Multimodal Structural and Functional Characterization of Retinal Vasculopathy with Cerebral Leukoencephalopathy.

OBJECTIVE: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. DESIGN: Cross sectional descriptive study from December 2021 to December 2022. PARTICIPANTS: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. METHODS: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (µm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. RESULTS: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 µm (range, 217-488 µm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18-1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9-6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. CONCLUSIONS: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Akinetic mutism and gait disturbance in a patient with delayed post-hypoxic leukoencephalopathy.

We report on a patient with delayed post-hypoxic leukoencephalopathy (DPHL) who showed akinetic mutism and gait disturbance, neural injuries that were demonstrated on diffusion tensor tractography (DTT). A patient was exposed to carbon monoxide (CO) and rapidly recovered; however, two weeks after onset, he began to show cognitive impairment and gait disturbance. At six weeks after CO exposure, he showed akinetic mutism and gait inability. DTT at 6-weeks post-exposure showed discontinuations in neural connectivities of the caudate nucleus to the medial prefrontal and orbitofrontal cortex in both hemispheres. In addition, the corticoreticulospinal tract revealed severe thinning in both hemispheres.

Differential associations between abnormal cardiac left ventricular geometry types and cerebral white matter disease.

OBJECTIVES: Reduced cardiac outflow due to left ventricular hypertrophy has been suggested as a potential risk factor for development of cerebral white matter disease. Our study aimed to examine the correlation between left ventricular geometry and white matter disease volume to establish a clearer understanding of their relationship, as it is currently not well-established. METHODS: Consecutive patients from 2016 to 2021 who were ≥18 years and underwent echocardiography, cardiac MRI, and brain MRI within one year were included. Four categories of left ventricular geometry were defined based on left ventricular mass index and relative wall thickness on echocardiography. White matter disease volume was quantified using an automated algorithm applied to axial T2 FLAIR images and compared across left ventricular geometry categories. RESULTS: We identified 112 patients of which 34.8 % had normal left ventricular geometry, 20.5 % had eccentric hypertrophy, 21.4 % had concentric remodeling, and 23.2 % had concentric hypertrophy. White matter disease volume was highest in patients with concentric hypertrophy and concentric remodeling, compared to eccentric hypertrophy and normal morphology with a trend-P value of 0.028. Patients with higher relative wall thickness had higher white matter disease volume (10.73 ± 10.29 cc vs 5.89 ± 6.46 cc, P = 0.003), compared to those with normal relative wall thickness. CONCLUSION: Our results showed that abnormal left ventricular geometry is associated with higher white matter disease burden, particularly among those with abnormal relative wall thickness. Future studies are needed to explore causative relationships and potential therapeutic options that may mediate the adverse left ventricular remodeling and its effect in slowing white matter disease progression.

Blood Pressure Rhythm and Blood Pressure Variability as Risk Factors for White Matter Lesions: A Cross-Sectional Study.

BACKGROUND White matter lesions are common in the elderly. The aim of this study was to explore the correlation between blood pressure rhythm and blood pressure variability with white matter lesions. MATERIAL AND METHODS A total of 144 subjects aged 40 to 80 years underwent MRI scanning to assess the degree of white matter lesions using the Fazekas scale. The regional cerebral blood flow was detected by brain perfusion imaging, and an ambulatory blood pressure monitor was used to measure the circadian blood pressure rhythm. Odds ratio and the 95% confidence interval was computed using logistics regression analysis. The relationship between various factors and blood pressure was calculated by curve simulation. RESULTS With the increase of white matter lesions, the regional cerebral blood flow at the lesion decreased gradually. Systolic blood pressure day/night difference ratio (OR=0.815, 95% CI 0.729-0.910), diastolic blood pressure day/night difference ratio (OR=0.895, 95% CI 0.831-0.964), systolic blood pressure coefficient of variation (OR=1.589, 95% CI 1.273-1.983), and diastolic blood pressure coefficient of variation (OR=1.363, 95% CI 1.150-1.616) were significantly associated with Fazekas score (P<0.05 for all). CONCLUSIONS Greater blood pressure variability and blood pressure rhythm disorders were associated with lower regional cerebral blood flow in patients with white matter lesions.

Effects of white matter hyperintensities distribution and clustering on late-life cognitive impairment.

White matter hyperintensities (WMH) are a key hallmark of subclinical cerebrovascular disease and are known to impair cognition. Here, we parcellated WMH using a novel system that segments WMH based on both lobar regions and distance from the ventricles, dividing the brain into a coordinate system composed of 36 distinct parcels ('bullseye' parcellation), and then investigated the effect of distribution on cognition using two different analytic approaches. Data from a well characterized sample of healthy older adults (58 to 84 years) who were free of dementia were included. Cognition was evaluated using 12 computerized tasks, factored onto 4 indices representing episodic memory, speed of processing, fluid reasoning and vocabulary. We first assessed the distribution of WMH according to the bullseye parcellation and tested the relationship between WMH parcellations and performance across the four cognitive domains. Then, we used a data-driven approach to derive latent variables within the WMH distribution, and tested the relation between these latent components and cognitive function. We observed that different, well-defined cognitive constructs mapped to specific WMH distributions. Speed of processing was correlated with WMH in the frontal lobe, while in the case of episodic memory, the relationship was more ubiquitous, involving most of the parcellations. A principal components analysis revealed that the 36 bullseye regions factored onto 3 latent components representing the natural aggrupation of WMH: fronto-parietal periventricular (WMH principally in the frontal and parietal lobes and basal ganglia, especially in the periventricular region); occipital; and temporal and juxtacortical WMH (involving WMH in the temporal lobe, and at the juxtacortical region from frontal and parietal lobes). We found that fronto-parietal periventricular and temporal & juxtacortical WMH were independently associated with speed of processing and episodic memory, respectively. These results indicate that different cognitive impairment phenotypes might present with specific WMH distributions. Additionally, our study encourages future research to consider WMH classifications using parcellations systems other than periventricular and deep localizations.

Clinical and genetic characterization of adult-onset leukoencephalopathy caused by CSF1R mutations.

OBJECTIVE: Mutations in the colony-stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult-onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult-onset leukoencephalopathy. METHODS: Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1-induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. RESULTS: Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1-induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin-like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3-4 years. Diffusion-restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. INTERPRETATION: CSF1R mutations account for 3.5% (5/149) of the adult-onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.

One Disease with two Faces: Semidominant Inheritance of a Novel HTRA1 Mutation in a Consanguineous Family.

OBJECTIVES: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. MATERIALS AND METHODS: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. RESULTS: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. CONCLUSION: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.

Association of Blood Pressure, White Matter Lesions, and Regional Cerebral Blood Flow.

BACKGROUND At present, the association between blood pressure, regional cerebral blood flow, and white matter lesions is not well understood. MATERIAL AND METHODS A total of 147 subjects aged from 40 to 80 years were assessed by the Fazekas score for white matter lesions, CT perfusion imaging for regional cerebral blood flow, and 24-h ambulatory blood pressure monitoring for blood pressure level and rhythm. Logistic regression analysis was used to obtain the odds ratio and 95% confidence interval between Fazekas scores and relevant factors. The relationship between blood pressure index and regional cerebral blood flow was analyzed through cubic curve estimation. RESULTS Fazekas score was negatively correlated with regional cerebral blood flow (r=-0.801; r=-0.831, P<0.001). For subcortical lesion, the regional cerebral blood flow of Fazekas grade 0 was 1.976 times that of Fazekas grade 3 (OR=1.976, 95% CI=1.576-2.477), and for periventricular lesion, the regional cerebral blood flow of Fazekas grade 0 was 2.034 times that of Fazekas grade 3 (OR=2.034, 95% CI=1.602-2.583). Increased nighttime systolic blood pressure may be more dangerous (OR=1.112, 95% CI=1.059-1.169). The day-night systolic blood pressure ratio (OR=0.801, 95% CI 0.711-0.902) and the day-night diastolic blood pressure ratio (OR=0.876, 95% CI 0.807-0.950) were significantly correlated with Fazekas score. CONCLUSIONS The decrease of white matter regional cerebral blood flow caused by hypertension is probably one of the important causes of white matter lesions. Patients with white matter lesions should also pay attention to the rhythm of blood pressure when controlling hypertension, especially if their blood pressure is too high or too low at night.

MRI Natural History of the Leukodystrophy Vanishing White Matter.

Background In vanishing white matter (VWM), a form of leukodystrophy, earlier onset is associated with faster clinical progression. MRI typically shows rarefaction and cystic destruction of the cerebral white matter. Information on the evolution of VWM according to age at onset is lacking. Purpose To determine whether nature and progression of cerebral white matter abnormalities in VWM differ according to age at onset. Materials and Methods Patients with genetically confirmed VWM were stratified into six groups according to age at onset: younger than 1 year, 1 year to younger than 2 years, 2 years to younger than 4 years, 4 years to younger than 8 years, 8 years to younger than 18 years, and 18 years or older. With institutional review board approval, all available MRI scans obtained between 1985 and 2019 were retrospectively analyzed with three methods: (a) ratio of the width of the lateral ventricles over the skull (ventricle-to-skull ratio [VSR]) was measured to estimate brain atrophy; (b) cerebral white matter was visually scored as percentage normal, hyperintense, rarefied, or cystic on fluid-attenuated inversion recovery (FLAIR) images and converted into a white matter decay score; and (c) the intracranial volume was segmented into normal-appearing white and gray matter, abnormal but structurally present (FLAIR-hyperintense) and rarefied or cystic (FLAIR-hypointense) white matter, and ventricular and extracerebral cerebrospinal fluid (CSF). Multilevel regression analyses with patient as a clustering variable were performed to account for the nested data structure. Results A total of 461 examinations in 270 patients (median age, 7 years [interquartile range, 3-18 years]; 144 female patients) were evaluated; 112 patients had undergone serial imaging. Patients with later onset had higher VSR [F(5) = 8.42; P < .001] and CSF volume [F(5) = 21.7; P < .001] and lower white matter decay score [F(5) = 4.68; P < .001] and rarefied or cystic white matter volume [F(5) = 13.3; P < .001]. Rate of progression of white matter decay scores [b = -1.6, t(109) = -3.9; P < .001] and VSRs [b = -0.05, t (109) = -3.7; P < .001] were lower with later onset. Conclusion A radiologic spectrum based on age at onset exists in vanishing white matter. The earlier the onset, the faster and more cystic the white matter decay, whereas with later onset, white matter atrophy and gliosis predominate. © RSNA, 2021.

Relationship Between Central Artery Stiffness, Brain Arterial Dilation, and White Matter Hyperintensities in Older Adults: The ARIC Study-Brief Report.

[Figure: see text].

Cerebrovascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.

Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is a small vessel disease caused by TREX1 mutations. RVCL-S is characterized by retinal vasculopathy and brain white matter lesions with and without contrast enhancement. We aimed to investigate cerebrovascular reactivity (CVR) in RVCL-S. In this cross-sectional observational study, 21 RVCL-S patients, 23 mutation-negative family members, and 31 healthy unrelated controls were included. CVR to a hypercapnic challenge was measured using dual-echo arterial spin labeling magnetic resonance imaging. Stratified analyses based on age were performed. We found that CVR was decreased in gray and white matter of RVCL-S patients compared with family members and healthy controls (ANCOVA; P < 0.05 for all comparisons). This was most noticeable in RVCL-S patients aged ≥40 years (ANCOVA, P < 0.05 for all comparisons). In RVCL-S patients aged < 40 years, only CVR in white matter was lower when compared to healthy controls (P < 0.05). Gray matter CVR was associated with white matter lesion volume in RVCL-S patients (r = -0.527, P = 0.01). In conclusion, impaired cerebrovascular reactivity may play an important role in the pathophysiology of RVCL-S and may be an useful early biomarker of cerebrovascular disease severity.

Clinical and Biological Correlates of White Matter Hyperintensities in Patients With Behavioral-Variant Frontotemporal Dementia and Alzheimer Disease.

OBJECTIVE: To test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy, and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses. METHODS: A total of 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI and clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy, and performance across different cognitive domains were assessed. RESULTS: Total WMH volumes were larger in patients with bvFTD than patients with AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. Patients with bvFTD and patients with AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD. CONCLUSION: Increased WMH are common in patients with bvFTD and patients with AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Furthermore, increased WMH in different regions contributes to cognitive deficits.

Diverse manifestations of a sickle cell crisis.

We describe the case of a 21-year-old man with a background of sickle cell disease (SCD) who was on acute presentation in a sickle cell crisis required immediate intensive care admission with red blood cell exchange and ventilatory support. He had right frontal lobe infarcts and extensive bilateral deep white matter lesions most likely secondary to fat embolism. Inpatient investigations demonstrated a patent foramen ovale, explaining the route of spread of the fat embolus. He then had a transcatheter closure of the atrial defect. The patient needed prolonged inpatient rehabilitation. He was discharged from hospital in a wheelchair secondary to severe lower limb neurology and bilateral knee heterotopic ossification. He lives with the possibility of early onset dementia and cognitive decline, requiring constant care. The case highlights the multiple manifestations of SCD and their diverse and debilitating consequences.

Another 'BEE'? - Brain-Eye-Ear (BEE) Disease Secondary to HbSC Disease Masquerading as Multiple Sclerosis.

Recurrent episodes of neurological dysfunction and white matter lesions in a young adult raise suspicion for multiple sclerosis (MS). However, occlusive retinopathy, hearing loss and absence of CSF oligoclonal bands are atypical for MS and should make the clinician consider an alternative diagnosis. We describe a man with hearing loss, visual signs and symptoms, and an accumulating burden of brain lesions, who was treated for a clinical diagnosis of MS for nearly two decades. Genetic testing revealed a unifying diagnosis.

Resection of cerebellar tumours causes widespread and functionally relevant white matter impairments.

Several diffusion tensor imaging studies reveal that white matter (WM) lesions are common in children suffering from benign cerebellar tumours who are treated with surgery only. The clinical implications of WM alterations that occur as a direct consequence of cerebellar disease have not been thoroughly studied. Here, we analysed structural and diffusion imaging data from cerebellar patients with chronic surgical lesions after resection for benign cerebellar tumours. We aimed to elucidate the impact of focal lesions of the cerebellum on WM integrity across the entire brain, and to investigate whether WM deficits were associated with behavioural impairment in three different motor tasks. Lesion symptom mapping analysis suggested that lesions in critical cerebellar regions were related to deficits in savings during an eyeblink conditioning task, as well as to deficits in motor action timing. Diffusion imaging analysis of cerebellar WM indicated that better behavioural performance was associated with higher fractional anisotropy (FA) in the superior cerebellar peduncle, cerebellum's main outflow path. Moreover, voxel-wise analysis revealed a global pattern of WM deficits in patients within many cerebral WM tracts critical for motor and non-motor function. Finally, we observed a positive correlation between FA and savings within cerebello-thalamo-cortical pathways in patients but not in controls, showing that saving effects partly depend on extracerebellar areas, and may be recruited for compensation. These results confirm that the cerebellum has extended connections with many cerebral areas involved in motor/cognitive functions, and the observed WM changes likely contribute to long-term clinical deficits of posterior fossa tumour survivors.

Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant.

INTRODUCTION: Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their correct tRNAs. Bi-allelic truncating variants in the AIMP1 gene have been associated with hypomyelinating leukodystrophy-3 (HLD3; MIM 260600), which is characterized by hypomyelination, microcephaly, seizures and decreased life expectancy. Although peripheral nerve involvement has been assumed for HLD3, no compelling evidence is available to date. CASE REPORT: The case was a first-born Filipino male. He showed profound developmental delay, failure to thrive, and spasticity in his limbs. At three months of age he developed refractory epilepsy. Serial magnetic resonance imaging (MRIs) showed profound myelination delay and progressive cerebral atrophy. He showed abnormal nerve conduction studies. Genetic testing revealed a homozygous pathogenic variant in the AIMP1 gene (NM_004757.3: c.115C > T: p.Gln39*). The parents were heterozygous for the same variant. CONCLUSION: Here, we report a patient with a homozygous nonsense AIMP1 variant showing peripheral neuropathy as well as HLD3. Our case suggests that AIMP1 plays a pivotal role in the peripheral nerve as well as the central nervous system.

Bronchopulmonary dysplasia precursors influence risk of white matter injury and adverse neurodevelopmental outcome in preterm infants.

BACKGROUND: Cumulative supplemental oxygen (CSO) and cumulative mean airway pressure (CMAP) are associated with bronchopulmonary dysplasia (BPD) in preterm infants, but their relationships to white matter injury (WMI) and neurodevelopment have not been evaluated. METHODS: Preterm infants <32 weeks' gestation were prospectively imaged with 3 T MRI near term. CSO and CMAP were retrospectively summed over the first 14 and 28 days. Neurodevelopment was assessed at 30 months adjusted using the Bayley-III. ROC and linear regression were used to evaluate the relationship between CSO, CMAP, and BPD with WMI and neurodevelopmental performance, respectively. RESULTS: Of the 87 infants, 30 (34.5%) had moderate-severe BPD, which was associated with WMI (OR 5.5, 95% CI 1.1-34.9, p = 0.012). CSO and CMAP predicted WMI as well as BPD (AUC 0.68-0.77). CSO was independently associated with decreased language and cognitive performance (mean difference at 14 days: -11.0, 95% CI -19.8 to -2.2, p = 0.015 and -9.8, 95% CI -18.9 to -0.7, p = 0.035, respectively) at 30 months adjusted. CONCLUSIONS: BPD precursors predict WMI as well as BPD. Cumulative supplemental oxygen over the first 14 days of life is independently associated with lower language and cognitive performances. These data suggest that early respiratory status influences the risk of adverse neurodevelopment in preterm infants. IMPACT: Respiratory precursors to bronchopulmonary dysplasia (BPD), cumulative supplemental oxygen and mean airway pressure, over the first 14-28 days performed as well as BPD for the prediction of white matter injury on MRI in preterm infants. Cumulative supplemental oxygen was independently associated with lower language and cognitive performance on the Bayley-III at 30 months adjusted. These data suggest that early respiratory status may help explain why BPD is independently associated with adverse neurodevelopmental outcomes in the preterm population and highlights the importance of interventions targeting respiratory status as a potential avenue to improve neurodevelopmental outcomes.

White Matter Hypoperfusion Associated with Leukoaraiosis Predicts Intracranial Hemorrhage after Intravenous Thrombolysis.

OBJECTIVES: White matter hyperintensity is common in patients receiving intravenous thrombolysis. Some studies have expressed concern about the increased risk of hemorrhagic transformation and poor prognosis for those patients with pre-existing leukoaraiosis. The purpose of this study was to evaluate hypoperfusion associated with leukoaraiosis before thrombolysis using CT perfusion and to explore whether chronic white matter hypoperfusion increases risks of intracranial hemorrhage and poor clinical prognosis. MATERIALS AND METHODS: We collected 175 patients underwent intravenous thrombolysis with complete CT perfusion data and follow-up MRI between June 2017 and January 2020. We measured cerebral blood flow, cerebral blood volume, mean transit time and transit time to the peak at both periventricular and subcortical layers in the cerebral hemisphere contralateral to the stroke. The differences of white matter perfusion were compared between groups with different leukoaraiosis severity. Univariate analysis was used to compare in incidence of hemorrhagic transformation and poor prognosis between the hypoperfusion and normal perfusion groups. Further, we examined association between white matter hypoperfusion and intracranial hemorrhage after thrombolysis using logistic regression. RESULTS: The length of periventricular transit time to the peak was independently associated with a higher risk of intracranial hemorrhage after thrombolysis (OR=4.740, 95%CI=1.624-13.837, P=0.004). The best predictive value was 4.012. But there was no significant difference in poor prognosis at 3 months between hypoperfusion (periventricular transit time to the peak≥4.012 s) and normal perfusion (periventricular transit time to the peak<4.012 s) group. CONCLUSIONS: Image presentations of white matter hypoperfusion reflected the severity of leukoaraiosis. White matter hypoperfusion was independently associated with intracranial hemorrhage after intravenous thrombolysis. However, hypoperfusion would not increase the risk of poor prognosis.

White Matter Injury Is Associated with Reduced Manual Dexterity and Elevated Serum Ceramides in Subjects with Cerebral Small Vessel Disease.

INTRODUCTION: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. METHODS: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. RESULTS: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (ß = -0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: ß = -0.03, p = 0.003, C20: ß = -0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (ß = -0.0103, p = 0.027). CONCLUSIONS: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.