.Design: Additional analysis of the prospective observational Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study.Setting: Single-center study at the Radboud university medical center, Nijmegen, The Netherlands, between January 2006 and September 2015.Patients: Five-hundred three participants (50-85 yr old) with cerebral small vessel disease were included and followed for 9 years.Measurements and Main Results: Participants underwent repeated cognitive measurements and brain MRI. Infectious events were collected. Sepsis episodes were analyzed, and additionally, patients were stratified in three groups: having had a severe infectious episode (e.g., sepsis or hospitalization for infection), a mild, or no infectious episode. Development of dementia, trajectories of cognition, and structural brain changes on MRI in the subsequent follow-up periods were compared between the groups. Complete infectious data were available from 331 patients (mean age 64 ± 8 yr, 57% males). Twenty-nine participants (9%) suffered from a sepsis episode, 69 (21%) from a severe, 201 (61%) from a mild, and 61 (18%) had no infectious episode during follow-up. After correction for age, baseline cognition, and brain volume, each sepsis episode remained associated with an 82% increased risk to develop dementia within the follow-up period (hazard ratio, 1.82; 95% CI, 1.07-3.10; p = 0.027). Infections had no effect on the trajectory of structural changes to the brain after correction for baseline differences.Conclusions: In this 9-year observational follow-up study, sepsis episodes were associated with subsequent development of dementia. Nonneurologic infections had no effect on the trajectory of structural cerebral changes. [ABSTRACT FROM AUTHOR]

Background: To investigate changes in gait performance over time and how these changes are associated with the decline in structural network efficiency and cognition in older patients with cerebral small vessel disease (SVD).Methods: In a prospective, single-center cohort with 217 older participants with SVD, we performed 1.5T MRI scans, cognitive tests, and gait assessments evaluated by Timed UP and Go (TUG) test twice over 4 years. We reconstructed the white matter network for each subject based on diffusion tensor imaging tractography, followed by graph-theoretical analyses to compute the global efficiency. Conventional MRI markers for SVD, that is, white matter hyperintensity (WMH) volume, number of lacunes, and microbleeds, were assessed.Results: Baseline global efficiency was not related to changes in gait performance, while decline in global efficiency over time was significantly associated with gait decline (ie, increase in TUG time), independent of conventional MRI markers for SVD. Neither baseline cognitive performance nor cognitive decline was associated with gait decline.Conclusions: We found that disruption of the white matter structural network was associated with gait decline over time, while the effect of cognitive decline was not. This suggests that structural network disruption has an important role in explaining the pathophysiology of gait decline in older patients with SVD, independent of cognitive decline. [ABSTRACT FROM AUTHOR]

This study investigated the prevalence of carotid artery stenosis (CS) and the association with various risk factors in male patients (>65 years) diagnosed with cardiovascular diseases. Duplex sonography of the carotid arteries was performed in 434 of 473 eligible patients of whom 118 (27.8%) patients had significant CS ≥50%. The prevalence and severity of CS did not differ between patients who presented with neurological symptoms or acute coronary syndrome/peripheral artery disease (30.8% vs 25.9%, respectively). Among patients with CS, a higher rate of current smoking, a higher systolic blood pressure, and a lower glomerular filtration rate were observed compared with patients without CS. A history of coronary artery bypass graft was a significant predictor of the presence of CS (P = .003, odds ratio [OR] = 2.70 [1.40-5.19]). The prevalence of CS in elderly males with manifest atherosclerotic disease is high, irrespective of presenting clinical manifestation. [ABSTRACT FROM PUBLISHER]

Purpose: Patients who have been irradiated at the neck have an increased risk of symptomatic stenosis of the carotid artery during follow-up. Carotid angioplasty and stenting (CAS) can be a preferable alternative treatment to carotid endarterectomy, which is associated with increased operative risks in these patients. Methods and Materials: We performed a prospective cohort study of 24 previously irradiated patients who underwent CAS for symptomatic carotid stenosis. We assessed periprocedural and nonprocedural events including transient ischemic attack (TIA), nondisabling stroke, disabling stoke, and death. Patency rates were evaluated on duplex ultrasound scans. Restenosis was defined as a stenosis of >50% at the stent location. Results: Periprocedural TIA rate was 8%, and periprocedural stroke (nondisabling) occurred in 4% of patients. After a mean follow-up of 3.3 years (range, 0.3–11.0 years), only one ipsilateral incident event (TIA) had occurred (4%). In 12% of patients, a contralateral incident event was present: one TIA (4%) and two strokes (12%, two disabling strokes). Restenosis was apparent in 17%, 33%, and 42% at 3, 12, and 24 months, respectively, although none of the patients with restenosed vessels became symptomatic. The length of the irradiation to CAS interval proved the only significant risk factor for restenosis. Conclusions: The results of CAS for radiation-induced carotid stenosis are favorable in terms of recurrence of cerebrovascular events at the CAS site. [Copyright &y& Elsevier]

Background and aims: Given the unexplored potential of physical activity to reduce the progression of cerebral small vessel disease (cSVD, the purpose of this study was to prospectively (across nine-year follow-up) examine the relation between (baseline) physical activity and the (clinical and imaging) consequences of the whole spectrum of cerebral small vessel disease. Methods: Five hundred and three patients with cerebral small vessel disease from the RUNDMC study were followed for nine years. Physical activity was assessed using a questionnaire in 2006, 2011, and 2015. Clinical events (i.e. all-cause mortality, cerebrovascular events (by stroke subtype)) were collected with a structured questionnaire. Patients underwent magnetic resonance imaging scanning for the assessment of magnetic resonance imaging markers of cerebral small vessel disease (i.e. white matter hyperintensities, lacunes, and microbleeds) and microstructural integrity of the white matter at three timepoints. Results: The mean age at baseline was 66 (SD 9.0) years; 44% were women. A higher baseline physical activity level was independently associated with a lower all-cause mortality (HR: 0.69, 95%CI: 0.49-0.98, p=0.03) and incidence of cerebrovascular disease (HR: 0.58, 95%CI: 0.36-0.96, p=0.03). However, we found no relation between physical activity and incident lacunar stroke or progression of magnetic resonance imaging markers of cerebral small vessel disease. Conclusions: Whilst regular physical activity was not related to the progression of magnetic resonance imaging markers of cerebral small vessel disease across a nine-year follow-up, results from our study prove that high levels of physical activity in patients with cerebral small vessel disease are associated with a lower all-cause mortality and lower incidence of cerebrovascular events. [ABSTRACT FROM AUTHOR]

Deficits in facial emotion recognition occur frequently after stroke, with adverse social and behavioural consequences. The aim of this study was to investigate the neural underpinnings of the recognition of emotional expressions, in particular of the distinct basic emotions (anger, disgust, fear, happiness, sadness and surprise). A group of 110 ischaemic stroke patients with lesions in (sub)cortical areas of the cerebrum was included. Emotion recognition was assessed with the Ekman 60 Faces Test of the FEEST. Patient data were compared to data of 162 matched healthy controls (HC's). For the patients, whole brain voxel‐based lesion–symptom mapping (VLSM) on 3‐Tesla MRI images was performed. Results showed that patients performed significantly worse than HC's on both overall recognition of emotions, and specifically of disgust, fear, sadness and surprise. VLSM showed significant lesion–symptom associations for FEEST total in the right fronto‐temporal region. Additionally, VLSM for the distinct emotions showed, apart from overlapping brain regions (insula, putamen and Rolandic operculum), also regions related to specific emotions. These were: middle and superior temporal gyrus (anger); caudate nucleus (disgust); superior corona radiate white matter tract, superior longitudinal fasciculus and middle frontal gyrus (happiness) and inferior frontal gyrus (sadness). Our findings help in understanding how lesions in specific brain regions can selectively affect the recognition of the basic emotions. [ABSTRACT FROM AUTHOR]

This review investigates the severity and nature of post-stroke working memory deficits with reference to the multi-component model of working memory. We conducted a systematic search in PubMed up to March 2019 with search terms for stroke and memory. Studies on adult stroke patients, that included a control group, and assessed working memory function, were selected. Effect sizes (Hedges' g) were extracted from 50 studies (in total 3,084 stroke patients) based on the sample size, mean and standard deviation of patients and controls. Performance of stroke patients was compared to healthy controls on low-load (i.e. capacity) and high-load (executively demanding) working memory tasks, grouped by modality (verbal, non-verbal). A separate analysis compared patients in the sub-acute and the chronic stage. Longitudinal studies and effects of lesion location were systematically reviewed. Stroke patients demonstrated significant deficits in working memory with a moderate effect size for both low-load (Hedges' g = -.58 [-.82 to -.43]) and high-load (Hedges' g = -.59 [-.73 to -.45]) tasks. The effect sizes were comparable for verbal and non-verbal material. Systematically reviewing the literature showed that working memory deficits remain prominent in the chronic stage of stroke. Lesions in a widespread fronto-parietal network are associated with working memory deficits. Stroke patients show decrements of moderate magnitude in all subsystems of working memory. This review clearly demonstrates the global nature of the impairment in working memory post-stroke. [ABSTRACT FROM AUTHOR]

Background: Reduced hippocampal volume and increased prevalence of subcortical white matter lesions are associated with both recurrent early onset depression (EOD) and late onset depression (LOD). It is not clear whether these two factors differentially affect the age of onset of first depression. Therefore, we wished to investigate the relationship between age of first depression onset and hippocampal volume, with adjustment for subcortical white matter lesions. Methods: MRI brain scans were used to compare hippocampal volumes and white matter lesions between age matched female patients (>60 years) with recurrent EOD and LOD and healthy controls. Results: When comparing the three groups and adjusting for age, the Mini-Mental State Examination score, total brain volume and total hippocampal volume were significantly smaller in patients with EOD compared with controls (5.6 vs 6.1 ml; p=0.04). The prevalence of larger subcortical white matter lesions was higher in patients with LOD compared with patients with EOD (47% vs 8%; p=0.002). Patients with LOD did not differ in hippocampal volume from patients with EOD or from controls. Conclusions: In late life depression, age of first depression onset may distinguish between different independent neuro- pathological mechanisms. A small hippocampus volume may be a neuranatomical marker of EOD depression and larger subcortical white matter lesions could be an intermediate between cerebrovascular disease and LOD. [ABSTRACT FROM AUTHOR]

Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI—ex vivo MRI—histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI−/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts. [ABSTRACT FROM AUTHOR]

Brain atrophy is increasingly evaluated in cerebral small vessel diseases. We aim at systematically reviewing the available data regarding its extent, correlates and cognitive consequences. Given that in this context, brain atrophy measures might be biased, the first part of the review focuses on technical aspects. Thereafter, data from the literature are analyzed in light of these potential limitations, to better understand the relationships between brain atrophy and other MRI markers of cerebral small vessel diseases. In the last part, we review the links between brain atrophy and cognitive alterations in patients with cerebral small vessel diseases. [ABSTRACT FROM AUTHOR]

Objective: To determine the contribution of acute infarcts, evidenced by diffusion-weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers.Methods: We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high-resolution multishell DWI, and 3-dimensional fluid-attenuated inversion recovery, T1, and susceptibility-weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions.Results: We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow-up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow-up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005-0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow-up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds.Interpretation: DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one-third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582-592. [ABSTRACT FROM AUTHOR]

Importance: Stroke remains the second leading cause of death worldwide. Approximately 10% to 15% of all strokes occur in young adults. Information on prognosis and mortality specifically in young adults is limited.Objective: To determine short- and long-term mortality risk after stroke in young adults, according to age, sex, and stroke subtype; time trends in mortality; and causes of death.Design, Setting, and Participants: Registry- and population-based study in the Netherlands of 15 527 patients aged 18 to 49 years with first stroke between 1998 and 2010, and follow-up until January 1, 2017. Patients and outcomes were identified through linkage of the national Hospital Discharge Registry, national Cause of Death Registry, and the Dutch Population Register.Exposures: First stroke occurring at age 18 to 49 years, documented using International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes for ischemic stroke, intracerebral hemorrhage, and stroke not otherwise specified.Main Outcomes and Measures: Primary outcome was all-cause cumulative mortality in 30-day survivors at end of follow-up, stratified by age, sex, and stroke subtype, and compared with all-cause cumulative mortality in the general population.Results: The study population included 15 527 patients with stroke (median age, 44 years [interquartile range, 38-47 years]; 53.3% women). At end of follow-up, a total of 3540 cumulative deaths had occurred, including 1776 deaths within 30 days after stroke and 1764 deaths (23.2%) during a median duration of follow-up of 9.3 years (interquartile range, 5.9-13.1 years). The 15-year mortality in 30-day survivors was 17.0% (95% CI, 16.2%-17.9%). The standardized mortality rate compared with the general population was 5.1 (95% CI, 4.7-5.4) for ischemic stroke (observed mortality rate 12.0/1000 person-years [95% CI, 11.2-12.9/1000 person-years]; expected rate, 2.4/1000 person-years; excess rate, 9.6/1000 person-years) and the standardized mortality rate for intracerebral hemorrhage was 8.4 (95% CI, 7.4-9.3; observed rate, 18.7/1000 person-years [95% CI, 16.7-21.0/1000 person-years]; expected rate, 2.2/1000 person-years; excess rate, 16.4/1000 person-years).Conclusions and Relevance: Among young adults aged 18 to 49 years in the Netherlands who were 30-day survivors of first stroke, mortality risk compared with the general population remained elevated up to 15 years later. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Five hundred and three participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi‐automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: β = .067; 95%CI[.024–0.111]; p < .01; EM: β = .061; 95%CI[.025–.098]; p < .01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, χ2[1] = 9.3, p < .01) and for EM (likelihood ratio test, χ2[1] = 10.7, p < .01). Mediation models showed that both baseline WMH volume (β = −.170; p = .001) and hippocampal atrophy (β = 0.126; p = .009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p value indirect effect: 0.572). Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies contribute to the memory decline observed in elderly with SVD. [ABSTRACT FROM AUTHOR]

Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD. [ABSTRACT FROM AUTHOR]

Incidence of ischemic stroke and transient ischemic attack in young adults is rising. However, etiology remains unknown in 30–40% of these patients when current classification systems designed for the elderly are used. Our aim was to identify risk factors according to a pediatric approach, which might lead to both better identification of risk factors and provide a stepping stone for the understanding of disease mechanism, particularly in patients currently classified as “unknown etiology”. Risk factors of 656 young stroke patients (aged 18–50) of the FUTURE study were categorized according to the “International Pediatric Stroke Study” (IPSS), with stratification on gender, age and stroke of “unknown etiology”. Categorization of risk factors into ≥1 IPSS category was possible in 94% of young stroke patients. Chronic systemic conditions were more present in patients aged <35 compared to patients ≥35 (32.6% vs. 15.6%, p < 0.05). Among 226 patients classified as “stroke of unknown etiology” using TOAST, we found risk factors in 199 patients (88%) with the IPSS approach. We identified multiple risk factors linked to other mechanisms of stroke in the young than in the elderly. This can be a valuable starting point to develop an etiologic classification system specifically designed for young stroke patients. [ABSTRACT FROM AUTHOR]

Epidemiological evidence suggests that the incidence of ischaemic stroke in young adults (18-50 years) has increased substantially. These patients have a long life expectancy after stroke, and the costs of long-term care pose huge challenges to health-care systems. Although the current recommendations for treatment of young and old (>50 years) patients with stroke are similar, the optimal management of young adult patients with stroke is unknown. They are usually not included in trials, and specific subanalyses limited to young adult patients with stroke are usually not done, owing to lower incidence of stroke and lower prevalence of vascular risk factors in young adults. Progress has been made in identifying patients with a considerable risk of stroke occurrence, such as those with patent foramen ovale. Future prevention studies might result in a decrease in the incidence of stroke and its sequelae in young adults. The development of guidelines specifically devoted to the management of stroke in young adults will be an important step in achieving this aim. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (SVD) is commonly observed on neuroimaging among elderly individuals and is recognized as a major vascular contributor to dementia, cognitive decline, gait impairment, mood disturbance and stroke. However, clinical symptoms are often highly inconsistent in nature and severity among patients with similar degrees of SVD on brain imaging. Here, we provide a new framework based on new advances in structural and functional neuroimaging that aims to explain the remarkable clinical variation in SVD. First, we discuss the heterogeneous pathology present in SVD lesions despite an identical appearance on imaging and the perilesional and remote effects of these lesions. We review effects of SVD on structural and functional connectivity in the brain, and we discuss how network disruption by SVD can lead to clinical deficits. We address reserve and compensatory mechanisms in SVD and discuss the part played by other age-related pathologies. Finally, we conclude that SVD should be considered a global rather than a focal disease, as the classically recognized focal lesions affect remote brain structures and structural and functional network connections. The large variability in clinical symptoms among patients with SVD can probably be understood by taking into account the heterogeneity of SVD lesions, the effects of SVD beyond the focal lesions, the contribution of neurodegenerative pathologies other than SVD, and the interaction with reserve mechanisms and compensatory mechanisms. [ABSTRACT FROM AUTHOR]

This expert working group report proposes an updated approach to subtype definition of vascular parkinsonism (VaP) based on a review of the existing literature. The persistent lack of consensus on clear terminology and inconsistent conceptual definition of VaP formed the impetus for the current expert recommendation report. The updated diagnostic approach intends to provide a comprehensive tool for clinical practice. The preamble for this initiative is that VaP can be diagnosed in individual patients with possible prognostic and therapeutic consequences and therefore should be recognized as a clinical entity. The diagnosis of VaP is based on the presence of clinical parkinsonism, with variable motor and non-motor signs that are corroborated by clinical, anatomic or imaging findings of cerebrovascular disease. Three VaP subtypes are presented: (1) The acute or subacute post-stroke VaP subtype presents with acute or subacute onset of parkinsonism, which is typically asymmetric and responds to dopaminergic drugs; (2) The more frequent insidious onset VaP subtype presents with progressive parkinsonism with prominent postural instability, gait impairment, corticospinal, cerebellar, pseudobulbar, cognitive and urinary symptoms and poor responsiveness to dopaminergic drugs. A higher-level gait disorder occurs frequently as a dominant manifestation in the clinical spectrum of insidious onset VaP, and (3) With the emergence of molecular imaging biomarkers in clinical practice, our diagnostic approach also allows for the recognition of mixed or overlapping syndromes of VaP with Parkinson's disease or other neurodegenerative parkinsonisms. Directions for future research are also discussed. [ABSTRACT FROM AUTHOR]

Purpose: As a single-shot sequence with a long train of refocusing pulses, Half-Fourier Acquisition Single-Shot Turbo-Spin-Echo (HASTE) suffers from high power deposition limiting use at high resolutions and high field strengths, particularly if combined with acceleration techniques such as simultaneous multi-slice (SMS) imaging. Using a combination of multiband (MB)-excitation and PINS-refocusing pulses will effectively accelerate the acquisition time while staying within the SAR limitations. In particular, uncooperative and young patients will profit from the speed of the MB-PINS HASTE sequence, as clinical diagnosis can be possible without sedation. Materials and MethodsMB-excitation and PINS-refocusing pulses were incorporated into a HASTE-sequence with blipped CAIPIRINHA and TRAPS including an internal FLASH reference scan for online reconstruction. Whole brain MB-PINS HASTE data were acquired on a Siemens 3T-Prisma system from 10 individuals and compared to a clinical HASTE protocol. ResultsThe proposed MB-PINS HASTE protocol accelerates the acquisition by about a factor 2 compared to the clinical HASTE. The diagnostic image quality proved to be comparable for both sequences for the evaluation of the overall aspect of the brain, the detection of white matter changes and areas of tissue loss, and for the evaluation of the CSF spaces although artifacts were more frequently encountered with MB-PINS HASTE. ConclusionsMB-PINS HASTE enables acquisition of slice accelerated highly T2-weighted images and provides good diagnostic image quality while reducing acquisition time. [ABSTRACT FROM AUTHOR]

Introduction. Subjective cognitive impairment (SCI), depressive symptoms, and fatigue are common after stroke and are associated with reduced quality of life. We prospectively investigated their prevalence and course after a transient ischemic attack (TIA) or nonfocal transient neurological attack (TNA) and the association with diffusion-weighted imaging (DWI) lesions. Methods. The Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, and Subjective Fatigue subscale from the Checklist Individual Strength were used to assess subjective complaints shortly after TIA or TNA and six months later. With repeated measure analysis, the associations between DWI lesion presence or clinical diagnosis (TIA or TNA) and subjective complaints over time were determined. Results. We included 103 patients (28 DWI positive). At baseline, SCI and fatigue were less severe in DWI positive than in DWI negative patients, whereas at follow-up, there were no differences. SCI (p=0.02) and fatigue (p=0.01) increased in severity only in DWI positive patients. There were no differences between TIA and TNA. Conclusions. Subjective complaints are highly prevalent in TIA and TNA patients. The short-term prognosis is not different between DWI-positive and DWI negative patients, but SCI and fatigue increase in severity within six months after the event when an initial DWI lesion is present. [ABSTRACT FROM AUTHOR]

Objectives: The extent of vascular cognitive impairment (VCI) after stroke varies greatly across individuals, even when the same amount of brain damage is present. Education level is a potentially protective factor explaining these differences, but results on its effects on VCI are inconclusive. Methods: First, we performed a meta-analysis on formal education and VCI, identifying 21 studies (N=7770). Second, we examined the effect of formal education on VCI in young-stroke patients who were cognitively assessed on average 11.0 (SD=8.2) years post-stroke (the FUTURE study cohort). The total sample consisted of 277 young-stroke patients with a mean age at follow-up 50.9 (SD=10.3). Age and education-adjusted expected scores were computed using 146 matched stroke-free controls. Results: The meta-analysis showed an overall effect size (z') of 0.25 (95% confidence interval [0.18–0.31]), indicating that formal education level had a small to medium effect on VCI. Analyses of the FUTURE data showed that the effect of education on post-stroke executive dysfunction was mediated by age (β age −0.015; p<.05). Below-average performance in the attention domain was more frequent for low-education patients (χ2(2)=9.8; p<.05). Conclusions: While education level was found to be related to post-stroke VCI in previous research, the effects were small. Further analysis in a large stroke cohort showed that these education effects were fully mediated by age, even in relatively young stroke patients. Education level in and of itself does not appear to be a valid indicator of cognitive reserve. Multi-indicator methods may be more valid, but have not been studied in relation to VCI. (JINS, 2017, 23, 223–238) [ABSTRACT FROM AUTHOR]

Purpose: White matter hyperintensities (WMH) are seen on FLAIR-MRI in several neurological disorders, including multiple sclerosis, dementia, Parkinsonism, stroke and cerebral small vessel disease (SVD). WMHs are often used as biomarkers for prognosis or disease progression in these diseases, and additionally longitudinal quantification of WMHs is used to evaluate therapeutic strategies. Human readers show considerable disagreement and inconsistency on detection of small lesions. A multitude of automated detection algorithms for WMHs exists, but since most of the current automated approaches are tuned to optimize segmentation performance according to Jaccard or Dice scores, smaller WMHs often go undetected in these approaches. In this paper, the authors propose a method to accurately detect all WMHs, large as well as small. Methods: A two-stage learning approach was used to discriminate WMHs from normal brain tissue. Since small and larger WMHs have quite a different appearance, the authors have trained two probabilistic classifiers: one for the small WMHs (≤3 mm effective diameter) and one for the larger WMHs (>3 mm in-plane effective diameter). For each size-specific classifier, an Adaboost is trained for five iterations, with random forests as the basic classifier. The feature sets consist of 22 features including intensities, location information, blob detectors, and second order derivatives. The outcomes of the two first-stage classifiers were combined into a single WMH likelihood by a second-stage classifier. Their method was trained and evaluated on a dataset with MRI scans of 362 SVD patients (312 subjects for training and validation annotated by one and 50 for testing annotated by two trained raters). To analyze performance on the separate test set, the authors performed a free-response receiving operating characteristic (FROC) analysis, instead of using segmentation based methods that tend to ignore the contribution of small WMHs. Results: Experimental results based on FROC analysis demonstrated a close performance of the proposed computer aided detection (CAD) system to human readers. While an independent reader had 0.78 sensitivity with 28 false positives per volume on average, their proposed CAD system reaches a sensitivity of 0.73 with the same number of false positives. Conclusions: The authors have developed a CAD system with all its ingredients being optimized for a better detection of WMHs of all size, which shows performance close to an independent reader. [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD.Methods: We developed a novel magnetic resonance imaging marker based on diffusion tensor imaging, skeletonization of white matter tracts, and histogram analysis. The marker (peak width of skeletonized mean diffusivity [PSMD]) was assessed along with conventional SVD imaging markers. We first evaluated associations with processing speed in patients with genetically defined SVD (n = 113). Next, we validated our findings in independent samples of inherited SVD (n = 57), sporadic SVD (n = 444), and memory clinic patients with SVD (n = 105). The new marker was further applied to healthy controls (n = 241) and to patients with Alzheimer's disease (n = 153). We further conducted a longitudinal analysis and interscanner reproducibility study.Results: PSMD was associated with processing speed in all study samples with SVD (p-values between 2.8 × 10(-3) and 1.8 × 10(-10) ). PSMD explained most of the variance in processing speed (R(2) ranging from 8.8% to 46%) and consistently outperformed conventional imaging markers (white matter hyperintensity volume, lacune volume, and brain volume) in multiple regression analyses. Increases in PSMD were linked to vascular but not to neurodegenerative disease. In longitudinal analysis, PSMD captured SVD progression better than other imaging markers.Interpretation: PSMD is a new, fully automated, and robust imaging marker for SVD. PSMD can easily be applied to large samples and may be of great utility for both research studies and clinical use. Ann Neurol 2016;80:581-592. [ABSTRACT FROM AUTHOR]