TY - JOUR AB - Importance: Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective: To estimate the worldwide burden of SAH. Design, setting, and participants: Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures: SAH and 14 modifiable risk factors. Main outcomes and measures: Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor-specific population attributable fractions (PAFs). Results: In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and relevance: Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH. AU - GBD 2021 Global Subarachnoid Hemorrhage Risk Factors Collaborators (Breitner-Busch, S.) C1 - 74787 C2 - 57618 CY - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa TI - Global, regional, and national burden of nontraumatic subarachnoid hemorrhage: The global burden of disease study 2021. JO - JAMA Neurol. PB - Amer Medical Assoc PY - 2025 SN - 2168-6149 ER - TY - JOUR AB - IMPORTANCE: A leading cause of surgically remediable, drug-resistant focal epilepsy is focal cortical dysplasia (FCD). FCD is challenging to visualize and often considered magnetic resonance imaging (MRI) negative. Existing automated methods for FCD detection are limited by high numbers of false-positive predictions, hampering their clinical utility. OBJECTIVE: To evaluate the efficacy and interpretability of graph neural networks in automatically detecting FCD lesions on MRI scans. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter diagnostic study, retrospective MRI data were collated from 23 epilepsy centers worldwide between 2018 and 2022, as part of the Multicenter Epilepsy Lesion Detection (MELD) Project, and analyzed in 2023. Data from 20 centers were split equally into training and testing cohorts, with data from 3 centers withheld for site-independent testing. A graph neural network (MELD Graph) was trained to identify FCD on surface-based features. Network performance was compared with an existing algorithm. Feature analysis, saliencies, and confidence scores were used to interpret network predictions. In total, 34 surface-based MRI features and manual lesion masks were collated from participants, 703 patients with FCD-related epilepsy and 482 controls, and 57 participants were excluded during MRI quality control. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, and positive predictive value (PPV) of automatically identified lesions. RESULTS: In the test dataset, the MELD Graph had a sensitivity of 81.6% in histopathologically confirmed patients seizure-free 1 year after surgery and 63.7% in MRI-negative patients with FCD. The PPV of putative lesions from the 260 patients in the test dataset (125 female [48%] and 135 male [52%]; mean age, 18.0 [IQR, 11.0-29.0] years) was 67% (70% sensitivity; 60% specificity), compared with 39% (67% sensitivity; 54% specificity) using an existing baseline algorithm. In the independent test cohort (116 patients; 62 female [53%] and 54 male [47%]; mean age, 22.5 [IQR, 13.5-27.5] years), the PPV was 76% (72% sensitivity; 56% specificity), compared with 46% (77% sensitivity; 47% specificity) using the baseline algorithm. Interpretable reports characterize lesion location, size, confidence, and salient features. CONCLUSIONS AND RELEVANCE: In this study, the MELD Graph represented a state-of-the-art, openly available, and interpretable tool for FCD detection on MRI scans with significant improvements in PPV. Its clinical implementation holds promise for early diagnosis and improved management of focal epilepsy, potentially leading to better patient outcomes. AU - Ripart, M.* AU - Spitzer, H. AU - Williams, L.Z.J.* AU - Walger, L.* AU - Chen, A.* AU - Napolitano, A.* AU - Rossi-Espagnet, C.* AU - Foldes, S.T.* AU - Hu, W.* AU - Mo, J.* AU - Likeman, M.* AU - Rüber, T.* AU - Caligiuri, M.E.* AU - Gambardella, A.* AU - Guttler, C.* AU - Tietze, A.* AU - Lenge, M.* AU - Guerrini, R.* AU - Cohen, N.T.* AU - Wang, I.* AU - Kloster, A.* AU - Pinborg, L.H.* AU - Hamandi, K.* AU - Jackson, G.* AU - Tortora, D.* AU - Tisdall, M.* AU - Conde-Blanco, E.* AU - Pariente, J.C.* AU - Perez-Enriquez, C.* AU - Gonzalez-Ortiz, S.* AU - Mullatti, N.* AU - Vecchiato, K.* AU - Liu, Y.* AU - Kälviäinen, R.* AU - Sokol, D.* AU - Shetty, J.* AU - Sinclair, B.* AU - Vivash, L.* AU - Willard, A.* AU - Winston, G.P.* AU - Yasuda, C.* AU - Cendes, F.* AU - Shinohara, R.T.* AU - Duncan, J.S.* AU - Cross, J.H.* AU - Baldeweg, T.* AU - Robinson, E.C.* AU - Iglesias, J.E.* AU - Adler, S.* AU - Wagstyl, K.* AU - Fawaz, A.* AU - De Benedictis, A.* AU - De Palma, L.* AU - Zhang, K.* AU - Labate, A.* AU - Barba, C.* AU - You, X.* AU - Gaillard, W.D.* AU - Tang, Y.* AU - Wang, S.* AU - Davies, S.* AU - Semmelroch, M.* AU - Severino, M.* AU - Striano, P.* AU - Chari, A.* AU - D'Arco, F.* AU - Mankad, K.* AU - Bargallo, N.* AU - Pascual-Diaz, S.* AU - Delgado-Martinez, I.* AU - O'Muircheartaigh, J.* AU - Abela, E.* AU - Kandasamy, J.* AU - McLellan, A.* AU - Desmond, P.* AU - Lui, E.* AU - O'Brien, T.J.* AU - Whitaker, K.* C1 - 73450 C2 - 57076 SP - 397-406 TI - Detection of epileptogenic focal cortical dysplasia using graph neural networks: A MELD Study. JO - JAMA Neurol. VL - 82 IS - 4 PY - 2025 SN - 2168-6149 ER - TY - JOUR AB - Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies. Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase. Design, Setting, and Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016. Main Outcomes and Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies. Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities onmagnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation. Conclusions and Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies. AU - Charif, M.* AU - Nasca, A.* AU - Thompson, K.* AU - Gerber, S.* AU - Makowski, C.* AU - Mazaheri, N.* AU - Bris, C.* AU - Goudenège, D.* AU - Legati, A.* AU - Maroofian, R.* AU - Shariati, G.* AU - Lamantea, E.* AU - Hopton, S.* AU - Ardissone, A.* AU - Moroni, I.* AU - Giannotta, M.* AU - Siegel, C.* AU - Strom, T.M. AU - Prokisch, H. AU - Vignal-Clermont, C.* AU - Derrien, S.* AU - Zanlonghi, X.* AU - Kaplan, J.* AU - Hamel, C.P.* AU - Leruez, S.* AU - Procaccio, V.* AU - Bonneau, D.* AU - Reynier, P.* AU - White, F.E.* AU - Hardy, S.A.* AU - Barbosa, I.A.* AU - Simpson, M.A.* AU - Vara, R.* AU - Trujillo, Y.P.* AU - Galehdari, H.* AU - Deshpande, C.* AU - Haack, T.B. AU - Rozet, J.M.* AU - Taylor, R.W.* AU - Ghezzi, D.* AU - Amati-Bonneau, P.* AU - Lenaers, G.* C1 - 52730 C2 - 44227 CY - Chicago SP - 105-113 TI - Neurologic phenotypes associated with mutations in RTN4IP1 (OPA10) in children and young adults. JO - JAMA Neurol. VL - 75 IS - 1 PB - Amer Medical Assoc PY - 2018 SN - 2168-6149 ER - TY - JOUR AB - Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. Objectives: To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. Design, Setting, and Participants: In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. Main Outcomes and Measures: The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. Results: Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; β = -0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005). Conclusions and Relevance: This study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder. AU - Karch, C.M.* AU - Wen, N.* AU - Fan, C.C.* AU - Yokoyama, J.S.* AU - Kouri, N.* AU - Ross, O.A.* AU - Höglinger, G.U.* AU - Müller, U.* AU - Ferrari, R.* AU - Hardy, J.* AU - Schellenberg, G.D.* AU - Sleiman, P.M.* AU - Momeni, P.* AU - Hess, C.P.* AU - Miller, B.L.* AU - Sharma, M.* AU - van Deerlin, V.M.* AU - Smeland, O.B.* AU - Andreassen, O.A.* AU - Dale, A.M.* AU - Desikan, R.S.* AU - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. AU - Lichtner, P.) C1 - 55467 C2 - 46173 SP - 860-875 TI - Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. JO - JAMA Neurol. VL - 75 IS - 7 PY - 2018 SN - 2168-6149 ER - TY - JOUR AB - Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. Main Outcome and Measures: The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Results: Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes. Conclusions and Relevance: The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder. AU - Sommerville, E.W.* AU - Ng, Y.S.* AU - Alston, C.L.* AU - Dallabona, C.* AU - Gilberti, M.* AU - He, L.* AU - Knowles, C.* AU - Chin, S.L.* AU - Schaefer, A.M.* AU - Falkous, G.* AU - Murdoch, D.* AU - Longman, C.* AU - de Visser, M.* AU - Bindoff, L.A.* AU - Rawles, J.M.* AU - Dean, J.C.* AU - Petty, R.K.* AU - Farrugia, M.E.* AU - Haack, T.B. AU - Prokisch, H. AU - McFarland, R.* AU - Turnbull, D.M.* AU - Donnini, C.* AU - Taylor, R.W.* AU - Gorman, G.S.* C1 - 50913 C2 - 42964 CY - Chicago SP - 686-694 TI - Clinical features, molecular heterogeneity, and prognostic implications in YARS2-related mitochondrial myopathy. JO - JAMA Neurol. VL - 74 IS - 6 PB - Amer Medical Assoc PY - 2017 SN - 2168-6149 ER - TY - JOUR AB - IMPORTANCE: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. OBJECTIVES: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. DESIGN, SETTING, AND PARTICIPANTS: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. MAIN OUTCOMES AND MEASURES: The primary outcomewas a list of novel loci and their pathways involved in PD and autoimmune diseases. RESULTS: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes inmethylation or expression levels of adjacent genes. CONCLUSIONS AND RELEVANCE: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents. AU - Witoelar, A.W.* AU - Jansen, I.E.* AU - Wang, Y.* AU - Desikan, R.S.* AU - Gibbs, J.R.* AU - Blauwendraat, C.* AU - Thompson, W.K.* AU - Hernandez, D.G.* AU - Djurovic, S.* AU - Schork, A.J.* AU - Bettella, F.* AU - Ellinghaus, D.* AU - Franke, A.* AU - Lie, B.A.* AU - McEvoy, L.K.* AU - Karlsen, T.H.* AU - Lesage, S.* AU - Morris, H.R.* AU - Brice, A.* AU - Wood, N.W.* AU - Heutink, P.* AU - Hardy, J.* AU - Singleton, A.B.* AU - Dale, A.M.* AU - Gasser, T.* AU - Andreassen, O.A.* AU - Sharma, M.* AU - Nalls, M.A.* AU - Plagnol, V.* AU - Sheerin, U.M.* AU - Saad, M.* AU - Simon-Sanchez, J.* AU - Schulte, C.* AU - Sveinbjörnsdóttir, S.* AU - Arepalli, S.* AU - Barker, R.A.* AU - Ben-Shlomo, Y.* AU - Berendse, H.W.* AU - Berg, D.* AU - Bhatia, K.P.* AU - de Bie, R.M.A.* AU - Biffi, A.* AU - Bloem, B.* AU - Bochdanovits, Z.* AU - Bonin, M.* AU - Bras, J.M.* AU - Brockmann, K.* AU - Brooks, J.M.* AU - Burn, D.J.* AU - Majounie, E.* AU - Illig, T. AU - Lichtner, P. AU - Weale, M.E.* C1 - 51600 C2 - 43528 SP - 780-792 TI - Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JO - JAMA Neurol. VL - 74 IS - 7 PY - 2017 SN - 2168-6149 ER -