Background and Objectives Generalized myasthenia gravis (gMG) is a chronic fluctuating neuromuscular disease. Some patients keep experiencing symptoms or adverse events (AEs) despite tailored therapeutic schemes. The aim of this study was to characterize adequately controlled gMG and describe patients' evolution and outcomes, including estimated direct health costs in a universal health care system.Methods Spanish expert neurologists developed a definition of adequately controlled gMG using Delphi methodology. This was applied to an existing cohort of patients recently diagnosed with gMG during 1998-2020 in a Spanish referral neuromuscular diseases' unit. Control status, clinical outcomes, AEs, and health care resource utilization (HCRU) were described biennially.Results We assessed 220 patients diagnosed with gMG (54.5% women; mean age at onset of 58 years; 84% anti-AChR, 6% anti-MuSK, 10% seronegative). Adequately controlled gMG was defined as achieving Myasthenia Gravis Foundation of America Post-Intervention Status classification of clinical stable remission, pharmacologic remission, or minimal manifestations stable for a year; having an MG-ADL score <= 2; experiencing no clinical exacerbations during the last year requiring a change in immunosuppressive therapy or rescue therapy; and having no or mild AE to therapies (100% of experts in agreement or total agreement). The proportion adequately controlled (AC) patients increased from 62.0% at 2 years after first visit to 81.9% after 8 years of follow-up. 47.3% of patients remained AC in every observation, and 17.7% remained not adequately controlled (NC) in every observation. No features were significantly associated with adequate control. AE-related drug interruption rates were higher in NC patients (ranging from 50% to 100% during the study). The mean cost per patient/year ranged from 2,718.6 & euro; in the first biennial period to 843.1 & euro; in the last biennial period for AC patients and from 10,190.1 & euro; to 5,827.4 & euro; for NC patients.Discussion Based on the new gMG control consensus definition, almost 1 in 5 patients do not reach disease control even after 8 years of evolution. Those patients lacked specific clinical features, underscoring the unpredictability of the gMG course. Burden of AE-related drug interruptions, HCRU, and costs per patients/year were higher among those patients NC. However, our study is unicentric and included patients from a referral unit, with a possible overrepresentation of NC patients.
Background and Objectives Blood-based biomarkers are strongly correlated with amyloid positivity in research settings, but their long-term performance in heterogeneous populations remains unclear. Our aim was to determine their long-term prediction accuracy for incident all-cause dementia on their own and when used alongside known risk factors in community-dwelling older adults.Methods This was a retrospective study based on the UK Whitehall II longitudinal, population-based cohort study established in 1985 among civil servants that includes a clinical examination every 4-5 years. Blood samples stored at the 2013-2013 wave were assayed in 2024 for measures of amyloid-beta (A beta) 42 and 40, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau protein 217 (p-tau217). Incident all-cause dementia, from 2012 to 2013 to 2025, was ascertained from linked medical records, and Cox regression was used to examine associations of biomarkers with dementia, followed by estimation of prediction statistics.Results Of the 5,225 (27.2% female) participants (mean age in 2012-2013, 69.4 +/- 5.7 years), 516 (30.0% female) had a dementia diagnosis over a 12.2-year median follow-up. Participants with values in the worst quartile of amyloid-beta 42 (A beta 42)/40 ratio (hazard ratio [HR] 1.88; 95% CI 1.57-2.24), p-tau217 (HR 3.74; 95% CI 3.12-4.50), NfL (HR 1.88; 95% CI 1.56-2.28), and GFAP (HR 2.25; 95% CI 1.87-2.72) had higher risk of dementia. The C-index for predicting dementia was highest for p-tau217 (0.693; 95% CI 0.672-0.714), lowest for A beta 42/40 ratio (0.587; 95% CI 0.566-0.608), and was 0.760 (0.738, 0.781) for all biomarkers together. Sensitivity (between 41.7% and 59.5%) and positive predictive value (between 16.4% and 23.5%) of all biomarkers were modest, but specificity (between 76.8% and 78.8%) and negative predictive value (92.3%-94.7%) were good. A second approach to prediction modeling showed a model containing sociodemographic, behavioral, and health-related risk factors to have a C-index of 0.765 (95% CI 0.746-0.785); adding all biomarkers to this model led to a C-index of 0.813 (95% CI 0.795-0.830).Discussion The long-term predictive ability of blood-based biomarkers for incident dementia in community-dwelling older adults was modest due to poor sensitivity and similar to that of a model containing known risk factors.
Background and Objectives Epilepsy is linked to late-onset dementia, but evidence for young-onset dementia (YOD; <65 years) is limited. We assessed the epilepsy-YOD association in France and Sweden and YOD risk after midlife epilepsy. Methods We conducted 3 nationwide analyses. A French nested case-control analysis included patients with incident YOD aged 40-64 years, diagnosed between January 1, 2016, and December 31, 2018. Index date was the first YOD-related health care event; controls were risk-set matched on age, sex, and region. A Swedish nested case-control replication included patients with YOD diagnosed between January 1, 1987, and December 31, 2016, with matched controls. In both studies, epilepsy-related diagnoses and antiseizure medication (ASM) dispensations were assessed up to 10 years before index date. Odds ratios (ORs) were estimated with conditional logistic regression. A French retrospective cohort included adults aged 30-55 years with incident epilepsy in 2008, matched to individuals with prevalent epilepsy before 2008 or no epilepsy. The cohort index was the first ASM reimbursement in the incident epilepsy group or the matched date for comparators. Follow-up ended at YOD, death, or 10 years. We estimated 10-year cumulative incidence and adjusted (comorbidities, deprivation) hazard ratios (HRs), treating death as a competing event. Sensitivity analyses included lagged entry up to 5 years. Results Case-control studies included 11,360 cases and 113,600 controls in France and 16,433 cases and 164,330 controls in Sweden. In France, 12.5% of YOD cases vs 1.2% of controls had previous epilepsy-related codes (adjusted OR 3.76, 95% CI 3.42-4.14), and 27.3% vs 10.3% had ASM dispensations (adjusted OR 1.44, 95% CI 1.36-1.52). The French cohort included 12,901 individuals with incident epilepsy, 64,083 with prevalent epilepsy, and 129,010 without epilepsy (mean age 44.0 years; 55.5% female participants). Ten-year cumulative YOD incidence was 2.20% (95% CI 1.94-2.48) with incident epilepsy (adjusted HR compared with individuals without epilepsy 6.02, 95% CI 4.98-7.26), 1.74% (1.64-1.85) with prevalent epilepsy (adjusted HR 5.38, 95% CI 4.64-6.25), and 0.21% (0.19-0.24) without epilepsy. Associations attenuated with longer lags but persisted beyond 5 years. Discussion Across 2 countries and complementary designs, epilepsy was strongly associated with YOD. Epilepsy conferred higher YOD risk in midlife, especially with multimorbidity, supporting epilepsy inclusion in YOD risk stratification and prevention.
Background and Objectives Stroke is a major differential diagnosis in patients with acute vertigo/dizziness or imbalance. Current diagnostic algorithms such as head impulse test, gaze-evoked nystagmus, and test of skew are optimized for presentations with spontaneous nystagmus (SPN), traditionally called acute vestibular syndrome (AVS). However, in recent studies, a relevant proportion of patients with stroke-related vertigo/dizziness had no SPN, but rather postural or gait imbalance, a phenotype lately termed acute imbalance syndrome (AIS). We aimed to outline the pathoanatomical differences of stroke-related AIS vs AVS and its clinical implications.Methods Patients with MRI-proven stroke-related acute vertigo/dizziness or imbalance were included in this emergency department (ED) cohort study at LMU Hospital prospectively. Vestibular, ocular motor, and postural signs were documented (including SPN presence/intensity by video oculography, postural imbalance by posturography). Patients were classified as suffering from AIS or AVS based on the presence of SPN. Stroke lesion distribution was depicted in Montreal Neurological Institute space and supplemented by structural disconnectome mapping from the lesion cores. Multivariate lesion symptom-mapping based on support-vector regression and disconnectome mapping was applied for SPN intensity and sway path as surrogate markers for AVS and AIS.Results Of 75 patients (age: 65.7 +/- 13.3 years, 40% female), 58.7% were diagnosed with AIS, 38.7% with AVS, and 2.7% with central positional vertigo. In AIS, the lesion core was located in the anterior cerebellar lobe and deep cerebellar nuclei (superior cerebellar artery/posterior inferior cerebellar artery territory) connecting to the bilateral pontomesencephalic tegmentum through the superior cerebellar peduncle. AVS stroke lesions were mostly located in the posterior cerebellar/flocculonodular lobe (posterior inferior cerebellar artery/anterior inferior cerebellar artery territory) and connected to the ipsilesional vestibular nucleus (VN) and bilateral medial longitudinal fascicle (MLF) through the inferior cerebellar peduncle. SPN intensity correlated with voxels in the cerebellar lobules VI-IX connecting to VN and MLF. Postural sway was associated with a small local cluster in the cerebellar Crus I.Discussion AIS accounts for more than half of patients with stroke-related vertigo/dizziness or imbalance. AIS lesions were located in the anterior cerebellar lobe, disturbing cerebellar-pontomesencephalic networks for posture and gait control. AVS lesions affected the posterior cerebellar/flocculonodular lobe and associated vestibulo-ocular reflex networks. Recognition of both clinical phenotypes is essential to identify all strokes among patients with vertigo/dizziness in the emergency setting.Trial Registration Information DRKS00008992; U1111-1172-8719.
Background and Objectives Plasma phosphorylated tau (p-tau) 217 is increasingly used for Alzheimer disease (AD) diagnosis and treatment decisions but may be discordant with established AD biomarkers. False-positive (FP) plasma results may lead to overtreatment and false-negative (FN) results to missed or delayed disease-modifying therapies. We evaluated factors associated with discordant results. Methods This retrospective study included participants enrolled in memory and aging studies at Mayo Clinic with "positive" (>0.324 pg/mL) or "negative" (<0.186 pg/mL) plasma p-tau217 results and confirmatory AD biomarkers. Plasma results were classified as true positive (TP), true negative (TN), FP, or FN, referencing amyloid-PET and CSF p-tau181/beta-amyloid (A beta) 42. Clinical and laboratory variables were compared using univariate analyses; multivariable logistic regression evaluated independent associations with discordance. Results Among 706 participants (median 70.0 [interquartile range 15.8] years; 54% male), 60 (8.5%) had discordant plasma p-tau217 results. FN results (5.6%) were more frequent than FP results (2.8%; p = 0.007). Discordance was associated with older age (odds ratio [OR] 1.61 per decade, 95% CI 1.23-2.14) and obstructive sleep apnea (OR 1.94, 95% CI 1.08-3.49). FN (vs TP) results were associated with milder clinical stage (global Clinical Dementia Rating [CDR] <= 0.5 vs CDR >= 1; p < 0.001), higher Mini-Mental State Examination scores (OR 1.20 per point, 95% CI 1.05-1.36), obstructive sleep apnea (OR 2.01, 95% CI 1.01-4.3), higher body mass index (OR 1.11/kg/m(2), 95% CI 1.03-1.20), and higher estimated glomerular filtration rate (eGFR: OR 1.33/10 mL/min/1.73 m(2), 95% CI 1.05-1.69). In age-adjusted models, body mass index (OR 1.14, 95% CI 1.03-1.25), eGFR (OR 1.63/10 mL/min/1.73 m(2), 95% CI 1.22-2.16), and earlier clinical stage (CDR <= 0.5) were independently associated with FN results. FP (vs TN) results were associated with older age (OR 2.37, 95% CI 1.36-4.09), thyroid disease (OR 4.41, 95% CI 1.36-14.3), lower eGFR (OR 0.48/10 mL/min/1.73 m(2), 95% CI 0.31-0.66), and advanced disease stage (CDR >= 1). In age-adjusted models, eGFR (OR 0.54/10 mL/min/1.73 m(2), 95% CI 0.35-0.82) and advanced disease stage (CDR >= 1 vs CDR 0: OR 11.11, 95% CI 2.0-50.0; vs CDR 0.5: OR 4.55, 95% CI 1.12-16.67) were independently associated with FP results. Discussion Plasma p-tau217 results and established AD biomarkers were discordant in 8.5% of participants. Clinical stage and factors related to brain amyloid clearance, renal clearance, and volume of distribution were associated with discordant results. These insights may inform mechanisms of discordance and identify patients requiring confirmatory biomarker measures.
