Severe White Matter Disease Research Articles

Morphological Associations between White Matter Disease and Index Stroke Lesion

Annotation. The aim of the research is to investigate the associations between white matter disease (WMD) parameters and index stroke lesion characteristics in patients with acute stroke. There are a number of studies that have examined the effect of WMD on the consequences of cerebral stroke, but few of them have addressed the issues of its effect on stroke focus parameters. The aim of the study is to establish relationships between WMD parameters and stroke focus characteristics in patients with acute cerebral stroke. 294 consecutive patients with acute stroke were enrolled. All participants underwent magnetic resonance imaging (MRI) and computed tomography (CT). Assessment for WMD markers and index stroke lesion parameters as well as clinical-neurological testing were performed. Statistical analysis was performed using the jamovi project (2022). Jamovi (Version 2.2.5) [Computer Software]. Sydney, Australia. In the multivariable analysis, WMD grade 3 significantly associated with stroke volume (b = 30.0; 95% CI 3.6 - 56.5, p = 0.026), more severe brain edema (OR = 2.4; 95% CI 1.0 - 5.8, p = 0.047). Irregular shape of WMD associated with brain edema (b = 0.4; 95% CI 0.1 - 0.7, p = 0.019) and ischemic penumbra growth (b = -0.7; 95% CI –1.2 - -0.1, p = 0.014). Patients with severe WMD had significantly higher prevalence of hemorrhagic transformation: 2 (3%) vs 29 (13%), p < 0.05 and more often had neuroimaging evidence of previous stroke lesions: 3 (5%) vs 34 (32%), p <0.001. Thus, WMD characteristics are independent predictors of larger index stroke volume, brain edema growth, early ischemic changes preceding thrombolytic therapy and hemorrhagic transformation of ischemic stroke lesion, which is important for better prognosis and preventive strategies.

Infection, delirium, and risk of dementia in patients with and without white matter disease on previous brain imaging: a population-based study

The increased risk of dementia after delirium and infection might be influenced by cerebral white matter disease (WMD). In patients with transient ischaemic attack (TIA) and minor stroke, we assessed associations between hospital admissions with delirium and 5-year dementia risk and between admissions with infection and dementia risk, stratified by WMD severity (moderate or severe vs absent or mild) on baseline brain imaging. We included patients with TIA and minor stroke (National Institutes of Health Stroke Score <3) from the Oxford Vascular Study (OXVASC), a longitudinal population-based study of the incidence and outcomes of acute vascular events in a population of 94 567 individuals, with no age restrictions, attending eight general practices in Oxfordshire, UK. Hospitalisation data were obtained through linkage to the Oxford Cognitive Comorbidity, Frailty, and Ageing Research Database-Electronic Patient Records (ORCHARD-EPR). Brain imaging was done using CT and MRI, and WMD was prospectively graded according to the age-related white matter changes (ARWMC) scale and categorised into absent, mild, moderate, or severe WMD. Delirium and infection were defined by ICD-10 coding supplemented by hand-searching of hospital records. Dementia was diagnosed using clinical or cognitive assessment, medical records, and death certificates. Associations between hospitalisation with delirium and hospitalisation with infection, and post-event dementia were assessed using time-varying Cox analysis with multivariable adjustment, and all models were stratified by WMD severity. From April 1, 2002, to March 31, 2012, 1369 individuals were prospectively recruited into the study. Of 1369 patients (655 with TIA and 714 with minor stroke, mean age 72 [SD 13] years, 674 female and 695 male, and 364 with moderate or severe WMD), 209 (15%) developed dementia. Hospitalisation during follow-up occurred in 891 (65%) patients of whom 103 (12%) had at least one delirium episode and 236 (26%) had at least one infection episode. Hospitalisation without delirium or infection did not predict subsequent dementia (HR 1·01, 95% CI 0·86-1·20). In contrast, hospitalisation with delirium predicted subsequent dementia independently of infection in patients with and without WMD (2·64, 1·47-4·74; p=0·0013 vs 3·41, 1·91-6·09; p<0·0001) especially in those with unimpaired baseline cognition (cognitive test score above cutoff; 4·01, 2·23-7·19 vs 3·94, 1·95-7·93; both p≤0·0001). However, hospitalisation with infection only predicted dementia in those with moderate or severe WMD (1·75, 1·04-2·94 vs 0·68, 0·39-1·20; pdiff=0·023). The increased risk of dementia after delirium is unrelated to the presence of WMD, whereas infection increases risk only in patients with WMD, suggesting differences in underlying mechanisms and in potential preventive strategies. National Institute for Health and Care Research and Wellcome Trust.

Abstract TP264: Does Cerebral White Matter Disease Predict Post-Stroke Fatigue or Depression in an Afro-Caribbean Cohort?

Background and Purpose: Fatigue and depression frequently occur after ischemic stroke and are associated with worse Health-Related Quality of Life. While there has been research on the correlation between the burden of white matter disease (WMD) and the onset of depressive symptoms, this relationship has yet to be validated in patients with stroke from minority groups. Methods: An IRB-approved retrospective, cross-sectional study. The study sampled a cohort of patients aged ≥18 years old who had stroke within the last 3 years and were assessed with standardized questionnaires for fatigue (Fatigue Assessment Scale [FAS], score range 10-50) and depression (Beck’s Depression Inventory, score range 0-63). Exclusion criteria included patients with prior depression or severely disabling pre-existing conditions that would confound assessment. Patients with available MRI were evaluated using the Fazekas scale (score range 0-3), a validated visual scale (correlates significantly with automated software), to grade WMD. Grading was conducted blinded to patient's fatigue and depression scores. The collected ordinal data presented a non-parametric distribution thus was analyzed using the Spearman correlation coefficient. Results: Of 72 patients with available MRI, 96% identified as African or Caribbean; mean age = 66, median FAS score = 19 (IQR 14-26), and median BDI score = 6 (IQR 2-11). The prevalence of stroke-related disability (modified ranking scale ≥ 2) was 38%. Within the Fazekas grading, the score was 0 in 12.4%, 1 in 41.4%, 2 in 31.7%, and 3 in 13.8%. Spearman correlation coefficients showed non significant associations between WMD severity and either depression ( R s =0.058, p=0.62, 95%CI -0.17,0.29) or fatigue ( R s =0.059, p=0.62, 95% CI -0.18,0.30). Conclusion: Our results suggest no association between WMD severity and the development of post-stroke fatigue or depression in an Afro-Caribbean population. However, the lack of statistical significance might be due to limited sample size and patient heterogeneity, since few patients exhibited high scores for fatigue and depression. Additional studies are needed to validate the absence of correlation.

64 Neuroimaging Evidence of Neurodegenerative Disease in Former Professional American Football Players Who “Fail” Validity Testing: A Case Series

Objective:Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).Participants and Methods:Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 &lt; 45 and RDS &lt; 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.Results:All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications &lt; 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z &lt; -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).Conclusions:Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.

Aphasia severity is modulated by race and lesion size in chronic survivors: A retrospective study

IntroductionIn stroke survivors with aphasia (SWA), differences in behavioral language performance have been observed between Black and White Americans. These racial differences in aphasia outcomes may reflect biological stroke severity, disparities in access to care, potential assessment bias, or interactions between these factors and race. Understanding the origin of disparities in aphasia outcomes is critical to any efforts to promote health equity among SWA. In this study, we explore aphasia outcomes by examining the relationship between race, socioeconomic status, and neurological factors in SWA. MethodEighty-five chronic left-hemisphere SWA (31 Black, 54 White) participated in the study. The primary aphasia outcome measure was the Western Aphasia Battery-Revised (WAB-R). Lesion size was measured based on manual lesion segmentations. FLAIR and T2 images were scored for severity of white matter disease. Independent sample t-tests were used to determine differences by race in education, age, income, aphasia severity, white matter disease, and lesion size. A linear regression model was used to explore factors that predicted aphasia severity on the WAB-R. ResultLevel of education and estimated income differed by race in our sample. For predictors of aphasia severity, the regression model revealed a significant effect of lesion size on WAB Aphasia Quotient and an interaction of race x lesion size, such that Black and White participants with small lesions had similar WAB scores, but in individuals with larger lesions, Black participants had lower WAB scores than White participants. ConclusionWe suggest two explanations for the difference between Black and White SWA in the relationship between lesion size and aphasia severity. First, the impact of disparities in access to rehabilitation after stroke may be more evident when a stroke is larger and causes significant aphasia. Additionally, an assessment bias in aphasia outcome measures may be more evident with increasing severity of aphasia. Future studies should further discern the drivers of observed disparities in aphasia outcomes in order to identify opportunities to improve equity in aphasia care.

Development of Parkinson Disease and Its Relationship with Incidentally Discovered White Matter Disease and Covert Brain Infarction in a Real-World Cohort.

This study aimed to examine the relationship between covert cerebrovascular disease, comprised of covert brain infarction and white matter disease, discovered incidentally in routine care, and subsequent Parkinson disease. Patients were ≥50 years and received neuroimaging for non-stroke indications in the Kaiser Permanente Southern California system from 2009 to 2019. Natural language processing identified incidentally discovered covert brain infarction and white matter disease and classified white matter disease severity. The Parkinson disease outcome was defined as 2 ICD diagnosis codes. 230,062 patients were included (median follow-up 3.72 years). A total of 1,941 Parkinson disease cases were identified (median time-to-event 2.35 years). Natural language processing identified covert cerebrovascular disease in 70,592 (30.7%) patients, 10,622 (4.6%) with covert brain infarction and 65,814 (28.6%) with white matter disease. After adjustment for known risk factors, white matter disease was associated with Parkinson disease (hazard ratio 1.67 [95%CI, 1.44, 1.93] for patients <70 years and 1.33 [1.18, 1.50] for those ≥70 years). Greater severity of white matter disease was associated with increased incidence of Parkinson disease(/1,000 person-years), from 1.52 (1.43, 1.61) in patients without white matter disease to 4.90 (3.86, 6.13) in those with severe disease. Findings were robust when more specific definitions of Parkinson disease were used. Covert brain infarction was not associated with Parkinson disease (adjusted hazard ratio=1.05 [0.88, 1.24]). Incidentally discovered white matter disease was associated with subsequent Parkinson disease, an association strengthened with younger age and increased white matter disease severity. Incidentally discovered covert brain infarction did not appear to be associated with subsequent Parkinson disease. ANN NEUROL 2022;92:620-630.

Vestibular findings in patients with white matter disease

BackgroundOlder people develop gait and balance dysfunction that is associated with the gradual onset of cerebral white matter disease. White matter disease is easily detected by neuroimaging, whereas small vessels are not; hence, the term small vessel disease is frequently used to describe the parenchyma lesions rather than the underlying small vessel alterations. This study was done to investigate the relationship between the presence and/or absence of white matter disease identified on magnetic resonance imaging with the vestibular findings in elderly patients with dizziness. The current study was conducted on a total number of 30 elderly patients complaining of dizziness and/or instability. The inclusion criteria are patients above 55 years old and a history of vertigo and/or instability. All the study groups were subjected to full neuro-otological history, hearing assessment, video-nystagmography test (VNG), assessment of the risk of fall by functional gait assessment test (FGA), and radiological assessment: magnetic resonance stroke protocol.ResultsFGA total scores were significantly lower in patients with white matter disease (0.047) specifically PVWM score 3 (0.04) and DWM score 3 (0.19). Abnormal VNG test results were significantly higher in patients with atherosclerotic changes (0.04). The most common VNG finding abnormality was positional nystagmus.ConclusionsNormal VNG findings in elderly dizzy patients should be complemented with FGA test to assess the risk of falls. The presence of risk factors for white matter disease (WMD) as hypertension, diabetes mellitus, ischemic heart disease, hyperlipidemia, and migraine is an indication for requesting a further radiological assessment. The most frequent VNG abnormality in elderly patients with white matter disease is positional and positioning nystagmus, and a significant number of patients had positional nystagmus of the non-localizing criteria. FGA test scores are significantly related to the severity of white matter disease. The presence of atherosclerotic changes is significantly related to the presence of VNG test abnormality. It is important to ask the patient about the past history of migraine as it has an effect on VNG, FGA, and radiological findings.

Abstract TMP41: Local Epidemiology And Diagnostic Results Of Truly Occult Emboli In Patients With ESUS

Introduction: Ipsilateral nonstenotic (&lt;50%) internal carotid artery (ICA) plaque, cardiac atriopathy, and patent foramen ovale (PFO) may account for a substantial proportion of embolic stroke of undetermined source (ESUS). Methods: Consecutive stroke patients at our center (2019-2021) with unilateral, anterior ESUS were categorized into the following mutually exclusive etiologies: (1) nonstenotic ipsilateral ICA plaque (≥3mm), (2) atriopathy (sex-adjusted mod-to-severe atrial enlargement) &amp; (3) PFO. Clinical and diagnostic results were compared between patients in each group, and against those with “true ESUS” (who failed to meet criteria for these 3 groups). Results: Of 133 included patients, there was minimal overlap between the mutually exclusive ESUS etiologies (2 having nonstenotic plaque + atriopathy, and 1 having atriopathy + PFO). Older patients more frequently had atriopathy, while patients with PFO had fewer vascular risk factors when compared to the other groups (padj≤0.1; Table). Patients with nonstenotic plaque had more frequent tobacco use (p=0.06), more severe white matter disease (p=0.07), and greater ipsilateral v. contralateral plaque (p&lt;0.01). Twice as many patients with atriopathy presented with an ICA/M1/basilar occlusion (54%) when compared to other groups (p=0.03). Atriopathy was independently associated with older age (ORadj 1.09/year, 95%CI 1.02-1.17) and proximal occlusion (ORadj 16.47, 95%CI 2.86-94.65), with tobacco use associated with a non-atriopathic origin (ORadj 5.56/year, 95%CI 1.07-29.01). Five of 8 patients with atriopathy (63%) monitored with outpatient telemetry had atrial fibrillation, while 3/30 (10%) “true ESUS” and 0/12 (0%) nonstenotic plaque patients had atrial fibrillation. Conclusions: Certain clinical and radiographic features may be useful in predicting the proximal source of occult cerebral emboli, and can be used for cost-effective outpatient diagnostic testing.

Extent of white matter lesion is associated with early hemorrhagic transformation in acute ischemic stroke related to atrial fibrillation.

BackgroundHemorrhagic transformation (HT) after stroke, related to atrial fibrillation (AF), is a frequent complication, and it can be associated with a delay in the (re‐)initiation of oral anticoagulation therapy. We investigated the effect of the presence and severity of white matter disease (WMD) on early HT after stroke related to AF.MethodsA consecutive series of patients with recent (<4 weeks) ischemic stroke and AF, treated at the Hyper Acute Stroke Unit of the Imperial College London between 2010 and 2017, were enrolled. Patients with brain MRI performed 24–72 h from stroke onset and not yet started on anticoagulant treatment were included. WMD was graded using the Fazekas score.ResultsAmong the 441 patients eligible for the analysis, 91 (20.6%) had any HT. Patients with and without HT showed similar clinical characteristics. Patients with HT had a larger diffusion‐weighted imaging (DWI) infarct volume compared to patients without HT (p < .001) and significant difference in the distribution of the Fazekas score (p = .001). On multivariable analysis, HT was independently associated with increasing DWI infarct volume (odd ratio (OR), 1.03; 95% confidence interval (CI), 1.01–1.05; p < .001), higher Fazekas scores (OR, 1.94; 95% CI, 1.47–2.57; p < .001) and history of previous intracranial hemorrhage (OR, 4.80; 95% CI, 1.11–20.80; p = .036).ConclusionsPresence and severity of WMD is associated with increased risk of development of early HT in patients with stroke and AF. Further evidence is needed to provide reliable radiological predictors of the risk of HT in cardioembolic stroke.

Diffusion along perivascular spaces reveals evidence supportive of glymphatic function impairment in Parkinson disease

BackgroundReduced diffusion along perivascular spaces in adults with Alzheimer's-disease-related-dementias has been reported and attributed to reduced glymphatic function. ObjectivesTo apply quantitative measures of diffusion along, and orthogonal to, perivascular spaces in a cohort of older adults with and without clinical symptoms of alpha-synuclein related neurodegeneration. Methods181 adults with Parkinson disease (PD) or essential tremor (ET) additionally sub-classified by the presence of cognitive impairment underwent 3 T MRI. Diffusion-tensor-imaging (spatial resolution = 2x2x2 mm; b-value = 1000 s/mm2; directions = 33) measures of diffusion (mm2/s) parallel and orthogonal to perivascular spaces at the level of the medullary veins, and the ratio of these measures (ALPS-index), were calculated. Regions were identified by a board-certified neuroradiologist from T1-weighted and T2-weighted MRI. Evaluations of motor impairment and mild cognitive impairment (MCI) were interpreted by a board-certified neurologist and neuropsychologist, respectively. Multiple regression with false discovery rate correction was applied to understand how diffusion metrics related to (i) disease category (PD vs. ET), (ii) cognition (MCI status), and (iii) white matter disease severity from the Fazekas score. ResultsThe ALPS-index was reduced in PD compared to ET participants (p = 0.037). No association between the ALPS-index and MCI status, but an inverse association between the ALPS-index and Fazekas score (p = 0.002), was observed. The ALPS-index was inversely associated with age (p = 0.007). ConclusionDiffusion aberrations near perivascular spaces are evident in patients with alpha-synuclein related neurodegenerative disorders, and are related to age and white matter disease severity.

Agreement between neuroimages and reports for natural language processing-based detection of silent brain infarcts and white matter disease

BackgroundThere are numerous barriers to identifying patients with silent brain infarcts (SBIs) and white matter disease (WMD) in routine clinical care. A natural language processing (NLP) algorithm may identify patients from neuroimaging reports, but it is unclear if these reports contain reliable information on these findings.MethodsFour radiology residents reviewed 1000 neuroimaging reports (RI) of patients age > 50 years without clinical histories of stroke, TIA, or dementia for the presence, acuity, and location of SBIs, and the presence and severity of WMD. Four neuroradiologists directly reviewed a subsample of 182 images (DR). An NLP algorithm was developed to identify findings in reports. We assessed interrater reliability for DR and RI, and agreement between these two and with NLP.ResultsFor DR, interrater reliability was moderate for the presence of SBIs (k = 0.58, 95 % CI 0.46–0.69) and WMD (k = 0.49, 95 % CI 0.35–0.63), and moderate to substantial for characteristics of SBI and WMD. Agreement between DR and RI was substantial for the presence of SBIs and WMD, and fair to substantial for characteristics of SBIs and WMD. Agreement between NLP and DR was substantial for the presence of SBIs (k = 0.64, 95 % CI 0.53–0.76) and moderate (k = 0.52, 95 % CI 0.39–0.65) for the presence of WMD.ConclusionsNeuroimaging reports in routine care capture the presence of SBIs and WMD. An NLP can identify these findings (comparable to direct imaging review) and can likely be used for cohort identification.

Abstract P329: White Matter Score Does Not Predict Post-tPA Hemorrhage in Elderly Patients Evaluated Acutely via Telestroke

Background: While tPA may be safe in the elderly, increasing age appears to augment risk of post-tPA symptomatic intracranial hemorrhage (sICH). Age-related white matter changes (ARWMC) are associated with increased sICH. Patients evaluated for acute ischemic stroke (AIS) via telestroke (TS) may not have access to MRI to allow incorporation of microbleeds in tPA decisions. We assessed if increased CT-based ARWMC was associated with increased sICH in elderly patients. Methods: Patients 80 years and older who received tPA for AIS at spoke hospitals were selected from our TS network registry from 9/2015 to 12/2018. TS spoke CT scans from patient presentation were reviewed by three of the authors for periventricular white matter (PWMC) and deep white matter (DWMC) changes. Total ARWMC score, based on the Fazekas score, was collected. Total ARWMC score was either mild (0-2), moderate (3-4), or severe (5-6). PWMC and DWMC were either mild (0-1) or moderate-severe (2-3). Logistic regression adjusted for age, sex, race, ethnicity, NIHSS and premorbid mRS was used to analyze relationship of ARWMC scores with sICH and patient-outcomes. Results: Of 241 patients, median age overall was 86 years (IQR 83-90), and 66% were female. The overall median ARWMC score was 3 (IQR 2-5). Regression analysis showed that more severe ARWMC scores did not lead to higher frequency of post-tPA ICH (moderate OR 0.57, CI 0.19-1.71; severe OR 1.32, CI 0.48-3.65) including sICH (moderate OR 0.78, CI 0.21-2.94; severe OR 2.09, CI 0.62-7.02). Similarly, severe PWMC and DWMC were not associated with increased risk of post-tPA ICH (PWMC OR 1.31, CI 0.51-3.38; DWMC OR 1.25, CI 0.52-3.01), including sICH (PWMC OR 1.61, CI 0.51-5.08; DWMC OR 1.81, CI 0.65-5.01). In our cohort, older patients had no difference in hemorrhage (ICH OR 0.93 CI 0.85-1.00: sICH OR 0.95 CI 0.86-1.04), and patients with less severe stroke were more likely to have hemorrhage (ICH OR 1.06 CI 1.02-1.10; sICH OR 1.08 CI 1.03-1.13). IRR among the CT scan readers was moderate (k=0.504). Conclusions: ARWMC scores were not associated with post-tPA ICH in the elderly. Our analysis lends support for the use of tPA despite severity of white matter disease. ARWMC should not be used to assist in tPA decision-making in elderly patients via telestroke.

Hemorrhagic risk after intravenous thrombolysis for ischemic stroke in patients with cerebral microbleeds and white matter disease

ObjectivesAim of this study was to evaluate the association between cerebral microbleeds (CMBs) and white matter disease (WMD) with intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) with rt-PA. We also evaluated whether CMBs characteristics and WMD burden correlate with symptomatic ICH and outcome.MethodsWe included acute ischemic stroke (AIS) patients treated with IVT. The number and location of CMBs as well as severity of WMD were rated analyzing pre- or post-treatment MRI. Multivariable regression analysis was used to determine the impact of CMB and WMD on ICH subgroups and outcome measures.Results434 patients were included. CMBs were detected in 23.3% of them. ICH occurred in 34.7% of patients with CMBs. Independent predictors of parenchymal hemorrhage were the presence of CMBs (OR 2.724, 95% CI 1.360–5.464, p = 0.005) as well as cortical-subcortical stroke (OR 3.629, 95% CI 1.841–7.151, p < 0.001) and atherothrombotic stroke subtype (OR 3.381, 95% CI 1.335–8.566, p = 0.010). Either the presence, or number, and location of CMBs, as well as WMD, was not independently associated with the development of SICH. No independent association between the presence, number, or location of CMBs or WMD and outcome measures was observed.ConclusionsThe results of our study suggest that the exclusion of eligible candidates to administration of IV rt-PA only on the basis of CMBs presence is not justified. The clinical decision should be weighed with a case-by-case approach. Additional data are needed to evaluate the benefit-risk profile of rt-PA in patients carrying numerous microbleeds.

In the Kingdom of Triphasic Waves, White Matter Is the Eminence Grise.

Triphasic waves (TWs) have been associated with multiple conditions and adverse outcomes. This study explores the role of white matter disease (WMD) in the generation of TWs when other common causes associated with these discharges are absent. This is a retrospective case series performed at Johns Hopkins Bayview Medical Center from January 2016 to May 2018, which screened for patients with severe WMD, who had TWs on EEG without the presence of commonly cited provoking factors, including (1) hepatic disease; (2) severe uremia over baseline; (3) the drugs cefepime, ifosfamide, lithium, and baclofen; or (4) global hypoxic-ischemic injury. A control population with no WMD or abnormal electrographic findings outside of theta-delta slowing was also identified. Eleven patients were identified. The most common comorbid condition was infection, occurring in 82% of patients. Infections were urinary tract infection (36%), respiratory (27%), and central nervous system (18%). Metabolic abnormalities included glucose aberrations (36%), calcium derangements (18%), and hypernatremia (9%). Structural abnormalities included acute stroke (9%) and chronic central nervous system abscess (9%). All except one patient had one or more structural, metabolic, or infectious abnormalities in addition to WMD. Comorbidities were not statistically different in the control population. This is the first series to demonstrate convincingly the presence of TWs in patients with WMD in the absence of commonly cited risk factors. The authors hypothesize that less recognized risk factors of WMD and mild metabolic or infectious abnormalities may be drivers of TWs. With a growing elderly population, the presence of WMD will increase, and treating physicians need to look beyond the common causes of TWs.

The assessment of cerebral white matter microstructure in cerebral small vessel disease based on the diffusion-weighted magnetic resonance imaging

Introduction. Multidimensional or biophysical modelling approaches are actively used to examine the complex microstructure of brain matter in diffusion-weighted MRI, where tissue structures are schematically simplified and divided into separate regions to calculate the diffusion values. This approach demonstrates greater specificity when compared with the widely used diffusion tensor MRI (DT-MRI) and its metrics. The aim of the study was to compare DT-MRI and the biophysical diffusion models, and to evaluate their possible use in a more precise studying of the affected white matter in cerebral small vessel disease (CSVD). Materials and methods. We examined 96 patients (including 65 women; mean age 61.0±6.6 years) with CSVD and 23 healthy volunteers, comparable in age and gender (including 15 women; mean age 58±6 years). The patients were divided into 3 groups according to the severity of white matter disease as measured using the Fazekas scale. All study subjects underwent a brain MRI (3 T) with diffusion-weighted MRI (b = 0, 1000 and 2500 sec/mm 2 , 64 gradient directions) followed by the data processing; we obtained DT-MRI metric maps, as well as white matter tract integrity model and model using the spherical mean technique. Results. Significant differences were found between the study groups (except groups F0 and F1) in all metrics when the overall value of the white matter skeleton was examined ( p £ 0.05): there was a decrease in tissue anisotropy and axonal density in the white matter, as well as increased intra- and extra-axonal coefficients with more severe white matter disease. Analysis of individual white matter regions showed that the radial diffusion values had greater intergroup differences than the axial diffusion values in the corpus callosum (particularly, in the body and splenium). Conclusion. Biophysical models allow us to evaluate white matter disease in patients with CSVD using structural tissue features and indirect measures of intra- and extracellular diffusion. To clarify and increase the statistical significance of the obtained results, it is necessary to analyse the diffusion metrics using data from a larger patient sample.

White Matter Disease and Outcomes of Mechanical Thrombectomy for Acute Ischemic Stroke.

The increased severity of white matter disease is associated with worse outcomes and an increased rate of intracerebral hemorrhage in patients with ischemic stroke undergoing thrombolytic treatment. However, whether white matter disease is associated with outcomes in patients undergoing endovascular treatment remains unclear. In this prespecified exploratory analysis of our prospective multi-institutional study that enrolled consecutive adult patients with anterior circulation ischemic stroke undergoing endovascular treatment from November 2017 to September 2018, we compared the following outcomes between patients with none-to-minimal (van Swieten score, 0-2) and moderate-to-severe (van Swieten score, 3-4) white matter disease using logistic regression: 90-day mRS 3-6, death, intracerebral hemorrhage, successful recanalization, and early neurologic recovery. Of the 485 patients enrolled in the Blood Pressure after Endovascular Stroke Therapy (BEST) study, 389 had white matter disease graded (50% women; median age, 68 years; range, 58-79 years). A van Swieten score of 3-4 (n = 74/389, 19%) was associated with a higher rate of 90-day mRS of 3-6 (45% versus 18%; adjusted OR, 2.73; 95% CI, 1.34-5.93; P = .008). Although the death rate was higher in patients with van Swieten scores of 3-4 (26% versus 15%), the adjusted likelihood was not significantly different (adjusted OR, 1.14; 95% CI, 0.56-2.26; P = .710). Ordered regression revealed a shift toward worse mRS scores with increasing van Swieten scores (adjusted common OR, 3.04; 95% CI, 1.93-4.84; P < .001). No associations between white matter disease severity and intracerebral hemorrhage, successful recanalization, and early neurologic recovery were observed. Moderate-to-severe white matter disease is associated with worse outcomes in patients undergoing endovascular treatment without a significant increase in hemorrhagic complications. Studies comparing patients with and without endovascular treatment are necessary to determine whether the benefit of endovascular treatment is attenuated with greater white matter disease.

Editors' note: WMH and long-term outcomes in ischemic stroke: A systematic review and meta-analysis

Cerebral microvascular ischemic disease is a leading cause of dementia in the adult population. In their meta-analysis of data from more than 70,000 patients with ischemic stroke, Dr. Georgakis and colleagues examined the association between severity of white matter disease on baseline CT or MRI with 4 outcome measures—all-cause dementia, long-term functional impairment, recurrent stroke, or death due to any cause. Using an elegant mixed-effects regression model, adjusting for multiple hypothesis testing, the investigators observed a significant increased risk of each of these outcome measures among patients with moderate to severe white matter disease when compared with patients with mild to no white matter disease. In response, Dr. Gupta reminds the reader that white matter disease is etiologically heterogeneous and does not always indicate microvascular ischemia—it may be migraine or medication-related—and therefore may not universally portend an increased risk of vascular dementia or other morbidity. The investigators acknowledge this limitation of their meta-analysis; however, the relationship between (nonspecific) white matter disease and clinical outcomes remains robust. Whether the effect may be more strongly driven by patients with microvascular white matter disease and is attenuated by patients with toxic or nonvascular white matter disease remains to be clarified. Cerebral microvascular ischemic disease is a leading cause of dementia in the adult population. In their meta-analysis of data from more than 70,000 patients with ischemic stroke, Dr. Georgakis and colleagues examined the association between severity of white matter disease on baseline CT or MRI with 4 outcome measures—all-cause dementia, long-term functional impairment, recurrent stroke, or death due to any cause.

Abstract TMP19: MRI Characteristics and Predictors of Diffusion Weighted Hyperintense Lesions After Spontaneous Intracerebral Hemorrhage: A Secondary Analysis of MISTIE-III

Introduction: Mechanisms of diffusion weighted hyperintense lesions (DWIHL) after spontaneous intracerebral hemorrhage (ICH) are controversial. We evaluated mechanism and outcome of DWIHL. Methods: Protocolized MRI scans within 7 days from ICH were reviewed from MISTIE-III trial. Imaging analysis included DWIHL, leukoariosis (Fazekas score), enlarged perivascular space (EPVS), and cerebral microbleeds. Multivariable logistic regression analysis was performed to assess predictors and outcomes of having DWIHLs. Favorable outcome was defined as modified Rankin Score 0-3 at 12 months. Results: Of 499 patients, 300 underwent DWI studies (62% lobar ICH; 38% deep ICH) and 178 (59%) had acute DWIHLs (66% lobar; 34% deep). DWIHL locations were perihematomal in 140 (79%); and remote in 96 (54%). In multivariable regression analysis, DWIHLs were associated with initial mean arterial pressure [MAP] (odds ratio [OR]: 1.004; 95% confidence interval [CI]: 1.002-1.01), initial ICH volume (OR: 1.004; 95%CI: 1.001-1.01), NIHSS at randomization (OR: 1.01; 95%CI: 1.01-1.02), hypertension history (OR: 1.41; 95%CI: 1.04-1.93), and Fazekas score (OR: 1.04; 95%CI: 1.01-1.08). Patients with DWIHLs were less likely to have favorable outcome (66% vs. 50%; OR: 0.89; 95%CI: 0.81-0.99) after adjusting for ICH severity; however, the presence of DWIHLs did not confer an independent mortality risk at 12 months. In addition, perihematomal DWIHLs were associated with ICH volume (OR: 1.003; 95%CI: 1.00-1.01), NIHSS (OR: 1.01; 95%CI: 1.00-1.02), deep location (OR: 1.25; 95%CI: 1.10-1.42), and centrum semiovale EPVS score (OR: 0.99; 95% CI: 0.99-1.00). Remote DWIHLs were associated with Fazekas score (OR: 1.17; 95%CI: 1.06-1.29), centrum semiovale EPVS score (OR: 1.01; 95%CI: 1.00-1.01), atrial fibrillation (OR: 1.40; 95%CI: 1.04-1.90), and maximal ΔMAP on first 24 hours (OR: 1.004; 95%CI: 1.001-1.006). Conclusions: DWIHLs were common (59%) in patients after spontaneous ICH, predominantly in lobar locations and were associated with unfavorable neurologic outcome. While perihematomal DWIHLs were associated with ICH severity, remote DWIHLs suggested different mechanisms including acute blood pressure reduction, cardiac emboli, and white matter disease severity.

Abstract 156: Recurrent Stroke in Middle-Aged Lacunar Stroke Survivors: Understanding Risk Factors and Vulnerability in an Important Target Population

Background: The precise role of stroke risk factors in middle-aged people remains a significant knowledge gap. Confounding risk factors conferred by young and elderly stroke are largely avoided, providing a unique opportunity to understand the relationship between traditional risk factors and stroke. We aimed to determine the predictors of stroke and myocardial infarction (MI) in a unique middle-aged cohort with MRI-defined lacunar stroke. Methods: We conducted a reanalysis of data from the Secondary Prevention of Small, Subcortical Strokes (SPS3) clinical trial. We focused on middle-aged study participants, defined as those aged 40-60 years at study entry. We used multivariate Cox regression models to estimate the risk of recurrent stroke or MI. Results: Out of 3,020 total subjects from SPS3, 1,312 (mean age 53 [SD 5], 445 females [34%]) were in the middle-aged category and were included in this analysis. Of these, there were 619 (47%) white, 297 (23%) black, and 283 (22%) Hispanic subjects. Over a mean follow-up time of 3.90 years, there were 123 strokes (2.6% per patient-year) and 33 MIs (0.7% per patient-year). The rates (% per patient-year) of having a stroke or MI differed significantly across white (n=59, 2.7%), black (n=54, 5.1%), and Hispanic (n=27, 2.8%) ethnic groups (p=0.006). Significant risk factors for recurrent stroke or MI are described for middle-aged and all SPS3 subjects in the table. Conclusions: In middle-aged individuals with prior stroke, diabetes, greater white matter disease severity, black race, and family history were potent predictors of recurrent stroke. Male sex, diabetes, and heart disease were potent predictors of MI. Compared to the entire SPS3 cohort, these predictors confer a greater risk for recurrent stroke or MI in the middle-aged. These data identify modifiable risk factors and target populations that are especially vulnerable to vascular events or complications.

Cognitive Correlates of MRI-defined Cerebral Vascular Injury and Atrophy in Elderly American Indians: The Strong Heart Study.

American Indians experience substantial health disparities relative to the US population, including vascular brain aging. Poorer cognitive test performance has been associated with cranial magnetic resonance imaging findings in aging community populations, but no study has investigated these associations in elderly American Indians. We examined 786 American Indians aged 64 years and older from the Cerebrovascular Disease and its Consequences in American Indians study (2010-2013). Cranial magnetic resonance images were scored for cortical and subcortical infarcts, hemorrhages, severity of white matter disease, sulcal widening, ventricle enlargement, and volumetric estimates for white matter hyperintensities (WMHs), hippocampus, and brain. Participants completed demographic, medical history, and neuropsychological assessments including testing for general cognitive functioning, verbal learning and memory, processing speed, phonemic fluency, and executive function. Processing speed was independently associated with the presence of any infarcts, white matter disease, and hippocampal and brain volumes, independent of socioeconomic, language, education, and clinical factors. Other significant associations included general cognitive functioning with hippocampal volume. Nonsignificant, marginal associations included general cognition with WMH and brain volume; verbal memory with hippocampal volume; verbal fluency and executive function with brain volume; and processing speed with ventricle enlargement. Brain-cognition associations found in this study of elderly American Indians are similar to those found in other racial/ethnic populations, with processing speed comprising an especially strong correlate of cerebrovascular disease. These findings may assist future efforts to define opportunities for disease prevention, to conduct research on diagnostic and normative standards, and to guide clinical evaluation of this underserved and overburdened population.