Relationship between White Matter Lesions and Gray Matter Atrophy in Multiple Sclerosis

Background and Objectives: There is currently no consensus about the extent of gray matter (GM) atrophy that can be attributed to secondary changes after white matter (WM) lesions or the temporal and spatial relationships between the 2 phenomena. Elucidating this interplay will broaden the understanding of the combined inflammatory and neurodegenerative pathophysiology of multiple sclerosis (MS), and separating atrophic changes due to primary and secondary neurodegenerative mechanisms will then be pivotal to properly evaluate treatment effects, especially if these treatments target the different processes individually. To untangle these complex pathologic mechanisms, this systematic review provides an essential first step: an objective and comprehensive overview of the existing in vivo knowledge of the relationship between brain WM lesions and GM atrophy in patients diagnosed with MS. The overall aim was to clarify the extent to which WM lesions are associated with both global and regional GM atrophy and how this may differ in the different disease subtypes. Methods: We searched MEDLINE (through PubMed) and Embase for reports containing direct associations between brain GM and WM lesion measures obtained by conventional MRI sequences in patients with clinically isolated syndrome and MS. No restriction was applied for publication date. The quality and risk of bias in included studies were evaluated with the Quality Assessment Tool for observational cohort and cross-sectional studies (NIH, Bethesda, MA). Qualitative and descriptive analyses were performed. Results: A total of 90 articles were included. WM lesion volumes were related mostly to global, cortical and deep GM volumes, and those significant associations were almost without exception negative, indicating that higher WM lesion volumes were associated with lower GM volumes or lower cortical thicknesses. The most consistent relationship between WM lesions and GM atrophy was seen in early (relapsing) disease and less so in progressive MS. Discussion: The findings suggest that GM neurodegeneration is mostly secondary to damage in the WM during early disease stages while becoming more detached and dominated by other, possibly primary neurodegenerative disease mechanisms in progressive MS.publishedVersio

MR Spectroscopy Shows Long Propylene Glycol Half-Life in Neonatal Brain

Introduction: Neonatal propylene glycol (PG) clearance is low with long plasma half-life. We hypothesized that neonatal brain PG clearance is diminished and may be related to perinatal asphyxia, infection, or stroke, via different blood-brain barrier permeability. This study aimed to estimate cerebral PG half-life with a clearance model including PG measured with MR spectroscopy (MRS) in neonates that received phenobarbital as the only PG source and to evaluate whether PG clearance was related to intracerebral pathology, for example, perinatal asphyxia, infection, or stroke. Methods: In this retrospective cohort study, 45 neonates receiving any dose of phenobarbital underwent MRS (short echo time single-voxel MRS at 1.5 T). Cumulative phenobarbital/PG doses were calculated. MRS indications were perinatal asphyxia (n = 22), infection (n = 4), stroke (n = 10), metabolic disease (n = 4), and others (n = 5). Results: Medians (interquartile range) included gestational age 39.4 (3.1) weeks, birth weight 3,146 (1,340) g, and cumulative PG dose 700 (1,120) mg/kg. First-order kinetics with mono-exponential decay showed cerebral PG half-life of 40.7 h and volume of distribution of 1.6 L/kg. Zero-order kinetics showed a rate constant of 0.048 mM/h and a volume of distribution of 2.3 L/kg, but the fit had larger residuals than the first-order model. There were no differences in ΔPG (i.e., PG estimated with clearance model minus PG observed with MRS) in infants with perinatal asphyxia, infection, or stroke. Discussion/Conclusion: This study showed a long cerebral PG half-life of 40.7 h in neonates, unrelated to perinatal asphyxia, infection, or stroke. These findings should increase awareness of possible toxic PG concentrations in neonatal brain due to intravenous PG-containing drugs

Longitudinal changes in neurometabolite concentrations in the dorsal anterior cingulate cortex after concentrated exposure therapy for obsessive-compulsive disorder

Background The dorsal anterior cingulate cortex (dACC) plays an important role in the pathophysiology of obsessive-compulsive disorder (OCD) due to its role in error processing, cognitive control and emotion regulation. OCD patients have shown altered concentrations in neurometabolites in the dACC, particularly Glx (glutamate+glutamine) and tNAA (N-acetylaspartate+N-acetyl-aspartyl-glutamate). We investigated the immediate and prolonged effects of exposure and response prevention (ERP) on these neurometabolites. Methods Glx and tNAA concentrations were measured using magnetic resonance spectroscopy (1H-MRS) in 24 OCD patients and 23 healthy controls at baseline. Patients received concentrated ERP over four days. A subset was re-scanned after one week and three months. Results No Glx and tNAA abnormalities were observed in OCD patients compared to healthy controls before treatment or over time. Patients with childhood or adult onset differed in the change over time in tNAA (F(2,40) = 7.24, ɳ2p= 0.27, p = 0.004): concentrations increased between one week after treatment and follow-up in the childhood onset group (t(39) = -2.43, d = -0.86, p = 0.020), whereas tNAA concentrations decreased between baseline and follow-up in patients with an adult onset (t(42) = 2.78, d = 1.07, p = 0.008). In OCD patients with versus without comorbid mood disorders, lower Glx concentrations were detected at baseline (t(38) = -2.28, d = -1.00, p = 0.028). Glx increased after one week of treatment within OCD patients with comorbid mood disorders (t(30) = -3.09, d = -1.21, p = 0.004). Limitations Our OCD sample size allowed the detection of moderate to large effect sizes only. Conclusion ERP induced changes in neurometabolites in OCD seem to be dependent on mood disorder comorbidity and disease stage rather than OCD itself.publishedVersio

Linking resting state metabolite concentrations in the dorsal anterior cingulate cortex to response inhibition in OCD, a combined fMRI-MRS study

Introduction Obsessive-compulsive disorder (OCD) has been associated with abnormal brain activation in regions related to response inhibition, such as the dorsal anterior cingulate cortex (dACC), as well as dysregulation of the glutamate system. We studied how the neurometabolites glutamate and glutamine (Glx) in the dACC are related to task performance and task-related brain activation during a response inhibition task in OCD patients and healthy controls (HC). Methods We combined resting-state magnetic resonance spectroscopy (1H-MRS) in the dACC and functional MRI (fMRI) during the Stop Signal Task (SST), using data from two sites (43 OCD patients and 41 HC). For fMRI data, region of interest (ROI) and whole brain analyses were performed during successful inhibition and error processing. Subsequently, the relation between baseline Glx concentrations, task-related activation, functional connectivity, and task performance was tested using correlational analyses. Results In HC, Glx concentration in dACC showed a positive correlation with inhibition-related activation in the right thalamus (based on ROI analyses) and the brain stem (based on whole brain analyses). No relation between Glx and task-related activation was observed in patients with OCD. SST performance was not different between groups and was not associated with dACC Glx concentrations. Limitations Although we attempted to link neurometabolite levels and brain activation, the non-simultaneous acquisition of 1H-MRS with fMRI made it difficult to interpret the results. Conclusions We conclude that dACC Glx is associated with inhibition-related activation and network function in HC, but not in OCD, suggesting altered inhibition processing in OCD.publishedVersio

Longitudinal volumetric analysis of gray matter atrophy in metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross-sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment

A second case of glutaminase hyperactivity: Expanding the phenotype with epilepsy

Glutaminase (GLS) hyperactivity was first described in 2019 in a patient with profound developmental delay and infantile cataract. Here, we describe a 4-year-old boy with GLS hyperactivity due to a de novo heterozygous missense variant in GLS, detected by trio whole exome sequencing. This boy also exhibits developmental delay without dysmorphic features, but does not have cataract. Additionally, he suffers from epilepsy with tonic clonic seizures. In line with the findings in the previously described patient with GLS hyperactivity, in vivo 3 T magnetic resonance spectroscopy (MRS) of the brain revealed an increased glutamate/glutamine ratio. This increased ratio was also found in urine with UPLC-MS/MS, however, inconsistently. This case indicates that the phenotypic spectrum evoked by GLS hyperactivity may include epilepsy. Clarifying this phenotypic spectrum is of importance for the prognosis and identification of these patients. The combination of phenotyping, genetic testing, and metabolic diagnostics with brain MRS and in urine is essential to identify new patients with GLS hyperactivity and to further extend the phenotypic spectrum of this disease

Neurodegenerative disease after hematopoietic stem cell transplantation in metachromatic leukodystrophy

Objective: Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. Methods: Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. Results: The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. Interpretation: Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation

Serial isotropic three-dimensional fast FLAIR imaging: Using image registration and subtraction to reveal active multiple sclerosis lesions

OBJECTIVE. Image registration and subtraction to detect the change of disease burden in multiple sclerosis on serial MR images should benefit from the use of high-resolution isotropic voxels. We compared 1.2-mm isotropic three-dimensional (3D) fast fluid-attenuated inversion recovery (FLAIR) images with standard 3-mm two-dimensional spin-echo images for the detection of new or enlarging lesions in longitudinal studies. SUBJECTS AND METHODS. Serial MR images were obtained at baseline, month 6 (n = 20), and month 7 (n = 16). For the half-yearly intervals, subtracted 3D FLAIR images and T2-weighted spin-echo images were compared. For the monthly intervals, subtracted 3D FLAIR images were compared with triple-dose contrast-enhanced T1-weighted spin-echo images. New, enlarging, and enhancing lesions were marked in consensus by two radiologists. RESULTS. At the half-yearly intervals, 3D FLAIR imaging detected more new or enlarging lesions than T2-weighted spin-echo imaging, both at the initial interpretation (80 vs 52; p 0.05). CONCLUSION. Isotropic 3D FLAIR imaging holds great promise for the detection of new or enlarging lesions in multiple sclerosis using registration and subtraction techniques certainly at longer intervals

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Correction for desynchronization of EEG and fMRI clocks through data interpolation optimizes artifact reduction

Co-registration of EEG (Electroencephalogram)-and fMRI (functional magnetic resonance imaging) remains a challenge due to the large artifacts induced on the EEG by the MR (magnetic resonance) sequence gradient and RF pulses. We present an algorithm, based on the average-subtraction method, which is able to correct EEG data for gradient and RF pulse artifacts. We optimized artifact reduction by correcting the misalignment of EEG and fMRI data samples, resulting from the asynchronous sampling of EEG and fMRI data, through interpolation of EEG data. A clustering algorithm is proposed to account for the variability of the pulse artifact. Results show that the algorithm was able to keep the spontaneous brain activity while removing gradient and pulse artifacts with only a subtraction of selectively averaged data. Pulse artifact clustering showed that most of the variability was due to the time jitter of the pulse artifact markers. We show that artifact reduction by average-subtraction is optimized by interpolating the EEG data to correct for asynchronously sampled EEG and fMRI data