Bruce A. Chase

Background/Objectives: Migraine is a common neurological disorder with highly variable characteristics. While genome-wide association studies have identified genetic risk factors that implicate underlying pathways, the influence of genetic susceptibility on disease characteristics or treatment response is incompletely understood. We examined the relationships between a previously developed standardized integrative migraine polygenic genetic risk score (PRS) and migraine characteristics in a real-world, treated patient cohort. Methods: This retrospective cohort study used covariate-adjusted regression to comprehensively evaluate associations between the PRS and clinical characteristics in 1653 treated migraine cases with European ancestry at baseline and, in 800 cases, after one year. Cases were deeply phenotyped by neurologists during extensive interviews, using structured clinical documentation tools to record ~200 discrete data elements. Results: In treated patients, higher standardized PRS showed associations with two common migraine symptoms: photophobia (odds ratio [confidence interval]: 1.33 [1.13–1.56], p = 0.001) and stabbing pain (1.21 [1.08–1.36], p = 0.001]; both retained significance at Q = 0.05. Associations with phonophobia, nausea, emesis, and unilateral headache had similar effect sizes but did not survive correction for multiple tests. In this population, the PRS was not associated with other symptoms of migraine attacks, objective measures of migraine disability, frequency, severity, average duration, time-to-peak intensity of migraine attacks, chronification, emergency department visits, triptan responsiveness, or changes at follow-up. Conclusions: In treated patients, genetic risk was associated with common migraine symptoms but not with the severity of migraine characteristics or treatment outcomes. This suggests that in treated patients, other genetic and non-genetic factors influence migraine symptom severity and disease course more strongly than genetic susceptibility.

Background/Objective: Genome-wide association studies (GWASs) demonstrate a complex genetic landscape for migraine risk. Migraine polygenic risk scores (PRSs) developed from GWAS data may have utility for predicting disease course. We analyzed the strength of association between an integrative migraine PRS and age at onset and chronification. Methods: In this retrospective clinical/genetic case–control study, PGS004799 was calculated for adults with European ancestry from two real-world community cohorts. In the DodoNA cohort, 1653 treated, deeply phenotyped migraine cases, diagnosed using International Classification of Headache Disorders 3rd edition criteria, were followed for a mean (range) of 2.3 (1–10) years and compared to 3460 controls (without migraine diagnosis). In the GHI cohort, 2443 cases were identified using the first migraine ICD code as a proxy for migraine onset and compared to 8576 controls (without migraine ICD codes). PRS associations with age at onset (DodoNA) or first migraine ICD code (GHI) and chronification (DodoNA) were evaluated. Results: In both cohorts, PRS was higher in cases (DodoNA mean (range) cases: 0.82 (0.07–1.76), controls: 0.78 (0.04–1.56); t (5111) = −6.1, p = 1.4 × 10⁻⁹, GHI: cases: 0.79 (0.003–1.68), controls: 0.75 (−0.06–1.53); t (11,017) = −7.69, p = 1.6 × 10⁻¹⁴), and a higher PRS was associated with earlier onset in females (HR [95% CI] DodoNA: 2.1 [1.6–2.6, p < 0.001; GHI: 1.8 [1.4–2.1], p < 0.001) and in males (DodoNA: 2.5 [1.3–4.7], p = 0.005; GHI: 1.6 [1.1–2.6], p = 0.027). PRS was not different in cases with or without chronification (t (1651) = −1.67, p = 0.094) and was not associated with earlier chronification (1.2 [0.8–1.6], p = 0.424). Conclusions: Higher genetic risk was associated with earlier onset and increased risk of migraine well into adulthood, but not with chronification. This suggests that the PRS quantifies genetic susceptibility that is distinct from factors influencing disease course.

To assess the relationship between lipids and cognitive dysfunction, we retrospectively analyzed blood-lipid levels in clinically well-characterized individuals with stable mild cognitive impairment (MCI) or Alzheimer’s disease (AD) over the decade prior to first cognitive symptoms. In this case/control cohort study, AD and MCI cases were diagnosed using DSM-IV criteria; MCI cases had not progressed to dementia for ≥5 years; and controls were propensity matched to cases at age of symptom onset (MCI: 116 cases, 435 controls; AD: 215 cases, 483 controls). Participants were grouped based on longitudinal trajectories and quintile of variability independent of the mean (VIM) for total cholesterol, HDL-C, LDL-C, non-HDL-C and ln(triglycerides). Models for the risk of cognitive dysfunction evaluated trajectory and VIM groups, APOE genotype, polygenic risk scores (PRS) for AD and lipid levels, age, comorbidities, and longitudinal correlates of blood-lipid concentrations. Lower HDL-C trajectories (OR = 3.8, 95% CI = 1.3–11.3) and the lowest VIM quintile of non-HDL-C (OR = 2.2, 95% CI = 1.3–3.0) were associated with higher MCI risk. Lower HDL-C trajectories (OR = 3.0, 95% CI = 1.6–5.7) and the lowest VIM quintile of total cholesterol (OR = 2.4, 95% CI = 1.5–3.9) were associated with higher AD risk. The inclusion of lipid-trajectory and VIM groups improved risk-model predictive performance independent of APOE genotype or PRS for AD and lipid levels. These results provide an important real-world perspective on the influence of lipid metabolism and blood-lipid levels on the development of stable MCI and AD.

Background: As gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.Methods: We conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Through the use of biotinylated-bungarotoxin and monoclonal antibodies, the nicotinic acetylcholine receptor (nAChR) was localized in the subneural apparatus of mammalian motor end plates of the flexor digitorum brevis muscle of the adult rat at the light and electron microscopic levels. Under normal conditions, nAChR was located in the primary post-synaptic membrane of the neuromuscular junction, and the depths of the junctional folds constituting the secondary post-synaptic membrane did not contain any nAChR. Up to 75 days after repeated transection of the related motor nerve (sciatic), there was no major alteration in the light-microscopic localization of junctional nAChR in the subneural apparatus, except for a moderate shrinkage and increased immunocytochemical reactivity of the subneural apparatus. At the electron microscopic level, however, immunocytochemical reactivity gradually occupied the entire extent of the secondary post-synaptic membrane, including the depths of the junctional folds, which exhibited extensive branching. In non-innervated portions of the muscle fibers, nAChR receptor appeared in a linear localization on the surfaces of denervated muscle fibers. This linear reaction was not continuous with the nAChR reaction of the motor end plates. It is concluded that denervation supersensitivity might not be due to spreading of junctional nAChR from the end-plate area, but rather to expression of nAChR in non-innervated portions of the muscle fiber and to the infraterminal (subsynaptic) spreading of nAChR into the depths of junctional folds.