Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration

Neurologic disorders often disproportionately affect specific brain regions, and different apoptotic mechanisms may contribute to white matter pathology in leukodystrophies or gray matter pathology in poliodystrophies. We previously showed that neural progenitors that generate cerebellar gray matter depend on the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in these progenitors produces spontaneous apoptosis and cerebellar hypoplasia, while similar conditional deletion of Mcl-1 produces no phenotype. Here we show that, in contrast, postnatal oligodendrocytes depend on MCL-1. We found that brain-wide Mcl-1 deletion caused apoptosis specifically in mature oligodendrocytes while sparing astrocytes and oligodendrocyte precursors, resulting in impaired myelination and progressive white matter degeneration. Disabling apoptosis through co-deletion of Bax or Bak rescued white matter degeneration, implicating the intrinsic apoptotic pathway in Mcl-1-dependence. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mouse model of the leukodystrophy vanishing white matter disease (VWMD), suggesting the potential for MCL-1 deficiency to contribute to clinical neurologic disease. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 deficiency in white matter pathology, and suggest apoptosis inhibition as a leukodystrophy therapy.

Multiparametric characterization of white matter alterations in early stage Huntington disease

Huntington’s disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS), on the other hand, quantifies the motion of brain metabolites in vivo, thus enabling the investigation of microstructural alteration of specific cell populations. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. Twenty patients at an early stage of HD and 20 healthy controls were recruited in a monocentric study. Using diffusion imaging we observed alterations to the brain microstructure and their morphology in patients with HD. Furthermore, FBA revealed specific fiber populations that were affected by the disease. Moreover, the mean diffusivity of the intra-axonal metabolite N-acetylaspartate, co-measured with N-acetylaspartylglutamate (tNAA), was significantly reduced in the corpus callosum of patients compared to controls. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD.

White matter microstructure associations with episodic memory in adults with Down syndrome: a tract-based spatial statistics study

Background Nearly all persons with Down syndrome will show pathology of Alzheimer’s disease in their 40s. There is a critical need for studies to identify early biomarkers of these various pathological changes of Alzheimer’s disease in the Down syndrome population and understand the relationship of these biomarkers to cognitive symptoms in order to inform clinical trials. Although Alzheimer’s disease is often considered a disease of gray matter, white matter degeneration has been documented during the preclinical stage of Alzheimer’s disease. The current study examined the association between diffusion tensor imaging (DTI) measures of white matter microstructure and episodic memory performance in 52 adults with Down syndrome. Methods Seventy (N = 70) participants (M = 40.13, SD = 7.77 years) received baseline scans as part of the Neurodegeneration in Aging Down Syndrome (NiAD) study at two imaging facilities (36 at the University of Wisconsin-Madison [UW-Madison] and 34 at the University of Pittsburgh Medical Center [UPMC]). All participants had genetically confirmed trisomy 21. Fifty-two (N = 52) participants remained after QC. The DTI measures, fractional anisotropy (FA) and mean diffusivity (MD), were calculated for each participant. A combined measure of episodic memory was generated by summing the z-scores of (1) Free and Cued Recall test and (2) Rivermead Behavioural Memory Test for Children Picture Recognition. The DTI data were projected onto a population-derived FA skeleton and tract-based spatial statistics analysis was conducted using the FSL tool PALM to calculate Pearson’s r values between FA and MD with episodic memory. Results A positive correlation of episodic memory with FA and a negative correlation of episodic memory and MD in the major association white matter tracts were observed. Results were significant (p < 0.05) after correction for chronological age, imaging site, and premorbid cognitive ability. Conclusion These findings suggest that white matter degeneration may be implicated in early episodic memory declines prior to the onset of dementia in adults with Down syndrome. Further, our findings suggest a coupling of episodic memory and white matter microstructure independent of chronological age.

Fixel-Based Analysis of White Matter Degeneration in Patients With Progressive Supranuclear Palsy or Multiple System Atrophy, as Compared to Parkinson's Disease

Introduction: White matter degeneration may contribute to clinical symptoms of parkinsonism.Objective: We used fixel-based analysis (FBA) to compare the extent and patterns of white matter degeneration in different parkinsonian syndromes—including idiopathic Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP).Methods: This is a retrospective interpretation of prospectively acquired data of patients recruited in previous studies during 2008 and 2019. Diffusion-weighted images were acquired on a 3-Tesla scanner (diffusion weighting b = 1000 s/mm2–applied along either 64 or 30 non-collinear directions) from 53 patients with PD (men/women: 29/24; mean age: 65.06 ± 5.51 years), 47 with MSA (men/women: 20/27; mean age: 63.00 ± 7.19 years), and 50 with PSP men/women: 20/30; mean age: 65.96 ± 3.14 years). Non-parametric permutation tests were used to detect intergroup differences in fixel-related indices—including fiber density, fiber cross-section, and their combination.Results: Patterns of white matter degeneration were significantly different between PD and atypical parkinsonisms (MSA and PSP). Compared with patients with PD, those with MSA and PSP showed a more extensive white matter involvement—noticeably descending tracts from primary motor cortex to corona radiata and cerebral peduncle. Lesions of corpus callosum were specific to PSP and absent in both MSA and PD.Discussion: FBA identified specific patterns of white matter changes in MSA and PSP patients compared to PD. Our results proved the utility of FBA in evaluation of implied biological processes of white matter changes in parkinsonism. Our study set the stage for future applications of this technique in patients with parkinsonian syndromes.