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Different pathological processes for acute white matter lesions in multiple sclerosis

Alturkustani M, Bahakeem B, Zhang Q, Ang LC

Malays J Pathol, 2020 Aug;42(2):187-194.
PMID: 32860370

INTRODUCTION: Multiple sclerosis (MS) has variable clinical presentations, prognoses, pathogeneses, and pathological patterns. We conducted a pathological review of acute MS-associated lesions that focused on the degree of axonal injury, myelin loss, and glial reaction to determine whether the observed demyelination was of the primary or secondary type.
MATERIALS AND METHODS: After searching the records for a 15-year period at the London Health Sciences Centre Pathology Department, we identified 8 cases of surgical acute lesion biopsies in which clinical MS diagnoses were made before or after the biopsy.
RESULTS: The white matter pathologies in these cases could be sorted into 3 morphological patterns. The first pattern, which represents typical demyelinated plaques, was observed in 4 cases and was characterised by nearly complete demyelination accompanied by variable degrees of axon preservation and axonal swelling. The second pattern was observed in 3 cases and was characterised by demyelinating lesions containing variable numbers of myelinated axons mixed with a few demyelinated axons and variable numbers of axonal swellings. The myelinated axons ranged from scattered fibres to bands of variable thickness, and the demyelination was a mixture of primary and secondary demyelination. The third pattern was observed in 1 case and was characterised by well-demarcated areas of reduced myelin staining and numerous apoptotic nuclei. Axonal staining revealed many fragmented axons with reduced myelin staining but no definitely demyelinated axons.
CONCLUSIONS: This report shows that the predominant pathology underlying acute MS-related lesions is not limited to demyelination but can include axonal degeneration alone or in combination with primary demyelination which reflect different pathogenesis for these acute lesions.

Matched MeSH terms: White Matter/pathology*
Fulltext Impaired Resting-State Functional Connectivity in Cerebral Autosomal-Dominant Arteriopathy, Subcortical Infarcts, and Leukoencephalopathy Mutant Mice

Aykan SA, Lai JH, Sugimoto K, Aykan O, Fung WY, Ho D, et al.

Stroke, 2025 Apr;56(4):987-995.
PMID: 39882613 DOI: 10.1161/STROKEAHA.124.049772

BACKGROUND: Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy is the most prevalent monogenic inherited cause of cerebral small vessel disease. Despite its prevalence, there is currently no proven therapy to prevent or reverse the progression of the disease.
METHODS: This study aimed to characterize the functional integrity of long white matter tracts in cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy transgenic mice expressing R169C mutant Notch3 (Notch3R169C) compared with wild type littermates (Notch3WT), both with and without a superimposed focal white matter lesion in the corpus callosum, utilizing optical resting-state functional connectivity imaging alongside behavioral examinations. In addition, we examined the efficacy of tocotrienol, a neuroprotective derivative of vitamin E derived from palm oil, which has shown promise in preventing white matter disease progression in clinical trials involving patients with small vessel disease.
RESULTS: At baseline, resting-state interhemispheric and intrahemispheric functional connectivity was significantly lower in Notch3R169C than in Notch3WT (P=0.004), and the grid walk test revealed a higher number of foot faults in the Notch3R169C group compared with Notch3WT. Sex did not interact with the genotype on the primary outcomes. Introducing a lesion in the corpus callosum compromised functional connectivity and behavior outcomes in both genotypes to a similar extent; lesion volumes did not differ between the genotypes. Tocotrienol treatment did not show any protective effect on any end point.
CONCLUSIONS: These data show impaired resting-state functional connectivity and increased foot faults in the Notch3R169C mutant model of cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy. Future work will aim to test therapeutic or preventive interventions in cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy mutants using these measures.

Matched MeSH terms: White Matter/pathology
Fulltext Magnetic resonance image tissue classification using an automatic method

Yazdani S, Yusof R, Riazi A, Karimian A

Diagn Pathol, 2014;9:207.
PMID: 25540017 DOI: 10.1186/s13000-014-0207-7

Brain segmentation in magnetic resonance images (MRI) is an important stage in clinical studies for different issues such as diagnosis, analysis, 3-D visualizations for treatment and surgical planning. MR Image segmentation remains a challenging problem in spite of different existing artifacts such as noise, bias field, partial volume effects and complexity of the images. Some of the automatic brain segmentation techniques are complex and some of them are not sufficiently accurate for certain applications. The goal of this paper is proposing an algorithm that is more accurate and less complex).

Matched MeSH terms: White Matter/pathology*
Fulltext Association of Whole-Genome and NETRIN1 Signaling Pathway-Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank

Barbu MC, Zeng Y, Shen X, Cox SR, Clarke TK, Gibson J, et al.

Biol Psychiatry Cogn Neurosci Neuroimaging, 2019 01;4(1):91-100.
PMID: 30197049 DOI: 10.1016/j.bpsc.2018.07.006

BACKGROUND: Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure.
METHODS: We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390).
RESULTS: We found significantly lower FA in the superior longitudinal fasciculus (β = -.035, pcorrected = .029) and significantly higher MD in a global measure of thalamic radiations (β = .029, pcorrected = .021), as well as higher MD in the superior (β = .034, pcorrected = .039) and inferior (β = .029, pcorrected = .043) longitudinal fasciculus and in the anterior (β = .025, pcorrected = .046) and superior (β = .027, pcorrected = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts.
CONCLUSIONS: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.

Matched MeSH terms: White Matter/pathology*