Brain White Matter Lesions Research Articles

7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

Incidence of interattack asymptomatic brain lesions in NMO spectrum disorder

To determine whether aquaporin-4 (AQP4) antibody-seropositive patients with neuromyelitis optica spectrum disorder (NMOSD) develop new asymptomatic brain lesions during the interattack period. Of 296 consecutive AQP4 antibody-seropositive patients in the NMOSD database of the National Cancer Center from May 2005 to November 2019, 145 patients, who had serial brain MRI scans over an interval of at least 1 year during relapse-free period after immunosuppressive therapy, with 370 longitudinally assessed brain MRI scans were included in this study. We retrospectively analyzed them for presence of new subclinical brain lesions during the relapse-free period. Five of 145 patients (3.4%) had detectable new, asymptomatic brain lesions in the deep white matter over a total observed relapse-free period of 708 person-years. All the lesions were smaller than 6 mm and assessed to be nonspecific. No brain lesion characteristic of NMOSD or gadolinium-enhancing lesion was identified. Asymptomatic brain lesions are rarely observed on conventional MRI in clinically stable AQP4 antibody-seropositive patients with NMOSD after immunosuppressive therapy and brain MRI lesions characteristic of NMOSD are not seen in the relapse-free period. These findings may provide further insight regarding currently known diagnostic and disease-monitoring strategies in NMOSD.

White matter brain lesions in infantile-onset Pompe disease are not metabolically active using 18F-FDG PET/MR imaging

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Diagnostic value of 3D-FLAIR magnetic resonance sequence in detection of white matter brain lesions in multiple sclerosis

BackgroundMS is common demyelinating disease in which standard T2 and 2D-FLAIR MRI sequences play important role in its diagnosis. Recently, 3D-FLAIR sequence is used and has a role that is evaluated compared to standard sequences.ResultsThis study was performed on 20 selected MS patients. Brain MRI was performed using routinely used T2 and 2D FLAIR sequences, and 3D-FLAIR sequence was added. 3D-FLAIR images were reformatted, and all images were blindly analyzed. Lesions were counted in each sequence and classified according to their location into supratentorial lesions including periventricular, deep white matter, and juxta-cortical, and infratentorial lesions and relative comparison of lesion number on 3D-FLAIR versus 2D-FLAIR and T2 imaging, respectively, were expressed as percentage gain or a loss.3D-FLAIR sequence showed significantly more lesions compared to 2D FLAIR and T2 sequences in all locations with relative ratio of 29% and 41%, respectively, in periventricular region; 22% and 30%, respectively, in deep WM; 180% and 147%, respectively, in juxta-cortical region; and 80% and 13%, respectively, in infratentorial region.Conclusion3D-FLAIR sequence is of greater sensitivity than standard 2D-FLAIR and T2 sequences in MS brain lesions depiction, and it is recommended to be included in MR protocol of MS.

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.

4329 Investigating the role of Klotho in neurocognitive outcomes, brain volumes, and white matter changes in pediatric brain tumor survivors

OBJECTIVES/GOALS: Klotho is a protein linked to improved cognition in aging adults. A specific KLOTHO gene variant, KL-VS, increases circulating levels of Klotho. The current study aims to identify if the KL-VS haplotype and Klotho levels are associated with improved neurocognition in pediatric brain tumor survivors. METHODS/STUDY POPULATION: We are actively accruing pediatric brain tumor patients at UCSF alongside an existing multi-institutional cohort study investigating radiation-induced vasculopathies and cognitive outcomes in this population. Normal controls are being enrolled in parallel. Each patient undergoes: 1) single nucleotide polymorphism genotyping to identify KL-VS haplotype status, 2) enzyme-linked immunosorbent assays to measure circulating Klotho, 3) neurocognitive assessments with a computer-based, validated Cogstate battery, and 4) brain volume and white matter lesion segmentation analyses using MRI sequences obtained as part of routine care. RESULTS/ANTICIPATED RESULTS: Genotyping has been performed on 99 enrolled patients. KL-VS heterozygosity was seen in 22.7% of patients. To date, KL-VS status is not associated with neurocognitive outcomes at baseline or Year 1 testing. Association between KL-VS status, circulating Klotho levels, neurocognitive outcomes, brain volume and white matter lesion segmentation analyses is ongoing. We hypothesize that elevated Klotho levels will be associated with improved neurocognition, increased brain volumes in regions of interest and decreased white matter lesion volumes. DISCUSSION/SIGNIFICANCE OF IMPACT: If circulating Klotho leads to improved neurocognition in pediatric brain tumor survivors, Klotho levels might serve as a prognostic biomarker. Furthermore, as Klotho is being investigated for therapeutic indications, it may represent an intervention to prevent cognitive deficits in these patients.

Utility of a diffusion-weighted arterial spin labeling (DW-ASL) technique for evaluating the progression of brain white matter lesions

PurposeTo investigate the utility of diffusion-weighted arterial spin labeling (DW-ASL) for detecting the progression of brain white matter lesions. Materials and methodsA total of 492 regions of interest (ROIs) in 41 patients were prospectively analyzed. DW-ASL was performed using the diffusion gradient prepulse of five b-values (0, 25, 60, 102, and 189) before the ASL readout. We calculated the water exchange rate (Kw) with post-processing using the ASL signal information for each b-value. The cerebral blood flow (CBF) was also calculated using b0 images. Using the signal information in FLAIR (fluid-attenuated inversion recovery) images, we classified the severity of white matter lesions into three grades: non-lesion, moderate, and severe. In addition, the normal Kw level was measured from DW-ASL data of 60 ROIs in five control subjects. The degree of variance of the Kw values (Kw-var) was calculated by squaring the value of the difference between each Kw value and the normal Kw level. All patient's ROIs were divided into non-progressive and progressive white matter lesions by comparing the present FLAIR images with those obtained 2 years before this acquisition. ResultsCompared to the non-progressive group, the progressive group had significantly lower CBF, significantly higher severity grades in FLAIR, and significantly greater Kw-var values. In a receiver operator characteristic curve analysis, a high area under the curve (AUC) of 0.89 was obtained with the use of Kw-var. In contrast, the AUCs of 0.59 for CBF and 0.72 for severity grades in FLAIR were obtained. ConclusionsThe DW-ASL technique can be useful to detect the progression of brain white matter lesions. This technique will become a clinical tool for patients with various degrees of white matter lesions.

CVSnet: A machine learning approach for automated central vein sign assessment in multiple sclerosis.

The central vein sign (CVS) is an efficient imaging biomarker for multiple sclerosis (MS) diagnosis, but its application in clinical routine is limited by inter-rater variability and the expenditure of time associated with manual assessment. We describe a deep learning-based prototype for automated assessment of the CVS in white matter MS lesions using data from three different imaging centers. We retrospectively analyzed data from 3 T magnetic resonance images acquired on four scanners from two different vendors, including adults with MS (n = 42), MS mimics (n = 33, encompassing 12 distinct neurological diseases mimicking MS) and uncertain diagnosis (n = 5). Brain white matter lesions were manually segmented on FLAIR* images. Perivenular assessment was performed according to consensus guidelines and used as ground truth, yielding 539 CVS-positive (CVS+ ) and 448 CVS-negative (CVS- ) lesions. A 3D convolutional neural network ("CVSnet") was designed and trained on 47 datasets, keeping 33 for testing. FLAIR* lesion patches of CVS+ /CVS- lesions were used for training and validation (n = 375/298) and for testing (n = 164/150). Performance was evaluated lesion-wise and subject-wise and compared with a state-of-the-art vesselness filtering approach through McNemar's test. The proposed CVSnet approached human performance, with lesion-wise median balanced accuracy of 81%, and subject-wise balanced accuracy of 89% on the validation set, and 91% on the test set. The process of CVS assessment, in previously manually segmented lesions, was ~ 600-fold faster using the proposed CVSnet compared with human visual assessment (test set: 4 seconds vs. 40 minutes). On the validation and test sets, the lesion-wise performance outperformed the vesselness filter method (P < 0.001). The proposed deep learning prototype shows promising performance in differentiating MS from its mimics. Our approach was evaluated using data from different hospitals, enabling larger multicenter trials to evaluate the benefit of introducing the CVS marker into MS diagnostic criteria.

Gadolinium Enhancement of the Aneurysm Wall in Extracranial Carotid Artery Aneurysms.

The natural history and optimal treatment of extracranial carotid artery aneurysms are unknown. Gadolinium enhancement of the aneurysm wall may reflect aneurysm wall inflammation and instability. In this study, we investigated the feasibility of extracranial carotid artery aneurysm wall imaging and explored a potential relationship of aneurysm wall enhancement with aneurysm growth and the presence of (silent) brain infarcts and white matter lesions. Fourteen conservatively treated patients with 15 asymptomatic extracranial carotid artery aneurysms underwent gadolinium-enhanced 3T MR imaging at 2 time points with a 12-month interval. Primary outcome was growth of the aneurysm sac (≥2.0 mm); secondary outcomes were the presence of (silent) brain infarcts and white matter lesions at baseline and follow-up. MR images were reviewed by 2 independent observers, and inter- and intraobserver reproducibility was assessed. Seven (50%) patients were men; the median age was 55 years (range, 40-69 years). Eleven extracranial carotid artery aneurysms (73%) were saccular (median size, 11 mm; range, 5.0-38.5 mm), and 4 were fusiform (median size, 21.5 mm; range, 10.0-40.0 mm). Eleven of 15 aneurysms (73%) exhibited gadolinium enhancement at baseline. Four aneurysms (27%) showed growth at follow-up imaging, 2 gadolinium-positive (+) and 2 gadolinium-negative (-) (P = .245). Three patients (21%) had ipsilateral brain infarcts at baseline; 1 of them showed a new silent brain infarct at follow-up imaging (gadolinium+). Nine patients (64%) showed bilateral white matter lesions at baseline. In 3 patients, increased white matter lesion severity was observed at follow-up (2 gadolinium+). All observations showed excellent inter- and intraobserver reproducibility. In this explorative study, we demonstrated that extracranial carotid artery aneurysm wall imaging was feasible. Future well-powered studies are needed to investigate whether extracranial carotid artery aneurysm gadolinium enhancement predicts aneurysm growth and thromboembolic complications.

Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation

BackgroundThe common GLA gene mutation p.F113L causes late-onset phenotype of Fabry disease (FD) with predominant cardiac manifestations. A founder effect of FD due to this mutation was found in the Portuguese region of Guimarães. Our study aims to deepen the knowledge on the natural history of this late-onset variant. Methods203 consecutive adult Fabry patients with p.F113L mutation (79 males; mean age 46 ± 18 years), from this region, were submitted at baseline to a predefined diagnostic protocol. The occurrence of FD manifestations was analyzed in each decade of age in both genders. ResultsIn males, left ventricular hypertrophy (40.2%) and late gadolinium enhancement (21.4%) arose over 30 years; heart failure (HF) (21.9%), ventricular tachycardia (8.9%) and conduction disorders over 40 years; and bifascicular (13.1%) and complete atrioventricular blocks (5.9%) beyond 50 years of age. Cardiac manifestations occurred more commonly and 1–2 decades earlier in males; their frequency increased with age. Septum and posterior wall thickness, LV mass, QRS interval duration and pro-BNP levels increased with age in both genders. Mean survival free from HF (64 ± 1 vs. 76 ± 2 years) and pacemaker (71 ± 2 vs. 86 ± 1 years) was higher in females (p < .001). Albuminuria A2/A3 (33.7%), brain white matter lesions (50.3%) and sensorineural deafness (44.7%) arose before 30 years of age in both genders, increasing with age. Renal failure and stroke were rare. Lysosomal inclusions were demonstrated in podocytes of patients with proteinuria. ConclusionThis study improves the knowledge on natural history of late-onset variants of FD, carrying major impact on clinical decisions and guidelines.

Distinct influence of different vascular risk factors on white matter brain lesions in multiple sclerosis

ObjectiveTo determine if vascular risk factor (VRF), that is, smoking, arterial hypertension (HT), dyslipidaemia and diabetes, have an effect on multiple sclerosis (MS) pathology as measured by MS typical brain...

Multivariate neuroanatomical correlates of behavioral and psychological symptoms in dementia and the moderating role of education

Neuropsychiatric symptoms are commonly observed as brain pathology progresses with dementia. Behavioral and affective disturbances underly the distinct neuroanatomical basis of typical symptoms of cognitive impairment; however it remains unclear whether enriched intellectual experience, such as educational attainment, can mitigate the effect of brain structural patterns on neuropsychiatric symptom severity. We utilized the Open Access Series of Imaging Studies (OASIS-3) dataset, which includes brain structural MRI and behavioral symptom evaluation. We included 904 older adults who were mostly cognitively normal, clinically diagnosed with very mild to moderate Alzheimer’s disease, or other types of dementia. Canonical correlation analysis was used to identify the patterns of multivariate association between the gray matter structure and neuropsychiatric symptom severity. First, we identified two canonical modes capturing the distinct neuroanatomical basis of common and mood-specific factors of neuropsychiatric symptoms. The first common pattern reflected a smaller volume in the amygdala and adjacent temporal regional thickness. The second mood-specific pattern reflected patterns in lateral and orbital prefrontal regional thickness. In the external correlational analysis, the two canonical correlations reflected global brain volume and white matter lesions; however, the second pattern was not associated with functional impairments or cognitive function. Moreover, older adults with higher education showed an attenuated severity of behavioral symptoms, even with the presence of a brain structural pattern. Our findings suggest that educational attainment, as a proxy of cognitive reserve, can mitigate the severity of behavioral and affective symptoms of dementia.

TAPAS: A Thresholding Approach for Probability Map Automatic Segmentation in Multiple Sclerosis.

Total brain white matter lesion (WML) volume is the most widely established magnetic resonance imaging (MRI) outcome measure in studies of multiple sclerosis (MS). To estimate WML volume, there are a number of automatic segmentation methods available, yet manual delineation remains the gold standard approach. Automatic approaches often yield a probability map to which a threshold is applied to create lesion segmentation masks. Unfortunately, few approaches systematically determine the threshold employed; many methods use a manually selected threshold, thus introducing human error and bias into the automated procedure. In this study, we propose and validate an automatic thresholding algorithm, Thresholding Approach for Probability Map Automatic Segmentation in Multiple Sclerosis (TAPAS), to obtain subject-specific threshold estimates for probability map automatic segmentation of T2-weighted (T2) hyperintense WMLs. Using multimodal MRI, the proposed method applies an automatic segmentation algorithm to obtain probability maps. We obtain the true subject-specific threshold that maximizes the Sørensen-Dice similarity coefficient (DSC). Then the subject-specific thresholds are modeled on a naive estimate of volume using a generalized additive model. Applying this model, we predict a subject-specific threshold in data not used for training. We ran a Monte Carlo-resampled split-sample cross-validation (100 validation sets) using two data sets: the first obtained from the Johns Hopkins Hospital (JHH) on a Philips 3 Tesla (3T) scanner (n = 94) and a second collected at the Brigham and Women's Hospital (BWH) using a Siemens 3T scanner (n = 40). By means of the proposed automated technique, in the JHH data we found an average reduction in subject-level absolute error of 0.1 mL per one mL increase in manual volume. Using Bland-Altman analysis, we found that volumetric bias associated with group-level thresholding was mitigated when applying TAPAS. The BWH data showed similar absolute error estimates using group-level thresholding or TAPAS likely since Bland-Altman analyses indicated no systematic biases associated with group or TAPAS volume estimates. The current study presents the first validated fully automated method for subject-specific threshold prediction to segment brain lesions.

White matter hyperintensities and their relationship to cognition: Effects of segmentation algorithm

White matter hyperintensities (WMHs) are brain white matter lesions that are hyperintense on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans. Larger WMH volumes have been associated with Alzheimer’s disease (AD) and with cognitive decline. However, the relationship between WMH volumes and cross-sectional cognitive measures has been inconsistent. We hypothesize that this inconsistency may arise from 1) the presence of AD-specific neuropathology that may obscure any WMH effects on cognition, and 2) varying criteria for creating a WMH segmentation. Manual and automated programs are typically used to determine segmentation boundaries, but criteria for those boundaries can differ. It remains unclear whether WMH volumes are associated with cognitive deficits, and which segmentation criteria influence the relationships between WMH volumes and clinical outcomes.In a sample of 260 non-demented participants (ages 55–90, 141 males, 119 females) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we compared the performance of five WMH segmentation methods, by relating the WMH volumes derived using each method to both clinical diagnosis and composite measures of executive function and memory. To separate WMH effects on cognition from effects related to AD-specific processes, we performed analyses separately in people with and without abnormal cerebrospinal fluid amyloid levels.WMH volume estimates that excluded more diffuse, lower-intensity lesions were more strongly correlated with clinical diagnosis and cognitive performance, and only in those without abnormal amyloid levels. These findings may inform best practices for WMH segmentation, and suggest that AD neuropathology may mask WMH effects on clinical diagnosis and cognition.

Neuroimaging correlates of cognitive changes after bariatric surgery.

Obesity has been associated with cognitive deficits and increased risk for developing dementia. Bariatric surgery may result in improved cognitive function; however, the underlying structural and functional brain correlates are unclear. This longitudinal study explores the hypothesis that specific brain regions and networks underlie cognitive changes after bariatric surgery. University Hospital, United States. Seventeen patients were recruited for this prospective cohort study, including 9 patients undergoing bariatric surgery, and 8 age-, sex-, and education level-matched healthy, nonobese control patients. Bariatric patients underwent longitudinal neuropsychologic tests and magnetic resonance imaging (MRI) scans both before and 6 months after surgery. One patient was lost to follow-up. The same neuropsychologic tests and MRI scans were performed for control patients. Differences in MRI and neuropsychologic testing between bariatric patients and control patients, and longitudinal changes within bariatric patients were assessed. At baseline, bariatric patients demonstrated deficits in cognitive function relative to control patients, including pattern comparison (P = .009) and picture sequence memory (P = .004), which improved after significant weight loss. Baseline cognitive deficits in bariatric patients were accompanied by significantly lower left executive control network connectivity on resting-state functional MRI relative to control patients (P = .028), but differences resolved or diminished after bariatric surgery. Longitudinal improvements in pattern comparison performance correlated significantly with increases in left executive control network connectivity (r = .819; P = .013). No significant group or longitudinal differences were found in brain perfusion or brain white matter lesions. Individuals with obesity undergoing bariatric surgery exhibit deficits in cognitive function and specific alterations of brain networks; however, cognitive performance can improve, and executive control network connectivity can increase after weight loss from bariatric surgery.

Diffusion basis spectrum imaging for identifying pathologies in MS subtypes.

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal‐appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and nonrestricted isotropic fraction (representing edema). This study provides preliminary evidence supporting the ability of DBSI as a potential noninvasive biomarker of MS neuropathology.

Association of brain white matter lesions and atrophy with cognitive function in chronic kidney disease.

Cognitive impairment is common in patients with chronic kidney disease (CKD), possibly leading to poor outcomes. However, the correlation between brain structural abnormalities and cognitive impairment remains unclear. The aim of this study was to investigate the impairment of specific cognitive domains and their association with brain structural abnormalities. Patients with CKD of at least stage 3 who were not on hemodialysis were enrolled. All participants underwent comprehensive neuropsychological testing in five cognitive domains. Ventricular atrophy, sulcal atrophy, medial temporal atrophy, and white matter changes were assessed using brain magnetic resonance imaging according to standard protocols. Eighty-seven patients and 50 controls were enrolled. Patients with CKD exhibited decreased cognitive function relative to controls. Compared with patients with stage 3 CKD, those with advanced stage (stages 4 or 5) had poorer cognitive performance, more pronounced white matter hyperintensity (WMH) and more severe ventricular atrophy. Among CKD patients, executive function (β = -.23, P = .043) and attention (β = -.29, P = .004) were associated with WMH in controlled analyses. However, no cognitive impairment was associated with ventricular atrophy. Patients with CKD exhibited cognitive impairment and brain structural abnormalities including WMH and general brain atrophy. Impairment of attention and executive dysfunction were associated with WMH.

Different magnetic resonance imaging features between MOG antibody- and AQP4 antibody-mediated disease: A Chinese cohort study

Few studies have compared radiological features obtained on magnetic resonance imaging (MRI) between myelin oligodendrocyte glycoprotein antibody (MOG-ab)- and aquaporin 4 antibody (AQP4-ab)-positive patients. In this study, 77 MOG-ab and 92 AQP4-ab patients were enrolled. The results demonstrated that the brain MRI-based incidence of subcortical white matter lesions was higher in MOG-ab patients (p < .000) than in AQP4-ab patients and that the former therefore had a higher incidence of periventricular lesions (p = .003). The posterior limb of the internal capsule was more prone to lesions in MOG-ab patients (p = .019). Large lesions and U- or S-shaped lesions were also more frequent in MOG-ab (p < .000 and p = .013, respectively). Half of the MOG-ab patients had spinal cord involvement, and 36.5% presented with longitudinally extensive transverse myelitis (LETM). However, among the MOG-ab and AQP4-ab patients with spinal attack, there was no significant difference in the proportion with LETM (p = .057). In conclusion, a higher proportion of MOG-ab patients than AQP4-ab patients had brain lesions in white matter. Among MOG-ab patients who had an attack in the spinal cord, 65.5% also had LETM during the disease course. Conus medullaris lesions were rare in Chinese MOG-ab patients.

Founder effect of Fabry disease due to p.F113L mutation: Clinical profile of a late-onset phenotype

BackgroundKnowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region. Methods and ResultsFD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a predefined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria>30 mg/24 h 36.1%, chronic kidney disease≥G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations. ConclusionA founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis

We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 days a year. Participants consent to donate their brain and spinal cord. Most patients were followed by neurologists at the Cleveland Clinic Mellen Center for MS Treatment and Research. Their clinical courses and neurological disabilities are well-characterized. Soon after death, the body is transported to the MS Imaging Center, where the brain is scanned in situ by 3 T magnetic resonance imaging (MRI). The body is then transferred to the autopsy room, where the brain and spinal cord are removed. The brain is divided into two hemispheres. One hemisphere is immediately placed in a slicing box and alternate 1 cm-thick slices are either fixed in 4% paraformaldehyde for two days or rapidly frozen in dry ice and 2-methylbutane. The short-fixed brain slices are stored in a cryopreservation solution and used for histological analyses and immunocytochemical detection of sensitive antigens. Frozen slices are stored at -80 °C and used for molecular, immunocytochemical, and in situ hybridization/RNA scope studies. The other hemisphere is placed in 4% paraformaldehyde for several months, placed in the slicing box, re-scanned in the 3 T magnetic resonance (MR) scanner and sliced into centimeter-thick slices. Postmortem in situ MR images (MRIs) are co-registered with 1 cm-thick brain slices to facilitate MRI-pathology correlations. All brain slices are photographed and brain white-matter lesions are identified. The spinal cord is cut into 2 cm segments. Alternate segments are fixed in 4% paraformaldehyde or rapidly frozen. The rapid procurement of postmortem MS tissues allows pathological and molecular analyses of MS brains and spinal cords and pathological correlations of brain MRI abnormalities. The quality of these rapidly-processed postmortem tissues (usually within 6 h of death) is of great value to MS research and has resulted in many high-impact discoveries.