Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies.

Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10-8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid ß plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid ß plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.

Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer's disease.

The lack of strong association between brain beta-amyloid deposition and cognitive impairment has been a challenge for the Alzheimer's disease (AD) field. Although beta-amyloid is necessary for the pathologic diagnosis of AD, it is not sufficient to make the pathologic diagnosis or cause dementia. We sought to identify the genetic modifiers of the relation between cortical beta-amyloid burden (measured using [18F]Florbetapir-PET) and cognitive dysfunction (measured using ADAS-cog) by conducting a genome-wide interaction study on baseline data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) phases GO/2 (n=678). Near genome-wide significant interaction effect was observed for rs73069071 within the IAPP (amylin) and SLCO1A2 genes (P=6.2 × 10-8). Congruent results were found using data from participants followed up from ADNI-1 (Pone-tailed=0.028, n=165). Meta-analysis across ADNI-GO/2 and ADNI-1 revealed a genome-wide significant interaction effect (P=1.1 × 10-8). Our results were further supported by similar interaction effects on temporal lobe cortical thickness (whole-brain voxelwise analysis: familywise error corrected P=0.013) and longitudinal changes in ADAS-cog score and left middle temporal thickness and amygdalar volume (Pone-tailed=0.026, 0.019 and 0.003, respectively). Using postmortem beta-amyloid immunohistochemistry data from 243 AD participants in the Religious Orders Study and Memory and Aging Project, we also observed similar rs73069071-by-beta-amyloid deposition interaction effect on global cognitive function (Pone-tailed=0.005). Our findings provide insight into the complexity of the relationship between beta-amyloid burden and AD-related cognitive impairment. Although functional studies are required to elucidate the role of rs73069071 in AD pathophysiology, our results support the recently growing evidence on the role of amylin in AD.

FASTKD2 is associated with memory and hippocampal structure in older adults.

Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.

Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.

A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility.

Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.

Low testosterone is associated with disability in men with multiple sclerosis.

BACKGROUND: Gonadal steroids may modulate disease course in multiple sclerosis (MS). OBJECTIVE: To assess the prevalence and clinical associations of hypogonadism in men with MS. METHODS: Male patients, aged 18-65 years, with relapsing-remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually. RESULTS: Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012). CONCLUSIONS: Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. A potential neuroprotective role for testosterone warrants further investigation.

Multiple sclerosis susceptibility loci do not alter clinical and MRI outcomes in clinically isolated syndrome.

It has not yet been established whether genetic predictors of multiple sclerosis (MS) susceptibility also influence disease severity and accumulation of disability. Our aim was to evaluate associations between 16 previously validated genetic susceptibility markers and MS phenotype. Patients with clinically isolated syndrome verified by positive magnetic resonance imaging (MRI) and cerebrospinal fluid findings (n=179) were treated with interferon-ß. Disability and volumetric MRI parameters were evaluated regularly for 2 years. Sixteen single-nucleotide polymorphisms (SNPs) previously validated as predictors of MS susceptibility in our cohort and their combined weighted genetic risk score (wGRS) were tested for associations with clinical (conversion to MS, relapses and disability) and MRI disease outcomes (whole brain, grey matter and white matter volumes, corpus callosum cross-sectional area, brain parenchymal fraction, T2 and T1 lesion volumes) 2 years from disease onset using mixed-effect models. We have found no associations between the tested SNPs and the clinical or MRI outcomes. Neither the combined wGRS predicted MS activity and progression over 2-year follow-up period. Power analyses confirmed 90% power to identify clinically relevant changes in all outcome variables. We conclude that the most important MS susceptibility loci do not determine MS phenotype and disease outcomes.

Apolipoprotein E and change in episodic memory in blacks and whites.

BACKGROUND: Apolipoprotein E (APOE) ε4 is related to faster decline in episodic memory in Whites, but the relation is unknown in Blacks. The purpose of this study was to determine whether ε4 has a selective effect on decline in episodic memory in Blacks. METHODS: Data are from two cohort studies with similar design. The sample consisted of 1,211 participants [28.4% Blacks, mean age = 78.6 years (SD = 7.4), education = 14.7 years (SD = 3.1)] without dementia at baseline, who underwent annual clinical evaluations for up to 6 years. Summary measures of 5 cognitive abilities were derived from 18 neuropsychological tests. RESULTS: In mixed models that controlled for age, sex, education, and race, possession of ε4 (present in 32.9% of Blacks and 21.0% of Whites, p < 0.001) was related to faster decline in episodic memory and 4 other cognitive abilities (all p values <0.01). In separate models that examined the interaction of race and ε4 on decline, there was no significant difference between Blacks and Whites in the effect of ε4 on decline in episodic memory, perceptual speed, or visuospatial ability. By contrast, the effect of ε4 differed for semantic memory and working memory. Results were similar after adjusting for vascular conditions. CONCLUSIONS: The results suggest that APOE ε4 is related to a faster rate of decline in episodic memory in Blacks similar to Whites. In addition, there were racial differences in the effect of ε4 in other cognitive abilities such that the ε4 allele was related to faster decline in semantic memory and working memory for Whites but not for Blacks.

Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations.

BACKGROUND: Recent genetic studies of stroke and related risk factors have identified a growing number of susceptibility loci; however, the relationship of these alleles to ischemic stroke is unknown. The challenge in finding reproducible loci of ischemic stroke susceptibility may be in part related to the etiologic heterogeneity in clinically defined stroke subtypes. In this study, we tested whether known single nucleotide polymorphisms (SNPs) associated with stroke or putative stroke risk factors are associated with neuropathologically defined micro- or macroscopic infarcts and with arteriolosclerosis. METHODS: Measures of neuropathology and genotyping were available from 755 deceased participants from the Religious Orders Study and the Rush Memory and Aging Project. All donated brains were examined by a board-certified neuropathologist using standardized protocol for the presence of microscopic infarct, macroscopic infarct and arteriolosclerosis (lipohyalinosis). In primary analysis, 74 candidate SNPs previously associated (p < 5 × 10(-8)) with ischemic stroke or known risk factors, including atrial fibrillation (AF), hypertension, diabetes, low-density lipoprotein (LDL) level and carotid artery stenosis, were evaluated for association with neuropathologic endpoints. We performed a secondary exploratory analysis to include 93 additional SNPs associated with putative ischemic stroke risk factors including SNPs associated with high-density lipoprotein (HDL), triglyceride serum levels, myocardial infarction (MI), coronary artery disease and cerebral white matter disease. Regression models relating SNPs to cerebrovascular neuropathology were adjusted for age at death, gender and cohort membership. RESULTS: The strongest associations seen for both macroscopic and microscopic infarcts were risk variants associated with diabetes. The diabetes risk variant rs7578326 located near the IRS1 locus was associated with both macroscopic (OR = 0.73, p = 0.011) and microscopic (OR = 0.71, p = 0.009) infarct pathology. Another diabetes susceptibility locus (rs12779790) located between the calcium/calmodulin-dependent protein kinase ID (CAMK1D) and cell division cycle 123 homolog (CDC123) genes is also associated with both macroscopic (OR = 1.40, p = 0.0292) and microscopic infarcts (OR = 1.43, p = 0.0285). The diabetes risk variant rs864745 within JAZF1 was associated with arteriolosclerosis (OR = 0.80, p = 0.014). We observed suggestive associations with the diabetes risk variant rs7961581 (p = 0.038; between TSPAN8 and LGR5) and rs5215 (p = 0.043; KCNJ11), the LDL risk variant rs11206510 (p = 0.045; PCSK9), as well as the AF risk locus ZFHX3. The CDKN2A/B locus (rs2383207, 9p21), identified initially as a susceptibility allele for MI and recently implicated in large vessel stroke, was associated with macroscopic infarct pathology in our autopsy cohort (OR = 1.26, p = 0.031). CONCLUSION: Our results suggest replication of the candidate CDKN2A/B stroke susceptibility locus with directly measured macroscopic stroke neuropathology, and further implicate several diabetes and other risk variants with secondary, pleiotropic associations to stroke-related pathology in our autopsy cohort. When coupled with larger sample sizes, cerebrovascular neuropathologic phenotypes will likely be powerful tools for the genetic dissection of susceptibility for ischemic stroke.

RNA- and ATAC-sequencing Reveals a Unique CD83+ Microglial Population Focally Depleted in Parkinson's Disease.

All brain areas affected in Parkinson's disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A- expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study.

Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P=0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P=0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P=0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P=0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.

Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonß therapy in multiple sclerosis.

Interferon-ß (IFNß) therapy is effective in approximately half of the patients with relapsing-remitting multiple sclerosis (RRMS). Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, we carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNß treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNß compared with patients carrying the respective G-alleles (P=0.0006 and P=0.0023, respectively). Moreover, patients with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFNß treatment (P=0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P=0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFNß treatment and MRI-based non-responder status was observed (P=0.103 and P=0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P=0.037). These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFNß therapy that might have relevance as biomarker to predict the response to IFNß in multiple sclerosis.

Multiple sclerosis susceptibility alleles in African Americans.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

A non-synonymous SNP within membrane metalloendopeptidase-like 1 (MMEL1) is associated with multiple sclerosis.

Several single-nucleotide polymorphism (SNP) genome-wide association studies (GWASs) have been completed in multiple sclerosis (MS). Follow-up studies of the variants with the most promising rankings, especially when supplemented by informed candidate gene selection, have proven to be extremely successful. In this study we report the results of a multi-stage replication analysis of the putatively associated SNPs identified in the Wellcome Trust Case Control Consortium non-synonymous SNP (nsSNP) screen. In total, the replication sample consisted of 3444 patients and 2595 controls. A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10⁻6) in MS susceptibility.

A Dopamine Receptor genetic variant enhances perceptual speed in cognitive healthy subjects.

Cognition is under strong genetic control, yet the specific genes are unknown. To investigate genetic influences on specific cognitive domains, 153 cognitive healthy subjects of European ancestry from the Reference Abilities Study (RANN) were genotyped for 1,160 variants within 446 neuropsychiatric genes. Adjusted linear regression models evaluated the association between the genetic variants and four reference abilities, which capture variance in age-related cognitive function (Vocabulary, Episodic Memory, Perceptual Speed, and Reasoning). 159 variants nominally significant in the RANN cohort were then re-evaluated in an independent cohort of 868 cognitive healthy subjects from the Religious Orders Study and Rush Memory Aging Project. Meta-analysis yielded a Bonferroni adjusted statistically significant association between perceptual speed and a variant located in the promoter of the dopamine receptor D4 gene, rs3756450 (ß=0.23, SE=0.05, P meta =2.3 × 10-5). Our data suggest that genetic variation in a dopamine pathway gene influences perceptual speed performance in cognitively healthy individuals.

Women's experiences of menopause in an online MS cohort: A case series.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal. Previously reported findings from an online MS cohort suggested that earlier, surgical menopause may be associated with higher patient-reported MS severity scores. OBJECTIVE: To explore experiences of menopause in a series of MS women responding to a reproductive survey from an online research platform, PatientsLikeMe (PLM). METHODS: The free-text responses from a detailed reproductive history survey deployed to PLM members were analyzed using grounded theory approach. RESULTS: Of the 208 free text responses, 127 responses related to menopause. Five themes emerged: (1) perimenopausal onset of MS symptoms, (2) overlap of MS and menopausal symptoms, (3) MS exacerbations and pseudo-exacerbations triggered by hot flashes, (4) escalation of disease course after menopause, including increasing fatigue, cognitive disturbance, and other symptoms; and (5) effect of HRT on MS symptoms. Some women reported no effects of menopause or HRT. CONCLUSION: Given an aging population and a median age of individuals currently living with MS very close to menopausal age in many cohorts, there is a pressing need to understand the impact of menopause on MS course. Qualitative responses in this study illustrated several specific themes that require quantitative testing in clinic-based cohorts.

Neurodegeneration in Lurcher mice occurs via multiple cell death pathways.

Lurcher (Lc) is a gain-of-function mutation in the delta2 glutamate receptor (GRID2) that results in the cell-autonomous death of cerebellar Purkinje cells in heterozygous lurcher (+/Lc) mice. This in turn triggers the massive loss of afferent granule cells during the first few postnatal weeks. Evidence suggests that the death of Purkinje cells as a direct consequence of GRID2(Lc) activation and the secondary death of granule cells because of target deprivation occur by apoptosis. We have used mice carrying null mutations of both the Bax and p53 genes to examine the roles of these genes in cell loss in lurcher animals. The absence of Bax delayed Purkinje cell death in response to the GRID2(Lc) mutation and permanently rescued the secondary death of granule cells. In contrast, the p53 deletion had no effect on either cell death pathway. Our results demonstrate that target deprivation induces a Bax-dependent, p53-independent cell death response in cerebellar granule cells in vivo. In contrast, Bax plays a minor role in GRID2(Lc)-mediated Purkinje cell death.

Patients report worse MS symptoms after menopause: findings from an online cohort.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown. OBJECTIVE: To investigate patient-reported impact of menopause in a large online research platform, PatientsLikeMe (PLM). METHODS: A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM׳s prospectively collected patient-reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores. RESULTS: Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age (p<0.001) and was associated with more hormone replacement therapy use (p=0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores (p≤0.01) in regressions adjusting for age, disease type and duration. CONCLUSION: Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings.