Degree Of White Matter Hyperintensities Research Articles

Association of vulnerable plaques with white matter hyperintensities on high-resolution magnetic resonance imaging.

One of the widespread manifestations of cerebral small vessel disease (CSVD) of the brain parenchyma is white matter lesion, which appears as white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI). Previous studies have illustrated that large artery atherosclerosis is related to CSVD, but the precise progress of pathogenesis remains unknown. High-resolution MRI (HR-MRI) has the ability to delineate intracranial vascular walls, enabling a thorough exploration of the structure and composition of unstable plaques. This study aimed to apply HR-MRI to characterize the wall changes and plaque characteristics of middle cerebral arteries in patients with WMHs and to investigate the correlation between plaque vulnerability parameters and different degrees of WMHs. In this study, 138 patients with acute ischemic stroke at Harbin Medical University's First Clinical Hospital (May 2021 to October 2023) were cross-sectionally reviewed and underwent conventional brain and HR-MRI using T1-weighted 3D volumetric isotropic turbo spin echo acquisition (T1W-3D-VISTA) of the unilateral middle cerebral artery (MCA). According to Fazekas grade (0-6), the patients were divided into two groups: Fazekas score 0-2, no-or-mild WMHs; and Fazekas 3-6, moderate-to-severe WMHs. The intraplaque hemorrhage, plaque distribution, plaque enhancement, plaque load, remodeling pattern, and stenosis of the two groups were measured. Binary logistic regression analysis was conducted to evaluate the relationship between vulnerable plaques and WMHs. Of the participants who were initially considered for inclusion, 71 were deemed eligible, among whom 34 were placed in the no-or-mild WMH group and 37 in the moderate-to-severe WMH group. Between the two groups, there were significant differences in intraplaque hemorrhage (P=0.01), a wide distribution (P=0.02), and plaque enhancement (P=0.02). Univariate analysis showed that WMHs were associated with age [odds ratio (OR) =1.080; 95% confidence interval (CI): 1.020-1.144; P=0.008], hypertension (OR =3.500; 95% CI: 1.276-9.597; P=0.01), intraplaque hemorrhage (OR =3.955; 95% CI: 1.247-12.538; P=0.02), a wide distribution (OR =3.067; 95% CI: 1.159-8.115; P=0.02), and significant plaque enhancement (OR =4.372; 95% CI: 1.101-17.358; P=0.03); however, the multivariate results showed that the only independent factors associated with WMHs were age (OR =1.095; 95% CI: 1.019-1.176; P=0.01) and intraplaque hemorrhage (OR =5.88; 95% CI: 1.466-23.592; P=0.01). Our findings suggest that age and intraplaque hemorrhage may be associated with more severe WMHs in patients with acute ischemic stroke, which may be helpful for further clinical examination and intervention treatment.

Machine learning-based prediction of mild cognitive impairment among individuals with normal cognitive function.

Previous studies mainly focused on risk factors in patients with mild cognitive impairment (MCI) or dementia. The aim of the study was to provide basis for preventing MCI in cognitive normal populations. The data came from a longitudinal retrospective study involving individuals with brain magnetic resonance imaging scans, clinical visits, and cognitive assessment with interval of more than 3 years. Multiple machine-learning technologies, including random forest, support vector machine, logistic regression, eXtreme Gradient Boosting, and naïve Bayes, were used to establish a prediction model of a future risk of MCI through a combination of clinical and image variables. Among these machine learning models; eXtreme Gradient Boosting (XGB) was the best classification model. The classification accuracy of clinical variables was 65.90%, of image variables was 79.54%, of a combination of clinical and image variables was 94.32%. The best result of the combination was an accuracy of 94.32%, a precision of 96.21%, and a recall of 93.08%. XGB with a combination of clinical and image variables had a potential prospect for the risk prediction of MCI. From clinical perspective, the degree of white matter hyperintensity (WMH), especially in the frontal lobe, and the control of systolic blood pressure (SBP) were the most important risk factor for the development of MCI. The best MCI classification results came from the XGB model with a combination of both clinical and imaging variables. The degree of WMH in the frontal lobe and SBP control were the most important variables in predicting MCI.

Abstract WP186: The Burden of White Matter Hyperintensities on Function Outcomes in Patients Treated for Acute Ischemic Stroke: A Post-Hoc Analysis of the IMS-III Trial

Objective: This study is a post-hoc analysis of the Interventional Management of Stroke (IMS) III trial investigating the burden of white matter hyperintensities (WMH), using the van Swieten Scale (VSS), on functional outcomes for acute ischemic stroke (AIS) patients treated with either intravenous thrombolysis (IVT) or IVT with mechanical thrombectomy (MT). Background: WMH are a well-established marker for underlying cerebral microvascular disease. VSS quantifies the disease burden from zero to four with higher numbers signifying more advanced disease. A higher burden of WMH is associated with poor functional outcomes after IVT. However, early studies regarding WMH and outcomes after MT have been conflicting. Methods: We included IMS-III trial patients in either treatment arm whose VSS was graded on initial brain CT and 90-day function outcomes were not missing. The primary study outcome was a 90-days modified Rankin Scale of 0-2, termed good outcome. Results: There was a total of 656 patients enrolled in the trial and 618 patients were included in this analysis. The VSS grades of WMH range from 0-4 and included 476 (77.02%), 56 (9.06%), 38 (6.15%), 24 (3.88%), and 24 (3.88%) patients, respectively. Overall, higher VSS grade was associated with a lower probability of achieving a good functional outcome, even after adjustments (Figure 1). Of the 142 patients with any degree of WMH, only 22.5% had a good functional outcome compared to 46.6% of 476 patients without WMH (Table 1). Conclusions: Patients enrolled in the IMS-III trial with any burden of WMH on brain CT had a statistically significant lower odds of a good functional outcome compared to patients without WMH.

Effects of white matter hyperintensities on isolated executive function assessed by the Trail Making Test.

White matter hyperintensities (WMHs) on MRI are associated with cognitive dysfunction, particularly slow processing speed and executive dysfunction. However, it is not clear whether WMHs burden affects isolated executive function independent of aging when WMHs are assessed separately in periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH). To assess the relationship between the degree of WMHs and the performance on the Trail Making Test (TMT), which can evaluate isolated ability of set-shifting and working memory. 74 participants who visited our memory clinic and underwent the TMT subtests (TMT-A and TMT-B) and the Mini-Mental State Examination (MMSE). All subjects performed the TMT within the time limits and their MMSE scores were 24 or higher, and they were diagnosed as having normal cognition or mild cognitive impairment. The extent of PVH and DSWMH was graded from 0 to 3 using the Fazekas scale. We obtained testing time to complete the TMT-A and TMT-B, and calculated TMT-B minus TMT-A. We performed correlation analyses between the degree of WMHs and the time measures of the TMT subtests with adjustment of age. Average scores of the MMSE were not different among the groups either by PVH grade or by DSWMH grade. In contrast, average time required for the TMT-A, TMT-B, and TMT-B minus TMT-A increased along with exacerbation of PVH and DSWMH grade. After the adjustment of age we found significant association between only DSWMH grade and the time difference of TMT-B minus TMT-A. Exacerbation of PVH and DSWMH differentially affected isolated executive functions assessed by the TMT subtests independent of age and general cognitive function.

Cerebral Small Vessel Disease in Elderly Patients With Menière's Disease.

Menière's disease (MD) is an inner ear disease characterized by vertigo attacks, progressive hearing loss, tinnitus, and the sensation of aural fullness. Although the exact pathophysiology of MD is unknown, endolymphatic hydrops is considered to be its histopathological hallmark. It has been suggested that endolymphatic hydrops results from lowered perfusion pressure due to cardiovascular comorbidity. Cardiovascular risk factors can cause cerebral small vessel disease (CSVD), visible on MRI. The presence of CSVD in turn raises the risk of developing a stroke. This study aimed to compare the presence of CSVD and cardiovascular risk factors in elderly patients with MD to a control cohort. Patients diagnosed with MD, aged 50 years and older, were retrospectively reviewed and compared with a control cohort. The primary outcome was the difference in CSVD on MRI imaging, which was assessed by the number of white matter hyperintensities using the ordinal Fazekas scale. The secondary outcome was the presence of brain infarctions on MRI. A total of 111 patients with MD were compared with a control cohort of 111 patients. No difference in the degree of white matter hyperintensities (P = 0.890) was found between the MD and control cohort. Brain infarctions were seen in 8 of 111 patients with MD and 14 of 111 patients from the control cohort (P = 0.261). CSVD is not more frequently visible on MRI in elderly patients with MD than in controls. This result does not support hypoperfusion-induced ischemia in the pathophysiology of MD.

Impaired Kidney Function Small Vessel Disease Markers and Its Association with Periventricular White Matter Hyperintensities (P3-5.016)

<h3>Objective:</h3> We hypothesize that impaired kidney function is differentially associated with brain markers of SVD, and the association is greater with SVD markers restricted to deep, penetrating arteries. <h3>Background:</h3> Small vessel disease (SVD) is a condition associated with aging and vascular risk factors to which the brain and kidney are susceptible. However, whether kidney dysfunction may directly contribute to brain SVD as opposed to both organs being affected as an epiphenomenon of aging is less clear. <h3>Design/Methods:</h3> We leveraged existing data from our institution stroke registry. Odds ratio (OR), estimate, confidence intervals (CI), and p values were calculated. We rated visually the presence an anatomical location of cerebral microbleeds and chronic lacunar infarcts and used the Fazekas scale to semi-quantitate white matter hyperintensities. We created linear regression models adjusted for age, sex, race/ethnicity and vascular risk factors to evaluate the relationship between kidney function (defined as self-reported chronic kidney disease or creatinine on admission). <h3>Results:</h3> We included 973 patients (mean age 65±16 years, 51 % female). The prevalence of self-reported CKD/ESRD was 14% and the mean creatinine on admission was 1.61±2.04 mg/dl. The prevalence of chronic brain infarct was 40%, cerebral microbleeds 24%, and all had some degree of white matter hyperintensity. Calculated OR for deep location CMB in CKD/ESRD patients was 1.83 (p= 0.076). Beta estimate for periventricular WMH was 0.40 (p= 0.031) in CKD/ESRD patients and 0.51 (p= ≤0.01) in relation to the creatinine levels on admission. <h3>Conclusions:</h3> There is association between previous history of CKD-ESRD and creatinine levels on admission with periventricular WMH. These data also hint a possible association between CMB of deep location with history of CKD-ESRD, but a bigger sample is required for significance. <b>Disclosure:</b> Dr. Murguia Fuentes has nothing to disclose. Dr. Khasiyev has nothing to disclose. Dr. Gurel has nothing to disclose. Dr. Spagnolo-Allende has nothing to disclose. Dr. Rahman has nothing to disclose. Dr. Bueno has nothing to disclose. Mr. Murguia Fuentes has nothing to disclose. The institution of Dr. Marshall has received research support from NIH. Dr. Marshall has received publishing royalties from a publication relating to health care. Dr. Elkind has received personal compensation for serving as an employee of American Heart Association. Dr. Elkind has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Atria Academy. The institution of Dr. Elkind has received research support from BMS-Pfizer Alliance for Eliquis. The institution of Dr. Elkind has received research support from Roche. Dr. Elkind has received publishing royalties from a publication relating to health care. Dr. Elkind has a non-compensated relationship as a Officer with American Heart Association that is relevant to AAN interests or activities. Dr. Gutierrez has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Roetzel &amp; Andress, JOHN ASTUNO, JR. L.L.C.. The institution of Dr. Gutierrez has received research support from NIH. Dr. Gutierrez has received publishing royalties from a publication relating to health care. Dr. Gutierrez has received publishing royalties from a publication relating to health care.

Abstract TP183: Impaired Kidney Function Small Vessel Disease Markers And Its Association With Periventricular White Matter Hyperintensities

Introduction: Small vessel disease (SVD) is a condition associated with aging and vascular risk factors to which the brain and kidney are susceptible. However, whether kidney dysfunction may directly contribute to brain SVD as opposed to both organs being affected as an epiphenomenon of aging is less clear. We hypothesize that impaired kidney function is differentially associated with brain markers of SVD, and the association is greater with SVD markers restricted to deep, penetrating arteries. Methods: We leveraged existing data from the Columbia University Irving Medical Center/ New York Presbyterian Hospital Stroke Registry. Odds ratio (OR), estimate, confidence intervals (CI), and p values were calculated. We rated visually the presence an anatomical location of cerebral microbleeds and chronic lacunar infarcts and used the Fazekas scale to semi-quantitate white matter hyperintensities. We created linear regression models adjusted for age, sex, race/ethnicity and vascular risk factors to evaluate the relationship between kidney function (defined as self-reported chronic kidney disease or creatinine on admission). Results: We included 973 patients (mean age 65±16 years, 51 % female). The prevalence of self-reported CKD/ESRD was 14% and the mean creatinine on admission was 1.61±2.04 mg/dl. The prevalence of chronic brain infarct was 40%, cerebral microbleeds 24%, and all had some degree of white matter hyperintensity. Conclusion: There is association between previous history of CKD-ESRD and creatinine levels on admission with periventricular WMH. These data also hint a possible association between CMB of deep location with history of CKD-ESRD, but a bigger sample is required for significance.

Subjective vs informant-reported cognitive complaints have differential clinical significance in covert cerebral small vessel disease

ObjectiveSubjective cognitive complaints are common in patients with cerebral small vessel disease (cSVD), yet their relationship with informant evaluations, objective cognitive functions and severity of brain changes are poorly understood. We studied the associations of subjective and informant reports with findings from comprehensive neuropsychological assessment and brain MRI. MethodIn the Helsinki SVD Study, 152 older adults with varying degrees of white matter hyperintensities (WMH) but without stroke or dementia were classified as having normal cognition or mild cognitive impairment (MCI) based on neuropsychological criteria. The measures also included continuous domain scores for memory and executive functions. Cognitive complaints were evaluated with the subjective and informant versions of the Prospective and Retrospective Memory Questionnaire (PRMQ) and Dysexecutive Questionnaire (DEX); functional abilities with the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL); and depressive symptoms with the Geriatric Depression Scale (GDS-15). ResultsSubjective cognitive complaints correlated significantly with informant reports (r=0.40–0.50, p<0.001). After controlling for demographics, subjective and informant DEX and PRMQ were not related to MCI, memory or executive functions. Instead, subjective DEX and PRMQ significantly associated with GDS-15 and informant DEX and PRMQ with WMH volume and A-IADL. ConclusionsNeither subjective nor informant-reported cognitive complaints associated with objective cognitive performance. Informant-evaluations were related to functional impairment and more severe WMH, whereas subjective complaints only associated with mild depressive symptoms. These findings suggest that awareness of cognitive impairment may be limited in early-stage cSVD and highlight the value of informant assessments in the identification of patients with functional impairment.

Serum Homocysteine, Vitamin B12, Folate, and Their Association with Mild Cognitive Impairment and Subtypes of Dementia.

Although elevated levels of homocysteine (Hcy) are associated with cognitive impairment and dementia, the relevance of Hcy, vitamin B12, and folate levels to subtypes of dementia are still unknown. To investigate the changes of Hcy, vitamin B12, and folate levels in mild cognitive impairment (MCI) and subtypes of dementia including Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and Lewy body dementia (LBD), and their relationships with cognitive function and magnetic resonance imaging (MRI) markers. We measured serum levels of Hcy, vitamin B12, and folate in 257 subjects. Each subject underwent cognitive function assessment and brain MRI test. The Fazekas and temporal lobe atrophy (MTA) visual rating scales were used to assess the degree of white matter hyperintensities and MTA, respectively. Serum levels of Hcy was higher and vitamin B12 was lower in AD, VaD, FTD, and LBD groups than cognitively normal controls. No significant differences of folate levels were found among 6 groups. Hcy levels were positively correlated with MTA total score in AD (r = 0.448, p < 0.001). Vitamin B12 levels were positively correlated with MoCA in VaD (r = 0.497), and negatively correlated with MTA total score in AD (r = - 0.325) (ps < 0.05). Hyperhomocysteinemia may increase the risk of AD (OR = 2.744), VaD (OR = 3.600), and FTD (OR = 3.244) in the adjusted model (ps < 0.05). Hcy and vitamin B12 levels are associated with MTA in AD. Vitamin B12 levels are associated with general cognition in VaD. Hyperhomocysteinemia is a risk factor for not only AD and VaD but also FTD.

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

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). 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. 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). 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.

Neuropsychiatric symptoms are associated with exacerbated cognitive impairment in covert cerebral small vessel disease.

Neuropsychiatric symptoms are related to disease progression and cognitive decline over time in cerebral small vessel disease (SVD) but their significance is poorly understood in covert SVD. We investigated neuropsychiatric symptoms and their relationships between cognitive and functional abilities in subjects with varying degrees of white matter hyperintensities (WMH), but without clinical diagnosis of stroke, dementia or significant disability. The Helsinki Small Vessel Disease Study consisted of 152 subjects, who underwent brain magnetic resonance imaging (MRI) and comprehensive neuropsychological evaluation of global cognition, processing speed, executive functions, and memory. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory Questionnaire (NPI-Q, n = 134) and functional abilities with the Amsterdam Instrumental Activities of Daily Living questionnaire (A-IADL, n = 132), both filled in by a close informant. NPI-Q total score correlated significantly with WMH volume (rs = 0.20, p = 0.019) and inversely with A-IADL score (rs=-0.41, p < 0.001). In total, 38% of the subjects had one or more informant-evaluated neuropsychiatric symptom. Linear regressions adjusted for age, sex, and education revealed no direct associations between neuropsychiatric symptoms and cognitive performance. However, there were significant synergistic interactions between neuropsychiatric symptoms and WMH volume on cognitive outcomes. Neuropsychiatric symptoms were also associated with A-IADL score irrespective of WMH volume. Neuropsychiatric symptoms are associated with an accelerated relationship between WMH and cognitive impairment. Furthermore, the presence of neuropsychiatric symptoms is related to worse functional abilities. Neuropsychiatric symptoms should be routinely assessed in covert SVD as they are related to worse cognitive and functional outcomes.

Increased Serum NSE and S100B Indicate Neuronal and Glial Alterations in Subjects Under 71 Years With Mild Neurocognitive Disorder/Mild Cognitive Impairment.

BackgroundMild cognitive impairment (MCI) is considered a pre-stage of different dementia syndromes. Despite diagnostic criteria refined by DSM-5 and a new term for MCI – “mild neurocognitive disorder” (mild NCD) – this diagnosis is still based on clinical criteria.MethodsTo link mild NCD to the underlying pathophysiology we assessed the degree of white matter hyperintensities (WMH) in the brain and peripheral biomarkers for neuronal integrity (neuron-specific enolase, NSE), plasticity (brain-derived neurotrophic factor, BDNF), and glial function (S100B) in 158 community-dwelling subjects with mild NCD and 82 healthy controls. All participants (63–79 years old) were selected from the Leipzig-population-based study of adults (LIFE).ResultsSerum S100B levels were increased in mild NCD in comparison to controls (p = 0.007). Serum NSE levels were also increased but remained non-significant after Bonferroni-Holm correction (p = 0.04). Furthermore, age by group interaction was significant for S100B. In an age-stratified sub-analysis, NSE and S100B were higher in younger subjects with mild NCD below 71 years of age. Some effects were inconsistent after controlling for potentially confounding factors. The discriminatory power of the two biomarkers NSE and S100B was insufficient to establish a pathologic threshold for mild NCD. In subjects with mild NCD, WMH load correlated with serum NSE levels (r = 0.20, p = 0.01), independently of age.ConclusionOur findings might indicate the presence of neuronal (NSE) and glial (S100B) injury in mild NCD. Future studies need to investigate whether younger subjects with mild NCD with increased biomarker levels are at risk of developing major NCD.

Synergistic associations of cognitive and motor impairments with functional outcome in covert cerebral small vessel disease.

Cognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their combined effects on functional outcome have not been elucidated. This study investigated the interactions and mediating effects of cognitive and motor functions on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH). Participants of the Helsinki Small Vessel Disease Study (n=152) were assessed according to an extensive clinical, physical, neuropsychological and MRI protocol. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Cognitive (global cognition, executive functions, processing speed, memory) and motor functions (gait speed, single-leg stance, timed up-and-go) had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on informant-evaluated IADL, but not on self-evaluated quality of life. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up-and-go performance. The results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than their individual effects. Patients with both impairments are at disproportionate risk for poor outcome. WMH and brain atrophy contribute to disability through cognitive and motor impairment.

Association between carotid artery perivascular fat density and cerebral small vessel disease.

Studies aiming to identify the significance of the carotid artery perivascular fat density are limited. The present study investigated the distribution pattern of pericarotid fat and its association with imaging markers of cerebral small vessel disease (CSVD). In total, 572 subjects who underwent both neck computed tomography angiography and cranial magnetic resonance imaging were analyzed. The pericarotid fat density near the origin of the internal carotid artery (ICA) and imaging markers of CSVD, such as lacunes, white matter hyperintensities (WMHs) and dilated perivascular spaces (PVSs), were assessed. We found that an increased pericarotid fat density was associated with the presence of lacunes and a higher WMH grade in all subjects, but in the patients with acute ischemic stroke, there was a difference only among the WMH grades. There was no significant difference in the pericarotid fat density in different grades of PVSs. The patients with acute ischemic stroke had a significantly higher mean pericarotid fat density than those without stroke. In conclusion, our study provides evidence suggesting that an increased pericarotid fat density is associated with the presence and degree of WMHs and lacunes. Our findings suggested that features that appear to extend beyond the vessel lumen of the ICA may be linked to CSVD.

The neurophysiology and seizure outcomes of late onset unexplained epilepsy

ObjectiveTo investigate neurophysiologic and neuroimaging characteristics of patients with late onset unexplained epilepsy (LOUE). MethodsWe performed a retrospective chart review of elderly patients with ICD9 diagnosis codes consistent with epilepsy/seizures. Inclusion criteria included unprovoked seizures, and absence of cortical lesions on magnetic resonance imaging (MRI). Electroencephalograms (EEGs) findings were also analyzed. MRI images were scored for degree of white matter hyperintensities (Fazekas Scale) and mesial temporal atrophy (MTA). Vascular risk factors, and Framingham Heart Study general cardiovascular disease (FHS-CVD) risk scores were compared to controls from the Harvard Aging Brain study (HABS). ResultsWe identified 224 LOUE patients and 8% were drug resistant. Epileptiform abnormalities were captured on EEG in 35%. The location was temporal with left sided predominance in 49%. Fazekas scale consisted of 25% beginning of confluent lesions, and 10% large confluent lesions. MTA scores consisted of 21% moderate-severe hippocampal atrophy. LOUE patients had on average a 2.3% (adjusted), 7.4% (unadjusted) increased FHS-CVD score. ConclusionsOur findings highlight LOUE as pharmacosensitive and left temporal predominant. Given the higher prevalence of vascular risk factors, investigations are needed to study their role in pathophysiology. SignificancePhysicians caring for patients with LOUE should evaluate for vascular risk factors and investigate the presence of hippocampal atrophy.

Correlation between White Matter Hyperintensities Related Gray Matter Volume and Cognition in Cerebral Small Vessel Disease

Background and AimThe relationship between severity of cerebral small vessel disease, as defined by white matter hyperintensities classification, and gray matter volume of different brain regions has not been well defined. This study aimed to investigate brain regions with significant differences in gray matter volume associated with different degrees of white matter hyperintensities in patients with cerebral small vessel disease. Meanwhile, we examined whether correlations existed between gray matter volume in different brain regions and cognitive ability. Methods110 cerebral small vessel disease patients underwent 3.0T Magnetic resonance imaging scans and neuropsychological cognitive assessments. White matter hyperintensities of each subject was graded according to Fazekas grade scale and was divided into two groups: (A) White matter hyperintensities score of 1–2 points (n = 64), (B) White matter hyperintensities score of 3–6 points (n = 46). Gray matter volume was analyzed using voxel-based morphometry implemented in Statistical Parametric Mapping 12 software. ResultsBrain regions with significant differences in gray matter volume between groups were diffused throughout the brain. Patients with high white matter hyperintensities scores exhibited decreased gray matter volume in some subregions of the frontal lobes, the temporal lobes, the parahippocampal gyrus, hippocampus and thalamus (p < 0.05). Among them, gray matter volume in the ventrolateral area of right inferior temporal gyrus, together with the right posterior parietal and occipital thalamus were positively correlated with Montreal Cognitive Assessment scores (p < 0.05). Gray matter volume in the extreme ventrolateral area of right inferior temporal gyrus along with the entorhinal cortex of left parahippocampal gyrus were positively correlated with both Montreal Cognitive Assessment and Mini-Mental Status Examination scores (p < 0.05). ConclusionsCerebral small vessel disease is considered as a whole brain disease and local white matter lesions can influence the gray matter in remote areas. Reducing the severity and progression of white matter hyperintensities may help to prevent secondary brain atrophy and cognitive impairment.

Higher white matter hyperintensity lesion load is associated with reduced long-range functional connectivity.

Cerebral small vessel disease is a common disease in the older population and is recognized as a major risk factor for cognitive decline and stroke. Small vessel disease is considered a global brain disease impacting the integrity of neuronal networks resulting in disturbances of structural and functional connectivity. A core feature of cerebral small vessel disease commonly present on neuroimaging is white matter hyperintensities. We studied high-resolution resting-state EEG, leveraging source reconstruction methods, in 35 participants with varying degree of white matter hyperintensities without clinically evident cognitive impairment in an observational study. In patients with increasing white matter lesion load, global theta power was increased independently of age. Whole-brain functional connectivity revealed a disrupted network confined to the alpha band in participants with higher white matter hyperintensities lesion load. The decrease of functional connectivity was evident in long-range connections, mostly originating or terminating in the frontal lobe. Cognitive testing revealed no global cognitive impairment; however, some participants revealed deficits of executive functions that were related to larger white matter hyperintensities lesion load. In summary, participants without clinical signs of mild cognitive impairment or dementia showed oscillatory changes that were significantly related to white matter lesion load. Hence, oscillatory neuronal network changes due to white matter lesions might act as biomarker prior to clinically relevant behavioural impairment.

Naturally occurring NOTCH3 exon skipping attenuates NOTCH3 protein aggregation and disease severity in CADASIL patients.

CADASIL is a vascular protein aggregation disorder caused by cysteine-altering NOTCH3 variants, leading to mid-adult-onset stroke and dementia. Here, we report individuals with a cysteine-altering NOTCH3 variant that induces exon 9 skipping, mimicking therapeutic NOTCH3 cysteine correction. The index came to our attention after a coincidental finding on a commercial screening MRI, revealing white matter hyperintensities. A heterozygous NOTCH3 c.1492G>T, p.Gly498Cys variant, was identified using a gene panel, which was also present in four first- and second-degree relatives. Although some degree of white matter hyperintensities was present on MRI in all family members with the NOTCH3 variant, the CADASIL phenotype was mild, as none had lacunes on MRI and there was no disability or cognitive impairment above the age of 60 years. RT-PCR and Sanger sequencing analysis on patient fibroblast RNA revealed that exon 9 was absent from the majority of NOTCH3 transcripts of the mutant allele, effectively excluding the mutation. NOTCH3 aggregation was assessed in skin biopsies using electron microscopy and immunohistochemistry and did not show granular osmiophilic material and only very mild NOTCH3 staining. For purposes of therapeutic translatability, we show that, in cell models, exon 9 exclusion can be obtained using antisense-mediated exon skipping and CRISPR/Cas9-mediated genome editing. In conclusion, this study provides the first in-human evidence that cysteine corrective NOTCH3 exon skipping is associated with less NOTCH3 aggregation and an attenuated phenotype, justifying further therapeutic development of NOTCH3 cysteine correction for CADASIL.

Tissue Plasminogen Activator and MRI Signs of Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is one of the leading causes of cognitive impairment and stroke. The importance of endothelial dysfunction and high blood–brain barrier (BBB) permeability in pathogenesis, together with ischemia, is under discussion. The aim of this study was to clarify the relationship between tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), and magnetic resonance imaging (MRI) signs of SVD. We examined 71 patients (23 men and 48 women; mean age: 60.5 ± 6.9 years) with clinical and MRI signs of SVD, and 21 healthy volunteers with normal MRIs. All subjects underwent 3T MRI and measurements of t-PA and PAI-1 levels. An increase in t-PA level is correlated with the volume of white matter hyperintensities (WMH) (R = 0.289, p = 0.034), severity on the Fazekas scale (p = 0.000), and with the size of subcortical (p = 0.002) and semiovale (p = 0.008) perivascular spaces. The PAI-1 level is not correlated with the t-PA level or MRI signs of SVD. The correlation between t-PA and the degree of WMH and perivascular spaces’ enlargement, without a correlation with PAI-1 and lacunes, is consistent with the importance of t-PA in BBB disruption and its role in causing brain damage in SVD.

Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy.

To identify the association between brain vascular changes and cortical volumes on MRI and late-onset epilepsy. In 1993-1995, 1,920 participants (median age 62.7, 59.9% female) in the community-based Atherosclerosis Risk in Communities (ARIC) Study underwent MRI, and white matter hyperintensities were measured. In addition, in 2011-2013, 1,964 ARIC participants (median age 72.4, 61.1% female) underwent MRI, and cortical volumes and white matter hyperintensities were measured. We identified cases of late-onset epilepsy (starting at age 60 or later) from ARIC hospitalization records and Medicare claims data. Using the 1993-1995 MRI, we evaluated the association between white matter hyperintensities and subsequent epilepsy using survival analysis. We used the 2011-2013 MRI to conduct cross-sectional logistic regression to examine the association of cortical volumes and white matter hyperintensities with late-onset epilepsy. All models were adjusted for demographics, hypertension, diabetes, smoking, and APOE ε4 allele status. Ninety-seven ARIC participants developed epilepsy after having an MRI in 1993-1995 (incidence 3.34 per 1,000 person-years). The degree of white matter hyperintensities measured at ages 49-72 years was associated with the risk of late-onset epilepsy (hazard ratio 1.27 per age-adjusted SD, 95% confidence interval [CI] 1.06-1.54). Lower cortical volume scores were associated cross-sectionally with higher odds of late-onset epilepsy (odds ratio 1.87, 95% CI 1.16-3.02) per age-adjusted SD. This study demonstrates associations between earlier-life white matter hyperintensities on MRI and later-life incident epilepsy, and between cortical volumes measured later in life and late-onset epilepsy. These findings may help illuminate the causes of late-onset epilepsy.