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.

Decrement of the Purkinje Cells Diameter after Oral Intake of Lithium in Albino Rats

Background: The histology of Cerebellar gray matter consists of a middle Purkinje cells layer with flask shaped Purkinje cells. The field of Neurology has documented that different organic compounds and metals are lethal to the excitatory Purkinje Neurons. Researches have proved Lithium to be hazardous to nervous tissue and especially Cerebellum For the past sixty years Lithium is the favorable drug for treatment of Bipolar Disorder. Aim: To Analyse and record the changes of decrement of the size of Purkinje cell Diameter after chronic Lithium ingestion. Methods: Sixteen albino rats were selected and were treated with lithium for a period of fifteen days and the data for changes in Purkinje cells Diameter was observed. Results: The Observations of Our study showed highly significantly decreased diameter of the Purinje cells in Group B (Lithium Carbonate) animals as compared to Group A Animals which were on Lab Diet Conclusion: The Morphometric Data proved that Lithium Carbonate is Toxic to Purkinje cells, and it educated our Population to use Lithium with caution. Keywords: Purkinje cell Diameter, Gray matter, Hazardous

Restoration of Cerebellar Gray Matter Thickness by Methylcobalamin (6 Weeks Study)

Background: Methylcobalamin is essential vitamin required for DNA synthesis during cell division therefore maintain the architecture of nervous tissue distorted by soft metals such as Lithium Carbonate. Accurate documentation of the thickness cerebellar cortical thickness was required in subjects who were injected with methylcobalamin distorted by Lithium Carbonate. Aim: To provide data of cerebellar gray matter thickness distorted by Lithium Carbonate by the anti-oxidant effect of methylcobalamin. Methods: Fifteen albino rats were maintained on food and diet in Animal House of the Basic Medical Sciences Institute, JPMC Karachi for a period of 6 weeks. Results: The results obtained of the thickness of cerebellar gray matter distorted by Lithium Carbonate was restored by methylcobalamin in our study. Conclusion: To observe the neuroprotective effect of B12 on distorted cerebellar cortex treated by Lithium Carbonate. Keywords: Methylcobalamin, Lithium Carbonate, Gray Matter, Cerebellum

Cerebellar White Matter Abnormalities in Patients with Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary peripheral neuropathy. Brain volumetry and diffusion tensor imaging (DTI) were performed in CMT patients with PMP22 duplication, MFN2, GJB1, or NEFL mutations to investigate for structural changes of the cerebellum.Volume in cerebellar white matter (WM) was significantly reduced in CMT patients with NEFL mutations. Abnormal DTI findings ​​were observed in the superior, middle, and inferior cerebellar peduncles predominantly in NEFL mutations, and partly in GJB1 mutations. Cerebellar ataxia was more prevalent in the NEFL mutation (72.7%) than GJB1 mutation (9.1%), but not observed in other genotypic subtypes, which indicates that structural cerebellar abnormalities were associated with the presence of cerebellar ataxia. However, NEFL and GJB1 mutations did not affect cerebellar gray matter (GM), and neither cerebellar GM nor WM abnormalities were observed in PMP22 duplication or MFN2 mutations. We found structural evidence of cerebellar WM abnormalities in CMT patients with NEFL and GJB1 mutations and the association between cerebellar WM involvement and cerebellar ataxia in these genetic subtypes, especially in the NEFL subgroup. Therefore, we suggest that neuroimaging such as MRI volumetry or DTI in CMT patients could play an important role in detecting abnormalities of the cerebellar WM.

Comparison of Early F-18 Florbetaben PET/CT to Tc-99m ECD SPECT Using Voxel, Regional, and Network Analysis

This study aimed to validate early-phase F-18 Florbetaben positron emission tomography (eFBB PET) as a brain perfusion test and determine the optimal reference region. A total of 27 patients with early Parkinson’s disease with ethyl cysteinate dimer single positron emission tomography (ECD SPECT) and FBB PET were included. Six reference regions, including whole brain (GN), pons, central white matter (CWM), whole cerebellum (WC), WC with brain stem (WC + B), and cerebellar gray matter (CG), were applied to obtain SUVR. Correlations of SUVRs between eFBB PET and ECD SPECT were calculated for each normalization method. Voxel-wise comparison of the two imaging studies was done with paired t-test. Pearson’s r for SUVRs were 0.791 for GN (p < 0.001), 0.422 for pons (p = 0.028), -0.005 for CWM (p = 0.982), 0.886 for WC (p < 0.001), 0.897 for WC + B (p < 0.001), and 0.904 for CG (p < 0.001), respectively. Early phase FBB PET had significantly higher voxel-wise SUVR in cerebral cortices, striatum, midbrain regions, and lower voxel-wise SUVR in white matter, concordantly in both GN and CG normalization method (FDR adjusted-p < 0.05). Our findings suggest that eFBB PET is a reliable perfusion test based on a high correlation of SUVR with ECD SPECT. High gray-to-white matter contrast would be another advantage of eFBB PET for clinical use.

Regional SUV quantification in hybrid PET/MR, a comparison of two atlas-based automatic brain segmentation methods

Background：Quantitative analysis of brain positron-emission tomography (PET) depends on structural segmentation, which can be time-consuming and operator-dependent when performed manually. Previous automatic segmentation usually registered subjects’ images onto an atlas template (defined as RSIAT here) for group analysis, which changed the individuals’ images and probably affected regional PET segmentation. In contrast, we could register atlas template to subjects’ images (RATSI), which created an individual atlas template and may be more accurate for PET segmentation. We segmented two representative brain areas in twenty Parkinson disease (PD) and eight multiple system atrophy (MSA) patients performed in hybrid positron-emission tomography/magnetic resonance imaging (PET/MR). The segmentation accuracy was evaluated using the Dice coefficient (DC) and Hausdorff distance (HD). and the standardized uptake value (SUV) measurements of these two automatic segmentation methods were compared, using manual segmentation as a reference. Results：The DC of RATSI increased and the HD decreased significantly (P < 0.05) compared with the RSIAT in PD, while the results of one-way analysis of variance (ANOVA) found no significant differences in the SUVmean and SUVmax among the two automatic and the manual segmentation methods. Further, RATSI was used to compare regional differences in cerebral metabolism pattern between PD and MSA patients. The SUVmean in the segmented cerebellar gray matter for the MSA group was significantly lower compared with the PD group (P<0.05), which is consistent with previous reports. Conclusion：The RATSI was more accurate for the caudate nucleus and putamen automatic segmentation, and can be used for regional PET analysis in hybrid PET/MR.

The depression GWAS risk allele predicts smaller cerebellar gray matter volume and reduced SIRT1 mRNA expression in Chinese population

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, the genetic and phenotypic heterogeneity of the illness has hampered the discovery of its genetic determinants. In this study, in an independent Han Chinese sample (1824 MDD cases and 3031 controls), we conducted replication analyses of two genetic loci highlighted in a previous Chinese MDD genome-wide association study (GWAS), and confirmed the significant association of a single nucleotide polymorphism (SNP) rs12415800 near SIRT1. Subsequently, using hypothesis-free whole-brain analysis in two independent Han Chinese imaging samples, we found that individuals carrying the MDD risk allele of rs12415800 exhibited aberrant gray matter volume in the left posterior cerebellar lobe compared with those carrying the non-risk allele. Besides, in independent Han Chinese postmortem brain and peripheral blood samples, the MDD risk allele of rs12415800 predicted lower SIRT1 mRNA levels, which was consistent with the reduced expression of this gene in MDD patients compared with healthy subjects. These results provide further evidence for the involvement of SIRT1 in MDD, and suggest that this gene might participate in the illness via affecting the development of cerebellum, a brain region that is potentially underestimated in previous MDD studies.