Neurology

BackgroundCardiovascular health optimization during middle age benefits brain health. The American Heart Associations Lifes Simple 7 recently added sleep duration as a key determinant of cardiovascular health becoming the Lifes Essential 8. We tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle-aged adults. MethodsWe conducted a prospective MRI neuroimaging study in middle-aged persons without stroke, dementia, or multiple sclerosis enrolled in the UK Biobank. Self-reported sleep duration was categorized as short (<7 hours), optimal (7-<9 hours), or long ([&ge;]9 hours). Evaluated neuroimaging markers of brain health included white matter hyperintensities (presence and volume) and diffusion tensor imaging metrics (fractional anisotropy and mean diffusivity) evaluated in 48 distinct neuroanatomical regions. We used multivariable logistic and linear regression models, as appropriate, to test for association between sleep duration and neuroimaging markers of brain health. ResultsWe evaluated 39,502 middle-aged persons (mean age 55, 53% female). Of these, 28,712 (72.7%) had optimal, 8,422 (21.3%) short, and 2,368 (6%) long sleep. Compared to optimal sleep, short sleep was associated with higher risk (OR 1.11; 95% CI 1.05-1.17; P<0.001) and larger volume (beta=0.06, SE=0.01; P<0.001) of white matter hyperintensities, while long sleep was associated with higher volume (beta=0.04, SE=0.02; P=0.01) but not higher risk (P>0.05) of white matter hyperintensities. Short (beta=0.03, SE=0.01; P=0.004) and long sleep (beta=0.07, SE=0.02; P<0.001) were associated with worse fractional anisotropy, while only long sleep associated with worse mean diffusivity (beta=0.05, SE=0.02; P=0.005). ConclusionsAmong middle-aged adults without clinically observed neurological disease, suboptimal sleep duration is associated with poorer neuroimaging brain health profiles. Because the evaluated neuroimaging markers precede stroke and dementia by several years, our findings support early interventions aimed at correcting this modifiable risk factor.

Background and ObjectivesWhite matter hyperintensities (WMHs) relate to cognitive and physical impairment. Although WMHs typically increase/progress with time, regression/decreasing has also been observed. We tested which baseline clinical phenotypes predict subsequent WMH volume change in UK Biobank (UKB). MethodsWe included participants with total volume of WMHs at first brain magnetic resonance imaging (MRI) and follow-up brain MRI. We assessed whether 107 pre-selected clinical phenotypes at baseline related to follow-up WMH volume change. We derived a measure of WMH change as the residual from a linear regression of follow-up WMH volume on baseline WMH volume. We pre-processed clinical phenotypes using PHESANT. We ran (i) linear regressions for continuous WMH change as the outcome and (ii) multinomial logistic regressions comparing progression, regression, and stable groups after categorising WMH volume change using a quintile-based approach. Models were unadjusted, partially adjusted (age, sex, total brain tissue volume, follow-up time), or fully adjusted (further adding blood pressure; BP). We corrected all P-values for multiple testing using false discovery rate (FDR) correction. ResultsWe included 4329 participants (median age=52; IQR=12), 54.6% female. Median follow-up was 2.3 years (range=1-7 years). On average, total brain volume decreased across follow-up (mean decrease=16,058 mm3) and WMH volume increased (median increase=293 mm3; both p<0.001). WMHs progressed in 53.9% of participants, regressed in 26.01%, and remained stable in 20%. Fully-adjusted associations with WMH increase included an increased risk of diabetes-related eye disease and higher diastolic BP (FDR-adjusted p<0.05). In group comparisons, progressors were older than regressors and stable individuals, on average. Regressors and progressors had higher BMI than the stable group. Regressors had the highest baseline WMH burden. In unadjusted models, progressors versus stable were more likely to have cataract and higher BP, while regressors had higher weight and systolic BP. These associations did not survive covariate adjustment. DiscussionWell-established vascular risk factors related to subsequent WMH volume change. Distinct clinical and demographic profiles characterized WMH progression, regression, and stable groups. Results suggest that vascular factors relate to WMH change but are sensitive to covariate control. Further studies should establish factors differentially related to WMH progression, regression, and stability.

Sleep is often disrupted after stroke. However, little is known about how stroke lesion extent or location influences sleep, particularly at the chronic stage of recovery. In this pragmatic study, we aimed to explore whether lesion characteristics could explain sleep variability in chronic stroke survivors. We analysed previously collected structural brain images (Magnetic Resonance Imaging) from 38 stroke participants (11 female, mean (SD) age 64 (12), mean (SD) time since stroke 95 (66) months) and sleep data (questionnaires (N=38, actigraphy (N=37), and electrophysiology (N=18)) which were collected in their home environment. Neither lesion volume nor lesion overlap with regions of interest (brainstem, basal ganglia, amygdala, hippocampus, thalamus) significantly predicted interindividual variability in subjective or objective sleep measures. However, a data-driven approach revealed clusters of voxels disconnected by the stroke lesions were linked to lower spindle density and amplitude (threshold free cluster enhancement p < 0.050). Overall, these results provide preliminary insights that lesion induced brain disconnection, rather than the extent and overlap of the lesion with grey matter regions, may be more informative when explaining sleep variability. However, larger prospective studies are needed to fully understand the effect of stroke lesions on sleep.

INTRODUCTIONSelf-reported sleep duration is associated with dementia-risk and vascular brain injury markers, including white matter hyperintensities (WMHs), yet how additional cerebrovascular pathology alters these relationships remains unclear. METHODIn a deeply-phenotyped cohort (735) including healthy and Alzheimers continuum individuals (subjective and mild cognitive impairment (MCI), dementia (AD), MCI and AD with high vascular burden (+V)), sleep was assessed using the Pittsburgh Sleep Quality Index. Individuals were classified as WMH-only or WMH+ (WMHs with microbleeds, infarcts, or cerebral amyloid angiopathy). Linear models tested interactions between sleep duration, WMH+ status, and diagnostic group on WMH burden and cognition. RESULTSIn MCI+V and AD, WMH+ significantly amplified the association between shorter sleep and greater WMH burden. In AD, longer sleep related to better cognition in WMH+, but worse cognition in WMH-only (exploratory). DISCUSSIONAdditional vascular brain injury modifies how sleep relates to WMH burden and cognition across the AD continuum, highlighting the importance of moving beyond WMHs alone.

Background and AimsEpilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predispositions role in post-acute brain injury epilepsy remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises post-stroke or Transient Ischemic Attack (TIA) survivors risk of Post-Stroke Epilepsy (PSE). MethodsWe conducted a three-stage genetic analysis. First, we identified independent epilepsy-associated (p<5x10-8) genetic variants from public data. Second, we estimated PSE-specific variant weights in stroke/TIA survivors from the UK Biobank. Third, we tested for an association between a polygenic risk score (PRS) and PSE risk in stroke/TIA survivors from the All of Us Research Program. Primary analysis included all ancestries, while a secondary analysis was restricted to European ancestry only. A sensitivity analysis excluded TIA survivors. Association testing was conducted via multivariable logistic regression, adjusting for age, sex, and genetic ancestry. ResultsAmong 19,708 UK Biobank participants with stroke/TIA, 805 (4.1%) developed PSE. Likewise, among 12,251 All of Us participants with stroke/TIA, 394 (3.2%) developed PSE. After establishing PSE-specific weights for 39 epilepsy-linked genetic variants in the UK Biobank, the resultant PRS was associated with elevated odds of PSE development in All of Us (OR:1.16[1.02-1.32]). A similar result was obtained when restricting to participants of European ancestry (OR:1.23[1.02-1.49]) and when excluding participants with a TIA history (OR:1.18[1.02-1.38]). ConclusionsOur findings suggest that akin to other forms of epilepsy, genetic predisposition plays an essential role in PSE. Because the PSE data were sparse, our results should be interpreted cautiously.

Chronic traumatic encephalopathy-neuropathologic change (CTE-NC) has been primarily studied in contact sport athletes with repetitive head impacts (RHI). An association with isolated traumatic brain injury (TBI) is less clear. We systematically reviewed the autopsied cohort of Late Effects of TBI (LETBI), characterized primarily by isolated TBI but also including RHI, for features of CTE-NC. A consecutive series of 44 brains underwent comprehensive neuropathologic evaluation, exceeding recommended CTE consensus protocols. Of the 44, 6 (13.6%) (age range, 3rd-7th decades; median, 6th decade) had CTE-NC, forming the basis for this exploratory analysis. Ex vivo neuroimaging (in 4 of 6) highlighted traumatic and white matter microvascular lesions, facilitating histological sampling of subtle neuropathologies that might otherwise have been missed by conventional sectioning. Macroscopically, 5 had cortical (contusional) and white matter (torsional) volume loss, with septal lesions and hydrocephalus ex vacuo (i.e., structural lesions of moderate-severe TBI). Microscopically, tau-immunopositive neuronal and astrocytic pathology in a perivascular arrangement within sulcal depths met current pathognomonic criteria for CTE-NC in 5 (3 "low" and 2 "high" burden); 1 had more limited findings considered "suspicious" for CTE-NC. Five of 6 cases with any CTE-NC reported substantial exposure to RHI, through contact sport ranging over at least 16 years. One case had no known exposure to RHI: this case (death: 6th decade) had 2 isolated severe TBIs (sustained 30y and 3y prior to death). Of note, one case with "high" CTE also had Alzheimer Disease Neuropathologic Change (high stage), Lewy Body Disease (limbic), and TDP43 accumulation ("polyproteinopathy"). Aging-related tau astrogliopathy, mostly subpial, was seen in 4 cases. Glial tau was also noted around old cavitary contusions in 2. These findings converge with prior studies demonstrating that CTE is largely associated with RHI and is infrequent among individuals with isolated TBI.

BackroundNearly all individuals with type 1 diabetes develop diabetic retinopathy over time, known to relate to cerebral small vessel disease. We investigated associations between early vascular changes in the eye and brain by optical coherence tomography angiography (OCTA) and brain magnetic resonance imaging (MRI) in middle-aged, neurologically asymptomatic individuals with type 1 diabetes. Research Design and MethodsIndividuals with type 1 diabetes (n=159, median age 48.0 years, diabetes duration 29.3 years, 53% female) and 49 healthy controls underwent clinical and biochemical assessments, brain MRI to evaluate cerebral microbleeds (CMBs) and white matter hyperintensities (WMHs), and macular 3x3 mm OCTA imaging to assess vessel densities of superficial (SCP) and deep (DCP) retinal capillary plexuses, and the area of the foveal avascular zone (FAZ). ResultsNo differences in OCTA parameters were observed between individuals with type 1 diabetes and healthy controls. However, SCP and DCP vessel densities (45.1% vs 46.5%, p=0.034, and 49.9% vs 52.9%, p<0.001, respectively), were smaller in individuals with type 1 diabetes with CMBs compared with those without. No such evidence was found for FAZ. In univariate linear regression models, SCP and DCP vessel densities were negatively associated with age, diabetes duration, blood pressure, kidney function (eGFR), number of CMBs, and WMHs. FAZ was related to diabetes duration, age of diabetes onset, and LDL cholesterol concentration. Of these, in multivariate models, diabetes duration remained associated negatively with vessel densities and positively with FAZ (SCP: standardized {beta} =-0.210 [p=0.014]; DCP: standardized {beta} =-0.275 [p<0.001]; FAZ: standardized {beta}=0.295 [p<0.001]). None of the retinal markers differed in individuals with or without WMHs and type 1 diabetes. ConclusionIn middle-aged, neurologically asymptomatic adults with long-standing type 1 diabetes, lower SCP and DCP vessel densities were associated with cerebral microbleeds, suggesting OCTA may aid cerebrovascular risk stratification but not WMH assessment. Research insightsO_ST_ABSWhat is currently known about this topic?C_ST_ABSNearly all individuals with type 1 diabetes develop diabetic eye disease within 30 years following the diagnosis. We observed previously that one third of neurologically asymptomatic individuals with type 1 diabetes have cerebral microbleeds in routine brain magnetic resonance imaging. Cerebral microbleeds were more common among those with advanced forms of diabetic eye disease. What is the key research question?To investigate associations between markers of cerebral small vessel disease and metrics of optical coherence tomography angiography among individuals with type 1 diabetes. What is new?Vessel densities of the macula were smaller among those individuals with type 1 diabetes and cerebral microbleeds. Vessel densities were negatively and area of the foveal avascular zone positively associated with duration of diabetes. How might this study influence clinical practice?OCTA may aid cerebrovascular risk stratification among individuals with long-standing type 1 diabetes

ImportanceUnderstanding the cognitive trajectory of a neurological disease can provide important insight on underlying mechanisms and disease progression. Cognitive impairment is now well established as beginning many years before the diagnosis of Alzheimers disease, but pre-diagnostic profiles are unclear for other neurological conditions that may be associated with cognitive impairment. ObjectiveCompare pre-diagnostic and post-diagnostic cognition and global brain volume in ischaemic stroke, focal epilepsy, Parkinsons disease, multiple sclerosis, motor neurone disease (amyotrophic lateral sclerosis) and migraine using time-to-diagnosis and time-from-diagnosis data in relation to time of assessment. DesignAnalysis the prospective UK Biobank cohort with study baseline assessment performed between 2006-2010 and participants followed until 2021. SettingMulticenter, population-based study. ParticipantsSample of 497,252 participants, aged between 38 and 72 years, at baseline with an imaging sub-sample of 42,468 participants. ExposureParticipants with each neurological condition were compared to a healthy control group. Main outcomes and measuresA continuous measure of executive function and magnetic resonance imaging brain measures of total grey matter and hippocampal volume. ResultsOf the 497,252 participants (226,206 [45.5%] men, mean [SD] age, 57.5[8.1] years), 12,755 had ischaemic stroke, 6,758 had a diagnosis of focal epilepsy, 3,315 had Parkinsons disease, 2,315 had multiple sclerosis, 559 had motor neurone disease and 18,254 had migraine either at study baseline or diagnosed during the follow-up period. Apart from motor neurone disease, all conditions had lower pre-diagnosis executive function compared to controls (assessment performed median 7.4 years before diagnosis). Participants with focal epilepsy and multiple sclerosis showed a gradual worsening in executive function up to 15 years prior to diagnosis, while ischaemic stroke was characterised by a modest decline for a few years followed by a substantial reduction at the time of diagnosis. By contrast, participants with migraine showed improved post-diagnosis cognitive scores. Pre-diagnosis MRI grey matter volume was lower than controls for stroke, Parkinsons disease and multiple sclerosis (scans performed median 1.7 years before diagnosis), while other conditions had lower volumes post-diagnosis. ConclusionThese cognitive trajectory models reveal disease-specific temporal patterns, including a long cognitive prodrome associated with focal epilepsy and multiple sclerosis. The findings may help to prioritise risk management of individual diseases and inform clinical decision-making. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the pre-diagnosis cognitive profile across neurological conditions of ischaemic stroke, focal epilepsy, Parkinsons disease, multiple sclerosis, motor neurone disease and migraine? FindingsThis cohort study of 495 149 participants, aged between 38 and 72 years, identified gradual worsening of cognition up to 15 years prior to clinical diagnosis in participants with focal epilepsy and multiple sclerosis while stroke was associated with a modest decline for a few years followed by a substantial reduction at the time of diagnosis. Migraine was associated with post-diagnosis improvement in cognitive scores. MeaningCognitive trajectory models identify disease-specific temporal patterns that may help to prioritise risk management of individual diseases and inform clinical decision-making.

BackgroundSleep-wake disruption is common after stroke and may impede recovery. The Sleep Regularity Index (SRI) quantifies the probability that a person is in the same sleep or wake state at the same clock time on consecutive days. This study evaluates SRI during post-stroke recovery, estimating associations with stroke outcomes, and characterizing transitions between SRI states over time. MethodsWe analyzed data from 71 participants that were part of a larger on-going study exploring the impact of non-OSA sleep disorders post stroke. Data were collected at 10, 60, and 90 days post stroke. SRI was calculated from sleep-wake data that was collected from wrist worn actigraphy. Covariates included time, National Institutes of Health Stroke Scale (NIHSS), Stroke Impact Scale (SIS), steps/day, sedentary time/day, and Patient Health Questionnaire 9. Associations between SRI and covariates were estimated using generalized estimating equations. A logistic regression model was used to assess whether clinical variables were associated SRI improvement at 60 days. ResultsSRI was low at 10 days post stroke (32.68) and did not significantly change at 60 (34.01, p=0.98) or 90 (38.44, p=0.57) days post stroke. SRI was significantly associated with NIHSS (p=0.04) and SIS (p=0.02). Improvement in SRI was significantly associated with NIHSS (p=0.03). ConclusionsThis is the first study that we are aware of to investigate sleep regularity early after stroke. We found that sleep regularity was associated with QOL and stroke severity, and that sleep regularity did not improve after discharge from the hospital. Clinical Trial Registration: NCT05012605.

Persistent Postural-Perceptual Dizziness (PPPD) is among the most prevalent chronic neuro-otologic disorders, affecting 15-20% of adults seen in neurology and specialized dizziness clinics. Classified as a functional vestibular disorder and defined by established diagnostic criteria, PPPD typically follows peripheral or central otoneurological disorders. However, the mechanisms underlying the transition from these disorders to chronic perceptual dizziness remain unclear. Beyond maladaptive postural control and visual dependence, theoretical models implicate altered multisensory integration and disrupted predictive processing. Such mechanisms may extend to disturbances of the bodily self, a dimension increasingly recognized in functional neurological disorders, but not yet systematically investigated in PPPD. We characterized bodily self disturbances in PPPD by assessing depersonalization-derealization symptoms in a large cross-sectional study (n = 455), including 100 patients with PPPD, 180 patients with other otoneurological disorders, and 175 healthy controls. Depersonalization-derealization symptoms were assessed using the Cambridge Depersonalization Scale, alongside measures of anxiety, depression, dizziness-related impairment, and PPPD symptom severity. PPPD patients exhibited markedly elevated depersonalization-derealization symptoms compared to both other otoneurological disorders and healthy controls (all P < 0.001). Notably, 20% of PPPD patients met the threshold for clinical depersonalization-derealization, compared with 7.2% of other otoneurological disorders and <1% of controls. Depersonalization-derealization severity in PPPD overlapped with levels observed in other functional neurological disorders but remained lower than in primary dissociative disorders. Factor analyses identified three depersonalization-derealization dimensions: Bodily Self Disturbances, Cognitive and Affective Detachment, and Numbing. Only Bodily Self Disturbances, capturing disruptions in self-location, agency, body ownership, and first-person perspective, robustly differentiated PPPD from other otoneurological disorders ({superscript 2} = 0.20, P < 0.001). This dimension predicted PPPD diagnosis (odds ratio = 1.40, P < 0.001), and showed significant discriminative ability (AUC = 0.66). Individuals in the highest decile of Bodily Self Disturbances had nearly tenfold increased odds of PPPD. Structural equation modelling confirmed a direct effect of PPPD on Bodily Self Disturbances, partially mediated by depressive symptoms but independent of age, sex, migraine, and anxiety. These findings identify depersonalization-derealization as a previously unrecognized component of the PPPD phenotype and establish bodily self disturbances as a novel clinical marker for PPPD, refining phenotyping and informing pathophysiological models.

BackgroundStenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small vessel disease (cSVD) remain contentious. We investigated associations of large artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. MethodsWe prospectively recruited patients with lacunar or mild non-lacunar stroke, with demographic, stroke-related, cognitive, functional, and MRI (index and incident infarcts, cSVD markers) assessments at baseline and one year. LAS was defined as [&ge;]50% intracranial or cervical artery stenosis; basilar artery dolichoectasia (BADE) by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated using multivariable regression adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large artery pathology and cSVD. ResultsAmong 229 patients (mean age 65.9{+/-}11.1 years; 131 [57.2%] lacunar stroke), LAS and BADE were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio [OR], 0.49; 95%CI, 0.23-0.99) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, BADE was strongly associated with lacunar stroke (OR, 4.67; 95%CI, 1.87-13.14), higher cSVD scores (ordinal analysis; OR, 2.57; 95%CI, 1.28-5.25), incident infarcts (75% subcortical; OR, 2.29; 95%CI, 1.01-5.14), and greater progression of white matter hyperintensities over one year ({beta}, 0.15; 95%CI, 0.01-0.29; per log10-transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. ConclusionscSVD, including lacunar stroke, was unrelated to LAS, but strongly associated with dolichoectasia and wider arteries. These findings support a non-atheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABS[bullet] Large artery stenosis was unlikely to represent a causal mechanism for lacunar stroke and showed no association with cerebral small vessel disease (cSVD) imaging markers. [bullet]Dolichoectasia and intracranial arterial widening emerged as vascular phenotypes strongly associated with cSVD, including its progression and lacunar stroke subtype. What Are the Clinical Implications?[bullet] Distinct large artery phenotypes have divergent etiopathological implications for cSVD. Our findings support a non-atheromatous, intrinsic microvascular pathology as the principal mechanism of lacunar stroke and cSVD. [bullet]Mechanism-based therapeutic strategies for lacunar stroke and cSVD, moving beyond conventional approaches focused on atherosclerosis or cardioembolism, are warranted.

Structured abstractO_ST_ABSImportanceC_ST_ABSBrain health may facilitate resilience to detrimental consequences from neurological diseases. Infarct volume is associated with poor functional outcome after acute ischemic stroke (AIS), but potential mediating effects through stroke-related brain health loss have not been investigated. ObjectiveTo determine whether stroke-related brain health loss, quantified by change in MRI derived effective Reserve (eR), mediates the effect of acute infarct volume on functional outcome after AIS. DesignObservational multicenter cohort study. SettingWe analyzed data from the GASROS (n=488) and MRI-GENIE (n=560) cohorts, collected 2003-2011. ParticipantsAdult patients consecutively diagnosed with AIS, with available admission MRI. ExposureAt admission, white matter hyperintensity (WMH) and normal-appearing brain volumes were assessed on T2-FLAIR, and acute infarct volume on diffusion weighted imaging. WMH was normalized by brain volume, creating WMH load. We quantified brain health using eR, a latent variable incorporating age, WMH load, and normal-appearing brain volume. {Delta}eR reflected the change in eR when acute infarct volume was included, representing stroke-related brain health decline. Mediation analysis was used to determine if {Delta}eR mediates the effect of infarct volume on functional outcome (modified Rankin Scale [mRS] at 90 days). Main Outcome MeasureProportion of mediating effect. ResultsWe included 1,048 patients (median age 67y, 38% females). At baseline, median NIHSS score was 3 (IQR 1-7), median infarct volume 3.1mL (IQR 0.9-15.5). At 90 days, median mRS score was 1 (IQR 1-3) and 51 (5%) patients had died. In mediation analysis, {Delta}eR significantly mediated 36% (95% CI 16-56%) of the total effect of infarct volume on functional outcome (direct effect ({beta}=0.15 [95% CI 0.09-0.22], p<0.001; indirect effect mediated through {Delta}eR: {beta}=0.09 [95% CI 0.04 to 0.14], p=0.001). In subgroup-analyses, the mediative effect was apparent among female but not male, and among patients aged >67y but not [&le;]67y. Conclusions and RelevanceStroke-related structural brain health loss mediates about one third of the effect of acute infarct volume on functional outcome after ischemic stroke, with important sex and age differences. Brain health significantly influences outcome and recovery potential, and may be considered a key biomarker when modeling outcome after AIS. Key pointsO_ST_ABSQuestionC_ST_ABSDoes brain health loss associated with acute ischemic stroke mediate the relationship between acute infarct volume and functional outcome? FindingsIn this observational multicenter cohort study of 1,048 patients, mediation analysis suggests that reduction of the brain health MRI marker effective Reserve mediates 36% (95% CI 16-56%) of the total effect of acute infarct volume on functional outcome. The proportion of mediative effect was more pronounced among female compared to male and in older compared to younger patients. MeaningBrain health loss mediates one third of the effect of acute infarct volume on functional outcome after ischemic stroke.

INTRODUCTIONThe amyloid cascade hypothesis predicts that amyloid-beta (A{beta}) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between A{beta}40 and A{beta}42 and total Tau (t-Tau) plasma biomarkers. METHODSPlasma A{beta}40, A{beta}42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between A{beta}s and t-Tau. RESULTSNo clear evidence that A{beta}40 or A{beta}42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the A{beta} biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSIONPlasma A{beta}40 or A{beta}42 do not appear to have a direct causal impact on t-Tau. In contrast, A{beta} aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

BackgroundChronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. MethodsPatients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. ResultsSixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. ConclusionCRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.

BackgroundAlmost all biological and disease processes are influenced by circadian clocks and display [~]24-hour rhythms. Disruption of these rhythms may be an important novel risk factor for stroke. We evaluated the association between 24-h rest-activity rhythm measures, stroke risk, and major post-stroke adverse outcomes. MethodsIn this cohort study, we examined [~]100,000 participants in the UK Biobank (44-79 years old; [~]57% females) who underwent an actigraphy (6-7 days) and 5-year median follow-up. We derived: (1) most active 10 hours activity counts (M10) across the 24-h cycle and the timing of its midpoint (M10 midpoint); (2) the least active 5 hours counts (L5) and its midpoint timing (L5 midpoint); (3) relative amplitude (RA) - (M10-L5)/(M10+L5); (4) interdaily stability (IS): stability and (5) intradaily variability (IV), fragmentation of the rhythm. Cox proportional hazard models were constructed for time to (i) incident stroke (n=1,652); and (ii) post-stroke adverse outcomes (dementia, depression, disability, or death). ResultsSuppressed RA (lower M10 and higher L5) was associated with stroke risk after adjusting for demographics; the risk was highest in the lowest quartile [Q1] for RA (HR=1.62; 95% CI:1.36-1.93, p<0.001) compared to the top quartile [Q4]. Participants with later M10 midpoint timing (14:00-15:26, HR=1.26, CI:1.07-1.49, p=0.007) also had a higher risk for stroke than earlier (12:17-13:10) participants. A fragmented rhythm (IV) was also associated with a higher risk for stroke (Q4 vs. Q1; HR=1.27; CI:1.06-1.50, p=0.008), but differences in the stability of rhythms (IS) were not. Suppressed RA was associated with an increased risk of unfavorable post-stroke outcomes (Q1 vs. Q4; 1.78 [1.29-2.47]; p<0.001). All the associations were independent of age, sex, race, obesity, sleep disorders, cardiovascular diseases or risks, and other morbidity burdens. ConclusionSuppressed 24-h rest-activity rhythm may be a risk factor for stroke and an early indicator of major post-stroke adverse outcomes.

Background and ObjectivesVarious peripheral neuropathies, particularly those with sensory and autonomic dysfunction may occur during or shortly after acute COVID-19 illnesses. These appear most likely to reflect immune dysregulation. If similar manifestations can occur with the vaccination remains unknown. ResultsIn an observational study, we studied 23 patients (92% female; median age 40years) reporting new neuropathic symptoms beginning within 1 month after SARS-CoV-2 vaccination. 100% reported sensory symptoms comprising severe face and/or limb paresthesias, and 61% had orthostasis, heat intolerance and palpitations. Autonomic testing in 12 identified seven with reduced distal sweat production and six with positional orthostatic tachycardia syndrome. Among 16 with lower-leg skin biopsies, 31% had diagnostic/subthreshold epidermal neurite densities ([&le;]5%), 13% were borderline (5.01-10%) and 19% showed abnormal axonal swelling. Biopsies from randomly selected five patients that were evaluated for immune complexes showed deposition of complement C4d in endothelial cells. Electrodiagnostic test results were normal in 94% (16/17). Together, 52% (12/23) of patients had objective evidence of small-fiber peripheral neuropathy. 58% patients (7/12) treated with oral corticosteroids had complete or near-complete improvement after two weeks as compared to 9% (1/11) of patients who did not receive immunotherapy having full recovery at 12 weeks. At 5-9 months post-symptom onset, 3 non-recovering patients received intravenous immunoglobulin with symptom resolution within two weeks. ConclusionsThis observational study suggests that a variety of neuropathic symptoms may manifest after SARS-CoV-2 vaccinations and in some patients might be an immune-mediated process.

Background and objectivesNew onset persistent headache has been reported following acute COVID-19 and to some degree also after SARS-CoV-2 vaccination. The mechanisms for these headache types are unclear. The purpose of this study was to assess levels of amyloid related biomarkers in patients with persistent headache after COVID-19 and SARS-CoV-2 vaccine. MethodsIn this prospective observational cohort, patients with severe headache as the dominating symptom after COVID-19 (n=29) and SARS-CoV-2 vaccination (n=31), had neurological assessments with reassessments after 6 months. Plasma levels of amyloid precursor protein (APP), pregnancy zone protein (PZP), cathepsin L1 (CTSL) and serum Amyloid A (SAA1) were measured by ELISA in relation to levels in healthy controls (n=16). ResultsWe found a strong and persistent upregulation of APP in patients with headache after COVID-19 as compared to the two other groups. At both inclusion and after 6 months APP levels were also increased in those with accompanying cognitive symptoms. In contrast, plasma levels of PZP were elevated in patients with headache after SARS-CoV-2 vaccination at both inclusion and after 6 months as compared to healthy controls. CTSL was only elevated in those with COVID-19 associated as compared with those with vaccine associated headache at baseline, whereas SAA1 showed levels comparable in all groups. ConclusionAltered plasma levels of soluble markers potentially reflecting changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 where we also found some association with cognitive symptoms. NCT04576351 NCT05235776 What is already known on this topicNew onset persistent headache occurs in a subset of individuals after COVID-19 and to some extent after SARS-CoV-2 vaccine. However, the pathophysiological mechanisms are unknown. What this study addsAltered plasma levels of soluble markers that potentially could reflect changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 with association to cognitive symptoms. How this study might affect research, practice or policyOur data underscore the need for more long-time follow-up of patients with new onset headache following COVID-19 or SARS-CoV-2 vaccination and this follow-up might also include blood tests for amyloid processing and neuroinflammation.

ObjectivesTo characterize the survival of individuals with pathogenic PRNP variants -- including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. MethodsIn this single center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the U.S. National Prion Disease Pathology Surveillance Center (NPDPSC). Genetic test results and autopsy status were queried from the NPDPSC database, and public record searches were conducted using online tools. Results404 individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated sensitivity of 92.6%. Of 111 autopsied individuals, evidence of death was found in public record searches for 109, a sensitivity of 98.2%. Of 198 individuals who were asymptomatic at the time of testing, 32 since died of definite or possible prion disease. Among 20 of these who underwent autopsy, public record searches confirmed deaths of 18, for a sensitivity of 90%. Among 99 E200K individuals over 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. No significant difference was found for D178N, which appears highly penetrant, though the median age at death was numerically higher than seen in retrospective data. V210I was associated with just 2 deaths, both after age 90, consistent with minimal penetrance. DiscussionThese data support the accuracy of penetrance classifications for PRNP variants reported based on retrospective data, but may suggest an age of onset distribution shifted slightly later than that calculated retrospectively. Autopsy data and public death records in combination were sensitive and concordant, but additional prospective data should be gathered to support future preventive trials.

A prominent radiological manifestation of cerebral amyloid angiopathy (CAA) is enlargement of perivascular spaces (EPVS), which is suggested to result from fluid stagnation due to impaired perivascular clearance. Here, we report a novel observation of hypointense rims in cerebral white matter surrounding EPVS near haemorrhages on in vivo 7T Gradient Echo MRI. We hypothesised that the observed black rim pattern denotes iron accumulation that may be caused by incomplete clearance following bleeding. We investigated the occurrence and localisation of this marker on in vivo and ex vivo MRI and examined its histopathological correlates. From MRI data of the prospective longitudinal natural history study of hereditary Dutch-type CAA (D-CAA) at Leiden University Medical Centre, we selected the first 20 consecutive patients who underwent 7T imaging and assessed the presence of black rims on MRI. Post-mortem material was available from one donor with black rims on in vivo scans. Formalin-fixed coronal brain slabs were scanned at 7T MRI, including a high-resolution T2*-weighted sequence. Guided by ex vivo MRI, tissue blocks from representative areas with black rims were sampled for histopathological analysis. Serial sections were stained for iron, calcium, myelin, and general tissue morphology. On in vivo 7T MRI, 9 out of 20 participants exhibited one or several black rims, all located close to a haemorrhage. In the D-CAA donor, ex vivo MRI signal loss matched the in vivo contrast changes. Thirty-six vessels with ex vivo-observed black rims were retrieved and histopathologically examined, showing iron accumulation surrounding perivascular spaces, but the pattern and severity of iron deposition varied. Across groups, vessels displayed microvascular degeneration, including hyaline vessel wall thickening, adventitial fibrosis, and perivascular inflammation. We identified black rims on in vivo 7T MRI and confirmed their correspondence on ex vivo imaging. Iron deposition was determined as the underlying correlate of black rims, but the histopathology appears heterogeneous. The preferential deposition of iron around EPVS may indicate incomplete clearance of iron-positive blood-breakdown products after bleeding. The varied pattern of iron accumulation and microvascular alterations may reflect different pathophysiological mechanisms related to the formation and maintenance of black rims in D-CAA.

ImportanceExecutive function impairments are highly prevalent post-stroke and are a feature of vascular dementia. Computed tomography (CT) neuroimaging is routinely acquired in clinical settings. Therefore, determining the prognostic utility of CT-derived markers for post-stroke cognitive outcomes is of key clinical and academic interest. ObjectiveTo determine whether post-stroke executive function is associated with stroke-related white matter damage and/or white matter hypoattenuations of presumed vascular origin (WMHs) on routine CT brain scans. DesignRetrospective cross-sectional analysis of data collected within the Oxford Cognitive Screening (OCS) programme (2016-2020). SettingPatients were recruited at Oxford University Hospitals acute stroke unit. Follow-up cognitive assessment was conducted six-months post-stroke at patients homes. ParticipantsOCS programme recruited a consecutive patient sample with a confirmed diagnosis of stroke, who were minimum 18 years old, able to remain alert for 20 minutes, and able to provide informed consent. This study included all patients who completed six-month follow-up assessment with the Oxford Cognitive Screen-Plus (OCS-Plus) and had a usable acute CT scan with a visible stroke lesion. Main Outcome and MeasuresAssociation between post-stroke executive function and both stroke-specific white matter damage and WMHs on routine CT. Executive function was evaluated using the OCS-Plus Rule Finding task. Stroke lesions were manually delineated on CT, and stroke-related white matter damage was quantified then dichotomised using the HCP-842 atlas. WMHs were visually rated using the Age-Related White Matter Changes scale and dichotomised as present or absent. ResultsAmong 87 stroke patients (mean/SD age = 73.60/11.75; 41 female; 61 ischaemic stroke), multivariable linear regression analyses demonstrated that poorer executive function six-months post-stroke was associated with both stroke damage to the medial lemniscus (B= - 8.86, p< .001, 95% CI [-13.29 -4.43]) and the presence of WMHs (B= -5.42, p= .005, 95% CI [-9.12 -1.72]), after adjusting for covariates including age and education. Conclusions and RelevancePoorer post-stroke executive functioning was associated with both localised patterns of stroke-specific white matter damage and white matter degeneration. Our results confirm the necessary role of white matter integrity for executive functioning post-stroke and highlight the prognostic utility of CT-derived neuroimaging markers for long-term post-stroke cognitive outcomes.