Matute, Carlos

ABSTRACT Neurodegenerative pathologies including multiple sclerosis (MS) are consistently associated with energy deficit in the central nervous system (CNS). This might directly impact myelinating oligodendrocytes as these are particularly vulnerable to metabolic insults. Importantly, oligodendroglial dysfunction and myelin alterations occur in most, if not all neurodegenerative diseases, and are associated with axonal pathology/loss. Thus, elucidating metabolic mechanisms required for oligodendroglial myelin maintenance and axonal support might be crucial to identify therapeutic targets to achieve neuroprotection. While monocarboxylates are important energy fuels for the CNS, their role in myelinating oligodendrocyte function remains unclear. Here we show that, just like neurons, myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2) both in mice and humans, which is downregulated in progressive MS. While deletion of MCT2 in mouse oligodendrocytes did not affect the survival of these cells, it resulted in downregulation of lipid synthesis-associated enzymes and failure of myelin maintenance. Moreover, axonal upregulation of lactate dehydrogenase A concomitant with axonal damage was observed but could be alleviated by ketogenic diet. We conclude that oligodendroglial MCT2 is required for myelin maintenance and axonal support, which becomes altered in progressive MS, but may be compensated for by specific metabolic therapies. Graphical abstract

Introduction: In the current study, we examined the temporal trends in mortality across gender, race, and 10-year age groups over last two-decades. Methods: We conducted a retrospective population-based study using Centers for Disease Control and Prevention database. Subjects with underlying cause of death from AMI were identified using validated ICD10 codes. Age adjusted mortality rates were calculated for gender and race whereas crude rates were calculated for 10-year age group. Using Poisson regression, we estimated the rate ratio between race/ethnicity pairs adjusting for age and sex in order to analyze temporal trend. Results: We identified 2,709,173 subjects with reported underlying cause of death as AMI between January-2000 to December-2019 of which 54.7% were males (n=1,483,163). The age adjusted mortality rate per 100,000 was higher in males compared to females (52.4% vs 30.7%, OR: 1.66 [1.45-1.89]). Among ethnicities African American (AA) population had the highest age adjusted mortality rate per 100,000 [Table 1]. As expected, age group >85 years had the highest mortality rate per 100,000 constituting 30% of total deaths (78% of total deaths were noted in >65yr age group). AMI age adjusted mortality rates/100,000 showed significant decline across gender and race with highest decline in female population (66.5% decline). Highest percentage decline in mortality was noted in AA female population (68.2%) whereas in males it was the white population (62%). In females, highest percentage decline in mortality was noted in 75-84 age-group (70%) while it was >85 age-group (67%) in males. Conclusion: Over last two decades there has been a significant decline in AMI mortality rates across gender and race. AA continue to have higher age adjusted mortality rate among both male and female population (38% and 22% respectively). Further studies are needed to identify and provide targeted prevention and intervention strategies in high-risk populations.