White Matter Research Articles

Association of Cerebrovascular Reactivity With 1-Year Imaging and Clinical Outcomes in Small Vessel Disease: An Observational Cohort Study.

In patients with cerebral small vessel disease (SVD), impaired cerebrovascular reactivity (CVR) is related to worse concurrent SVD burden, but less is known about cerebrovascular reactivity and long-term SVD lesion progression and clinical outcomes. We investigated associations between cerebrovascular reactivity and 1-year progression of SVD features and clinical outcomes. Between 2018 and 2021, we recruited patients from the Edinburgh/Lothian stroke services presenting with minor ischemic stroke and SVD features as part of the Mild Stroke Study 3, a prospective observational cohort study (ISRCTN 12113543). We acquired 3T brain MRI at baseline and 1 year. At baseline, we measured cerebrovascular reactivity to 6% inhaled CO2 in subcortical gray matter, normal-appearing white matter, and white matter hyperintensities (WMH). At baseline and 1 year, we quantified SVD MRI features, incident infarcts, assessed stroke severity (NIH Stroke Scale), recurrent stroke, functional outcome (modified Rankin Scale), and cognition (Montreal Cognitive Assessment). We performed linear and logistic regressions adjusted for age, sex, and vascular risk factors, reporting the regression coefficients and odds ratios with 95% CIs. We recruited 208 patients of whom 163 (mean age and SD: 65.8 ± 11.2 years, 32% female) had adequate baseline CVR and completed the follow-up structural MRI. The median increase in WMH volume was 0.32 mL with (Q1, Q3) = (-0.48, 1.78) mL; 29% had a recurrent stroke or incident infarct on MRI. At 1 year, patients with lower baseline cerebrovascular reactivity in normal-appearing tissues had increased WMH (regression coefficient: B = -1.14 [-2.13, -0.14] log10 (%ICV) per %/mm Hg) and perivascular space volumes (B = -1.90 [-3.21, -0.60] log10 (%ROIV) per %/mm Hg), with a similar trend in WMH. CVR was not associated with clinical outcomes at 1 year. Lower baseline cerebrovascular reactivity predicted an increase in WMH and perivascular space volumes after 1 year. CVR should be considered in SVD future research and intervention studies.

Cerebral Oxygen Metabolic Stress in Children and Adults With Large Vessel Vasculopathy Due to Sickle Cell Disease.

Large vessel vasculopathy (LVV), or moyamoya syndrome, increases the risk of stroke in patients with sickle cell disease (SCD), yet effective treatments are lacking. In atherosclerotic carotid disease, previous studies demonstrated elevated oxygen extraction fraction (OEF) as a predictor of ipsilateral stroke. In a SCD cohort, we examined hemispheric hemodynamic and oxygen metabolic dysfunction as tissue-based biomarkers of cerebral ischemic risk in patients with LVV. Children and adults with SCD were recruited from a SCD clinic associated with a tertiary medical center and underwent prospective brain MRI and MR angiography. LVV was defined as ≥75% stenosis in a major anterior circulation artery, excluding occlusion or previous revascularization surgery. Baseline characteristics, cerebral blood flow (CBF), normalized OEF (nOEF), infarct volume, white matter microstructure, and brain volume were compared in hemispheres with vs without LVV. In a cross-sectional analysis, mixed-effects linear multivariable models examined the effect of LVV on: (1) CBF and nOEF, as tissue markers of hemodynamic and oxygen metabolic stress, respectively, and (2) endpoints of cerebral ischemic injury including infarct volume, white matter microstructure, and brain volume. Of 155 patients (22 [12-31] years, 57% female), 33 (21%) had ≥25% stenosis, 22 (14%) had ≥50% stenosis, 14 (9%) had 75%-99% stenosis, and 5 (3%) had 100% occlusion. After excluding hemispheres with previous revascularization surgery, LVV was present in 16 hemispheres from 11 patients. Hemispheres with (N = 16) vs without (N = 283) LVV had lower CBF (25.2 vs 32.1 mL/100 g/min, p = 0.01) and higher nOEF (0.99 vs 0.95, p = 0.02). On multivariable analysis, CBF was nonsignificantly lower (β = -0.16, p = 0.07) while nOEF remained higher in hemispheres with LVV (β = 0.04, p = 0.03). Moreover, LVV was associated with greater hemispheric infarct volume, microstructural disruption, and atrophy. Beyond greater infarct burden, LVV was associated with hemispheric atrophy and white matter microstructural injury. As an indicator of active hypoxia, elevated nOEF likely represents a compensatory response to flow-limiting stenosis in hemispheres with LVV. The study is limited by a small number of patients with severe stenosis. Future studies are needed to evaluate the potential of tissue-based CBF and nOEF in assessing stroke risk and guide timely treatment of vasculopathy in SCD.

White matter correlates of impulsive behavior in healthy individuals: A diffusion magnetic resonance imaging study.

To explore white matter (WM) tracts linked to impulsivity using the diffusion magnetic resonance imaging (DMRI) connectometry method. We analyzed 218 healthy participants from the Leipzig Study for Mind-Body-Emotion Interactions database. Impulsivity correlations with DMRI-derived WM changes were assessed using Urgency-Premeditation-Perseverance-Sensation (UPPS) Impulsive Behavior Scale subscales: lack of perseverance (PE), lack of premeditation (PM), sensation seeking (SS), and negative urgency. DMRI data were processed using connectometry, adjusting for sex and age, to examine WM tract integrity via quantitative anisotropy (QA). Also, two additional interaction analyses were conducted to separately examine the interaction effect between WM QA, and sex and age in predicting impulsive behavior scores. The significance level in our statistical analyses was set at a false discovery rate (FDR) below 0.05. QA in the bilateral cerebellum and middle cerebellar peduncle showed a negative association with PE and PM severity (FDR = 0.0004). QA in the middle cerebellar peduncle, corpus callosum body, and forceps major demonstrated a positive association with SS (FDR = 0.0001). Conversely, QA in forceps minor had a positive association with PM (FDR = 0.004), and QA in forceps minor and bilateral cingulum showed a positive association with SS (FDR = 0.0005). Age and sex had no significant effects on the association between WM QA and UPPS subscale scores. Impulsivity is linked to distinct WM integrity changes in various tracts, including the corpus callosum, cerebellum, and cingulum, offering insights into the pathophysiology of impulsivity and guiding future research.

Cognitive Impairment, Associated Clinical Factors, and MR Volumetric Measures in Myelin Oligodendrocyte Glycoprotein-IgG-Associated Disease.

Cognitive impairment is a common and challenging symptom in multiple sclerosis and neuromyelitis optica spectrum disease; however, data in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) remain scarce. In this cross-sectional study, we investigated the frequency of cognitive impairment, associated clinical factors, and MRI volumetric measures in MOGAD. Participants were investigated in a single center by certified psychologists and underwent a standardized 3-T-MRI protocol. MRI data were processed with FreeSurfer for gray and white matter volume estimation, presented as a fraction of total intracranial volume. Sera screening for antineural antibodies has been conducted using cell-based assays. The following clinical factors were included in the multivariate logistic regression analysis: sex, age, overall number of previous relapses, and specifically the history of acute disseminated encephalomyelitis (ADEM)/ADEM-like episodes and other brain relapses. Thirty-two patients with MOGAD (19 female, median age 29.4 years) after a median of 2 relapses with a median EDSS of 1.0 were recruited. Seven patients (21.9%) demonstrated cognitive impairment with the most prevalent deficits in mental flexibility (16.7%), attention (11.1%-14.8%), and verbal working memory (10.3%). 72.4% suffered from fatigue and 42.9% from signs of depression, moderate to severe in 28.6%. The overall number of previous relapses (odds ratio [OR] 1.789, 95% CI 1.041-3.074) and specifically ADEM/ADEM-like episodes (OR 16.929, 95% CI 1.228-233.427) were the only clinical factors associated with cognitive impairment in a multivariate logistic regression model. Screening for antineuronal antibodies remained negative. Cerebral white matter (WM) (0.300 vs 0.317, p = 0.003) and deep gray matter (DGM) (0.036 vs 0.038, p = 0.002) volumes were reduced in patients with MOGAD compared with healthy controls (n = 32). Both cognitive impairment (0.031 vs 0.036, p = 0.003) and history of ADEM/ADEM-like episodes (0.032 vs 0.036, p = 0.006) were associated with reduced DGM volume compared with unaffected patients with MOGAD. Despite a low overall disability, every 5th patient with MOGAD experiences cognitive impairment. Cognitive impairment is associated with a higher number of relapses and particularly ADEM/ADEM-like attacks. Although both WM and DGM atrophies are apparent in MOGAD, the latter only seems to have an association with cognitive impairment.

Efficient standardization of clinical T2-weighted images: Phase-conjugacy e-CAMP with projected gradient descent.

To standardize T -weighted images from clinical Turbo Spin Echo (TSE) scans by generating corresponding T maps with the goal of removing scanner- and/or protocol-specific heterogeneity. The T map is estimated by minimizing an objective function containing a data fidelity term in a Virtual Conjugate Coils (VCC) framework, where the signal evolution model is expressed as a linear constraint. The objective function is minimized by Projected Gradient Descent (PGD). The algorithm achieves accuracy comparable to methods with customized sampling schemes for accelerated T mapping. The results are insensitive to the tunable parameters, and the relaxed background phase prior produces better T maps compared to the strict real-value enforcement. It is worth noting that the algorithm works well with challenging T w-TSE data using typical clinical parameters. The observed normalized root mean square error ranges from 6.8% to 12.3% over grey and white matter, a clinically common level of quantitative map error. The novel methodological development creates an efficient algorithm that allows for T map generated from TSE data with typical clinical parameters, such as high resolution, long echo train length, and low echo spacing. Reconstruction of T maps from TSE data with typical clinical parameters has not been previously reported.

White matter organization abnormalities in adults with 47,XXX: a 7 Tesla MRI study

47,XXX (Triple X syndrome) is a sex chromosome aneuploidy characterized by the presence of a supernumerary X chromosome in affected females, and has been associated with a variable cognitive, behavioral, and psychiatric phenotype. Alterations in brain gray matter structure and function have been reported, but less is known about white matter (WM) organization in 47,XXX. Therefore, we conducted 7 T diffusion tensor imaging and characterized fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity of 22 adult women with 47,XXX and 22 age-matched typically developing females using tract-based spatial statistics. Relationships between phenotypic traits and WM organization characteristics in 47,XXX were also investigated. Adults with 47,XXX showed lower axial diffusivity in the body of the corpus callosum and the right superior longitudinal fasciculus. WM organization variability was not associated with IQ and social cognition and social functioning deficits in 47,XXX. Our findings indicate an effect of a supernumerary X chromosome in adult women on axonal integrity of the body of the corpus callosum and the right superior longitudinal fasciculus. These findings provide additional insight into the role of the X chromosome on WM organization. Future research is warranted to explore the clinical significant impact of altered WM organization in 47,XXX.

Impact of insurance status on MRI phenotypes in MS

BackgroundHealth insurance in the United States varies in coverage of essential diagnostic tests, therapies, and specialists. Health disparities between privately and publicly insured patients with MS have not been comprehensively assessed. The objective of this study is to evaluate the impact of public versus private insurance on longitudinal brain outcomes in MS. MethodsLesional, thalamic, and gray and white matter volumes were extracted from longitudinal MRI of 710 MS patients. Baseline volumes and atrophy rates of lesional, thalamic, and gray and white matter volumes were compared across insurance groups. ResultsAfter image quality assessment, 376 (284 private / 92 public), 638 (499 / 139), and 331 (250 / 81), patients were in MS lesion, thalamic, gray and white matter analyses respectively. Baseline lesion volume was higher for publicly insured patients but increased at a slightly higher rate in those privately insured (p = 0.01). Baseline gray matter measurements were lower for patients with public insurance, but thalamic (p < 0.01) and gray matter (p < 0.01) atrophy rates were slightly higher in the private insurance group. ConclusionInsurance type was associated with lesion, thalamic, and gray matter volumes. The results suggest that patients with public insurance may present with more advanced disease.

REPLY: Hippocampal atrophy and white matter lesions as predictors of the transition from VMCI to vascular dementia: Implications for early intervention

REPLY: Hippocampal atrophy and white matter lesions as predictors of the transition from VMCI to vascular dementia: Implications for early intervention

Bilateral Dentate Nuclei Hyperintensities and Response to 4-Aminopyridine in a Patient With Childhood-Onset GAA-FGF14-Related Ataxia.

To report a novel imaging finding of bilateral dentate nuclei hyperintensities in a case of childhood-onset GAA-FGF14-related ataxia (spinocerebellar ataxia 27B, SCA27B) and response to 4-aminopyridine (4-AP). A 53-year-old woman with unsolved progressive cerebellar ataxia of childhood onset underwent clinical and imaging assessment and extensive genetic investigation. After excluding Friedreich ataxia, most common spinocerebellar ataxia-related expansions, and pathogenic variants in ataxia-related genes through exome sequencing, targeted long-range PCR and repeat-primed PCR analysis revealed a heterozygous pathogenic (GAA)302 expansion in FGF14. Brain MRI showed bilateral dentate nuclei hyperintensities and peridentate white matter degeneration, a feature never reported before in SCA27B. Gait ataxia and frequency of falls improved after starting 4-AP. We confirm that SCA27B, initially considered a late-onset condition, can present with very early onset in childhood and describe a novel imaging feature of this common hereditary ataxia. Previous imaging studies had described a spectrum of findings, variably including cerebellar vermian and hemispheric atrophy, hyperintensities of the superior cerebellar peduncles, cerebral and brainstem atrophy, ventricular enlargement, and corpus callosum thinning. In this case, T2/FLAIR bilateral dentate nuclei hyperintensities and peridentate white matter degeneration expand the neuroradiologic spectrum associated with GAA-FGF14-related ataxia of long duration.

Delayed Deep White Matter Ischemia After Resection of Gliomas by Awake Surgery

BACKGROUND AND OBJECTIVES: Deep white matter (DWM) is perfused by the medullary arteries from the cortex, and ischemia sometimes occurs after glioma resection. However, the clinical significance of postoperative medullary artery–related ischemia has not been well studied. We retrospectively reviewed cases of delayed DWM ischemia after awake craniotomy to elucidate the clinical characteristics, mechanisms, and management of delayed ischemia. METHODS: We identified 4 cases of intra-axial brain tumors, mainly gliomas, that underwent tumor resection by awake craniotomy at our hospital and developed DWM ischemic symptoms after surgery, despite no worsening of neurological symptoms at the end of surgery. RESULTS: Four patients (3 men and 1 woman) presented with glioblastoma, oligodendroglioma, astrocytoma, and brain metastasis. The median age at surgery was 47.5 years (41-73 years). The tumors were located in the watershed area in the frontal lobe (n = 2) and the parietal lobe (n = 2), all of which were left-sided (n = 4). DWM ischemic symptoms, such as motor dysfunction, aphasia, dysarthria, and dysgraphia, developed at an average of 24 hours (14-48 hours) after resection by awake craniotomy. All 4 patients showed symptom improvement within a week after surgery and completely recovered within a month. CONCLUSION: DWM ischemia is caused by sacrifice of the medullary artery, which feeds the tumor and adjacent brain tissue during tumor resection, and should be considered when delayed aphasia or paralysis occurs postoperatively. These symptoms are often transient and recovery usually occurs. Tumors located in the frontal or parietal lobes, particularly in the watershed area, should be carefully monitored for postoperative ischemia.

Normative Population-Derived Data for MRI Manifestations of Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is manifested on magnetic resonance imaging (MRI) by white matter hyperintensities, lacunes, microbleeds, and atrophy. While these manifestations can be part of normal aging, a high burden has been associated with cognitive impairment and vascular events. Distinguishing between normal versus abnormal SVD lesion burden in clinical practice remains complex. Our objective is to establish age- and sex-specific normative data for MRI manifestations of SVD, to support clinical assessment in individual patients. We used 11 465 MRI scans from 5402 participants of the Rotterdam Study, the Netherlands, an ongoing prospective population-based cohort since 1990, to develop percentile curves for white matter hyperintensities and brain parenchymal fraction and probability curves for the prevalence and count of lacunes and microbleeds, across ages 45 to 100 years, stratified by sex. Participants were primarily White (≈97%), with a mean age at first scan of 64.7 (range, 45.7-97.9) years, and 55.7% being female participants. For all SVD MRI manifestations, the curves demonstrated nonlinear trends, with accelerating burden with advancing age (eg, doubling of white matter hyperintensity fraction every 10 years). Regarding brain parenchymal fraction, a decline was seen earlier in male participants (≈45 years) than female participants (≈60 years) and was more pronounced in male participants over time. Female participants had slightly higher white matter hyperintensity fractions compared with male participants across all ages. Lacunes and microbleeds were more frequently found in male participants than in female participants, and microbleeds were more prevalent than lacunes. We provide comprehensive normative data for different MRI manifestations of SVD, presented as percentile and probability curves by age, stratified by sex. This can aid clinicians to actually quantify the SVD burden on an individual patient's MRI scans and detect patterns of abnormality.

Unraveling contributions to the Z-spectrum signal at 3.5 ppm of human brain tumors.

To evaluate the influence of the confounding factors, direct water saturation (DWS), and magnetization transfer contrast (MTC) effects on measured Z-spectra and amide proton transfer (APT) contrast in brain tumors. High-grade glioma patients were scanned using an RF saturation-encoded 3D MR fingerprinting (MRF) sequence at 3 T. For MRF reconstruction, a recurrent neural network was designed to learn free water and semisolid macromolecule parameter mappings of the underlying multiple tissue properties from saturation-transfer MRF signals. The DWS spectra and MTC spectra were synthesized by solving Bloch-McConnell equations and evaluated in brain tumors. The dominant contribution to the saturation effect at 3.5 ppm was from DWS and MTC effects, but 25%-33% of the saturated signal in the gadolinium-enhancing tumor (13%-20% for normal tissue) was due to the APT effect. The APT# signal of the gadolinium-enhancing tumor was significantly higher than that of the normal-appearing white matter (10.1% vs. 8.3% at 1 μT and 11.2% vs. 7.8% at 1.5 μT). The RF saturation-encoded MRF allowed us to separate contributions to the saturation signal at 3.5 ppm in the Z-spectrum. Although free water and semisolid MTC are the main contributors, significant APT contrast between tumor and normal tissues was observed.

Subtle signs of atrial cardiomyopathy and left ventricular diastolic dysfunction are associated with reduced cognitive function: results from the Hamburg City Health Study.

Atrial fibrillation is associated with cognitive dysfunction. Atrial cardiomyopathy has been correlated with both entities. We aimed to characterize the association of echocardiographic parameters of atrial cardiomyopathy with cognitive function and cerebral changes. Participants of the population-based Hamburg City Health Study underwent in-depth transthoracic echocardiography and cognitive function testing, the Animal Naming Test (ANT), the Trail Making Test A (TMT-A) and B (TMT-B), 10-word learning test and cerebral magnetic resonance imaging. After excluding individuals with stroke or depression, data from 7852 individuals were available. In multi-variable-adjusted regression analyses, the E/e'-ratio was associated with the level of impairment in the ANT (-0.19 per one standard deviation [SD] increase, 95% confidence interval [CI] -0.36-[-0.01]) and the TMT-A (0.01 per one SD increase, 95% CI 0.003-0.020). Left atrial global peak strain was associated with positive performance in the TMT-A and B (-0.01 per one SD increase [95% CI -0.02-(-0.002)] and -0.02 per one SD increase [95% CI -0.03-(-0.01)], respectively) and the immediate recall of the 10-word learning test (0.11 per one SD increase, 95% CI 0.02-0.20). The E/e'-ratio was positively associated with the total and periventricular white matter hyperintensity load in age- and sex-adjusted regression analyses though statistical significance was lost after multi-variable adjustment. Subclinical echocardiographic signs of atrial cardiomyopathy and left ventricular diastolic dysfunction are associated with impaired performance in cognitive tests in the population. Our data provide evidence of the clinically important cardio-cerebral axis, relating cardiac dysfunction with cognitive performance.

Marital status, brain health, and cognitive reserve among diverse older adults.

Being married may protect late-life cognition. Less is known about living arrangement among unmarried adults and mechanisms such as brain health (BH) and cognitive reserve (CR) across race and ethnicity or sex/gender. The current study examines (1) associations between marital status, BH, and CR among diverse older adults and (2) whether one's living arrangement is linked to BH and CR among unmarried adults. Cross-sectional data come from the Washington Heights-Inwood Columbia Aging Project (N = 778, 41% Hispanic, 33% non-Hispanic Black, 25% non-Hispanic White; 64% women). Magnetic resonance imaging (MRI) markers of BH included cortical thickness in Alzheimer's disease signature regions and hippocampal, gray matter, and white matter hyperintensity volumes. CR was residual variance in an episodic memory composite after partialing out MRI markers. Exploratory analyses stratified by race and ethnicity and sex/gender and included potential mediators. Marital status was associated with CR, but not BH. Compared to married individuals, those who were previously married (i.e., divorced, widowed, and separated) had lower CR than their married counterparts in the full sample, among White and Hispanic subgroups, and among women. Never married women also had lower CR than married women. These findings were independent of age, education, physical health, and household income. Among never married individuals, living with others was negatively linked to BH. Marriage may protect late-life cognition via CR. Findings also highlight differential effects across race and ethnicity and sex/gender. Marital status could be considered when assessing the risk of cognitive impairment during routine screenings.

Impact of white matter hyperintensity volume on cognition among US Mexican American adults.

Higher white matter hyperintensity (WMH) volume is a marker of cardiovascular disease (CVD) risk. CVD risk factors increase risk for Alzheimer's disease and related dementias (ADRD). Mexican Americans (MA) and individuals of other Hispanic/Latino heritages have higher risk for CVD and ADRD. However, knowledge of associations between WMH volume and cognition in these groups remains limited. We conducted a cross-sectional study of associations between WMH volume and neuropsychological performance (attention/executive functioning, memory) in MA (n = 851) and non-Hispanic White (NHW; n = 747) adults in the Health and Aging Brain Study: Health Disparities. The MA group (mean age = 63.72 ± 7.90 years; 66.3% female) had higher rates of consensus diagnoses of hypertension and diabetes, whereas the NHW group (mean age = 69.18 ± 8.65 years; 55.2% female) had higher rates of diagnosed CVD (ps < .01). WMH volumes were higher among individuals with CVD risk factors/conditions (ps < .01). There were differential associations between WMH and neuropsychological performance across ethnoracial groups (ps < .001), wherein associations were steeper in the NHW group than in the MA group. Lower educational level was associated with higher WMH volume in the NHW group (p < .001), but no association was seen in the MA group (p > .05). Negative effects of pathological changes in the form of WMH on cognition may be less robust or consistent for MA adults than NHW adults. Furthermore, the impact of WMH on cognition in NHW adults may be mitigated by cognitive reserve related to educational attainment.

Association between hemoglobin levels and cerebral white matter volume in a general older Japanese population: the Iki-Iki study.

Although previous studies have reported that hemoglobin levels can affect the brain, very few have focused on the association between hemoglobin levels and brain volume. We aimed to identify the influence of hemoglobin levels on brain volume measured using magnetic resonance imaging (MRI) in a large elderly population. This cross-sectional study included 2153 participants (median age, 69 years; 60.2% female) who underwent 3T brain MRI. Multiple regression analyses were performed after adjusting for potential confounders. In the subgroup analyses, participants were divided into four groups according to sex and age threshold (lower age group [65-74] and higher age group [≥ 75]). After adjusting for potential confounders, total white matter volume reduction was found to be associated with decreased hemoglobin levels (females: standardized β = 0.059, [95% confidence interval (CI): 0.0032, 0.11], P = 0.038, males: standardized β = 0.069 [95% CI: -0.00023, 0.14], P = 0.051). This relationship was notable in younger age groups of both sexes. After adjustment, the total gray matter and hippocampal volumes were not significantly associated with hemoglobin levels. Low hemoglobin levels may have deleterious effects on white matter volume, which diminishes with age.

Short-Term Frequently Relapsing Ischemic Strokes Followed by Rapidly Progressive Dementia in CADASIL: A Case Report and Literature Review.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease with slow natural progression. Ischemic stroke and cognitive impairment are its most common clinical symptoms. Here, we report a rare 50-year-old woman who had rapid disease progression with c.457C>T, p.Argl53Cys heterozygous mutation in exon 4 of NOTCH3 and discuss the possible reasons. Furthermore, we summarized the clinical and neuroimaging characteristics of 14 CADASIL patients with Arg153Cys mutation in exon 4. The proband suffered acute ischemic stroke 5 times in 5 months, followed by rapidly progressive dementia (RPD) and inability to live independently, though she didn't have vascular risk factors and had been under standardized secondary prevention therapy since the first stroke. Magnetic resonance imaging showed extensive white matter hyperintensities, numerous ischemic infarcts and microbleeds, and severe brain atrophy. Her elder brother and other patients with Arg153Cys mutation in exon 4 all did not progress so quickly. Her multiple strokes may be associated with the poor self-regulation of vessels, which may promote the occurrence of RPD. Antiplatelet and anticoagulant drugs were difficult to prevent ischemic strokes. Severe imaging findings may indicate rapid progression of CADASIL. In addition, we found that headache was a very frequent symptom in CADASIL patients with Arg153Cys mutation in exon 4, accounting for 76.9%. CADASIL can also appear to have rapid progression, as illustrated by our proband, which is worthy of clinicians' attention and intervention timely. Headache may present in a relatively higher proportion of CADASIL patients with Arg153Cys mutation in exon 4.

MRI-Based Prediction of Macrovascular Causes of Intracerebral Hemorrhage: The MACRO Score.

Although most spontaneous intracerebral hemorrhages (ICHs) are due to cerebral small vessel diseases (SVDs), between 1 in 7 and 1 in 10 are due to a macrovascular cause. Rapid diagnosis has important therapeutic and prognostic implications but sometimes requires digital subtraction angiography (DSA), an invasive procedure which cannot be performed in all patients. MRI provides optimal sensitivity for markers of SVD but was not included in previous risk stratification scores. We aimed to create and validate a risk stratification score for macrovascular causes of ICH including MRI findings to guide diagnosis and further investigations. We pooled data from 2 large observational study cohorts (London/United Kingdom and Graz/Austria) of consecutive patients with ICH who had brain MRI and at least 1 angiographic modality within 90 days of symptom onset. The primary outcome was a macrovascular cause of ICH (arteriovenous malformation/dural arteriovenous fistula, aneurysm, cavernoma, or cerebral venous thrombosis), with the diagnosis based on neurovascular multidisciplinary meetings. Using lasso logistic regression, we built the MRI Assessment of the Causes of intRacerebral haemOrrhage (MACRO) score to assess the probability of a macrovascular cause. We performed internal validation using bootstrapping and external validation in an independent cohort (Bern/Switzerland). We included 1,043 patients with ICH (mean age 66 years, 42% female), 78 of whom had a macrovascular cause (7.5%). The final score includes age (0-39, 40-69, or ≥70), location of ICH (lobar, deep, or infratentorial), and SVD markers on MRI (≥1 microbleed, ≥1 lacune, presence of cortical superficial siderosis, or white matter hyperintensities using the Fazekas scale). The MACRO score showed an optimism-adjusted c-statistic of 0.90 (95% CI 0.88-0.93), superior to existing CT-based scores (p < 0.001). In external validation, the c-statistic was 0.87 (95% CI 0.80-0.94). MACRO scores ≥6 (59.5% of patients) indicated a very low risk of a macrovascular cause (0.2%), while scores ≤2 (9% of patients) indicated a high risk (48.9%). The MRI-based MACRO score shows excellent performance in predicting the likelihood of macrovascular causes of spontaneous intracerebral hemorrhage, making it useful in guiding further investigations. Important limitations include the observational study design and the performance of DSA in a minority of patients.

Estimated Brain Age in Healthy Aging and Across Multiple Neurological Disorders.

The brain aging in the general population and patients with neurological disorders is not well understood. To characterize brain aging in the above conditions and its clinical relevance. Retrospective. A total of 2913 healthy controls (HC), with 1395 females; 331 multiple sclerosis (MS); 189 neuromyelitis optica spectrum disorder (NMOSD); 239 Alzheimer's disease (AD); 244 Parkinson's disease (PD); and 338 cerebral small vessel disease (cSVD). 3.0 T/Three-dimensional (3D) T1-weighted images. The brain age was estimated by our previously developed model, using a 3D convolutional neural network trained on 9794 3D T1-weighted images of healthy individuals. Brain age gap (BAG), the difference between chronological age and estimated brain age, was calculated to represent accelerated and resilient brain conditions. We compared MRI metrics between individuals with accelerated (BAG ≥ 5 years) and resilient brain age (BAG ≤ -5 years) in HC, and correlated BAG with MRI metrics, and cognitive and physical measures across neurological disorders. Student's t test, Wilcoxon test, chi-square test or Fisher's exact test, and correlation analysis. P < 0.05 was considered statistically significant. In HC, individuals with accelerated brain age exhibited significantly higher white matter hyperintensity (WMH) and lower regional brain volumes than those with resilient brain age. BAG was significantly higher in MS (10.30 ± 12.6 years), NMOSD (2.96 ± 7.8 years), AD (6.50 ± 6.6 years), PD (4.24 ± 4.8 years), and cSVD (3.24 ± 5.9 years) compared to HC. Increased BAG was significantly associated with regional brain atrophy, WMH burden, and cognitive impairment across neurological disorders. Increased BAG was significantly correlated with physical disability in MS (r = 0.17). Healthy individuals with accelerated brain age show high WMH burden and regional volume reduction. Neurological disorders exhibit distinct accelerated brain aging, correlated with impaired cognitive and physical function. 4 TECHNICAL EFFICACY: Stage 2.

The effects of 3-month supplementation with synbiotic on patient-reported outcomes, exercise tolerance, and brain and muscle metabolism in adult patients with post-COVID-19 chronic fatigue syndrome (STOP-FATIGUE): a randomized Placebo-controlled clinical trial.

Considering the observed gastrointestinal issues linked to post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), beneficially modulating the gut microbiota could offer a safe, cost-effective nutritional strategy. This trial aimed to evaluate the effects of medium-term synbiotic supplementation on patient-reported outcomes, exercise tolerance, and tissue metabolism in patients with post-COVID-19 ME/CFS. Between September 2022 and December 2023, we investigated the impact of 3-month supplementation with a synbiotic mixture including L. rhamnosus DSM 32550, Humiome® L. plantarum DSM 34532, B. lactis DSM 32269, B. longum DSM 32946, fructooligosaccharides and zinc, on predetermined primary and secondary outcome measures in twenty six post-COVID-19 ME/CFS patients utilizing a parallel-group, randomized, placebo-controlled, double-blind design. Both the synbiotic and placebo intake resulted in a significant reduction in general fatigue after 3months compared to the baseline values (P ≤ 0.05). This was accompanied by a significant interaction effect (time vs. treatment) for post-exercise malaise (P = 0.02), with synbiotic superior to placebo to attenuate post-exercise malaise. The synbiotic also demonstrated a significant advantage over placebo in increasing choline levels at the thalamus (P = 0.02), and creatine levels at left frontal white matter (P = 0.05) and left frontal grey matter (P = 0.04). Taking the synbiotic mixture for three months improves tissue metabolism and mitigates clinical features of post-COVID-19 fatigue syndrome. The presented data show promise in addressing the widespread issue of ME/CFS following the COVID-19 pandemic; however, further validation is needed before endorsing the synbiotics within this clinical context. The study is registered at ClinicalTrials.gov (NCT06013072).