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Hexanucleotide repeat expansion (HRE) withinC9orf72is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, includingC9orf72HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheralC9orf72expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects ofC9orf72HRE and clinical diagnosis (n= 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheralC9orf72expression, TE activation, thalamic atrophy, and clinical severity (n= 114 individuals, male and female). We confirmed global thalamic atrophy and reducedC9orf72expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed thatC9orf72expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 elementL1HS.L1HSlevels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated thatC9orf72levels relate to clinical severity, and identified marked derepression of TEs, includingL1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENTPathogenic repeat expansion inC9orf72is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction ofC9orf72in blood and found broad dysregulation of transposable elements—genetic elements typically repressed in the human genome—in symptomaticC9orf72expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD.C9orf72expression was also associated with clinical severity, suggesting that peripheralC9orf72levels capture disease-relevant information.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread de-repression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used the FreeSurfer pipeline and its extensions to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78) on atrophy of thalamic nuclei. We also generated a novel, whole-blood RNA-seq dataset to determine the relationships between peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element, L1HS. L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from HRE carriers revealed atrophy of specific thalamic nuclei; demonstrated that C9orf72 levels relate to clinical severity; and identified marked de-repression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.Significance StatementPathogenic repeat expansion in C9orf72 is the most frequent genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). The clinical, neuroimaging, and pathological features of C9-FTD/ALS are well-characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we utilized a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements—genetic elements typically repressed in the human genome—in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

MicroRNAs (miRNAs) are small non-coding RNA that are powerful regulators of gene expression and can affect the expression of hundreds of genes. miRNAs can be packed in small extracellular vesicles (SEV) and released into the extracellular space by neurons and microglia to act locally as well as pass through the blood-brain barrier and act systemically. We sought to understand the differences in neuronal SEV miRNA expression between frontotemporal dementia (FTD), Alzheimer's disease (AD), and healthy aging. Plasma was obtained from FTD, AD, and healthy aging participants that were matched based on age, sex, and race/ethnicity. Additionally, a subset of participants also provided paired cerebrospinal fluid samples to compare neuronal SEV miRNAs in plasma and cerebrospinal fluid. Neuronal SEV were isolated using differential ultracentrifugation and antibody conjugated Dynabeads® for the neuronal surface marker, L1CAM. RNA sequencing was performed. 12 FTD, 11 with AD, and 10 healthy aging participants were enrolled in the study. In FTD, SEV miRNA-181c was downregulated compared to healthy controls. In AD, miRNA-122 and miRNA-3591 were downregulated compared to those in healthy controls and FTD. Using an FDR0.2, only miRNA-21-5p was found to have increased expression in the cerebrospinal fluid compared to plasma in a group of AD and FTD participants. SEV miRNA-181c is significantly downregulated in FTD compared to healthy controls and may mediate its effects through microglial-directed neuroinflammation and interaction with TAR DNA-binding protein 43 (TDP-43) based on pathway analysis. Additionally, the FOXO and Hippo pathways may be important mediators of FTD, based on pathway analysis. Lastly, because only one SEV miRNA was differentially expressed between the plasma and cerebrospinal fluid in paired samples, plasma represents an appropriate biofluid for studying neuronal SEV miRNA.

Apolipoprotein E alleles have been associated with both Alzheimer's disease (AD) and intracerebral hemorrhage (ICH). In addition, ICH is associated with a markedly high risk of subsequent dementia compared to other subtypes of stroke. We sought to evaluate if other genetic markers for AD were also associated with ICH. We examined whether published AD risk single nucleotide polymorphisms (SNPs) and haplotypes were associated with ICH utilizing genome-wide association study data from 2 independent studies (genetic and environmental risk factors for hemorrhagic stroke [GERFHS] study and genetics of cerebral hemorrhage with anticoagulation [GOCHA]). Analyses included evaluation by location of ICH. GERFHS and GOCHA cohorts contained 745 ICH cases and 536 controls for analysis. The strongest association was on 1q32 near Complement receptor type 1 (CR1), where rs6701713 was associated with all ICH (P = .0074, odds ratio [OR] = 2.07) and lobar ICH (P = .0073, OR = 2.80). The 51 most significant 2-SNP haplotypes associated with lobar ICH were identified within the Clusterin (CLU) gene. We identified that variation within CR1 and CLU, previously identified risk factors for AD, and are associated with an increased risk for ICH driven primarily by lobar ICH. Previous work implicated CR1 and CLU in cerebral amyloid clearance, the innate immune system, and cellular stress response.

Hexanucleotide repeat expansion (HRE) within

Background and Purpose: In intracerebral hemorrhage (ICH), preexisting cognitive impairment has been identified as a risk factor for increased mortality and morbidity. However, previous studies examined predominantly White populations; therefore, the prevalence and effect of preICH cognitive impairment has not been studied in a multiethnic cohort. This limits the generalizability of previous findings. We sought to investigate the role of preexisting cognitive impairment in a multiethnic population on short-term mortality and functional outcomes after ICH. Methods: Patients with ICH were prospectively enrolled as cases for the GERFHS III (Genetic and Environmental Risk Factors for Hemorrhagic Stroke) Study and the Ethnic/Racial Variations of ICH (ERICH) Study. Cognitive impairment before ICH was defined as positive history of dementia or treatment with donepezil, galantamine, memantine, or rivastigmine on chart abstraction or baseline interview. Specific outcomes—modified Rankin Scale score at 3 months (0–2 versus ≥3), Barthel Index score ( Results: Of the 3537 cases of ICH, 304 patients had cognitive impairment predating ICH. Cognitively impaired subjects were more likely to experience withdrawal of care during hospitalization, and for survivors, greater disability (modified Rankin Scale score of ≥3) and lower Barthel scores after ICH. After propensity score matching, preexisting cognitive impairment was associated with a lower modified Rankin Scale at 3 months in the White, Black, and Hispanic subgroups. Conclusions: Preexisting cognitive impairment was associated with loss of independence 3-month post-ICH, when matching for risk factors of cognitive impairment, in the White, Black, and Hispanic subgroups. This suggests that preexisting cognitive impairment has a negative effect in obtaining functional independence following ICH, irrespective of race/ethnicity.

The etiology of Frontotemporal Degeneration (FTD) is not well understood. Genetic studies have established common genetic variants (GVs) that are associated with increased FTD risk. We review previous genome wide association studies (GWAS) of FTD and nominate specific transcriptional regulators as potential key players in the etiology of this disease. A list of GVs associated with FTD was compiled from published GWAS. The regulatory element locus intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk GVs and the genomic coordinates of data from a collection of 10,000 chromatin immunoprecipitation (ChIP-seq) experiments. After linkage disequilibrium expansion of the previously reported tag associated GVs, we identified 914 GV at 47 independent risk loci. Using the RELI algorithm, we identified several transcriptional regulators with enriched binding at FTD risk loci (0.05 corrected P value 1.18 × 10-27), including Tripartite motif-containing 28 (TRIM28) and Chromodomain-Helicase DNA-binding 1 (CHD1) which have previously observed roles in FTD. FTD is a complex disease, and immune dysregulation has been previously implicated as a potential underlying cause. This assessment of established FTD risk loci and analysis of possible function implicates transcriptional dysregulation, and specifically particular transcriptional regulators with known roles in the immune response as important in the genetic etiology of FTD.

Background: Both intraventricular hemorrhage (IVH) and white matter lesion (WML) severity are associated with higher rates of death and disability among cases of intracerebral hemorrhage (ICH). Prior reports suggest higher WML burden is associated with propensity of IVH. However, those analyses were not stratified by location. Our objective was to investigate the hypothesis that a higher degree of WML would be associated with a higher risk of IVH after controlling for ICH location. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) III study was a prospective study of hemorrhagic stroke in the Greater Cincinnati/Northern Kentucky region. We utilized the interviewed cohort from the study and systematically graded WML using the Van Swieten Scale (0-4) and presence or absence of IVH in baseline head CT scans. Additional variables included ICH volume, location of ICH and vascular risk factors. We used multiple logistic regression with backward elimination to adjust for relevant covariates. Results: Among the included 426 ICH patients (mean± SD age 71.2± 13.8; 49% females), 161 (38%) had presence of IVH. In patients with IVH, the proportion of severe WML (39.7%) was significantly higher compared with patients without IVH (27.2%) (p=0.0044). The median volume of ICH was 14.4 mL (IQR, 4.9-46.3) in patients with IVH as compared with 8.9 ml (IQR, 2.6-20.8) in patients without IVH (p Conclusion: Moderate to severe white matter lesions are a risk for intraventricular hemorrhage. Further studies are needed to determine if greater severity of IVH or subsequent rupture into IVH are associated with higher grades of WML.

Introduction: Anticoagulant therapy after intracerebral hemorrhage (ICH) in patients with atrial fibrillation or deep vein thrombosis has been associated with a marked reduction of death. Prevention of ischemic stroke could explain this reduction. We sought to describe the causes of death after discharge and beyond 30 days in a longitudinal follow-up of a multi-racial/ethnic cohort of ICH. We hypothesized that recurrent ICH and ischemic stroke are the most common cause of death after ICH. Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study was a prospective, multi-center, case-control study of ICH among whites, blacks, and Hispanics. Subjects previously in the ERICH study were approached for enrollment in the Longitudinal Follow-up of ICH Survivors (ERICH-L) study. A standardized research interview was completed over the phone and 959 contacts were made with participants and surrogates to capture outcomes of interest at 6-month intervals, including information on ICH recurrence, ischemic stroke, cognitive performance, and cause of death. The median follow-up was 4.3 years with an IQR of 3.2-5.4. The cause of death categories were ICH, cardiac, ischemic CVA, other, cancer, pulmonary, renal, endocrine, accidents, infection, dementia and unknown. Results: There were 180 deaths (18.8%) reported by surrogates contacted in the ERICH-L study. Of those, 63 causes of death were unknown or considered unverifiable. The most common cause of death reported was decline from the index ICH (32.7%). The next most common cause of death was cardiac (14%), other (12.1%), infection (11.2%), cancer (10.3%) and ischemic stroke (1.9%). Some examples reported as other are liver failure, old age, myelodysplastic syndrome, suicide and Parkinson’s Disease. Recurrent ICH occurred in 4 out of 107 known causes of death. By year 5, cardiac causes surpassed ICH as the cause of death. Conclusion: Cardiac causes of death were more common than either recurrent ICH or ischemic stroke, surpassed only by decline from the index ICH. Future efforts to prevent causes of death after ICH should address cardiac disease and risk factors. This finding may explain the effect of restarting anticoagulant or antiplatelet therapy and improved mortality.

Introduction: Intracerebral hemorrhage (ICH) results in high mortality and high rate of disability among survivors. The effects of preexisting small vessel disease (SVD) on functional outcomes after ICH is uncertain and understanding manifestations of brain health such as white matter lesions (WML) and atrophy are a top priority for developing prognostic indicators. Our objective was to determine whether WML and brain atrophy is associated with functional outcomes in ICH patients. Hypothesis: We hypothesized that higher burden of WML and atrophy will have a poor outcome independent of age, ICH volume, ICH location, IVH, and presenting Glasgow Coma Scale (GCS) score. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) III study is a prospective study of hemorrhagic stroke in the Greater Cincinnati/Northern Kentucky region. We utilized the interviewed cohort from the study and systematically graded WML using the Van Swieten Scale (0-4) and measured brain atrophy (2 linear measurements) in baseline head CT scans. The outcome measures included modified Rankin Scale (mRS) at 3 months. Primary outcome was disability or death (mRS 3-6). Results: A total of 441 CT scans were graded; 48 patients were excluded due to missing mRS. Among the included 393 ICH patients (mean±SD age 71.5± 13.8; 48% females), old age, high ICH volume, low GCS score, severe WML (Van Swieten score 3-4), and atrophy were significantly associated with poor outcomes (mRS 3-6) in univariate analysis. In multivariate analysis, severe WML (p=0.039), atrophy (p= 0.0131), old age (p Conclusion: Poor brain health manifesting as cerebral SVD markers of WML and atrophy are simple and independent baseline predictors of poor outcome in acute ICH. Further study for inclusion into outcome measures such as ICH Score should be considered.

BACKGROUND: Intraventricular hemorrhage (IVH) and white matter lesion (WML) severity are associated with higher rates of death and disability in intracerebral hemorrhage (ICH). A prior report identified an increased risk of IVH with greater WML burden but did not control for location of ICH. We sought to determine whether a higher degree of WML is associated with a higher risk of IVH after controlling for ICH location. METHODS: Utilizing the patient population from two large ICH studies; the Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS III) Study and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study, we graded WML using the Van Swieten Scale (0-1 for mild, 2 for moderate, and 3-4 for severe WML) and presence or absence of IVH in baseline CT scans. We used multivariable regression models to adjust for relevant covariates. RESULTS: Among 3023 ICH patients, 1260 (41.7%) had presence of IVH. In patients with IVH, the proportion of severe WML (28.6%) was higher compared with patients without IVH (21.8%) (p

ObjectiveAPOE ε2 and ε4 alleles have been associated with lobar intracerebral hemorrhage (ICH) in predominately white populations; we sought to evaluate whether this held true among black and Hispanic populations.MethodsThe Ethnic/Racial Variations of Intracerebral Hemorrhage study is a prospective, multicenter case-control study of ICH among white, black, and Hispanic participants. Controls were recruited to match cases based on age, ethnicity/race, sex, and geographic location. APOE genotyping and ICH location was determined blinded to clinical data.ResultsThere were 907 cases of lobar ICH and 2,660 controls with APOE results. Both APOE ε2 (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.1–2.0, p = 0.01) and APOE ε4 (OR 2.0, 95% CI 1.5–2.6, p < 1 × 10−4) were associated with lobar ICH among white participants. Among black participants, neither APOE ε2 (OR 1.0, 95% CI 0.7–1.5, p = 0.97) nor APOE ε4 (OR 1.0, 95% CI 0.7–1.4, p = 0.90) were independent risk factors for lobar ICH. Similarly, among Hispanic participants, neither APOE ε2 (OR 1.0, 95% CI 0.6–1.8, p = 0.89) nor APOE ε4 (OR 1.2, 95% CI 0.8–1.7, p = 0.36) were associated with lobar ICH. Hypertension was a significant risk factor for lobar ICH in all 3 racial/ethnic groups.ConclusionIn contrast to Caucasian patients, in which amyloid risk factors predominate in lobar ICH, we found that hypertension was the predominant risk factor for lobar ICH. While APOE alleles are a risk factor for lobar ICH in white patients, they appear to have a much lower effect in lobar ICH in African American and Hispanic American populations. This suggests APOE ε2 and APOE ε4 do not affect lobar ICH risk homogeneously across ethnic populations. In addition, hypertension has a prominent role in lobar ICH risk, particularly among minorities.

INTRODUCTION:Orthostatic hypotension (OH) represents a frequent yet overlooked source of disability in Parkinson disease (PD). In particular, its impact on health care utilization has been insufficiently examined. We sought to determine the differential health care utilization in PD patients with (PDOH+) and without OH (PDOH-). METHODS:We quantified the emergency room (ER) visits, hospitalizations, outpatient clinic evaluations, phone calls, and e-mails from PD patients on whom supine and orthostatic blood pressure (BP) measurements were obtained during routine clinical practice between June 2013 and July 2016. Comparative costs between PDOH+ and PDOH- were adjusted for age, disease duration, motor severity, levodopa equivalent daily dose, and Montreal Cognitive Assessment. RESULTS:From a total of 317 PD patients, 29.3% were classified as PDOH+ (n = 93) and 70.6% as PDOH- (n = 224) over 30.2 ± 11.0 months, in which there were 247 hospitalizations, 170 ER visits, 2386 outpatient evaluations, and 4747 telephone calls/e-mails. After-adjusting for relevant covariates, PDOH+ was associated with more hospitalization days (+285%; p = 0.041), ER visits (+152%; p = 0.045), and telephone calls/e-mails than PDOH- (+142%; p = 0.009). The overall health care-related cost in PDOH+ was 2.5-fold higher than for PDOH- ($25,205 ± $6546 vs. $9831 ± $4167/person/year; p = 0.037). CONCLUSION:OH increases health care utilization in PD independently from age, disease duration, motor severity, dopaminergic treatment, and cognitive function. © This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

Background Disruption of the frontal lobes and its associated networks are a common consequence of neurodegenerative disorders. Given the wide range of cognitive, behavioral and motor processes in which the frontal lobes are involved, there can be a great variety of manifestations depending on the pathology distribution. The most common are the behavioral variant of frontotemporal dementia (bvFTD) and the frontal variant of Alzheimer’s disease (fvAD), which are particularly challenging to disentangle. Recognizing fvAD from bvFTD-related pathologies is a diagnostic challenge and a critical need in the management and counseling of these patients. Case presentation Here we present three pathology-proven cases of Alzheimer’s disease initially misdiagnosed as bvFTD and discuss the distinctive or less overlapping historical, examination, and laboratory findings of fvAD and bvFTD, deriving analogies for mnemonic endurance from the Wizard of Oz worldview. Conclusion The Yellow Brick Road to diagnosing these disorders may be served by the metaphor of fvAD as the irritable, paranoid, and tremulous Scarecrow and bvFTD the heartless, ritualistic, and rigid Tin Man. An Oz-inspired creative license may help the clinician recognize the differential disease progression, caregiver burden, and treatment response of fvAD compared with bvFTD. Electronic supplementary material The online version of this article (doi:10.1186/s40734-017-0052-4) contains supplementary material, which is available to authorized users.