Extensive White Matter Hyperintensities Research Articles

Neuropsychiatric symptoms and white matter hyperintensities in older adults without dementia.

We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS. Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set. Data were derived from 46 National Institute on Aging - funded Alzheimer's Disease Research Centers. NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH. Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU. Compared to CU individuals with no to mild WMH, the odds of having elation [9.87, (2.63-37.10)], disinhibition [4.42, (1.28-15.32)], agitation [3.51, (1.29-9.54)] or anxiety [2.74, (1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94, (1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status. Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.

Abstract WMP22: Higher Burden of Cerebral Small Vessel Disease is Associated With Risk of Incident Stroke in Community-Dwelling Individuals

Background: Mild manifestations of individual cerebral small vessel disease (CSVD) markers are common and may not denote increased risk, but high CSVD burden identifies individuals at increased risk of stroke and dementia. Scores incorporating multiple CSVD markers may better identify a person’s risk, but it remains unclear if they offer benefit beyond tools based on clinical factors alone such as the revised Framingham Stroke Risk Profile (FSRP). Therefore, we related a multi-marker CSVD score to risk of incident stroke and compared the findings with the FSRP in community-dwelling individuals. Methods: Framingham Heart Study (FHS) participants aged ≥55 years, free of stroke and dementia and with brain magnetic resonance imaging (MRI) ratings of CSVD markers were included. A multi-marker CSVD score reflecting increasing CSVD burden was used (one point each for presence of cerebral microbleeds, severe perivascular spaces, extensive white matter hyperintensities, covert brain infarcts, and cortical superficial siderosis, ranging 0-5). Multivariable Cox proportional hazards regression analyses were used to relate CSVD score to incident stroke. Results: Among 1,154 participants (46% male, mean age 70.9±8.7), 590 (51%) had score 0, 352 (31%) had score 1, 164 (14%) had score 2, and 48 (4%) had score ≥ 3. Over a median follow-up of 8.2 years (Q1-Q3: 5.1-12.5) from the time of MRI, 92 (8%) developed stroke. In models adjusting for time interval between clinic exam and MRI, FHS cohort, and FSRP score, number of CSVD manifestations was associated with increased risk of stroke in a dose-dependent manner: score 1 (HR: 1.73; 95% CI 1.05-2.84), score 2 (HR 1.83; 95% CI: 1.01-3.30), and score ≥ 3 (HR: 3.31; 95% CI: 1.50-7.28) in relation to participants with no CSVD markers. In comparison, a 5-percent increase in FSRP alone was associated with increased risk of stroke (HR: 1.25; 95% CI 1.15-1.36). Interpretation: Higher CSVD burden is associated with increased risk of stroke, beyond the effect explained by risk factors in the FSRP. These findings support consideration of CSVD burden to identify risk of stroke in community-dwelling individuals.

Abstract TP15: Association Between Prevalent Cardiovascular Disease Plus Atrial Fibrillation and Global Cerebral Small Vessel Disease- The Framingham Heart Study

Background: Cardiovascular diseases (CVD) contribute to stroke and dementia, which can be due to cerebral small vessel disease (CSVD) detectable on brain MRI. Aim: To determine the association between prevalent CVD and atrial fibrillation (AF) with CSVD. Methods: We assessed a composite of CVD including coronary heart disease, intermittent claudication, congestive heart failure (CHF) and AF, as well as the individual components. A multi-marker CSVD score was used to reflect increasing CSVD burden (cerebral microbleeds, high burden perivascular spaces, extensive white matter hyperintensity, or covert brain infarcts were assigned 1 point each, range 0-4). We related prevalent CVD or the individual components to the CSVD score using logistic regression analyses adjusted for age, sex, FHS cohort, time between MRI-clinic exam (model-1), and vascular risk factors (model-2). Results: In 3413 participants (mean age 59±14 years, 46.6% males), 8.4% had prevalent CVD, 4.1% had AF and 10.9% had both. One CSVD marker was seen in 22.7% participants, two in 7.1% and ≥3 in 1.82%. In multivariable-adjusted analyses prevalent CVD was associated with presence of one CSVD marker (OR 1.40, 95% confidence interval [CI] 1.07-1.84). The association with 2 or ≥3 markers did not reach statistical significance. The strongest association with subtype of CVD was between CHF and ≥3 CSVD markers (OR 5.67, 95% CI 1.90-16.9). Stratified analyses in subgroups by hypertension status, APOE- ε4 presence, and age < 65 years were limited by smaller number of events, with no significant differences. Interpretation: Prevalent CVD (including AF) is associated with presence of CSVD in community dwelling middle-aged adults free of stroke and dementia, with stronger associations with CHF.

Abstract TP39: Multi-Marker Cerebral Small Vessel Disease Score and Risk of Incident Depression: The Framingham Heart Study

Introduction: The vascular depression hypothesis postulates that cerebral small vessel disease (CSVD) contributes to the development of depression. A multi-marker CSVD score based on brain magnetic resonance imaging (MRI) could serve as a valuable tool for predicting the risk of developing vascular depression. This is important as depression can mimic cognitive impairment, dementia and is treatable. This study aimed to determine the relation of a MRI multi-marker CSVD score with incident depression in community-dwelling individuals. Methods: Framingham Heart Study participants from the Original and Offspring cohorts free of stroke, dementia and depression with available data on depression and CSVD ratings on MRI were included. Depression was defined as Center for Epidemiological Studies Depression scale score ≥16 or use of antidepressant medication. The multi-marker CSVD score was calculated by summing 1 point for individual CSVD markers present (covert brain infarcts, cerebral microbleeds, extensive white matter hyperintensities, high burden perivascular spaces, cortical superficial siderosis), ranging 0-5. Multivariable logistic regression models were used to relate the MRI-multi-marker CSVD score and incident depression in a primary analysis and individual CSVD biomarkers and depression in an exploratory analysis. Models were adjusted for age, sex, FHS cohort, time interval between MRI and clinic exam, body mass index, smoking, prevalent hypertension and diabetes. Results: In 1768 participants included (mean age 54.4±12.4 years, 54% male), the incidence of depression was 11% (median follow-up 6.0 years, IQR: 5.3-6.7). No CSVD score group had a statistically significant association with incident depression, however a CSVD score 3+ showed a trend towards increased odds of developing incident depression (OR 2.65 [0.87, 8.06], p =0.09). Among the individual CSVD markers, visible perivascular spaces had the highest odds for incident depression (OR 1.55 [0.96, 2.51] p =0.07). Conclusion: A higher multi-marker CSVD score might be associated with increased odds of incident depression. Further studies with a larger sample may help elucidate a potential association between this CSVD burden and onset of depression.

Abstract WMP16: Multi-Marker Cerebral Small Vessel Disease Score and Risk of Incident Dementia in the Framingham Heart Study

Background: Individual magnetic resonance imaging (MRI) markers of cerebral small vessel disease (CSVD) are associated with impaired cognition and dementia but may not reflect the overall burden of CSVD. It is unclear whether these markers provide additional value in evaluating the risk of dementia beyond assessments based solely on clinical risk factors. Thus, we aimed to determine whether the association of additive burden of multiple CSVD markers was independent of vascular risk factors and the Framingham Stroke Risk Profile (FSRP) and to also compare results with the FSRP. Methods: We included 1,152 Framingham Heart Study (FHS) participants over the age of 55, free of stroke and dementia, from the Original and Offspring cohorts with available MRI and FSRP data. CSVD score was calculated by summing the number of CSVD features detected in the MRI: cerebral microbleeds, cerebral brain infarcts, extensive white matter hyperintensities, severe perivascular spaces, and cortical superficial siderosis. Two Cox proportional hazards regression models were used to relate the multi-marker CSVD score to incident all-cause dementia and Alzheimer’s dementia. The first model adjusted for education, cohort, and clinical risk factors while the second adjusted for education, cohort, and FSRP. Results: Mean age was 70.9 years (SD: 8.7), 527 (46%) were male, and 211 (18%) had score ≥ 2. Over a median follow-up time of 6.4 years (Q1-Q3: 4.6-11.3), participants with score ≥ 2 had elevated risk of all-cause dementia compared to those with no CSVD markers after adjustment for FSRP (HR: 2.32; 95% CI: 1.46-3.69; p<0.001) and vascular risk factors (HR: 1.76; 95% CI: 1.10-2.81; p=0.02). Score ≥ 2 was also significantly associated with AD after adjustment for FSRP (HR: 2.05; 95% CI: 1.19-3.62; p<0.01), but not vascular risk factors (HR: 1.50; 95% CI: 0.87-2.60; p=0.15). In addition, a 5-percent increase in FSRP was independently associated with incident dementia after adjustment for education and FHS cohort (HR: 1.21; 95% CI: 1.13-1.30; p<0.001). Conclusions: Our results support the use of CSVD score as an indicator for dementia risk and it may be as robust as the FSRP. Further studies are necessary to validate the use of CSVD score in quantifying dementia risk.

White matter hyperintensity burden and collateral circulation in acute ischemic stroke with large artery occlusion

ObjectiveThis study aimed to investigate the association between white matter hyperintensity (WMH) burden and pial collaterals in acute strokes caused by intracranial large artery occlusion treated with mechanical thrombectomy in the anterior circulation, focusing on stroke subtypes.MethodsConsecutive patients undergoing mechanical thrombectomy between December 2019 and June 2022 were retrospectively screened. The Fazekas scale assessed WMH burden. Pial collaterals were categorized as either poor (0–2) or good (3–4) based on the Higashida score. A multivariable analysis was used to determine the relationship between WMH burden and pial collaterals. Subgroup analyses delved into associations stratified by stroke subtypes, namely cardioembolism (CE), tandem lesions (TLs), and intracranial atherosclerosis (ICAS).ResultsOf the 573 patients included, 274 (47.8%) demonstrated poor pial collaterals. Multivariable regression indicated a strong association between extensive WMH burden (Fazekas score of 3–6) and poor collaterals [adjusted OR 3.04, 95% CI 1.70–5.46, P < 0.001]. Additional independent predictors of poor collaterals encompassed ICAS-related occlusion (aOR 0.26, 95% CI 0.09–0.76, P = 0.014), female sex (aOR 0.63, 95% CI 0.41–0.96, P = 0.031), and baseline Alberta Stroke Program Early Computed Tomography scores (aOR 0.80, 95% CI 0.74–0.88, P < 0.001). Notably, an interaction between extensive WMH burden and stroke subtypes was observed in predicting poor collaterals (P = 0.001), being pronounced for CE (adjusted OR 2.30, 95% CI 1.21–4.37) and TLs (adjusted OR 5.09, 95% CI 2.32–11.16), but was absent in ICAS (adjusted OR 1.24, 95% CI 0.65–2.36).ConclusionsAmong patients treated with mechanical thrombectomy for anterior circulation large artery occlusion, extensive WMH burden correlates with poor pial collaterals in embolic occlusion cases (CE and TLs), but not in ICAS-related occlusion.

Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease

IntroductionThe standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. MethodWe identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. ResultsAll six IOPD patients (4 males/2 females) had been treated with ERT for 12–15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9–15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DiscussionAmong a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Reciprocal relationships between stress and depressive symptoms: the essential role of the nucleus accumbens.

Stress and depression have a reciprocal relationship, but the neural underpinnings of this reciprocity are unclear. We investigated neuroimaging phenotypes that facilitate the reciprocity between stress and depressive symptoms. In total, 22 195 participants (52.0% females) from the population-based UK Biobank study completed two visits (initial visit: 2006-2010, age = 55.0 ± 7.5 [40-70] years; second visit: 2014-2019; age = 62.7 ± 7.5 [44-80] years). Structural equation modeling was used to examine the longitudinal relationship between self-report stressful life events (SLEs) and depressive symptoms. Cross-sectional data were used to examine the overlap between neuroimaging correlates of SLEs and depressive symptoms on the second visit among 138 multimodal imaging phenotypes. Longitudinal data were consistent with significant bidirectional causal relationship between SLEs and depressive symptoms. In cross-sectional analyses, SLEs were significantly associated with lower bilateral nucleus accumbal volume and lower fractional anisotropy of the forceps major. Depressive symptoms were significantly associated with extensive white matter hyperintensities, thinner cortex, lower subcortical volume, and white matter microstructural deficits, mainly in corticostriatal-limbic structures. Lower bilateral nucleus accumbal volume were the only imaging phenotypes with overlapping effects of depressive symptoms and SLEs (B = -0.032 to -0.023, p = 0.006-0.034). Depressive symptoms and SLEs significantly partially mediated the effects of each other on left and right nucleus accumbens volume (proportion of effects mediated = 12.7-14.3%, p < 0.001-p = 0.008). For the left nucleus accumbens, post-hoc seed-based analysis showed lower resting-state functional connectivity with the left orbitofrontal cortex (cluster size = 83 voxels, p = 5.4 × 10-5) in participants with high v. no SLEs. The nucleus accumbens may play a key role in the reciprocity between stress and depressive symptoms.

Exploring HTRA1-Autosomal Dominant Disease: Literature Review of Clinical Features and Molecular Mechanisms

Heterozygous HTRA1-autosomal dominant disease is a gradually recognized hereditary cerebral small vessel disease (cSVD) characterized by debilitating conditions and extensive white matter hyperintensities (WMHs), but doubts remain on the underlying mechanisms of this disease. This review summarizes the clinical, MRI, and molecular genetics features of heterozygous HTRA1-autosomal dominant disease in combination with two better-studied hereditary cSVDs. A total of 31 mutations in HTRA1-autosomal dominant cases documented between 2020 and 2023 were also reviewed, characterizing the mutation features and clinical manifestations. This review aims to gain better insight into the unique characteristics of the disease and its correlations with other hereditary cSVDs.

Investigating the factors that explain white matter hyperintensity load in older Indians.

White matter hyperintensities are areas of hyperintense signal on MRI that typically represent cerebrovascular pathology. While focal white matter hyperintensities are common among older individuals, extensive white matter hyperintensities have been found to accelerate the progression of dementia. However, little is currently known about how various socioeconomic, health, lifestyle and environmental factors affect the severity of these lesions, particularly in low- and middle-income countries such as India. We investigated this question using cross-sectional MRI data (n = 126) from a pilot neuroimaging sub-study of an ongoing, nationally representative epidemiological study of late-life cognition in India. As a screening step, we estimated white matter hyperintensity load from fluid-attenuated inversion recovery MRI using a fully automated technique and tested for associations with each factor separately, controlling for age, sex and estimated total intracranial volume in each case. A combined model of white matter hyperintensity load included five factors which were significant after multiple comparisons correction: systolic blood pressure, body mass index, urbanicity status (urban versus rural living), daily chore hours and the frequency of store trips. This model explained an additional 27% of the variance in white matter hyperintensity load (54 versus 27% for the baseline model with only age, sex and estimated total intracranial volume). We accounted for the possibility of reverse causality by additionally controlling for concurrent markers of neurodegeneration and cognitive impairment, with no substantial change in our findings. Overall, our findings suggest that controlling high blood pressure and maintaining both a healthy body mass index and high levels of physical activity may reduce white matter hyperintensity load in older Indian adults, helping to prevent or delay dementia.

Enlarged perivascular spaces are linked to freezing of gait in Parkinson's disease.

ObjectiveFreezing of gait (FOG) is one of common and disabling gait impairments of Parkinson's disease (PD). White matter hyperintensity (WMH) and lacunes, as common manifestations of cerebral small vessel diseases (CSVD), have been reported to be associated with gait function in PD patients. However, in the cases with FOG which present with extensive WMH or lacunes, it actually is difficult to distinguish pure PD pathology from vascular origin or combined effects. So far little is known about the correlation between enlarged perivascular space (PVS) and FOG in PD patients. This study aims to explore the role of enlarged PVS in FOG in PD patients.MethodsA total of 95 patients with PD in the absence of obvious WMH and lacunes were included in our study, which were divided into PD-FOG (+) group and PD-FOG (-) group. Demographic and clinical data were investigated. Enlarged PVS in the centrum semiovale (CSO) and basal ganglia (BG) were assessed. The association between enlarged PVS and FOG in patients with PD was analyzed using the multivariate models and the Spearman's correlation.ResultsThere were 36 PD patients grouped into PD-FOG (+) (37.9%), with an older age, a longer PD disease duration, and larger numbers of enlarged PVS in CSO and BG compared with PD-FOG (-) group. The highest-severity degree of enlarged PVS burden in CSO was independently associated with FOG in patients with PD [adjusted odds ratio (OR), 3.869; p = 0.022 in multivariable model]. The percentages of FOG case increased accompanied by the aggravation of enlarged PVS located in CSO. The grade and count of enlarged PVS in CSO and BG both correlated with FOGQ score in PD patients.ConclusionEnlarged PVS, particularly in CSO, are associated with FOG in patients with PD, which provides a novel perspective for the mechanisms of FOG in PD.

NEUROLOGICALLY ASYMPTOMATIC PATIENTS FREQUENTLY PRESENT CEREBRAL INJURIES DURING MALIGNANT HYPERTENSION: A MRI STUDY

Objective: Acute and diffuse microvascular damage characterizes malignant hypertension (MHT), the deadliest form of hypertension. Although its ophthalmological, renal and cardiological repercussions are well known, brain involvement is considered rare with few descriptions, although it is one of the main causes of death. We aim to describe brain MRI abnormalities in patients admitted for MHT crisis but without objective neurological signs. Design and method: This single-center, cross-sectionnal observational study recruited patients with malignant Hypertension (MHT). MHT was defined by severe hypertension and severe hypertensive retinopathy OR subacute damage of three among the target organs: heart, kidney, brain, vessels (thrombotic microangiopathy). Patients under 18 years old, under chronic dialysis and not willing to participate were excluded. Brain MRI was performed within 21 days following diagnosis and was reviewed by a stroke neurologist who recorded the following markers: acute ischemic stroke(DWI and FLAIR positive), acute intracerebral hemorrhage (T2* and FLAIR positive), acute brain edema with extensive posterior white matter hyperintensity suggesting a PRES, and small vessel disease including old lacunar infarct, white matter hyperintensities (WMH), presence of dilated perivascular spaces. Results: We included 58 patients without neurological signs, 66% were men, and mean age was 45.6+/-11.3 years. Brain MRI were normal in 26% of patients but we found at least one acute abnormality on brain MRI in 29% and an Small Vessel Disease score (SVD score) of two or higher in 52%.In patients with neurological signs, these findings were 9, 53 and 70%, respectively. A PRES was found in 16% of asymptomatic patients and 31% had an ischemic stroke and/or a cerebral hematoma. Conclusions: PRES, recent hematoma, ischemic stroke and severe cerebral microangiopathy are common findings in MHT patients without neurological signs on admission. The impact of these findings on patient management, and their cerebrovascular and cognitive prognostic value, should be established. Brain MRI might need to become systematic in patients suffering from MHT episodes.

IS HEADACHE AT ADMISSION ASSOCIATED WITH HIGHER RATE OF RECENT BRAIN MRI INJURY DURING MALIGNANT HYPERTENSION CRISIS?

Objective: Reliable clinical signs associated with recent brain injuries in neurologically asymptomatic patients during malignant hypertension crisis are lacking. We aimed to compare the prevalence of brain MRI injuries between fully asymptomatic patients and those with isolated headache. Design and method: This single-center, cross-sectionnal observational study recruited patients with malignant Hypertension (MHT). MHT was defined by severe hypertension and severe hypertensive retinopathy OR subacute damage of three among the target organs: heart, kidney, brain, vessels (thrombotic microangiopathy). Patients under 18 years old, under chronic dialysis and not willing to participate were excluded. IBrain MRI was performed within 21 days following diagnosis and was reviewed by a stroke neurologist who recorded the following markers: acute ischemic stroke(DWI and FLAIR positive), acute intracerebral hemorrhage (T2* and FLAIR positive), acute brain edema with extensive posterior white matter hyperintensity suggesting a PRES, and small vessel disease including old lacunar infarct, white matter hyperintensities (WMH), presence of dilated perivascular spaces. Primary endpoint was the prevalence of recent brain injury in both group. Results: 92 patients were included. Among them, the average age was 47.8 years, 67 % were men, average admission systolic blood pressure and diastolic blood pressure were respectively 213 +/- 31 mmHg and 119 +/- 19 mmHg, 73 % had severe hypertensive retinopathy, median(IQR) creatininemia was 115 (92–180) mol/l and 11 % had systemic Hemolysis. Patients with no clinical symptoms or isolated headache presented respectively 39.5 % and 40 % of recent brain MRI abnormalities (cerebral Hematoma, ischemic stroke or PRES, p = 0.96). Patients with neurological signs on admission tended to have a higher frequency of recent brain injury than patients with isolated headaches (64,5%, p = 0,06), and a higher prevalence of chronic lacunar infarct (70,5% vs 44%, p = 0,04). We found no difference regarding cerebral microangiopathy in the 3 groups. Conclusions: Prevalence of recent brain injuries among patients with isolated headache and fully asymptomatic patients at admission of malignant hypertensive patients are similar and high. This raises the question of systematically performing brain MRI in patients with malignant hypertensive crisis.

Sex-Specific Causes and Consequences of White Matter Damage in a Middle-Aged Cohort.

ObjectiveTo evaluate potential sex-specific effects of multiple cardiovascular risk factors on white matter pathology in normal aging men and women, as well as potential sex-differences in the association of white matter pathology and cognitive functions.MethodsWe analyzed cross-sectional data of 581 participants (median age: 53 years, 54% women) of the population-based cohort of the BiDirect Study who completed clinical examinations, five neuropsychological tests, and an 3T MRI examination. White matter pathology was determined by the extent of white matter hyperintensities (WMH) on FLAIR images as well as the magnitude of global fractional anisotropy (FA) based on diffusion tensor imaging. Main effects, interaction as well as sex-stratified generalized linear regression models were used to evaluate the moderating effect of sex on the association of hypertension, diabetes mellitus, smoking, and obesity with WMH and FA, respectively. Associations of imaging markers with cognitive test results were determined with linear regression models.ResultsHypertension showed stronger associations with more extensive WMH and less FA in women compared to men. Current smoking was associated with more severe WMH in women only. Adjusted for age and education, WMH were not significantly associated with cognitive tests, but higher FA was associated with better performance in motor function in both sexes and with executive functions in men, even after adjustment for cardiovascular risk factors.ConclusionWe observed a stronger association of hypertension and smoking with white matter damage in women, suggesting a higher susceptibility for vascular pathology in women. However, there was no association of WMH with cognition, and FA was associated with executive function tests only in men, suggesting a higher cognitive reserve in women.

Impact of Encephalomalacia and White Matter Hyperintensities on ASPECTS in Patients With Acute Ischemic Stroke: Comparison of Automated and Radiologist-Derived Scores.

BACKGROUND. Automated software-based Alberta Stroke Program Early CT Score (ASPECTS) on unenhanced CT is associated with clinical outcomes after acute stroke. However, encephalomalacia or white matter hyperintensities (WMH) may result in a falsely low automated ASPECTS if such findings are interpreted as early ischemia. OBJECTIVE. The purpose of this study was to assess the impact of encephalomalacia and WMH on the automated ASPECTS in patients with acute stroke, in comparison with the radiologist-derived ASPECTS and clinical outcomes. METHODS. This retrospective three-center study included 459 patients (322 men, 137 women; median age, 65 years) with acute ischemic stroke treated by IV thrombolysis who underwent baseline unenhanced CT within 6 hours after symptom onset and MRI within 24 hours after treatment. ASPECTS was determined by automated software and by three radiologists in consensus. Presence of encephalomalacia and extent of WMH (categorized using the modified Scheltens score [mSS]) were also determined using MRI. Kappa coefficients were used to compare the ASPECTS between automated- and radiologist-derived methods. Multivariable logistic regression analyses and ROC analyses were performed to explore the predictive utility of the baseline ASPECTS for unfavorable clinical outcomes (90-day modified Rankin score of 3-6) after thrombolysis. RESULTS. The median automated software-derived ASPECTS was 9, and the median radiologist consensus-derived ASPECTS was 10. Agreement between automated and radiologist-consensus ASPECTS, expressed as kappa, was 0.68, though agreement was 0.76 in patients without encephalomalacia and 0.08 in patients with encephalomalacia. In patients without encephalomalacia, agreement decreased as the mSS increased (e.g., 0.78 in subgroup with mSS < 10 vs 0.19 in subgroup with mSS > 20). By anatomic region, agreement was highest for the lateral middle cerebral artery (κ, 0.52) and lowest for the internal capsule (κ, 0.18). In multivariable analyses, both the automated (odds ratio, 0.69) and the radiologist-consensus (odds ratio, 0.57) ASPECTS independently predicted an unfavorable clinical outcome. For unfavorable outcome, the automated ASPECTS had an AUC of 0.70, sensitivity of 60.4%, and specificity of 70.7%, whereas the radiologist-consensus ASPECTS had an AUC of 0.72, sensitivity of 60.4%, and specificity of 80.5%. CONCLUSION. Presence of encephalomalacia or extensive WMH results in a lower automated than radiologist-consensus ASPECTS, which may impact predictive utility of automated ASPECTS. CLINICAL IMPACT. When using an automated software-derived ASPECTS, radiologists should manually confirm the score in patients with encephalomalacia or extensive leukoencephalopathy.

Polymorphisms in EPHX2 and CYP2J2 moderate associations between white matter hyperintensities and temporal lobe atrophy.

White matter hyperintensities (WMH) of presumed vascular origin commonly coincide with neurodegeneration. Previous studies have reported heterogeneous relationships between WMH and atrophy. Cytochrome P450 (CYP) 2J2 (CYP2J2) is involved in the vascular ischemic response and soluble epoxide hydrolase (EPHX2) metabolizes its products, which have been implicated in vascular pathology and WMH. Here we investigate the potential moderation effect of CYP2J2 and EPHX2 single nucleotide polymorphisms (SNPs), individually and interactively, on the association between WMH and atrophy. Patients with vascular cognitive impairment or neurodegenerative diagnoses (n=447) from the Sunnybrook Dementia Study (NCT01800214), Vascular Brain Health (VBH) study, and the Brain-Eye Amyloid Memory (BEAM) study were genotyped for SNPs in EPHX2 and CYP2J2. SNPs were genotyped by the Illumina Neurochip and were selected a priori based on literature. All participants were confirmed to have European ancestry via multi-dimensional scaling using the genotype data. Imaging analysis was performed on 3D T1 and T2/PD weighted images for brain segmentation and volumetric acquisition using SABRE, and WMH volumes were acquired on T2/PD/FLAIR images using Lesion Explorer. Linear regression models controlling for age, sex, Mini Mental State Exam, and head size were used to assess moderation effects of the SNPs (WMH×SNP interactions) on associations between WMH and temporal atrophy using SPSS (v.26). Presence of minor alleles were assessed using a dominant genetic model. The intron variant EPHX2 rs7816586 G/A polymorphism had a trending moderation effect on the association between periventricular WMH and left temporal atrophy where the minor A-allele (frequency=11.52%) was protective (F=3.958, p=0.047) in extensive WMH. The promoter variant CYP2J2 rs10889162 C/T had a significant moderation effect on the association between deep WMH and right temporal atrophy where the minor T-allele (frequency=8.61%) was protective in cases of extensive WMH (F=5.771, p=0.017). No interaction between the EPHX2 and CYP2J2 SNPs was detected. We identified potential moderation effects of genetic variation in EPHX2 and CYP2J2 on the association between WMH and temporal lobe atrophy across neurodegenerative diagnoses. The lack of SNP×SNP interactions suggests that these genes may act independently, consistent with WMH×SNP interaction effects that occurred in association with different anatomical WMH locations.

Abstract P323: Stroke Lesion Pattern-Specific Influence of White Matter Hyperintensities on Stroke Severity in Acute Ischemic Stroke

Introduction: MRI-detected white matter hyperintensity (WMH) burden is linked to the overall brain health and incident stroke outcomes. However, data are limited as to whether specific acute stroke lesion patterns purport greater stroke severity in patients with extensive pre-existing WMH. In this analysis, we sought to investigate lesion pattern-specific WMH effects on AIS severity. Methods: We analyzed clinical and lesion data from 621 AIS patients enrolled in the multi-site MRI-GENIE study. The acute NIHSS was modelled via Bayesian hierarchical regression. Using ten stroke lesion patterns, that served as input variables of main interest, we introduced a hierarchical level differentiating between patients with higher and lower than median WMH volume (WMHv). Lesion pattern posterior distributions for higher and lower WMHv patients were subtracted to infer substantial differences. Results: In this AIS cohort [age: 65.3±14.6, 60% male], a higher WMHv was associated with greater stroke severity only when specific left-hemispheric brain regions were infarcted. This “lesion pattern 3” was mainly characterized by left middle and inferior frontal gyrus, insular and opercular cortex, pre- and post-central gyrus, and subcortical basal ganglia regions ( Fig ). Conclusions: Higher WMH burden appears to enhance the detrimental effect of acute stroke lesions involving left-hemispheric brain regions underlying language and motor functions. This effect might be due to an exacerbated disruption of functional network integrity by the combination of WMH and stroke lesions and could be explored further in functional imaging studies that simultaneously considered information from both lesion types.

Abstract P332: Cerebral Small Vessel Disease Score in CADASIL: Relationships to Cognitive Dysfunctions

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease (cSVD) linked to NOTCH3 mutations and leading to the early onset of stroke and vascular cognitive impairment. Neuroimaging features of CADASIL include extensive white matter hyperintensity, lacunes, cerebral microbleeds and enlarged perivascular spaces. Researchers from the Rotterdam study recently proposed a MRI-based cSVD Score reflecting the overall burden of cerebrovascular injury (Yilmaz et al., 2018). Here, we explored the relevance of this cSVD Score in distinguishing CADASIL subjects from non-carriers and its relationships to cognition. We evaluated 26 NOTCH3 mutation carriers and 25 non-carriers from large Colombian families. Of the CADASIL subjects, 4 had previous strokes (symptomatic) and 22 had no history of strokes (asymptomatic). All subjects underwent a 3T MRI and a neuropsychological evaluation. Structural MRI markers of cSVD, as well as the cSVD Score, were quantified in each subject following established protocols. Demographic, cognitive and neuroimaging features across groups are presented in Table 1. The cSVD Score significantly differed between groups, after adjusting for age (Figure 1-A). In CADASIL subjects, the cSVD Score was negatively related to performance in Memory, Processing Speed, Executive Function, after accounting for age and education (Figure 1-B). These results suggest that the cSVD Score could be a useful marker of disease severity in CADASIL. Longitudinal studies are now needed to determine if this score allows predicting clinical outcomes in CADASIL, such as stroke or dementia.

Clinical Relevance of Cerebral Small Vessel Diseases.

Clinical Relevance of Cerebral Small Vessel Diseases.

Enlarged Perivascular Spaces and Cerebral Small Vessel Disease in Spontaneous Intracerebral Hemorrhage Patients.

Background: Cerebral small vessel disease (SVD) is associated with cognitive decline, depression, increased mortality, and disability in stroke patients. MRI-visible perivascular spaces (PVS) are a sensitive neuroimaging marker of SVD. We aimed to explore the risk factors and associations with other SVD markers of PVS in two topographical regions (in the basal ganglia [BG] and centrum semiovale [CS]) in a cohort of spontaneous intracerebral hemorrhage (ICH) patients.Method: We included 306 consecutive patients from a prospective spontaneous ICH cohort. We rated PVS, white matter hyperintensities (WMH), cerebral microbleeds (CMB), and lacunes with validated visual rating scale. We collected clinical information using standardized forms. We predefined severe PVS as score > 2 and examined associations between PVS in both BG and CS regions and clinical and imaging markers of SVD by logistic regression.Results: In the multivariable logistic regression, increasing age (OR = 1.075; 95% CI = 1.038–1.113, p < 0.001), high CS PVS degrees (OR = 6.906; 95% CI = 3.024–15.774, p < 0.001), extensive periventricular WMH (OR = 2.878; 95% CI = 1.298–6.379, p = 0.009), and the presence of CMB (OR = 4.073, 95% CI = 1.869–8.877, p < 0.001) were independently associated with BG PVS severity. Alcohol-drinking habit (OR = 2.805; 95% CI = 1.451–5.422, p = 0.002), hyperlipidemia history (OR = 3.782; 95% CI = 1.582–8.783, p = 0.003), high BG PVS degrees (OR = 6.293; 95% CI = 2.755–14.371, p < 0.001) and the presence of strictly lobar CMB (OR = 2.556, 95% CI = 1.285–5.085, p = 0.008) were independent predictors of increased CS PVS severity.Conclusion: MRI-visible PVS in BG and CS regions are inter-related and have different risk factors in spontaneous ICH patients. Further studies are needed to explore the mechanism and clinical importance of PVS, with possible implications for cerebrovascular disease prevention and effective treatments.