We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive “multi-omic” analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.

Background and Purpose— We assessed ethnic differences in medication adherence 3 months poststroke in a population-based study as an initial step in investigating the increased stroke recurrence risk in Mexican Americans compared with non-Hispanic whites. Methods— Ischemic stroke cases from 2008 to 2015 from the Brain Attack Surveillance in Corpus Christi project in Texas were followed prospectively for 3 months poststroke to assess medication adherence. Medications in 5 drug classes were analyzed: statins, antiplatelets, anticoagulants, antihypertensives, and antidepressants. For each drug class, patients were considered adherent if they reported never missing a dose in a typical week. The χ 2 tests or Kruskal-Wallis nonparametric tests were used for ethnic comparisons of demographics, risk factors, and medication adherence. A multivariable logistic regression model was constructed for the association of ethnicity and medication nonadherence. Results— Mexican Americans (n=692) were younger (median 65 years versus 68 years, P <0.001), had more diabetes mellitus ( P <0.001) and hypertension ( P <0.001) and less atrial fibrillation ( P =0.003), smoking ( P =0.003), and education ( P <0.001) than non-Hispanic whites (n=422). Sex, insurance status, high cholesterol, previous stroke/transient ischemic attack history, excessive alcohol use, tPA (tissue-type plasminogen activator) treatment, National Institutes of Health Stroke Scale score, and comorbidity index did not significantly differ by ethnicity. There was no significant difference in medication adherence for any of the 5 drug classes between Mexican Americans and non-Hispanic whites. Conclusions— This study did not find ethnic differences in medication adherence, thus challenging this patient-level factor as an explanation for stroke recurrence disparities. Other reasons for the excessive stroke recurrence burden in Mexican Americans, including provider and health system factors, should be explored.

ObjectiveTo determine using a population-based study whether midlife stroke patients having a primary care physician (PCP) at the time of first stroke have a lower risk of stroke recurrence and mortality than those who do not have a PCP.MethodsFirst-ever ischemic stroke patients 45 to 64 years of age at stroke onset were ascertained through the Brain Attack Surveillance in Corpus Christi (BASIC) project from 2000 to 2013 in Texas. Cox proportional hazards models were used to examine the association between not having a PCP and stroke recurrence or all-cause mortality in separate models. Cases were followed up for up to 5 years or until December 31, 2013, whichever came first. Cases were censored for recurrence if they died before experiencing a recurrent event. We adjusted for clinical risk factors that could be associated with having a PCP and recurrence or mortality.ResultsThere were 663 first-occurrence ischemic stroke cases. Of these, 77% had a PCP, 43% were female, and average age was 55.6 years. Five-year recurrence risk was 14.6%, and mortality risk was 19.2%. Not having a PCP was associated with higher recurrence risk (adjusted hazard ratio 1.75, 95% confidence interval 1.02–3.02). Having a PCP was not associated with mortality. Sensitivity analyses showed that results were robust to different ways to adjust for chronic conditions.ConclusionThis study found lower rates of stroke recurrence among those with a PCP at the time of first stroke. Future studies could determine the value of establishing a PCP before stroke hospital discharge for secondary stroke prevention.

Background and Purpose-Do-not-resuscitate (DNR) orders are common after stroke, though there are limited data on trends over time. We investigated time trends in DNR orders in a community with a large minority population. Methods-Cases of ischemic stroke (IS) or intracerebral hemorrhage (ICH) were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) study from June 2007 through October 2016. Cox proportional hazards models were used to assess time to DNR orders, with an interaction term added to allow separate hazard ratios for early (≤24 hours) and late (>24 hours) DNR. Stroke-type specific calendar trends were assessed with an interaction term between calendar year (linear) and stroke type. Results-2,672 cases were included (ICH 14%). Mean age was 69, 50% were female, and raceethnicity was Mexican American (MA, 58%), non-Hispanic White (NHW, 37%), and African American (AA, 5%). Overall, 16% had a DNR order during the hospitalization. For ICH, DNR orders (early and late) were stable over the study period. However, early DNR orders became more common over time after IS (hazard ratio for 2016 vs 2007: 1.89, 95% CI 1.06, 3.39), with no change over time for late DNR orders after IS. MAs (HR 0.65, 95% CI 0.50, 0.86) and AAs (HR 0.17, 95% CI 0.04, 0.71) were less likely than NHWs to have early DNR orders, though there were no race-ethnic differences in late DNR orders. There was no change in race-ethnic difference in DNR orders over the time of the study (interaction p > 0.60).

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and lethal neurodegenerative diseases seen comorbidly in up to 15% of patients. Despite several decades of research, no effective treatment or disease-modifying strategies have been developed. We now understand more than before about the genetics and biology behind ALS and FTD, but the genetic etiology for the majority of patients is still unknown and the phenotypic variability observed across patients, even those carrying the same mutation, is enigmatic. Additionally, susceptibility factors leading to neuronal vulnerability in specific central nervous system regions involved in disease are yet to be identified. As the inherited but dynamic epigenome acts as a cell-specific interface between the inherited fixed genome and both cell-intrinsic mechanisms and environmental input, adaptive epigenetic changes might contribute to the ALS/FTD aspects we still struggle to comprehend. This chapter summarizes our current understanding of basic epigenetic mechanisms, how they relate to ALS and FTD, and their potential as therapeutic targets. A clear understanding of the biological mechanisms driving these two currently incurable diseases is urgent-well-needed therapeutic strategies need to be developed soon. Disease-specific epigenetic changes have already been observed in patients and these might be central to this endeavor.