Neurology

Background and objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease. Though neuropsychiatric symptoms (NPS) of CADASIL profoundly impact function and quality of life, these symptoms remain understudied. This analysis characterizes the prevalence, severity, and profile of NPS among individuals with CADASIL-causing NOTCH3 variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC). Methods: This cross-sectional analysis used multimodal baseline data from 12 enrollment sites across the country. Statistical analyses used nonparametric tests and regression models to compare clinical and neuropsychiatric outcomes across CADASIL risk tiers and controls, adjusting for age, sex, race, and education where appropriate. The primary outcome measure was the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-reported measure which assesses 12 categories of NPS. NPI-Q item severity and distress were evaluated for individuals with confirmed cysteine-altering NOTCH3 variants and compared with controls. Results: Four hundred fifty-nine USCC participants were included in the analytic cohort: 343 cases [256 high-risk (HR); 63 medium-risk (MR); 24 low-risk (LR)]; and 116 controls. Among participants with available NPI-Q data, at least one neuropsychiatric symptom was reported by 72.6% (n = 228/314) of cases compared with 53.2% (n = 58/109) of controls. Reported symptoms were more common among CADASIL cases than controls, occurring in 75.0%, 71.2%, and 72.7% of participants in the LR, MR, and HR groups, respectively, compared with 53.2% of controls. Compared with controls, participants in the MR group and HR group had higher NPI-Q severity scores. HR participants also had higher NPI-Q distress scores than controls. Discussion: Our findings support the notion that NPS are an important clinical manifestation of CADASIL. Beyond previously reported symptoms, additional neuropsychiatric manifestations were identified. Given the higher burden and variability in the neuropsychiatric presentation of CADASIL, the relationships among neuropsychiatric, neurological, and patient-reported outcomes merit further investigation. The NPS profile may enhance the evaluation of the safety and efficacy of different treatments to target these symptoms for CADASIL patients. Trial Registration Information: The study is registered at ClinicalTrials.gov (NCT05677880, 12/12/2022).

Abstract Background and Objectives Cerebral microhaemorrhages influence eligibility and monitoring for anti-amyloid therapies. Emerging evidence and expert opinion suggest that subcortical microhaemorrhages may be less closely related to cerebral amyloidosis than lobar lesions and may therefore warrant separate consideration in anti-amyloid treatment eligibility criteria. Using longitudinal MRI data from cognitively unimpaired individuals with preclinical Alzheimer disease in the A4 study, we hypothesised that lobar and subcortical microhaemorrhages would show distinct location-specific patterns of progression and associated risk profiles. Methods We conducted a retrospective longitudinal cohort analysis of centrally assessed MRI data from A4 study participants with at least two evaluable MRI examinations. Baseline and follow-up were defined as the first and last evaluable scans, respectively. Participants were classified according to the anatomical distribution of baseline microhaemorrhages as lobar or subcortical, and subsequent location-specific lesion accumulation was examined. Multivariable logistic regression was used to assess whether baseline lobar and subcortical microhaemorrhage counts were independently associated with the development of additional lobar and subcortical microhaemorrhages. Results Among 1,146 participants followed for a mean of 4.55 years (SD = 1.78), 38 had subcortical-only and 157 had lobar-only microhaemorrhages at baseline. Subsequent lesions preferentially accumulated in the same anatomical compartment. Baseline subcortical microhaemorrhage count was associated with additional subcortical lesions (OR 3.60, 95% CI 2.00-6.47), but not with additional lobar lesions (OR 1.25, 95% CI 0.73-2.15). Conversely, baseline lobar microhaemorrhage count was associated with additional lobar lesions (OR 2.74, 95% CI 2.06-3.64), but not with additional subcortical lesions (OR 1.08, 95% CI 0.77-1.53). White matter hyperintensity burden was associated with subcortical progression, while APOE4 homozygosity and greater cerebral amyloid burden were associated with lobar progression. Systolic blood pressure was directionally positive but not associated with lobar microhaemorrhage accumulation in either analysis. Discussion Our findings support the emerging view that subcortical and lobar microhaemorrhages exhibit distinct longitudinal patterns and associated risk profiles. Longitudinal studies in patients receiving contemporary plaque-clearing therapies are needed to determine whether microhaemorrhages should be considered differently according to anatomical location in treatment eligibility and monitoring guidelines.

Background and Objectives: Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID. Methods: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education. Results: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34). Discussion: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.

Background and Objectives. Prion disease is an untreatable, typically rapidly progressive dementia. New drug candidates designed to lower prion protein are now entering clinical trials. To support future pivotal trials, we sought to assemble and analyze a public dataset of natural history data characterizing the symptomatic course of prion disease in order to provide a quantitative basis for modelling and rational trial design. Methods. We extracted data from medical publications between 2000 and 2024 reporting on n[≥]5 prion disease patients. Information about demographics, ascertainment, and clinical milestones, such as time from onset to death, akinetic mutism, diagnostic testing and outcomes, were extracted for aggregate cohorts of [≥]2 patients and individual patient-level data (PLD). We computed summary statistics of cohorts and PLD, visualized survival through forest plots and Kaplan-Meier curves, analyzed covariates regarding survival, and identified biases and heterogeneity within the literature. Results. From 245 included publications we extracted 418 aggregate cohort medians and 1,400 rows of individual PLD. 90% of cohorts and 91% of individual patients had symptom-to-death milestones, while only 7% and 11% had a time interval from a clinical presentation milestone to death, respectively. Symptom-to-death intervals varied as much as 3.2-fold even between cohorts of the same histopathologic subtype, and akinetic mutism occurred 73% sooner than death when both endpoints were reported (N=53). Indicators of disease severity, such as a cognitive test, were rarely present in either aggregate data (11%) or PLD (6%). Discussion. Data routinely reported in publications can quantify diagnostic delay and covariates affecting survival time, but are limited in ability to inform pivotal trial design because most such data are aggregated, cross-sectional, lack indicators of disease severity, and present timelines beginning with onset rather than more relevant clinical milestones, such as diagnosis, that may better reflect the moment of potential for trial enrollment. There is a need for clinical data to report milestones such as intervals from diagnosis to death, for longitudinal cognitive and functional scores, and for deposition of publicly accessible PLD.

INTRODUCTION: Sleep-dependent memory consolidation is impaired early in Alzheimer's disease (AD). Closed-loop auditory stimulation (CLAS) of sleep slow oscillations enhances memory consolidation in healthy individuals, but its efficacy in AD remains unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial in 37 patients with biomarker-confirmed early symptomatic AD and an amnestic clinical phenotype. We assessed the effect of one night of CLAS, compared with one night of sham stimulation, on declarative memory retention, sleep electrophysiology, and sleep architecture. RESULTS: CLAS significantly improved overnight word-pair consolidation (Cohen's dz = 0.42, p = 0.04), enhanced stimulation-evoked slow-wave and fast spindle activity, and preserved sleep architecture and subjective sleep quality. DISCUSSION: This study provides the first demonstration that CLAS modulates sleep electrophysiology and improves overnight memory consolidation in patients with biomarker-confirmed AD. Further studies need to address the sustainability of such effects with multi-night interventions for a clinically meaningful intervention.

Background. Post-stroke anxiety and depression frequently co-occur, and whether each is independently associated with cognitive impairment remains unclear because most studies model one without adjusting for the other variable. In a five-year cohort, we tested whether anxiety and depression have distinct cognitive correlates and whether early affective status predicted subsequent cognitive recovery. Methods. Patients from the STROKDEM cohort were assessed at 6, 12, 36, and 60 months post-stroke for anxiety, depression, and five cognitive domains (memory, executive functioning, attention, visuospatial functioning, and language). Two symmetric random-intercept linear mixed models regressed each affective score on the cognitive domains while adjusting for other scores. Repeated-measures correlations, multiple imputations for attrition, and exploratory trajectory and prognostic models were also used. Results. After mutual adjustment and correction, depression was independently associated with executive and visuospatial function, whereas anxiety showed no independent cognitive correlation. Repeated-measures correlation confirmed this dissociation. The anxiety findings were stable across the sensitivity analyses and multiple imputations. Attrition was selective for baseline cognition, and exploratory associations between early affect and cognitive recovery did not survive multiple imputations and were inconclusive. Limitations. Attrition was substantial and selective on baseline cognition; the persistent anxiety subgroup was small, limiting the power for trajectory analyses; and psychiatric history, psychotropic medication, and cognitive reserve beyond education were unavailable. Conclusions. The cognitive burden of post-stroke affective disorders is carried by depression, rather than anxiety. Because anxiety-related cognitive impairment largely reflects comorbid depression, screening for depression rather than anxiety alone may better identify stroke survivors at risk of cognitive impairment.

Background: The Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS) is a brief rating scale of clinical severity in PSP. However, its longitudinal performance has not been evaluated. We aimed to assess the ability of the PSP-CDS to track disease progression over time and to compare progression across PSP phenotypes in a real-world Asian cohort. Methods: Patients who met the Movement Disorder Society PSP diagnostic criteria and underwent at least 2 PSP-CDS assessments were recruited from movement disorders clinics in Malaysia. Longitudinal progression was evaluated using linear mixed-effects models. Domain-specific progression and subtype-specific trajectories were also analyzed. Associations between annualized changes in PSP-CDS and Barthel Index (BI) scores were examined. Results: 104 patients (including 59 with PSP-Richardson's syndrome [PSP-RS], 28 with predominant parkinsonism [PSP-P], and 14 with progressive gait freezing [PSP-PGF]) contributed 394 PSP-CDS assessments over a median follow-up of 33.2 months (range, 8.7-73.1 months). PSP-CDS scores increased significantly over time ({beta}=0.126 points/month), corresponding to estimated increases of 1.13 points over 9 months and 2.27 points over 18 months. Subtype-specific analyses demonstrated the fastest progression in PSP-RS (0.156 points/month), followed by PSP-PGF (0.081 points/month) and PSP-P (0.077 points/month). Exploratory domain-level analyses showed that finger dexterity, communication, and dysphagia were the most rapidly worsening domains. Annualized PSP-CDS progression correlated significantly with annualized decline in BI scores (Spearman's {rho}=-0.474, P<0.001). Conclusions: The PSP-CDS is sensitive to longitudinal disease progression in PSP and captures clinically-meaningful functional decline. Its brevity and ability to distinguish differential progression across PSP phenotypes support its utility as a pragmatic outcome measure for routine clinical practice and research.

Background Optic pathway hypothalamic glioma (OPHG) can cause irreversible visual impairment. Radiotherapy and radiosurgery are used for progressive, recurrent, or treatment-refractory disease, but their effects on visual outcomes remain incompletely defined. Objective To synthesize visual outcomes following radiotherapy or radiosurgery for OPHG, with visual preservation as the primary outcome. Methods This prospectively registered systematic review and meta-analysis (PROSPERO CRD420261440136) followed the PRISMA 2020 statement. PubMed, Scopus, Web of Science, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were searched from inception to 1 June 2026. Eligible studies included patients with OPHG or related optic pathway or hypothalamic gliomas treated with radiotherapy or radiosurgery and reporting extractable visual outcomes. Visual preservation was defined as stable or improved vision. Random-effects meta-analyses of logit-transformed proportions were performed. Results Forty-nine studies were included in the systematic review, of which 19 contributed 494 visual outcome observations to the meta-analysis. The pooled visual preservation rate was 75.6% (95% CI 65.1% to 83.7%; I2 = 71.6%). Pooled rates of visual improvement, stability, and worsening were 24.7% (95% CI 19.5% to 30.8%), 46.7% (95% CI 37.0% to 56.6%), and 20.6% (95% CI 12.7% to 31.6%), respectively. Preservation was higher in pure radiotherapy or radiosurgery cohorts than in mixed-treatment cohorts (85% vs 66%; subgroup p = 0.0104), although differences in cohort composition and treatment attribution may have influenced this finding. Conclusion Radiotherapy and radiosurgery were associated with preservation of vision in approximately three-quarters of evaluable outcomes, predominantly through visual stability rather than recovery. Standardized visual outcome definitions are needed to improve future comparisons and treatment evaluation.

Background: Whether ethnoracial differences in cerebral small vessel disease (cSVD) appear in multimarker burden, particular MRI manifestations, or both, and how they relate to Life's Essential 8 (LE8) cardiovascular health and cognition, remain unclear. Methods: This cross-sectional study included 44,982 participants and an age- and sex-matched subsample of 1,426 with reviewed lacune and cerebral microbleed (CMB) ratings. White, South Asian, Black, Chinese and Mixed participants were compared on 0-2 (white matter hyperintensity [WMH]/enlarged perivascular space [ePVS]) and 0-4 (adding CMB and lacunes) composite scores and each marker. LE8 was related to WMH and composite burden, and cognitive means were compared by group. Models were age-, sex- and center-adjusted with false-discovery-rate correction. Results: Both composite scores differed across groups (0-2: P=0.00010; 0-4: P=0.0011), with greater burden in Black than South Asian (0-4: OR 1.66; 95% CI, 1.21-2.28) and Chinese participants (OR 2.36; 1.51-3.70), whereas Black-White contrasts were not detected. Black participants had higher WMH volume than White participants (=0.209; 0.110-0.308), robust to deprivation adjustment and segmentation method; South Asian participants had fewer ePVS (0.82; 0.72-0.93). No ethnoracial-group differences in lacune or CMB counts were detected after correction. Higher LE8 was associated with lower WMH volume (0.13 per SD; 0.17 to 0.09) and lower two-marker burden (OR 0.89 per SD; 0.87-0.91) without detected ethnoracial moderation. Black participants, who had the least favorable LE8 scores, and South Asian participants had lower global cognition than White participants (z 0.76 and 0.57 versus 0.24) despite differing WMH profiles; the pooled WMH-cognition association was null. Conclusions: Ethnoracial differences in multimarker cSVD burden were evident but marker-dependent: WMH showed the clearest Black-White difference; focal-lesion contrasts were inconclusive. Better cardiovascular health related to lower WMH and aggregate cSVD burden across groups, whereas cognitive differences did not track cSVD burden, supporting prospective prevention and cognition studies.

IMPORTANCE Autopsy evidence on sex-specific associations of education with neuropathology and cognition is limited. OBJECTIVE To test sex differences in education associations with neuropathologic burden and cognition. DESIGN Cohort study of data collected from September 2005 through August 2024. SETTING Multicenter autopsy cohort from the National Alzheimer's Coordinating Center. PARTICIPANTS Adults aged 55 years or older; cross-sectional eligibility required a final CDR-SB assessment within 2 years before death, and longitudinal eligibility additionally required at least 3 assessments. EXPOSURES Years of formal education. MAIN OUTCOMES AND MEASURES Neuropathologic measures and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Linear regression and mixed-effects models tested associations and interactions of education with sex, neuropathology, and linear and quadratic time. Benjamini-Hochberg correction addressed multiple comparisons. RESULTS Among 2592 participants (mean [SD] age at death, 81.6 [10.8] years; 1188 [45.8%] female), 1969 contributed to longitudinal analyses. In female participants, higher education was associated with lower Thal amyloid phase, diffuse plaques, neuritic plaques, and Braak stage ({beta} range, -0.097 to -0.071; qFDR<.026); none was significant among male participants. Education-by-sex interactions supported differences in Thal amyloid phase, and diffuse and neuritic plaques ({beta} range, -0.119 to -0.097; qFDR<.045). Education was unrelated to final CDR-SB among female ({beta}, -0.007; 95% CI, -0.052 to 0.038; P=.767) and male participants ({beta}, -0.026; 95% CI, -0.071 to 0.019; P=.254), with no education-by-sex interaction (P=.660). The education-by-Braak-stage-by-sex interaction indicated that higher education was associated with a weaker Braak stage-CDR-SB association among females than males ({beta}, -0.104; 95% CI, -0.171 to -0.038; qFDR=.022). Longitudinally, education was unrelated to linear CDR-SB change in either sex. Education-by-quadratic-time associations were observed among females ({beta}, 0.002; 95% CI, 0.001-0.003; P<.001) and male participants ({beta}, 0.001; 95% CI, 0-0.002; P=.037). The corresponding interaction with sex was also significant (P=.043). CONCLUSIONS AND RELEVANCE Among female participants, higher education was associated with lower selected Alzheimer's disease neuropathologic measures and weaker associations of tau pathology with cognition. Longitudinal trajectories were nonlinear, with slower earlier decline followed by later acceleration at higher education levels.

Objective: To evaluate whether educational attainment and Alzheimer disease genetic risk were associated with GLP-1 receptor agonist initiation and dementia incidence and whether adjustment for these measured factors materially changed the estimated association between GLP-1 receptor agonist initiation and incident dementia among adults with type 2 diabetes. Research Design and Methods: We conducted an observational cohort study using linked electronic health record, survey, and genetic data from 14,364 All of Us Research Program participants with type 2 diabetes. We estimated associations of educational attainment and Alzheimer disease genetic risk with treatment initiation and incident dementia and compared GLP-1 receptor agonist initiators with initiators of non-sodium-glucose cotransporter 2 inhibitor second-line therapies, with a separate sodium-glucose cotransporter 2 inhibitor comparison. Models were estimated before and after additional adjustment for educational attainment, APOE {varepsilon}4, and non-APOE genetic risk. Results: Among 14,364 participants (mean age, 60.2 years; 54.2% female), the mean follow-up duration was 4.3 years. The estimated hazard ratio for dementia comparing GLP-1 receptor agonist initiation with non-SGLT2 inhibitor second-line therapy was 0.85 (95% CI 0.64-1.12) before adjustment for education or Alzheimer disease genetic risk and 0.84 (95% CI 0.64-1.12) after adjustment for educational attainment, APOE {varepsilon}4, and non-APOE genetic risk. Conclusions: Among adults with type 2 diabetes, adjustment for measured educational attainment and Alzheimer disease genetic susceptibility produced little change in the estimated association between GLP-1 receptor agonist initiation and incident dementia. These findings do not exclude confounding by these factors in other populations or residual confounding from socioeconomic, clinical, behavioral, and health-care-related factors.

Background: The Boston Criteria v2.0 represent the gold standard for diagnosing Cerebral Amyloid Angiopathy (CAA), but their application is currently precluded in mixed small vessel disease (SVD), where deep and lobar hemorrhages coexist. The aims of this study are: (i) to determine which cerebrospinal fluid (CSF) biomarker (A{beta}42, A{beta}40, A{beta}42/40 ratio) is the best candidate to support the CAA diagnosis; (ii) to define a data-driven cut-off, and (iii) to explore if a biomarker-integrated classification significantly improves the phenotypical concordance with the suspected predominant SVD (CAA vs. arteriosclerosis). Methods: We analyzed data from a retrospective multicenter cohort of patients with suspected CAA, defined as probable CAA (Boston criteria v2.0) but allowing deep hemorrhagic lesions, and with available CSF biomarkers. We visually quantified MRI-visible SVD markers (e.g., cerebral microbleeds [CMB], cortical superficial siderosis [cSS], lacunes) and their association with MRI-visible SVD features. We employed a Gaussian Mixture Model (GMM) to identify a data-driven threshold for amyloid positivity (A+). Then, we compared the prevalence of MRI-visible manifestations of SVD between subgroups applying different frameworks, namely the current MRI-based classification (probable CAA vs. mixed SVD) and a CSF biomarker-integrated classification (A+ vs. A-). Results: We enrolled 121 patients (age: 72 [66-77] years; 60% probable CAA, 40% mixed SVD with suspected CAA). The CSF A{beta}42/40 ratio showed a bimodal distribution and consistent associations with all CAA-specific radiological features. The CSF biomarker-integrated reclassification, particularly using the GMM cut-off, significantly improved the distinction between subgroups regarding CAA- and arteriosclerosis-related MRI features (e.g., cSS presence: probable CAA vs. mixed SVD: aOR=2.84 [95%CI 1.27-6.39], p=0.011; A+ vs. A-: aOR=12.68 [95%CI 4.31-37.32], p<0.001; deep lacunes presence: probable CAA vs. mixed SVD: aOR=0.20 [95%CI 0.08-0.50], p<0.001; A+ vs. A-: aOR=0.04 [95%CI 0.01-0.11], p<0.001). Notably, patients classified as A+ never demonstrated more than four deep CMBs. Discussion: A CSF biomarker-integrated classification may improve the classification of CAA compared with the current MRI-based framework. These findings are cohort-specific and would benefit from further validation, especially with a neuropathological reference. Still, these results support a future transition toward an integrated biological-radiological framework, which may refine in vivo CAA diagnosis, particularly in mixed SVD.

Background: Therapy development in ultra-rare, progressive and fatal diseases like vanishing white matter (VWM) is hampered by very low patient numbers and ethical constraints regarding placebo-controlled studies. Under such conditions, standard randomized controlled trials may not be feasible. The use of historical control information could be part of a solution, but would require extra considerations regarding selection of patients and choice of endpoints. We used the VWM registry as a case study to outline key methodological considerations for informing trial design in ultra-rare disease. Methods: The study included 462 patients, available in the VWM registry. Prospective clinical data were collected since 2004 using VWM-specific questionnaire and Health Utility Index (HUI) assessments, while retrospective data from clinical charts were available from 1988 on. We evaluated methodological aspects relevant to trial design, including patient selection, drift in the disease course over time, endpoint selection, and clinically relevant stratification into subgroups. Results: Regarding patient selection, patients with comorbidities impacting disease course, and pre-symptomatic individuals without clinical onset were considered not suitable as historical controls. After excluding patients before 1991, we found no evidence of drift in the disease course from 1991 onwards. Regarding choice of endpoints, episodes of rapid decline were relatively infrequent and occurred mostly at disease onset, limiting their usefulness as trial endpoint. Multi-state modelling and clinical evaluation showed ambulation as preferable endpoint over survival. For longitudinal HUI multiscores, baseline imputation allowed modelling of early disease. The scores showed a distinct ordering, reflecting the association between multi-domain function and disease progression. Regarding stratification, the combination of data-driven analyses and clinical expertise informed revised age of onset groups. Females showed later onset and milder disease; adjustment for age of onset eliminated the effect of sex. Conclusion: This case study provides key considerations for evaluating registry data as historical control and demonstrates how these considerations can inform clinical trial design in ultra-rare diseases.

The photic sneeze reflex (PSR), in which exposure to bright light triggers sneezing, is widely recognised but inconsistently defined and measured. We conducted the first systematic review and meta-analysis of PSR prevalence to synthesise the epidemiological evidence, assess methodological quality, and identify priorities for future research. We included 18 articles comprising 31 study groups and extracted prevalence estimates, study characteristics, ascertainment methods, and epidemiological information. Fifteen eligible study groups classified as healthy were included in the primary meta-analysis. The pooled prevalence was 22% (95% CI, 15%-29%), with extreme between-study heterogeneity (I2 = 99.3%). Reported prevalence estimates and associations with participant characteristics varied widely, and nearly all studies were judged to be at high risk of bias. The pooled estimate should therefore be interpreted as a descriptive summary of the available evidence rather than a precise estimate of population prevalence. Future studies require a standardised operational definition, representative sampling, transparent reporting, and reproducible methods for assessing light-triggered sneezing.

This systematic review and meta-analysis has several major aims, including evaluation of global and continent wise prevalence of diabetic peripheral neuropathies (DPNs), a detail assessment of DPN associated risk factors and most importantly to explore mechanistic basis of DPN by capturing its different pathophysiological hallmarks Diabetic peripheral neuropathy (DPN) imposes a substantial global burden, yet its mechanistic underpinnings and integrated risk architecture remain incompletely characterized. This systematic review and meta-analysis of 74 studies across 24 countries (83,560 participants) provides the most comprehensive quantitative synthesis of DPN prevalence, hallmark-based pathogenesis, and multi-covariate risk profiling to date. The global pooled DPN prevalence was 57.42% (95% CI: 48.56 to 66.05), with continent-specific gradients: Americas (74.52%), Europe (59.95%), and Asia (45.44%). Hallmark stratified subgroup analyses encompassing neuronal damage, metabolic dysregulation, neuroinflammation, and microvascular alteration identified microvascular alteration as the sole statistically significant mechanistic determinant (Q = 15.78, p = 0.0004), with prevalence escalating monotonically from 53% to 92% across increasing hallmark severity scores, constituting a compelling dose response relationship. Risk factor meta analysis of 27 covariates identified 12 significant determinants, including the novel meta analytic confirmation of peripheral vascular disease (OR: 3.70; highest effect size), male sex (OR: 1.52), and height (OR: 1.26) as independent DPN risk factors. Notably, HbA1c, BMI, and blood pressure were nonsignificant, challenging glycemia-centric paradigms. These findings collectively support a precision medicine framework grounded in hallmark stratified phenotyping and mechanism-targeted pharmacotherapy for DPN.

Background: CADASIL caused by cysteine-altering NOTCH3 variants, the most frequent hereditary cerebral small vessel disease worldwide, is characterized by marked phenotypic variability. Mutation location within the EGFr domains of the NOTCH3 receptor has emerged as a key determinant of this variability. We investigated phenotypic variability and potential modifiers of CADASIL expression by comparing individuals harbouring the same pathogenic NOTCH3 variant across distinct recruitment settings in three European countries. Methods: We compared clinical features, MRI markers, and cardiovascular risk factors among individuals harbouring the p.Arg1231Cys NOTCH3 mutation across three distinct recruitment settings: a multigenerational founder population from Cilento, Italy (CILCAD), a population-based cohort from the UK Biobank (UKB), and a clinically referred cohort from a national referral centre in Lariboisiere Hospital, Paris, France (LRB). In addition, CILCAD carriers were compared with NON-Carriers from the same population. The NOTCH3 locus was finally analysed to define the shared haplotype in CILCAD and explore potential genetic contributions to phenotypic variability. Findings: By comparing populations from three European countries, this study showed marked context-dependent phenotypic variability associated with the sole pathogenic p.Arg1231Cys NOTCH3 variant. In CILCAD, a multigenerational founder population, the haplotype carrying the NOTCH3 mutation also predisposes to decreased LDL levels, resulting in an unusually low LDL cholesterol profile in this sample. Strikingly, these very low LDL levels were associated with a higher likelihood of stroke. Interpretation: In European carriers of NOTCH3 p.Arg1231Cys, factors beyond mutation location, including genetic background, may substantially shape disease expression, while exceptionally low LDL levels could paradoxically be associated with greater disease severity.

INTRODUCTION: Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer disease (AD), and healthy controls (HC). METHODS: Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain-Barr&eacute syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot-Marie-Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS: Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS: Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.

Objective: To describe the self-reported effects of incobotulinumtoxinA treatments on migraine-like headache in participants who experienced traumatic brain injury versus Anomalous Health Incidents. Background: Persistent headache attributed to traumatic injury to the head has been widely recognized as among the most common sequelae of concussion/mild traumatic brain injury. Such persistent headaches often have migraine-like characteristics and are typically treated similarly to idiopathic migraine. Patients who have experienced Anomalous Health Incidents have also commonly reported migraine-like headaches, but to our knowledge, no reports describing treatment for persistent headaches attributed to Anomalous Health Incidents have been published. Methods: We describe the self-reported effects of incobotulinumtoxinA treatments on headache with migraine-like characteristics in 19 participants with traumatic brain injury and 11 who had experienced Anomalous Health Incidents from a single center. Results: Self-reported benefits from incobotulinumtoxinA treatments were generally similar and statistically indistinguishable between groups. The Headache Impact Test-6 score decreased by a mean of 12 points in the traumatic brain injury group and 9.5 points in the Anomalous Health Incidents group from baseline to peak efficacy (p = 0.43), with concomitant reductions in work/school hours lost (62% vs. 50%) and family/leisure hours lost (75% vs. 33%). Furthermore, reductions in headache frequency (67% for the traumatic brain injury group vs. 57% for the Anomalous Health Incidents group), headache severity (36% vs. 23%), headache duration (37% vs. 50%), nausea/vomiting (50% vs. 25%), photophobia (34% vs. 29%), phonophobia (30% vs. 37%), visual aura (50% vs. 29%), vestibular aura (50% vs. 33%), and other aura (21% vs. 25%) from baseline to peak efficacy were similar in both groups. Likewise, time from treatment to response (6.5 vs. 7 days), duration of response (10.2 vs. 9.1 weeks), adverse effects (3/19 for the traumatic brain injury group, 3/11 for the Anomalous Health Incidents group), and improved efficacy of concomitant abortive treatments (30% vs. 50% for pain, 50% vs. 55% for aura) did not differ between groups. Osmophobia and cogniphobia, when present, did not improve on average in either group. Notably, the mean duration of response was less than 12 weeks in both groups, with only 3 participants with traumatic brain injury and 1 participant who had experienced Anomalous Health Incidents reporting benefit beyond the typical 12-week incobotulinumtoxinA treatment interval. Conclusion: Overall, these findings provisionally indicate that at least some patients who have experienced Anomalous Health Incidents may subjectively benefit from incobotulinumtoxinA treatment for persistent migraine-like headaches similarly to patients with traumatic brain injury. Limitations include the open-label, single-center, primarily retrospective design; small sample size; and limited representativeness. Further prospective controlled studies are needed to determine whether these groups truly respond similarly to incobotulinumtoxinA and other standard treatments.

Background: Stroke risk is increased in cancer patients, but variations by stroke type, cancer characteristics, and treatment timing remain incompletely characterized. We investigated stroke incidence after cancer diagnosis and temporal patterns of ischemic stroke around treatments. Methods: We conducted a retrospective multicenter cohort study using linked cancer registry and administrative data from 68 cancer hospitals in Osaka, Japan. Patients diagnosed between 2019 and 2022 were followed for up to 1 year. In diagnosis-based analyses, standardized incidence ratios (SIRs) compared stroke incidence with the general population. In treatment-based analyses, ischemic stroke incidence rates and adjusted incidence rate ratios (IRRs) were estimated from 14 days before through 365 days after cancer treatments (surgery, chemotherapy, or radiotherapy). Results: Among 190,471 patients, 1660 strokes occurred: 1296 (78.0%) ischemic strokes, 315 (19.0%) intracerebral hemorrhages, and 49 (3.0%) subarachnoid hemorrhages. In diagnosis-based analyses, the overall stroke SIR was 2.13 (95% CI, 2.03?2.24), with a 1.01% 1-year cumulative incidence. SIRs were 2.37 (95% CI, 2.24?2.50), 1.72 (95% CI, 1.53?1.92), and 1.22 (95% CI, 0.91?1.62) for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, respectively. SIRs peaked immediately after diagnosis and declined thereafter. Excess risk persisted through 180 days for ischemic stroke, 30 days for intracerebral hemorrhage, and 7 days for subarachnoid hemorrhage. In treatment-based analyses, ischemic stroke incidence increased transiently around treatments. After surgery, the adjusted IRR peaked during days 0?7 (12.27 [95% CI, 8.50?17.71]) and remained elevated through days 31?90 versus days 181?365. A postoperative increase was observed even in early-stage disease. For chemotherapy, incidence was relatively high before treatment initiation. Conclusions: Stroke risk after cancer diagnosis varied by stroke type, cancer characteristics, and time since diagnosis. Ischemic stroke incidence increased transiently around cancer treatment, including an early postoperative increase in patients with early-stage disease. These findings identify periods and patient groups that may warrant heightened clinical vigilance.

Background: Cardiovascular, kidney, and metabolic conditions have each been associated with hearing outcomes, but little is known about whether cardiovascular-kidney-metabolic (CKM) syndrome staging tracks objective hearing sensitivity in older adults. Methods: We analyzed NHANES 2017-March 2020 pre-pandemic data for adults aged 70-79 years. CKM syndrome Stages 0-4 were operationalized from ascertainable domains of the 2026 AHA/ACC/ADA/ASN guideline, including HbA1c and design-valid fasting plasma glucose criteria for dysglycemia. The outcome was bilateral pure-tone average at 0.5, 1, 2, and 4 kHz (PTA4). Survey-weighted models adjusted for age, sex, race/ethnicity, education, smoking, and occupational and nonoccupational noise exposure. Results: The primary CKM syndrome stage analysis included 285 participants (Stage 0, n=1; Stage 1, n=18; Stage 2, n=103; Stage 3, n=65; Stage 4, n=98). The five-stage omnibus Wald test was statistically significant (F(4,25)=21.405, p=9.01e-8), but Stage 0 contained only one participant and the adjusted means were nonmonotonic (9.49, 24.3, 31.0, 29.0, and 33.4 dB HL). None of the planned Stage 2-4 contrasts remained significant after Holm adjustment, and a Stage 2-4-only robustness analysis did not support overall heterogeneity (p=0.197). Waist circumference was the only one of nine continuous CKM-related measures retained after the nine-test Holm adjustment: bilateral PTA4 was 1.57 dB HL higher per 10 cm greater waist circumference (95% CI, 0.74-2.39; adjusted p=0.00547). A post-hoc spline diagnostic did not show clear evidence of nonlinearity (p=0.128). Five-stage component-by-stage interaction models were not estimable because Stage 0 contained a single participant; among Stages 2-4, none of six primary interaction tests met the Holm-adjusted threshold. Conclusions: The primary hypothesis of progressively poorer hearing with advancing CKM syndrome stage was not supported. Although the five-stage omnibus test was statistically significant, its interpretation was constrained by the single-participant Stage 0 category; analyses restricted to Stages 2-4 did not support a progressive stage pattern. Waist circumference showed a small secondary association with PTA4 after multiplicity adjustment, but its individual-level clinical significance remains uncertain.