Bilateral hypogeusia and food aversion due to lacunar infarct in the right dorsomedial pontine tegmentum.

A 70-year-old right-handed housewife suffered an acute loss of taste, an unpleasant change in the taste of foods and liquids, and a strong aversion to all kinds of food due to a small lacune in the right dorsomedial pontine tegmentum. Eating became so unpleasant that she lost 7 kg in three weeks. Olfaction and the sensibility of the tongue were spared. The right medial longitudinal fascicle, the central tegmental tract, or both, were injured by the tegmental lesion. A discrete right-sided lesion in the upper pontine tegmentum may cause a reversible syndrome consisting of bilateral hypogeusia which is more severe ipsilaterally.

Acute bilateral multiple subcortical infarcts as manifestation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterised by recurrent subcortical ischemic events, migraine with aura, dementia and mood disturbance. Strokes are typically lacunar infarcts; however, bilateral multiple subcortical lacunar infarcts have been described only sporadically. METHOD: We described four CADASIL patients who presented with acute bilateral multiple subcortical infarcts as the first manifestation. We also briefly summarised the case reports detailing the bilateral multiple infarcts in CADASIL. RESULTS: Patient 1 and patient 2 were family members, and they presented with cognitive impairment. Patient 3 and patient 4 presented with slurred speech and hemiparesis. Patients 1, 3 and 4 developed hemodynamic fluctuations before the occurrence of ischemic stroke. Laboratory tests revealed elevated fibrinogen levels in patients 3 and 4. The brain magnetic resonance imaging showed acute bilateral multiple subcortical infarcts on the periventricular white matter in all the patients. CONCLUSION: CADASIL, with a poor brain hemodynamic reserve, is vulnerable to hemodynamic alterations (e.g. blood pressure fluctuation, dehydration, blood loss and anaemia) and intolerable to ischemia and hypoxia of the brain. Furthermore, blood hypercoagulation may contribute to acute multiple bilateral infarctions in CADASIL. Therefore, it is necessary to avert these predispositions in CADASIL patients in their daily life.

Association between total cerebral small vessel disease score and cognitive function in patients with vascular risk factors.

Hypertension is the most important risk factor for cerebral small vessel disease (SVD). In this cross-sectional study, we tested the independent association of cerebral SVD burden with global cognitive function and each cognitive domain in patients with vascular risk factors. The Tokyo Women's Medical University Cerebral Vessel Disease (TWMU CVD) registry is an ongoing prospective, observational registry in which patients with any evidence of CVD in magnetic resonance imaging (MRI) and at least one vascular risk factor were consecutively enrolled. For SVD-related findings, we evaluated white matter hyperintensity, lacunar infarction, cerebral microbleeds, enlarged perivascular space, and medial temporal atrophy. We used the total SVD score as the SVD burden. They underwent the Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests, and each cognitive domain was evaluated. After excluding patients without MRI T2* images and those with MMSE score <24, we analyzed 648 patients. The total SVD score was significantly associated with MMSE and MoCA-J scores. After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and MoCA-J score remained significant. The total SVD score was independently associated with attention. In conclusion, the total SVD score, cerebral SVD burden, was independently association with global cognitive function and attention. A strategy to reduce SVD burden will have the potential to prevent cognitive decline. A total of 648 patients with any evidence of cerebral small vessel disease (SVD) in MRI and at least one vascular risk factor underwent Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests. The total SVD scores count the presence of each SVD-related findings (white matter hyperintensity, Lacunar infarction, cerebral microbleeds and enlarged perivascular space), ranging from 0 to 4, as the SVD burden. Total SVD scores were significantly associated with MoCA-J scores (r = -0.203, P < 0.001). After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and global cognitive scores remained significant.

Application value of T2 fluid-attenuated inversion recovery sequence based on deep learning in static lacunar infarction.

BACKGROUND: Regular monitoring of static lacunar infarction (SLI) lesions plays an important role in preventing disease development and managing prognosis. Magnetic resonance imaging is one method used to monitor SLI lesions. PURPOSE: To evaluate the image quality of the T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence using artificial intelligence-assisted compressed sensing (ACS) in detecting SLI lesions and assess its clinical applicability. METHODS: A total of 42 patients were prospectively enrolled and scanned by T2-FLAIR. Two independent readers reviewed the images acquired with accelerated modes 1D (acceleration factor 2) and ACS (acceleration factors 2, 3, and 4). The overall image quality and lesion image quality were analyzed, as were signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and number of lesions between groups. RESULTS: The subjective assessment of overall brain image quality and lesion image quality was consistent between the two readers. The lesion display quality and the overall image quality were better with the traditional 1D acceleration method than with the ACS accelerated method. There was no significant difference in the SNR of the lacunar infarction in the images between the groups. The CNR of the images with the 1D acceleration mode was significantly lower than that of images with the ACS acceleration mode. Images with the 1D, ACS2, and ACS3 acceleration modes showed no significant differences in terms of detecting lesions but scan time can be reduced by 40% (1D vs. ACS3). CONCLUSION: ACS acceleration mode can greatly reduce the scan time. In addition, the images have good SNR, high CNR, and strong SLI lesion detection ability.

Clinical features and pathogenicity assessment in patients with HTRA1-autosomal dominant disease.

BACKGROUND: Heterozygous mutations in HTRA1 were recently found to cause autosomal dominant cerebral small vessel disease (CSVD), and it was named HTRA1-autosomal dominant disease (AD-HTRA1) in the consensus recommendations of the European Academy of Neurology. This study aimed to investigate the clinical features of a mutation in HTRA1 and the effect of HTRA1 mutation on white matter hyperintensity (WMH). METHODS: A proband's brain magnetic resonance imaging (MRI) showed multiple lacunar infarctions and multiple WMH in the lateral ventricle, external capsule, frontal lobe and corpus callosum. The proband and family members were tested for CSVD-related genes by next-generation sequencing and the clinical data of the patients were collected. The published literature on AD-HTRA1 was collected, and the clinical characteristics and pathogenicity of the patients were summarized. Combined Annotation Dependent Depletion (CADD) is a tool for scoring the deleteriousness of single-nucleotide variants and insertion/deletion variants in the human genome. The relationship between the degree of WMH and the pathogenicity of the mutation was further analyzed. RESULT: It was found that the proband and her family members had a heterozygous missense mutation of c.854C > T (p.P285L) in the 4 exon of HTRA1 gene. A retrospective analysis of 5 families with c.854C > T mutation found that the patients had an early age of onset, cognitive impairment was more common, and alopecia and spondylosis could be combined at the same time. By univariate analysis, the severity of WMH was found to be significantly associated with the mutated CADD score (p < 0.05, Spearman's rho = 0.266). CONCLUSION: The clinical manifestations of AD-HTRA1 with mutation site c.854C > T (p.P285L) are similar to CARASIL, and brain MRI are mainly moderate or severe WMH and lacunar infarction (LI). WMH are affected by mutation sites. Therefore, our pathogenicity score for mutations can predict the severity of WMH.

5-Year Associations among Cerebral Arterial Pulsatility, Perivascular Space Dilation, and White Matter Lesions.

OBJECTIVE: High cerebral arterial pulsatility index (PI), white matter lesions (WMLs), enlarged perivascular spaces (PVSs), and lacunar infarcts are common findings in the elderly population, and considered indicators of small vessel disease (SVD). Here, we investigate the potential temporal ordering among these variables, with emphasis on determining whether high PI is an early or delayed manifestation of SVD. METHODS: In a population-based cohort, 4D flow MRI data for cerebral arterial pulsatility was collected for 159 participants at baseline (age 64-68), and for 122 participants at follow-up 5 years later. Structural MRI was used for WML and PVS segmentation, and lacune identification. Linear mixed-effects (LME) models were used to model longitudinal changes testing for pairwise associations, and latent change score (LCS) models to model multiple relationships among variables simultaneously. RESULTS: Longitudinal 5-year increases were found for WML, PVS, and PI. Cerebral arterial PI at baseline did not predict changes in WML or PVS volume. However, WML and PVS volume at baseline predicted 5-year increases in PI. This was shown for PI increases in relation to baseline WML and PVS volumes using LME models (R  ≥  0.24; p < 0.02 and R  ≥  0.23; p < 0.03, respectively) and LCS models ( ß  = 0.28; p = 0.015 and ß  = 0.28; p = 0.009, respectively). Lacunes at baseline were unrelated to PI. INTERPRETATION: In healthy older adults, indicators of SVD are related in a lead-lag fashion, in which the expression of WML and PVS precedes increases in cerebral arterial PI. Hence, we propose that elevated PI is a relatively late manifestation, rather than a risk factor, for cerebral SVD. ANN NEUROL 2022;92:871-881.

Brain structural alterations and clinical features of cognitive frailty in Japanese community-dwelling older adults: the Arao study (JPSC-AD).

Cognitive frailty (CF) is a clinical condition defined by the presence of both mild cognitive impairment (MCI) and physical frailty (PF). Elderly with CF are at greater risk of dementia than those with MCI or PF alone, but there are few known clinical or neuroimaging features to reliably distinguish CF from PF or MCI. We therefore conducted a population-based cross-sectional study of community elderly combining physical, cognitive, neuropsychiatric, and multisequence magnetic resonance imaging (MRI) evaluations. The MRI evaluation parameters included white matter (WM) lesion volumes, perivascular and deep subcortical WM lesion grades, lacunar infarct prevalence, microbleed number, and regional medial temporal lobe (MTL) volumes. Participants were divided into 4 groups according to the presence or absence of MCI and PF-(1) no MCI, PF (n = 27); (2) no PF, MCI (n = 119); (3) CF (MCI + PF) (n = 21), (4) normal controls (n = 716). Unique features of CF included shorter one-leg standing time; severe depressive symptoms; and MRI signs of significantly more WM lesions, lacunar infarcts, small-vessel disease lesions, microbleeds, and reduced MTL volumes. These unique deficits suggest that interventions for CF prevention and treatment should focus on motor skills, depressive symptoms, and vascular disease risk factor control.

sTWEAK is a leukoaraiosis biomarker associated with neurovascular angiopathy.

OBJECTIVE: Leukoaraiosis (LA) refers to white matter lesions of undetermined etiology associated with the appearance and worsening of vascular pathologies. The aim is to confirm an increased frequency and intensity of LA in symptomatic patients with neurovascular pathology compared with asymptomatic subjects, and its association with circulating serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). METHODS: An observational study was conducted in which two groups of patients were compared. Group I (N = 242) comprised of asymptomatic subjects with arterial hypertension and/or diabetes or with a history of transient ischemic attacks, and Group II (N = 382) comprised patients with lacunar stroke or deep hemispheric intracerebral hemorrhage (ICH) of hypertensive origin. Serum levels of sTWEAK were analyzed and correlated with prevalence and intensity of LA according to the Fazekas scale. RESULTS: The prevalence of LA was higher in symptomatic (85.1%) versus asymptomatic patients (62.0%). Logistic regression model showed a significant relation of LA with neurovascular pathologies (OR: 2.69, IC 95%: 1.10-6.59, p = 0.003). When stratified according to the Fazekas scale, LA of grade II (OR: 3.53, IC 95%: 1.10-6.59, p = 0.003) and specially grade III (OR: 4.66, 95% CI: 1.09-19.84, p = 0.037) showed correlation with neurovascular pathologies. Increased sTWEAK levels were found in the symptomatic group in all LA grades (p < 0.0001), and associated with 5.06 times more risk of presenting clinical symptoms (OR: 5.06, 95% CI: 2.66-9.75, p < 0.0001). INTERPRETATION: LA showed a higher prevalence in patients with symptomatic lacunar stroke or deep hemispheric ICH. There is an association between sTWEAK levels and LA degree.

Cerebral small vessel disease: A glymphopathy?

Small vessel disease (SVD) is a common instigator of dementia in the aging population. The hallmarks of SVD are enlargement of the perivascular spaces and white matter hyperintensities. The latter represents local fluid accumulation in white matter that either subsides or develops into lacunar infarcts. We here propose that failure of brain fluid transport-via the glymphatic system-plays a key role in initiation and progression of SVD. Our major case for this concept is that perivascular spaces are utilized as waterways for influx of cerebrospinal fluid. Stagnation of glymphatic transport may drive loss of brain fluid homeostasis leading to transient white matter edema, perivascular dilation, and ultimately demyelination. This review will discuss how glymphatic rodent studies of hypertension and diabetes have provided new insight into the pathogenesis of SVD.

Difficulty in articulation following left progressive blurred vision.

PURPOSE: To report a case of Paracentral acute middle maculopathy (PAMM) caused by severe internal carotid artery (ICA) stenosis and discuss the correlation between PAMM and ICA stenosis. CASE DESCRIPTION: A 67-year-old male patient presented with left acute blurred vision for 1 week. The best-corrected visual acuity of the left eye was 0.01. Funduscopic examination showed multiple grayish patches around the left macula. Optical coherence tomography (OCT) demonstrated train-track hyperreflective lesions over the inner nuclear layer of the left eye. Afterwards, he experienced sudden slurred speech with fair comprehension. Magnetic resonance imaging and angiography of the brain demonstrated left lacunar infarction with severe left ICA stenosis. After anticoagulant therapy, his dysarthria and left visual acuity were improved significantly. CONCLUSIONS: To our knowledge, PAMM in coincidence with lacunar infarction induced by ICA stenosis is firstly described in the literature. PAMM could be a critical warning of ICA stenosis, and this case can alert ophthalmologists to survey ICA stenosis in patients with PAMM.

Advances in Understanding the Pathogenesis of Lacunar Stroke: From Pathology and Pathophysiology to Neuroimaging.

Lacunar stroke (LS) accounts for about one-quarter of all acute ischemic strokes, represents an important marker of cerebral small vessel disease (CSVD), and has prognostic significance in terms of recurrent vascular events and vascular cognitive impairment. Our understanding of the etiology and pathogenesis of LS is largely based on the meticulous postmortem work of C. Miller Fisher in the late 1960s, with scarce subsequent pathological analysis of the "lacunar hypothesis" and no reliable approaches for direct in vivo imaging of the small intracranial vessels. The recent development of high-resolution MRI, which allows both large-vessel wall and perforating arteries to be imaged in one setting, provides the opportunity to advance understandings of the clinical mechanisms, imaging characteristics, and pathogenesis of LS. Given accumulating evidence of endothelial dysfunction and blood-brain-barrier disruption as early features of CSVD-related LS, advanced imaging may allow various underlying pathogenetic mechanisms to be defined and for better targeting of therapeutic approaches in LS. In this review, progress in understanding the pathogenesis of LS is outlined, covering pathology, pathophysiology, and imaging characteristics, with a focus toward future directions in the complex entity of LS.

Transient Receptor Potential Melastatin 3 Is Functionally Expressed in Oligodendrocyte Precursor Cells and Is Upregulated in Ischemic Demyelinated Lesions.

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into oligodendrocytes and myelinate axons. The number of OPCs is reportedly increased in brain lesions in some demyelinating diseases and during ischemia; however, these cells also secrete cytokines and elicit both protective and deleterious effects in response to brain injury. The mechanism regulating the behaviors of OPCs in physiological and pathological conditions must be elucidated to control these cells and to treat demyelinating diseases. Here, we focused on transient receptor potential melastatin 3 (TRPM3), a Ca2+-permeable channel that is activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Trpm3+/Pdgfra+ OPCs were detected in the cerebral cortex (CTX) and corpus callosum (CC) of P4 and adult rats by in situ hybridization. Trpm3 expression was detected in primary cultured rat OPCs and was increased by treatment with tumor necrosis factor α (TNFα). Application of PS (30-100 µM) increased the Ca2+ concentration in OPCs and this effect was inhibited by co-treatment with the TRP channel blocker Gd3+ (100 µM) or the TRPM3 inhibitor isosakuranetin (10 µM). Stimulation of TRPM3 with PS (50 µM) did not affect the differentiation or migration of OPCs. The number of Trpm3+ OPCs was markedly increased in demyelinated lesions in an endothelin-1 (ET-1)-induced ischemic rat model. In conclusion, TRPM3 is functionally expressed in OPCs in vivo and in vitro and is upregulated in inflammatory conditions such as ischemic insults and TNFα treatment, implying that TRPM3 is involved in the regulation of specific behaviors of OPCs in pathological conditions.

Lenticulostriate artery combined with neuroimaging markers of cerebral small vessel disease differentiate the pathogenesis of recent subcortical infarction.

Recent subcortical infarction (RSI) in the lenticulostriate artery (LSA) territory with a non-stenotic middle cerebral artery is a heterogeneous entity. We aimed to investigate the role of LSA combined with neuroimaging markers of cerebral small vessel disease (CSVD) in differentiating the pathogenic subtypes of RSI by whole-brain vessel-wall magnetic resonance imaging (WB-VWI). Fifty-two RSI patients without relevant middle cerebral artery (MCA) stenosis on magnetic resonance angiography were prospectively enrolled. RSI was dichotomized as branch atheromatous disease (BAD; a culprit plaque located adjacent to the LSA origin) (n = 34) and CSVD-related lacunar infarction (CSVD-related LI; without plaque or plaque located distal to the LSA origin) (n = 18). Logistic regression analysis showed lacunes (odds ratio [OR] 9.68, 95% confidence interval [CI] 1.71-54.72; P = 0.010) and smaller number of LSA branches (OR 0.59, 95% CI 0.36-0.96; P = 0.034) were associated with of BAD, whereas severe deep white matter hyperintensities (DWMH) (OR 0.11, 95% CI 0.02-0.71; P = 0.021) was associated with CSVD-related LI. In conclusion, the LSA branches combined with lacunes and severe DWMH may delineate subtypes of SSI. The WB-VWI technique could be a credible tool for delineating the heterogeneous entity of SSI in the LSA territory.

Cerebral magnetic resonance imaging of coincidental infarction and small vessel disease in retinal artery occlusion.

There are several reports in the literature on the association between non-arteritic retinal artery occlusion (NA-RAO) and acute ischemic stroke. We investigated the burden of small vessel disease (SVD) and cerebral coincident infarction observed on cerebral magnetic resonance imaging (MRI) in patients with newly diagnosed NA-RAO. In this retrospective, observational, case-series study, consecutive patients with NA-RAO who underwent cerebral MRI within one month of diagnosis between September 2003 and October 2018 were included. The classification of NA-RAO was based on ophthalmologic and systemic examinations. We also investigated the co-incident infarction and burden of underlying SVD, which were categorized as white matter hyperintensity lesion (WMH), cerebral microbleeds (CMB), and silent lacunar infarction (SLI). Among the 272 patients enrolled in the study, 18% presented co-incident infarction and 73% had SVD, which included WMH (70%), CMB (14%), and SLI (30%). Co-incident infarction, WMH, and SLI significantly increased with age: co-incident infarction was observed in 8% of young (< 50 years) patients and 30% of old (≥ 70 years) patients. The embolic etiology of RAO (large artery atherosclerosis, cardioembolism, and undetermined etiology) was significantly associated with the prevalence of SVD (82%: 70%: 64%, P = 0.002) and co-incident infarction (30%: 19%: 8%; P = 0.009). Therefore, high co-incidence of acute cerebral infarction and underlying SVD burden warrant careful neurologic examination and appropriate brain imaging, followed by management of NA-RAO. Urgent brain imaging is particularly pertinent in elderly patients with NA-RAO.

Neuroinflammation evoked by brain injury in a rat model of lacunar infarct.

Stroke is the leading cause of long-term, severe disability worldwide. Immediately after the stroke, endogenous inflammatory processes are upregulated, leading to the local neuroinflammation and the potentiation of brain tissue destruction. The innate immune response is triggered as early as 24 h post-brain ischemia, followed by adaptive immunity activation. Together these immune cells produce many inflammatory mediators, i.e., cytokines, growth factors, and chemokines. Our study examines the immune response components in the early stage of deep brain lacunar infarct in the rat brain, highly relevant to the clinical scenario. The lesion was induced by stereotactic injection of ouabain into the adult rat striatum. Ouabain is a Na/K ATPase pump inhibitor that causes excitotoxicity and brings metabolic and structural changes in the cells leading to focal brain injury. We have shown a surge of neurodegenerative changes in the peri-infarct area in the first days after brain injury. Immunohistochemical analysis revealed early microglial activation and the gradual infiltration of immune cells with a significant increase of CD4+ and CD8+ T lymphocytes in the ipsilateral hemisphere. In our studies, we identified the higher level of pro-inflammatory cytokines, i.e., interleukin-1α, interleukin-1ß, tumor necrosis factor-α, and interferon-γ, but a lower level of anti-inflammatory cytokines, i.e., interleukin-10 and transforming growth factor-ß2 in the injured brain than in normal rats. Concomitantly focal brain injury showed a significant increase in the level of chemokines, i.e., monocyte chemoattractant protein-1 and CC motif chemokine ligand 5 compared to control. Our findings provide new insights into an early inflammatory reaction in our model of the deep-brain lacunar infarct. The results of this study may highlight future stroke immunotherapies for targeting the acute immune response accompanied by the insult.

C-Reactive Protein Predicts Further Ischemic Events in Patients With Transient Ischemic Attack or Lacunar Stroke.

Patients who have experienced a first cerebral ischemic event are at increased risk of recurrent stroke. There is strong evidence that low-level inflammation as measured by high sensitivity C-reactive protein (hs-CRP) is a predictor of further ischemic events. Other mechanisms implicated in the pathogenesis of stroke may play a role in determining the risk of secondary events, including oxidative stress and the adaptive response to it and activation of neuroprotective pathways by hypoxia, for instance through induction of erythropoietin (EPO). This study investigated the association of the levels of CRP, peroxiredoxin 1 (PRDX1, an indicator of the physiological response to oxidative stress) and EPO (a neuroprotective factor produced in response to hypoxia) with the risk of a second ischemic event. Eighty patients with a diagnosis of lacunar stroke or transient ischemic attack (TIA) were included in the study and a blood sample was collected within 14 days from the initial event. Hs-CRP, PRDX1, and EPO were measured by ELISA. Further ischemic events were recorded with a mean follow-up of 42 months (min 24, max 64). Multivariate analysis showed that only CRP was an independent predictor of further events with an observed risk (OR) of 1.14 (P = 0.034, 95% CI 1.01-1.29). No association was observed with the levels of PRDX1 or EPO. A receiver operating curve (ROC) determined a cut-off CRP level of 3.25 µg/ml, with a 46% sensitivity and 81% specificity. Low-level inflammation as detected by hs-CRP is an independent predictor of recurrent cerebrovascular ischemic events.

Functional health and white matter hyperintensities as effect modifiers of blood pressure-lowering on cognitive function and vascular events in older Secondary Prevention of Small Subcortical Strokes trial participants.

OBJECTIVE: To determine whether cerebral small vessel disease or disability modify the effect of SBP treatment on cognitive and vascular outcomes in older patients with recent lacunar stroke. METHODS: Participants aged at least 65 years of the Secondary Prevention of Small Subcortical Strokes Trial were randomized to a higher (130-149 mmHg) or lower (<130 mmHg) SBP target. The primary outcome was change in cognitive function (Cognitive Abilities Screening Instrument); secondary outcomes were incident mild cognitive impairment, stroke, major vascular events (all-stroke, myocardial infarction), and all-cause death. Results were stratified by severity of white matter hyperintensities (WMH; none/mild, moderate, severe) on baseline MRI, and by disability (no vs. at least one limitation in activities of daily living). RESULTS: One thousand, two hundred and sixty-three participants (mean age 73.8 ±â€Š5.9 years, 40% women) were included. Participants with severe WMH or disability had worse cognitive function at baseline and after a mean follow-up of 3.9 years. No significant interactions existed between treatment group and effect modifiers (WMH, disability) for change in cognitive function (P for interaction 0.42 and 0.66, respectively). A lower SBP target appeared more beneficial among those with worse WMH burden for vascular outcomes (P for interaction = 0.01 for stroke and 0.03 for major vascular events). CONCLUSION: There was no difference in the effect of lowering SBP to less than 130 mmHg on cognitive function by cerebral small vessel disease or disability among older adults with a history of lacunar stroke. Those with evidence of small vessel disease may derive greater benefit from lower SBP on prevention of subsequent vascular events. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00059306.

Collateral Recruitment Is Impaired by Cerebral Small Vessel Disease.

Background and Purpose- Cerebral small vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate whether chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods- Consecutive patients with middle cerebral artery or internal carotid artery occlusion presenting within 6 hours after stroke symptom onset who underwent thrombectomy from 2012 to 2017 were included. The prespecified primary outcome was poor collateral flow, which was assessed on baseline computed tomographic angiography (poor, ≤50% filling; good, >50% filling). Markers of chronic SVD on brain magnetic resonance imaging were rated for the extent of white matter hyperintensities, enlarged perivascular spaces, chronic lacunar infarctions and cerebral microbleeds using the Standards for Reporting Vascular Changes on Neuroimaging criteria. Severity of SVD was quantified by adding the presence of each SVD feature, with a total possible score of 0 to 4; each SVD type was also evaluated separately. Multivariable logistic regression analyses were performed to evaluate the relationships between SVD and poor collaterals, with adjustment for potential confounders. Results- Of the 100 eligible patients, the mean age was 65±16 years, median National Institutes of Health Stroke Scale score was 15, and 68% had any SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals than patients without SVD (aOR, 1.9 [95% CI, 1.1-3.2]). Of the SVD types, poor collaterals were significantly associated with white matter hyperintensities (aOR, 2.9 per Fazekas increment [95% CI, 1.6-5.3]) but not with enlarged perivascular spaces (adjusted odds ratio [aOR], 1.3 [95% CI, 0.4-4.0]), lacunae (aOR, 2.1 [95% CI, 0.6-7.1]), or cerebral microbleeds (aOR, 2.1 [95% CI, 0.6-7.8]). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend P<0.001; adjusted P=0.056). There was a dose-dependent relationship between white matter hyperintensity burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1 to 3 (Ptrend=0.015). No patient with an SVD score of 4 had good collaterals. Conclusions- Chronic cerebral SVD is associated with poor recruitment of collaterals in large vessel occlusive stroke. A prospective study to elucidate the potential mechanism of how SVD may impair the recruitment of collaterals is ongoing.

Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke.

Ischemic stroke (IS), caused by obstruction of cerebral blood flow, is one of the leading causes of death. While neurologists agree on delineation of IS into three subtypes (cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS)), several subtyping systems exist. The most commonly used systems are TOAST (Trial of Org 10172 in Acute Stroke Treatment) and CCS (Causative Classification System for Stroke), but agreement is only moderate. We have compared two approaches to combining the existing subtyping systems for a phenotype suited for a genome-wide association study (GWAS). We used the NINDS Stroke Genetics Network dataset (SiGN, 11,477 cases with CCS and TOAST subtypes and 28,026 controls). We defined two new phenotypes: the intersect, for which an individual must be assigned the same subtype by CCS and TOAST; and the union, for which an individual must be assigned a subtype by either CCS or TOAST. The union yields the largest sample size while the intersect yields a phenotype with less potential misclassification. We performed GWAS for all subtypes, using the original subtyping systems, the intersect, and the union as phenotypes. In each subtype, heritability was higher for the intersect compared with the other phenotypes. We observed stronger effects at known IS variants with the intersect compared with the other phenotypes. With the intersect, we identify rs10029218:G>A as an associated variant with SVS. We conclude that this approach increases the likelihood to detect genetic associations in ischemic stroke.

Effect of cholinergic pathway disruption on cortical and subcortical volumes in subcortical vascular cognitive impairment.

BACKGROUND AND PURPOSE: The brain's cholinergic network has various interconnections with the cortical and subcortical structures. Disruption of cholinergic pathways by white matter hyperintensities (WMH) may cause pathologic changes within brain regions. Thus, WMH may represent an important pathological contributor to subcortical vascular cognitive impairment (scVCI). We aimed to investigate associations between the magnitude of WMH and volumetric changes in cortical and subcortical regions innervated by cholinergic neurons in patients with scVCI. METHODS: We enrolled patients with scVCI, defined as moderate to severe WMH or multiple (>2) lacunar infarcts outside the brainstem. Cholinergic Pathway HyperIntensities Scale (CHIPS) scores were used to quantify the magnitude of cholinergic pathway disruptions by WMH. We measured cortical thickness and subcortical volumes of 11 brain regions innervated by cholinergic neurons. Partial correlation of brain region volumes with total CHIPS scores was obtained using multiple linear regression. RESULTS: In total, 80 patients were enrolled. The mean age was 78.4 ± 6.5 years, median Mini-Mental State Examination score was 17 (interquartile range, 13-20) and median CHIPS score was 11 (interquartile range, 7-17). CHIPS scores were positively correlated with subcortical volumes of the putamen (r' = 0.46, P = 0.002) and pallidum (r' = 0.45, P = 0.002), and were negatively associated with inferior temporal (r' = -0.35, P = 0.002) and medial orbitofrontal (r' = -0.32, P = 0.002) cortical thickness. CONCLUSION: Our study suggested that WMH in cholinergic pathways may contribute to volumetric structural changes in cortical and subcortical structures innervated by cholinergic neurons.