ObjectiveThe objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological... Show moreObjectiveThe objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights.MethodsA total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses.ResultsThe estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Show less
Shan, L.; Linssen, S.; Harteman, Z.; Dekker, F. den; Shuker, L.; Balesar, R.; ... ; Fronczek, R. 2023
ObjectiveNarcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone ... Show moreObjectiveNarcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co-express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake-systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways.MethodsIn postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine-synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate-limited-synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid-brain and for norepinephrine in the locus coeruleus (LC).ResultsIn NT1, there was: a 234% increase in the percentage of CRH cells co-expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH-positive neurons in the substantia nigra compacta; while the density of TH-positive LC neurons was unchanged.InterpretationOur findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co-expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762–771 Show less
Kort, A.M. de; Kuiperij, H.B.; Marques, T.M.; Jäkel, L.; Berg, E. van den; Kersten, I.; ... ; Verbeek, M.M. 2023
ObjectiveVascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker... Show moreObjectiveVascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aβ38, Aβ40, Aβ42, and Aβ43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD).MethodsAβ peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI).ResultsWe found decreased levels of all Aβ peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aβ42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82–0.99; for validation: 0.94, 95% CI = 0.89–0.99) and Aβ43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88–1.00; for validation: 0.91, 95% CI = 0.83–1.0). All Aβ peptides except Aβ43 were also decreased in sCAA compared to AD (CSF Aβ38: AUC = 0.82, 95% CI = 0.71–0.93; CSF Aβ40: AUC = 0.88, 95% CI = 0.80–0.96; CSF Aβ42: AUC = 0.79, 95% CI = 0.66–0.92). Show less
Objective: Impaired amine metabolism has been associated with the etiology of migraine, that is, why patients continue to get migraine attacks. However, evidence from cerebrospinal fluid (CSF) is... Show moreObjective: Impaired amine metabolism has been associated with the etiology of migraine, that is, why patients continue to get migraine attacks. However, evidence from cerebrospinal fluid (CSF) is lacking. Here, we evaluated individual amine levels, global amine profiles, and amine pathways in CSF and plasma of interictal migraine patients and healthy controls.Methods: CSF and plasma were sampled between 8:30 AM and 1:00 PM, randomly and interchangeably over the time span to avoid any diurnal and seasonal influences, from healthy volunteers and interictal migraine patients, matched for age, sex, and sampling time. The study was approved by the local medical ethics committee. Individual amines (n = 31), global amine profiles, and specific amine pathways were analyzed using a validated ultraperformance liquid chromatography mass spectrometry platform. Results: We analyzed n = 99 participants with migraine with aura, n = 98 with migraine without aura, and n = 96 healthy volunteers. Univariate analysis with Bonferroni correction indicated that CSF L-arginine was reduced in migraine with aura (10.4%, p < 0.001) and without aura (5.0%, p = 0.03). False discovery rate-corrected CSF L-phenylalanine was also lower in migraine with aura (6.9%, p = 0.011) and without aura (8.1%, p = 0.001), p = 0.088 after Bonferroni correction. Multivariate analysis revealed that CSF global amine profiles were similar for both types of migraine (p = 0.64), but distinct from controls (p = 0.009). Global profile analyses were similar in plasma. The strongest associated path-ways with migraine were related to L-arginine metabolism. Interpretation: L-Arginine was decreased in the CSF (but not in plasma) of interictal patients with migraine with or without aura, and associated pathways were altered. This suggests that dysfunction of nitric oxide signaling is involved in susceptibility to getting migraine attacks. Show less
Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that... Show moreAutosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross-sectional and longitudinal biomarkers of D-CAA progression. ANN NEUROL 2022 Show less
Objective: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with... Show moreObjective: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). Methods: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. Results: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. Interpretation: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022 Show less
Objective: This study aimed to validate the Erasmus Guillain-Barre Syndrome Respiratory Insufficiency Score in the International Guillain-Barre Syndrome Outcome Study cohort, and to improve its... Show moreObjective: This study aimed to validate the Erasmus Guillain-Barre Syndrome Respiratory Insufficiency Score in the International Guillain-Barre Syndrome Outcome Study cohort, and to improve its performance and region-specificity. Methods: We examined data from the first 1,500 included patients, aged >= 6 years and not ventilated prior to study entry. Patients with a clinical variant or mild symptoms were also included. Outcome was mechanical ventilation within the first week from study entry. Model performance was assessed regarding the discriminative ability (area under the receiver operating characteristic curve) and the calibration (observed vs predicted probability of mechanical ventilation), in the full cohort and in Europe/North America and Asia separately. We recalibrated the model to improve its performance and region-specificity. Results: In the group of 1,023 eligible patients (Europe/North America n = 842, Asia n = 104, other n = 77), 104 (10%) required mechanical ventilation within the first week from study entry. Area under the curve values were >= 0.80 for all validation subgroups. Mean observed proportions of mechanical ventilation were lower than predicted risks: full cohort 10% versus 21%, Europe/North America 9% versus 21%, and Asia 17% versus 23%. After recalibration, predicted risks for the full cohort and Europe/North America corresponded to observed proportions. Interpretation: This prospective, international cohort study validated the Erasmus Guillain-Barre Syndrome Respiratory Insufficiency Score, and showed that the model can be used in the full spectrum of Guillain-Barre syndrome patients. In addition, a more accurate, region-specific version of the model was developed for patients from Europe/North America. Show less
Narcolepsy type 1 (NT1) is a chronic sleep disorder correlated with loss of hypocretin(orexin). In NT1 post-mortem brains, we observed 88% reduction in corticotropin-releasing hormone (CRH)... Show moreNarcolepsy type 1 (NT1) is a chronic sleep disorder correlated with loss of hypocretin(orexin). In NT1 post-mortem brains, we observed 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN) and significantly less CRH-positive fibers in the median eminence, whereas CRH-neurons in the locus coeruleus and thalamus, and other PVN neuronal populations were spared: that is, vasopressin, oxytocin, tyrosine hydroxylase, and thyrotropin releasing hormone-expressing neurons. Other hypothalamic cell groups, that is, the suprachiasmatic, ventrolateral preoptic, infundibular, and supraoptic nuclei and nucleus basalis of Meynert, were unaffected. The surprising selective decrease in CRH-neurons provide novel targets for diagnostics and therapeutic interventions. ANN NEUROL 2022 Show less
Objective Identifying common genetic variants that confergenetic risk for cluster headache. Methods We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis... Show moreObjective Identifying common genetic variants that confergenetic risk for cluster headache. Methods We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trondelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results An association was found with cluster headache for 4 independent loci (r(2) < 0.1) with genomewide significance (p < 5 x 10(-8)), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r(2) = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. Interpretation This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headaches with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021 Show less
Objective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome-wide association study,... Show moreObjective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 x 10(-17), odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 x 10(-17), OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 x 10(-8), OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 x 10(-8), OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021 Show less
Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 1.5 times more likely to develop PD compared to women with European ancestry. Over the... Show moreObjective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner.Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (similar to 20%).Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. Show less
Poole, O.V.; Pizzamiglio, C.; Murphy, D.; Falabella, M.; Macken, W.L.; Bugiardini, E.; ... ; Queen Square Genomics 2021
A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently... Show moreA rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty-four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021 Show less
Bruijn, M.A.A.M. de; Bastiaansen, A.E.M.; Mojzisova, H.; Sonderen, A. van; Thijs, R.D.; Majoie, M.J.M.; ... ; ACES Study Grp 2021
Objective Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This... Show moreObjective Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing.Methods In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic.Results We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score >= 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%.Interpretation Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff >= 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021 Show less
Martinez-Majander, N.; Artto, V.; Ylikotila, P.; Sarnowski, B. von; Waje-Andreassen, U.; Yesilot, N.; ... ; SECRETO Study Grp 2020
Objective To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO)... Show moreObjective To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO).Methods We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age- and sex-matched (+/- 5 years) stroke-free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist-to-hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen.Results The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63-3.76) and MA (OR = 3.50, 95% CI = 2.19-5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61-5.47; OR = 4.32 for MA, 95% CI = 2.16-8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32-4.61; OR = 3.61 for MA, 95% CI = 1.75-7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right-to-left shunt in patients with PFO.Interpretation MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2020 Show less
Mulder, I.A.; Li, M.; Vries, T. de; Qin, T.; Yanagisawa, T.; Sugimoto, K.; ... ; Ayata, C. 2020
Objective Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We,... Show moreObjective Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. Methods Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. Results Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21,p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle,p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold,p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. Interpretation Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020 Show less
Objective Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid beta (A beta) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time... Show moreObjective Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid beta (A beta) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. Methods We scanned intact formalin-fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions. Results In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole-brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of A beta-positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both A beta (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but A beta was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular A beta was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). Interpretation These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279-292 Show less
