Normal-appearing White Matter Research Articles

Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minutes, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03855332.

Multiparametric MRI dataset for susceptibility-based radiomic feature extraction and analysis

Multiple sclerosis (MS) is a progressive demyelinating disease impacting the central nervous system. Conventional Magnetic Resonance Imaging (MRI) techniques (e.g., T2w images) help diagnose MS, although they sometimes reveal non-specific lesions. Quantitative MRI techniques are capable of quantifying imaging biomarkers in vivo, offering the potential to identify specific signs related to pre-clinical inflammation. Among those techniques, Quantitative Susceptibility Mapping (QSM) is particularly useful for studying processes that influence the magnetic properties of brain tissue, such as alterations in myelin concentration. Because of its intrinsic quantitative nature, it is particularly well-suited to be analyzed through radiomics, including techniques that extract a high number of complex and multi-dimensional features from radiological images. The dataset presented in this work provides information about normal-appearing white matter (NAWM) in a cohort of MS patients and healthy controls. It includes QSM-based radiomic features from NAWM and its tracts, and MR sequences necessary to implement the pipeline: T1w, T2w, QSM, DWI. The workflow is outlined in this article, along with an application showing feature reliability assessment.

Prognostic implications of distinctive imaging characteristics in primary intracranial germ cell tumors: A retrospective analysis

PurposePrimary central nervous system (CNS) germ cell tumors (GCTs) are rare brain tumors that encompass two subtypes: germinomas and non-germinomatous germ cell tumors (NGGCTs), NGGCTs have less favorable outcome and require multi-modality treatment. Biopsy is recommended for disease diagnosis, the specimen may not adequately reflect the entire tumor. This study aimed to assess distinct imaging characteristics to differentiate between GCT subgroups and to identify possible initial image and subgroup features that influence survival. MethodThis retrospective study, conducted from January 2006 to March 2023, analyzed patient data and MRI findings of primary CNS GCTs. It evaluated tumor characteristics including cysts, seeding, multifocality, and hemorrhage. Tumor volumes and apparent diffusion coefficient (ADC) values of both tumoral and normal-appearing contralateral white matter were measured. These factors were correlated with overall and 5-year survival rates. ResultsThis study included 51 participants with CGTs, comprising 19 germinoma and 32 NGGCTs cases. GCTs with hemorrhage had worse overall (P = 0.03) and 5-year (P = 0.01) survival rates. No survival difference between germinoma and non-hemorrhagic NGGCT. NGGCTs were more likely to bleed (P < 0.001) than germ cell tumor, especially those with choriocarcinoma or yolk sac tumor components (P = 0.001). The ADC ratios of germinomas were significantly lower than those of NGGCTs (P = 0.03 for whole tumor; P < 0.01 or solid part), The ADC ratios of choriocarcinoma were also lower than mixed tumor (P = 0.01; P = 0.02). ConclusionHemorrhage indicates worse prognosis. Intratumoral hemorrhage and ADC ratios differentiate germinoma from NGGCTs. Larger cohorts and advanced MR techniques are needed for future study.

Microstructural changes of the white matter in systemic lupus erythematosus patients without neuropsychiatric symptoms: a multi-shell diffusion imaging study

BackgroundDiffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) provide more comprehensive and informative perspective on microstructural alterations of cerebral white matter (WM) than single-shell diffusion tensor imaging (DTI), especially in the detection of crossing fiber. However, studies on systemic lupus erythematosus patients without neuropsychiatric symptoms (non-NPSLE patients) using multi-shell diffusion imaging remain scarce.MethodsTotally 49 non-NPSLE patients and 41 age-, sex-, and education-matched healthy controls underwent multi-shell diffusion magnetic resonance imaging. Totally 10 diffusion metrics based on DKI (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis and radial kurtosis) and NODDI (neurite density index, orientation dispersion index and volume fraction of the isotropic diffusion compartment) were evaluated. Tract-based spatial statistics (TBSS) and atlas-based region-of-interest (ROI) analyses were performed to determine group differences in brain WM microstructure. The associations of multi-shell diffusion metrics with clinical indicators were determined for further investigation.ResultsTBSS analysis revealed reduced FA, AD and RK and increased ODI in the WM of non-NPSLE patients (P < 0.05, family-wise error corrected), and ODI showed the best discriminative ability. Atlas-based ROI analysis found increased ODI values in anterior thalamic radiation (ATR), inferior frontal-occipital fasciculus (IFOF), forceps major (F_major), forceps minor (F_minor) and uncinate fasciculus (UF) in non-NPSLE patients, and the right ATR showed the best discriminative ability. ODI in the F_major was positively correlated to C3.ConclusionThis study suggested that DKI and NODDI metrics can complementarily detect WM abnormalities in non-NPSLE patients and revealed ODI as a more sensitive and specific biomarker than DKI, guiding further understanding of the pathophysiological mechanism of normal-appearing WM injury in SLE.

Heterogeneous blood-brain barrier dysfunction in cerebral small vessel diseases.

We explored how blood-brain barrier (BBB) leakage rate of gadolinium chelates (Ktrans) and BBB water exchange rate (kw) varied in cerebral small vessel disease (cSVD) subtypes. Thirty sporadic cSVD, 40 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 13 high-temperature requirement factor A serine peptidase 1 (HTRA) -related cSVD subjects were investigated parallel to 40 healthy individuals. Subjects underwent clinical, cognitive, and MRI assessment. In CADASIL, no difference in Ktrans, but lower kw was observed in multiple brain regions. In sporadic cSVD, no difference in kw, but higher Ktrans was found in the whole brain and normal-appearing white matter. In HTRA1-related cSVD, both higher Ktrans in the whole brain and lower kw in multiple brain regions were observed. In each patient group, the altered BBB measures were correlated with lesion burden or clinical severity. In cSVD subtypes, distinct alterations of kw and Ktrans were observed. The combination of Ktrans and kw can depict the heterogeneous BBB dysfunction. We measured BBB leakage to gadolinium-based contrast agent (Ktrans) and water exchange rate (kw) across BBB in three subtypes of cSVD. CADASIL is characterized by lower kw, HTRA1-related cSVD exhibits both higher Ktrans and lower kw, while sporadic cSVD is distinguished by higher Ktrans. There are distinct alterations in kw and Ktrans among subtypes of cSVD, indicating the heterogeneous nature of BBB dysfunction.

Unconstrained quantitative magnetization transfer imaging: Disentangling T1 of the free and semi-solid spin pools

Abstract Since the inception of magnetization transfer (MT) imaging, it has been widely assumed that Henkelman’s two spin pools have similar longitudinal relaxation times, which motivated many researchers to constrain them to each other. However, several recent publications reported a T1s of the semi-solid spin pool that is much shorter than T1f of the free pool. While these studies tailored experiments for robust proofs-of-concept, we here aim to quantify the disentangled relaxation processes on a voxel-by-voxel basis in a clinical imaging setting, that is, with an effective resolution of 1.24mm isotropic and full brain coverage in 12min. To this end, we optimized a hybrid-state pulse sequence for mapping the parameters of an unconstrained MT model. We scanned four people with relapsing-remitting multiple sclerosis (MS) and four healthy controls with this pulse sequence and estimated T1f≈1.84s and T1s≈0.34s in healthy white matter. Our results confirm the reports that T1s≪T1f and we argue that this finding identifies MT as an inherent driver of longitudinal relaxation in brain tissue. Moreover, we estimated a fractional size of the semi-solid spin pool of m0s≈0.212, which is larger than previously assumed. An analysis of T1f in normal-appearing white matter revealed statistically significant differences between individuals with MS and controls.

Enhancing T1 signal of normal-appearing white matter with divided subtracted inversion recovery: A pilot study in mild traumatic brain injury.

Magnetic resonance imaging (MRI) and cognitive profiles in patients with mild traumatic brain injury (mTBI) are often discordant. Conventional MRI seldom captures the full extent of pathological changes in the normal-appearing white matter (NAWM). The divided subtracted inversion recovery (dSIR) technique may enhance T1 differences in NAWM, making them easily visible. We aimed to implement dSIR on a clinical scanner and tested results in mTBI patients. To produce dSIR images, Inversion Recovery-Turbo Spin Echo sequences were modified using six different inversion times (TI) on a 3-T scanner in healthy participants and patients with mTBI. The multiple TIs determined normal white (TIshort) and gray matter (TIlong) nulling points in healthy subjects, which were used to create dSIR images. In one patient, the protocol was repeated at 3 months to identify changes after rehabilitation. Diffusion tensor imaging (DTI)-derived mean diffusivity (MD) and fractional anisotropy (FA) maps were aligned to dSIR images to ensure that signal was not artefactual. Ten healthy participants (five females; age 24 ± 3 [95% CI: 21, 26] years) were included. TIshort and TIlong were set at 450 and 750 ms, respectively. In both patients (one male, age 17 years; one female, age 14 years), dSIR images revealed areas with increased T1 in the NAWM not visible on conventional MRI. dSIR-based hyperintensities corresponded to elevated MD and reduced FA. Substantial changes were found at follow-up with improvement in DTI-based parameters. dSIR images enhance subtle changes in the NAWM of patients with mTBI by amplifying their intrinsic T1 signal.

A novel PSMB8 isoform associated with multiple sclerosis lesions induces P-body formation.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Current therapies primarily target the inflammatory component of the disease and are highly effective in early stages of MS while limited therapies have an effect in the more chronic progressive stages of MS where resident glia have a larger role. MS lesions tend to be inflammatory even after the initial peripheral immune cell invasion has subsided and this inflammation is known to cause alternative splicing events. We used qPCR of normal-appearing white matter and white matter lesions from postmortem MS tissue, in vitro studies, and immunostaining in MS tissue to investigate the alternative splicing of one gene known to be important during recovery in an animal model of MS, PSMB8. We found a novel, intron-retained isoform which has not been annotated, upregulated specifically in MS patient white matter lesions. We found that this novel isoform activates the nonsense-mediated decay pathway in primary human astrocytes, the most populous glial cell in the CNS, and is then degraded. Overexpression of this isoform in astrocytes leads to an increased number of processing bodies in vitro, the primary site of mRNA decay. Finally, we demonstrated that MS white matter lesions have a higher burden of processing bodies compared to normal-appearing white matter, predominantly in GFAP-positive astrocytes. The increase in alternative splicing of the PSMB8 gene, the stress that this alternative splicing causes, and the observation that processing bodies are increased in white matter lesions suggests that the lesion microenvironment may lead to increased alternative splicing of many genes. This alternative splicing may blunt the protective or reparative responses of resident glia in and around white matter lesions in MS patients.

Differentiation of hemispheric white matter lesions in migraine and multiple sclerosis with similar radiological features using advanced MRI.

White matter hyperintensities (WMHs), presented on T2-weighted or fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequences, are lesions in the human brain that can be observed in both migraine and multiple sclerosis (MS). Seventeen migraine patients and 15 patients with relapsing-remitting multiple sclerosis with WMHs, and 17 healthy subjects age-and sex-matched to the migraine group were prospectively enrolled and underwent conventional and advanced MRI studies with diffusion-and perfusion-weighted imaging and single voxel proton magnetic resonance spectroscopy. In both disease groups, elevated T2 relaxation time, apparent diffusion coefficient (ADC) values, and decreased N-acetyl-aspartate levels were found in the intralesional white matter compared to the contralateral normal-appearing white matter (NAWM), while there was no difference between the hemispheres of the control subjects. Migraine patients had the lowest intralesional creatine + phosphocreatine and myo-inositol (mI) values among the three groups, while patients with MS showed the highest intralesional T1 and T2 relaxation times, ADC, and mI values. In the contralateral NAWM, the same trend with mI changes was observed in migraineurs and MS patients. No differences in perfusion variables were observed in any groups. Our multimodal study showed that tissue damage is detectable in both diseases. Despite the differences in various advanced MRI measures, with more severe injury detected in MS lesions, we could not clearly differentiate the two white matter lesion types.

Intrinsic and extrinsic contributors to subregional thalamic volume loss in multiple sclerosis.

To evaluate the intrinsic and extrinsic microstructural factors contributing to atrophy within individual thalamic subregions in multiple sclerosis using in vivo high-gradient diffusion MRI. In this cross-sectional study, 41 people with multiple sclerosis and 34 age and sex-matched healthy controls underwent 3T MRI with up to 300 mT/m gradients using a multi-shell diffusion protocol consisting of eight b-values and diffusion time of 19 ms. Each thalamus was parcellated into 25 subregions for volume determination and diffusion metric estimation. The soma and neurite density imaging model was applied to obtain estimates of intra-neurite, intra-soma, and extra-cellular signal fractions for each subregion and within structurally connected white matter trajectories and cortex. Multiple sclerosis-related volume loss was more pronounced in posterior/medial subregions than anterior/ventral subregions. Intra-soma signal fraction was lower in multiple sclerosis, reflecting reduced cell body density, while the extra-cellular signal fraction was higher, reflecting greater extra-cellular space, both of which were observed more in posterior/medial subregions than anterior/ventral subregions. Lower intra-neurite signal fraction in connected normal-appearing white matter and lower intra-soma signal fraction of structurally connected cortex were associated with reduced subregional thalamic volumes. Intrinsic and extrinsic microstructural measures independently related to subregional volume with heterogeneity across atrophy-prone thalamic nuclei. Extrinsic microstructural alterations predicted left anteroventral, intrinsic microstructural alterations predicted bilateral medial pulvinar, and both intrinsic and extrinsic factors predicted lateral geniculate and medial mediodorsal volumes. Our results might be reflective of the involvement of anterograde and retrograde degeneration from white matter demyelination and cerebrospinal fluid-mediated damage in subregional thalamic volume loss.

Ultra-High Contrast MRI: Using Divided Subtracted Inversion Recovery (dSIR) and Divided Echo Subtraction (dES) Sequences to Study the Brain and Musculoskeletal System.

Divided and subtracted MRI is a novel imaging processing technique, where the difference of two images is divided by their sum. When the sequence parameters are chosen properly, this results in images with a high T1 or T2 weighting over a small range of tissues with specific T1 and T2 values. In the T1 domain, we describe the implementation of the divided Subtracted Inversion Recovery Sequence (dSIR), which is used to image very small changes in T1 from normal in white matter. dSIR has shown widespread changes in otherwise normal-appearing white matter in patients suffering from mild traumatic brain injury (mTBI), substance abuse, and ischemic leukoencephalopathy. It can also be targeted to measure small changes in T1 from normal in other tissues. In the T2 domain, we describe the divided echo subtraction (dES) sequence that is used to image musculoskeletal tissues with a very short T2*. These tissues include fascia, tendons, and aponeuroses. In this manuscript, we explain how this contrast is generated, review how these techniques are used in our research, and discuss the current challenges and limitations of this technique.

Combined diffusion tensor imaging and quantitative susceptibility mapping to characterize normal-appearing white matter in self-limited epilepsy with centrotemporal spikes.

In brain development, Myelination is the characteristic feature of white matter maturation, which plays an important role in efficient information transmitting. The white matter abnormality has been reported to be associated with self-limited epilepsy with centrotemporal spikes (SeLECTS). This study aimed to detect the altered white matter region in the SeLECTS patients by the combination of diffusion tensor imaging (DTI) and quantitative susceptibility mapping (QSM) technique. 27 children with SeLECTS and 23 age- and gender-matched healthy children were enrolled. All participants were scanned with 3.0-T MRI to acquire the structure, diffusion and susceptibility-weighted data. The susceptibility and diffusion weighted data were processed to obtain quantitative susceptibility map and fraction anisotropy (FA) map. Then voxel-wise tract-based spatial statistics (TBSS) were used to analyze quantitative susceptibility and FA data. Both DTI and QSM revealed extensive white matter alterations in the frontal, parietal, and temporal lobes in SeLECTS patients. The overlapped region of DTI and QSM analyses was located in the fiber tracts of the corona radiata. The FA values in this overlapped region were negatively correlated with the magnetic susceptibility values. Our results suggest that TBSS-based QSM can be employed as a novel approach for characterizing alterations in white matter in SeLECTS. And the combination of QSM and DTI can provide a more comprehensive evaluation of white matter integrity by utilizing different biophysical features.

The Microglial Transcriptome of Age-Associated Deep Subcortical White Matter Lesions Suggests a Neuroprotective Response to Blood-Brain Barrier Dysfunction.

Age-associated deep-subcortical white matter lesions (DSCLs) are an independent risk factor for dementia, displaying high levels of CD68+ microglia. This study aimed to characterize the transcriptomic profile of microglia in DSCLs and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68+ microglia were isolated from white matter groups (n = 4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort using immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material in the CFAS cohort and identified significantly differentially expressed genes (DEGs). Functional grouping and pathway analysis were assessed using the Database for Annotation Visualization and Integrated Discovery (DAVID) software, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCLs compared to non-lesional control white matter identified 181 significant DEGs (93 upregulated and 88 downregulated). Functional clustering analysis in DAVID revealed dysregulation of haptoglobin-haemoglobin binding (Enrichment score 2.5, p = 0.017), confirmed using CD163 immunostaining, suggesting a neuroprotective microglial response to blood-brain barrier dysfunction in DSCLs. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p < 0.001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in ageing white matter pathology, highlighting a neuroprotective adaptation in DSCLs microglia and a potentially lesion-promoting phenotype in NAWM microglia.

Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (β = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. Data for this study are available from the corresponding author upon reasonable request.

The Time Trajectory of Choroid Plexus Enlargement in Multiple Sclerosis.

Choroid plexus (CP) can be seen as a watchtower of the central nervous system (CNS) that actively regulates CNS homeostasis. A growing body of literature suggests that CP alterations are involved in the pathogenesis of multiple sclerosis (MS) but the underlying mechanisms remain elusive. CPs are enlarged and inflamed in relapsing-remitting (RRMS) but also in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) stages, far beyond MS diagnosis. Increases in the choroid plexus/total intracranial volume (CP/TIV) ratio have been robustly associated with increased lesion load, higher translocator protein (TSPO) uptake in normal-appearing white matter (NAWM) and thalami, as well as with higher annual relapse rate and disability progression in highly active RRMS individuals, but not in progressive MS. The CP/TIV ratio has only slightly been correlated with magnetic resonance imaging (MRI) findings (cortical or whole brain atrophy) and clinical outcomes (EDSS score) in progressive MS. Therefore, we suggest that plexus volumetric assessments should be mainly applied to the early disease stages of MS, whereas it should be taken into consideration with caution in progressive MS. In this review, we attempt to clarify the pathological significance of the temporal CP volume (CPV) changes in MS and highlight the pitfalls and limitations of CP volumetric analysis.

Ultra-high b-value DWI accurately identifies isocitrate dehydrogenase genotypes and tumor subtypes of adult-type diffuse gliomas.

To distinguish isocitrate dehydrogenase (IDH) genotypes and tumor subtypes of adult-type diffuse gliomas based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5) in 2021 using standard, high, and ultra-high b-value diffusion-weighted imaging (DWI). This prospective study enrolled 70 patients with adult-type diffuse gliomas who underwent multiple b-value DWI. Apparent diffusion coefficient (ADC) values including ADCb500/b1000, ADCb500/b2000, ADCb500/b3000, ADCb500/b4000, ADCb500/b6000, ADCb500/b8000, and ADCb500/b10000 in tumor parenchyma (TP) and contralateral normal-appearing white matter (NAWM) were calculated. The ADC ratios of TP/NAWM were assessed for correlations with IDH genotypes, tumor subtypes, and Ki-67 status; diagnostic performances were compared. All ADCs were significantly higher in IDHmutant gliomas than in IDH wild-type gliomas (p < 0.01 for all); ADCb500/b8000 had the highest area under the curve (AUC) of 0.866. All ADCs were significantly lower in glioblastoma than in astrocytoma (p < 0.01 for all). ADCs other than ADCb500/b1000 were significantly lower in glioblastoma than in oligodendroglioma (p < 0.05 for all). ADCb500/b8000 and ADCb500/b10000 were significantly higher in oligodendroglioma than in astrocytoma (p = 0.034 and 0.023). The highest AUCs were 0.818 for ADCb500/b6000 when distinguishing glioblastoma from astrocytoma, 0.979 for ADCb500/b8000 and ADCb500/b10000 when distinguishing glioblastoma from oligodendroglioma, and 0.773 for ADCb500/b10000 when distinguishing astrocytoma from oligodendroglioma. Additionally, all ADCs were negatively correlated with Ki-67 status (p < 0.05 for all). Ultra-high b-value DWI can reliably separate IDH genotypes and tumor subtypes of adult-type diffuse gliomas using WHO CNS5 criteria. Ultra-high b-value diffusion-weighted imaging can accurately distinguish isocitrate dehydrogenase genotypes and tumor subtypes of adult-type diffuse gliomas, which may facilitate personalized treatment and prognostic assessment for patients with glioma. • Ultra-high b-value diffusion-weighted imaging can accurately distinguish subtle differences in water diffusion among biological tissues. • Ultra-high b-value diffusion-weighted imaging can reliably separate isocitrate dehydrogenase genotypes and tumor subtypes of adult-type diffuse gliomas. • Compared with standard b-value diffusion-weighted imaging, high and ultra-high b-value diffusion-weighted imaging demonstrate better diagnostic performances.

Cognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis.

The aim of this study was to investigate whether, compared to pediatric healthy controls (HCs), the glymphatic system is impaired in pediatric multiple sclerosis (MS) patients according to their cognitive status, and to assess its association with clinical disability and MRI measures of brain structural damage. Sixty-five pediatric MS patients (females = 62%; median age = 15.5 [interquartile range, IQR = 14.5;17.0] years) and 23 age- and sex-matched HCs (females = 44%; median age = 14.1 [IQR = 11.8;16.2] years) underwent neurological, neuropsychological and 3.0 Tesla MRI assessment, including conventional and diffusion tensor imaging (DTI). We calculated the diffusion along the perivascular space (DTI-ALPS) index, a proxy of glymphatic function. Cognitive impairment (Co-I) was defined as impairment in at least 2 cognitive domains. No significant differences in DTI-ALPS index were found between HCs and cognitively preserved (Co-P) pediatric MS patients (estimated mean difference [EMD] = -0.002 [95% confidence interval = -0.069; 0.065], FDR-p = 0.956). Compared to HCs and Co-P patients, Co-I pediatric MS patients (n = 20) showed significantly lower DTI-ALPS index (EMD = -0.136 [95% confidence interval = -0.214; -0.058], FDR-p ≤ 0.004). In HCs, no associations were observed between DTI-ALPS index and normalized brain, cortical and thalamic volumes, and normal-appearing white matter (NAWM) fractional anisotropy (FA) and mean diffusivity (MD) (FDR-p ≥ 0.348). In pediatric MS patients, higher brain WM lesion volume (LV), higher NAWM MD, lower normalized thalamic volume, and lower NAWM FA were associated with lower DTI-ALPS index (FDR-p ≤ 0.016). Random Forest selected lower DTI-ALPS index (relative importance [RI] = 100%), higher brain WM LV (RI = 59.5%) NAWM MD (RI = 57.1%) and intelligence quotient (RI = 51.3%) as informative predictors of cognitive impairment (out-of-bag area under the curve = 0.762). Glymphatic system dysfunction occurs in pediatric MS, is associated with brain focal lesions, irreversible tissue loss accumulation and cognitive impairment. ANN NEUROL 2024;95:1080-1092.

Subtle white matter intensity changes on fluid-attenuated inversion recovery imaging in patients with ischaemic stroke.

Leukoaraiosis is a neuroimaging marker of small-vessel disease that is characterized by high signal intensity on fluid-attenuated inversion recovery MRI. There is increasing evidence from pathology and neuroimaging suggesting that the structural abnormalities that characterize leukoaraiosis are actually present within regions of normal-appearing white matter, and that the underlying pathophysiology of white matter damage related to small-vessel disease involves blood-brain barrier damage. In this study, we aim to verify whether leukoaraiosis is associated with elevated signal intensity on fluid-attenuated inversion recovery imaging, a marker of brain tissue free-water accumulation, in normal-appearing white matter. We performed a cross-sectional study of adult patients admitted to our hospital with a diagnosis of acute ischaemic stroke or transient ischaemic attack. Leukoaraiosis was segmented using a semi-automated method involving manual outlining and signal thresholding. White matter regions were segmented based on the probabilistic tissue maps from the International Consortium for Brain Mapping 152 atlas. Also, normal-appearing white matter was further segmented based on voxel distance from leukoaraiosis borders, resulting in five normal-appearing white matter strata at increasing voxel distances from leukoaraiosis. The relationship between mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter and leukoaraiosis volume was studied in a multivariable statistical analysis using linear mixed modelling, having normal-appearing white matter strata as a clustering variable. One hundred consecutive patients meeting inclusion and exclusion criteria were selected for analysis (53% female, mean age 68 years). Mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter was higher in the vicinity of leukoaraiosis and progressively lower at increasing distances from leukoaraiosis. In a multivariable analysis, the mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter was positively associated with leukoaraiosis volume and age (B = 0.025 for each leukoaraiosis quartile increase; 95% confidence interval 0.019-0.030). This association was found similarly across normal-appearing white matter strata. Voxel maps of the mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter showed an increase in signal intensity that was not adjacent to leukoaraiosis regions. Our results show that normal-appearing white matter exhibits subtle signal intensity changes on fluid-attenuated inversion recovery imaging that are related to leukoaraiosis burden. These results suggest that diffuse free-water accumulation is likely related to the aetiopathogenic processes underlying the development of white matter damage related to small-vessel disease.

Three-dimensional identification of microvascular pathology and neurovascular inflammation in severe white matter hyperintensity: a case report

White matter hyperintensities (WMH) are the most prevalent markers of cerebral small vessel disease (SVD), which is the major vascular risk factor for dementia. Microvascular pathology and neuroinflammation are suggested to drive the transition from normal-appearing white matter (NAWM) to WMH, particularly in individuals with hypertension. However, current imaging techniques cannot capture ongoing NAWM changes. The transition from NAWM into WMH is a continuous process, yet white matter lesions are often examined dichotomously, which may explain their underlying heterogeneity. Therefore, we examined microvascular and neurovascular inflammation pathology in NAWM and severe WMH three-dimensionally, along with gradual magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) signal (sub-)segmentation. In WMH, the vascular network exhibited reduced length and complexity compared to NAWM. Neuroinflammation was more severe in WMH. Vascular inflammation was more pronounced in NAWM, suggesting its potential significance in converting NAWM into WMH. Moreover, the (sub-)segmentation of FLAIR signal displayed varying degrees of vascular pathology, particularly within WMH regions. These findings highlight the intricate interplay between microvascular pathology and neuroinflammation in the transition from NAWM to WMH. Further examination of neurovascular inflammation across MRI-visible alterations could aid deepening our understanding on WMH conversion, and therewith how to improve the prognosis of SVD.

Micro-diffusely abnormal white matter: An early multiple sclerosis lesion phase with intensified myelin blistering.

Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro-diffusely abnormal white matter, mDAWM). We used an in-depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. mDAWM-defined areas exhibit ill-defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo-myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.