Neurology

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.

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.

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.

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.

BackgroundLarge middle cerebral artery (MCA) infarctions can result in life-threatening cerebral edema. Quantitative brain atrophy may improve risk stratification for severe edema. We examined whether quantitative brain atrophy is associated with severe midline shift after large ischemic stroke and whether incorporating atrophy improves prediction beyond established clinical and radiographic predictors. MethodsThis was a retrospective observational cohort study of patients with [&ge;][1/2] MCA ischemic infarction, presentation within 24 hours of last known well, and at least one follow-up head CT, admitted to two academic hospitals with comprehensive stroke centers between 2006 and 2024. The study was approved by the institutional review boards of both centers. Brain atrophy was quantified as the inverse of standardized brain volume on admission head CT. The primary outcome was severe radiographic mass effect, defined as midline shift [&ge;]5 mm on follow-up CT. The secondary outcome was in-hospital mortality. Multivariable regression models assessed associations between quantified atrophy and outcomes. Incremental prognostic value was evaluated by comparing models with and without atrophy using measures of goodness of fit, calibration, and discrimination. ResultsAmong 565 patients (mean age 67.5{+/-}15.7 years; 49.9% female), 223 (39.5%) developed severe mass effect. Greater atrophy was associated with lower odds of midline shift [&ge;]5 mm (OR 0.44, 95% CI 0.34-0.58), but not with in-hospital mortality. Incorporation of atrophy significantly improved prediction of severe mass effect compared to the baseline model (likelihood ratio test {chi}{superscript 2} (1) = 41, p <0.001; AIC 703 vs. 741; BIC 733 vs. 767; AUC 0.68 vs. 0.60). ConclusionsQuantified brain atrophy is independently associated with a reduced risk of severe mass effect after large MCA stroke and improved the performance of established predictive models. Incorporation of this imaging biomarker may enhance early risk stratification, monitoring, and intervention planning for patients at risk of life-threatening cerebral edema.

OBJECTIVETo assess differences in the severity of Alzheimers disease neuropathological changes in disease epicenters of patients with logopenic variant PPA (lvPPA) with a history of learning differences/developmental dyslexia (LD) versus lvPPA patients without such history (non-LD). BACKGROUNDLearning differences, including developmental dyslexia, are overrepresented in the lvPPA population. It is not known whether a history of developmental differences is associated with a more severe phenotypic expression of Alzheimers disease pathology. DESIGN/METHODSWe quantified the cortical area fraction of phospho-tau immunohistochemistry (IHC) and beta-amyloid IHC in the angular gyrus and superior temporal gyrus of postmortem brains of 15 cases of lvPPA secondary to Alzheimers disease of which 9 non-LD cases (2 males and 7 females), and 6 LD cases (2 males and 4 females). Histological sections were digitally acquired, and foreground IHC-signal was automatically separated and thresholded to quantify the respective tau and beta-amyloid area fractions in each region. RESULTSThere were no differences in the mean age at death between the two groups. Disease duration was longer in the LD group (10.7 {+/-} 1.2 years) than in the non-LD group (8.1 {+/-} 0.8 years), p=0.09. When corrected for sex, age at death and Apo E4 carrier status, the LD group showed higher tau pathology burden in the superior temporal gyrus compared to the non-LD group (0.91% {+/-} 0.37, p=0.03). No differences in tau pathology burden between the groups were observed in the angular gyrus (0.39% {+/-} 0.41, p=0.37). There were no statistically significant differences in the area fraction of beta-amyloid between the two groups of patients in both the angular gyrus and the superior temporal gyrus. CONCLUSIONSOur data suggest that patients with lvPPA secondary to Alzheimers disease and a history of developmental differences have higher tau-pathology burden in the superior temporal gyrus compared to lvPPA-AD patients without such history.

BackgroundTheory of Mind (ToM) deficits are well-documented in right-hemisphere stroke but remain understudied in post-stroke aphasia. Prior work suggests that performance on tasks assessing ToM may be relatively preserved in aphasia and dissociable from language impairment, but these findings are based largely on small studies. This study examined performance on nonverbal false-belief tasks in post-stroke aphasia, its relationship with aphasia severity, and whether vascular brain health, operationalized using cerebral small vessel disease (CSVD) markers, contributed to variability in performance. MethodsForty-four individuals with aphasia completed two nonverbal belief-reasoning tasks assessing spontaneous perspective-taking and self-perspective inhibition. Task accuracy served as the primary outcome. Linear regression models examined associations between task performance, aphasia severity (Western Aphasia Battery-Revised Aphasia Quotient), and CSVD markers, including white matter hyperintensities, cerebral microbleeds, lacunes and enlarged perivascular spaces in the basal ganglia and centrum semiovale. ResultsPerformance was heterogeneous across tasks, with reduced performance observed in 23% of participants on the Reality-Unknown task and 36% on the Reality-Known task. Aphasia severity was not associated with task accuracy. Greater cerebral microbleed count was associated with lower accuracy on both tasks, while greater basal ganglia enlarged perivascular spaces burden showed a more selective association with lower performance. ConclusionsPerformance on nonverbal false-belief tasks in aphasia is variable and not explained by aphasia severity alone. These findings suggest that apparent ToM-related difficulties in aphasia may be shaped by broader vascular brain health, supporting a more multidimensional framework for interpreting social-cognitive task performance after stroke.

Background / ObjectivesWe investigated whether the interthalamic adhesion (IA), a midline structure connecting the thalami, is altered in MS and associated with thalamic damages and cognition. MethodsWe prospectively included 32 clinically isolated syndrome/early MS, 31 RRMS, 31 PPMS patients, and 103 matched controls. All underwent anatomical 3T MRI and completed a comprehensive cognitive battery. IA presence, subtype, and volume were assessed by two blinded readers. Thalamic nuclei and other brain structures were segmented automatically. We compared IA subtypes/volumes across groups, analyzed their predictors and explored cognitive associations with multivariate regressions. ResultsIA prevalence did not differ between MS and controls (81.9% vs 74.7%). MS patients showed a shift toward a short IA subtype and reduced IA volume (mean [SD], 146.8 [117.9] vs 230.2 [138.2] mm3; p<0.0001), worsening across phenotypes. Reduced IA volume was independently associated with medial and posterior thalamic nuclei volumes, but not with white matter lesion load or global atrophy. Among cognitive domains, smaller IA volume was independently associated only with executive dysfunction (OR = 0.89 [0.77-0.99], p = 0.021). ConclusionIA volume reduction in MS reflects vulnerability of adjacent thalamic nuclei and is associated with executive dysfunction, supporting IA as a marker of thalamic neurodegeneration. Trial RegistrationMICROSEP: NCT03692975; AUBACOG: NCT03768648; PROCOG: NCT03455582.

INTRODUCTIONSleep disturbance is common across the Alzheimers disease (AD) spectrum, yet the structural substrates linking sleep disruption and cognitive decline remain unclear. The hypothalamus regulates sleep-wake function and is affected by AD pathology, but its role across clinical stages is poorly defined. METHODS672 older adults classified as subjective cognitive decline, single- and multi-domain mild cognitive impairment, or probable AD underwent structural MRI. Subjective insomnia measures were available for the full cohort, and 209 underwent polysomnography. Associations between hypothalamic volume, sleep architecture, and cognition were examined. RESULTSHypothalamic volume declined progressively from SCD to MD-MCI and AD, with the greatest reductions in anterior subregions. Smaller hypothalamic volume associated with diminished slow-wave sleep, lower REM sleep in SD-MCI, poorer neuropsychological functions, and moderated the association between hippocampal volume and memory. CONCLUSIONHypothalamic atrophy emerges along the AD continuum, and relates to specific alterations in sleep quality and cognition.

Importance: NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ~165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective: To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants: This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure: Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures: Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results: 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance: NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.

Migraine is a common and disabling neurological disorder linked to alterations in neuronal activity and waste clearance in the brain. MRI-visible perivascular spaces (PVS) are key components of the glymphatic system which may serve as imaging biomarker of such disorder. We hypothesised that higher frequency of migraine episodes would be associated with increased PVS burden, reflecting greater levels of impaired glymphatic clearance. In this retrospective case-control study of 90 participants (20 episodic migraineurs, 18 chronic migraineurs, and 52 age- and sex-matched healthy controls; 58 females, median [Q1, Q3] age=28.6 [25.1, 39.4] years) we investigated PVS alterations in episodic migraineurs (n=20) and 18 chronic migraineurs (n=18). PVS volumes and cluster counts were quantified in the white matter (WM), basal ganglia (BG), midbrain, and hippocampus. We stratified PVS metrics by white matter lobes and arterial vascular territories. After adjusting for age, sex, and total brain volume, episodic migraineurs exhibited significantly lower BG-PVS volumes (exp({beta})=0.76, 95%CI [0.61, 0.94], p=0.01) compared to controls. Chronic migraineurs exhibited significantly lower PVS cluster counts in the parietal (exp({beta})=0.8, 95%CI [0.68, 0.94], p=0.01) and temporal lobes (exp({beta})=0.72, 95%CI [0.53, 0.96], p=0.03) and middle cerebral artery territory (exp({beta})=0.82, 95%CI [0.68, 0.97], p=0.03) compared to healthy controls. Within migraineurs, those with aura (n=20) exhibited significantly lower PVS burden in all brain regions, vascular territories, and across the frontal, parietal, and temporal lobes (all pFDR<0.05). Our findings suggest that the aura symptom, rather than the migraine disorder itself, may primarily drive changes in perivascular spaces, with effects varying across brain regions.

ObjectivesFunctional neurological symptoms which do not meet clinical definitions of functional neurological disorder (FND) are common in clinical practice. Understanding the distinction between these benign functional symptoms and FND is crucial in defining FND as an entity for study, and as a clinical syndrome. We aimed to measure the frequency of functional symptoms in people who do not have FND. MethodsA survey was administered to 95 clinicians who attended an international conference on FND. Participants were asked to report the occurrence and characteristics of experiences with features of functional sensory or motor symptoms, or dissociation. ResultsOf the 95 people who responded to the survey, 57.4% reported having experienced any functional symptoms, and 47.9% reported having experienced functional motor or sensory symptoms. The symptoms reported were generally short-lived and caused only mild distress and disruption. Most respondents who reported having experienced a functional symptom reported having had multiple events through their lives. InterpretationThe results suggest that the lifetime occurrence of functional neurological symptoms is at least two orders of magnitude higher than the prevalence of FND. The high prevalence of functional symptoms in people who have never had FND challenges the common assumption that the occurrence of functional neurological symptoms is synonymous with FND. We propose that FND is better conceived of as a failure of the mechanisms by which functional neurological symptoms resolve, rather than the occurrence of functional symptoms per se. This reconceptualization implies new research directions for the underlying aetiology of FND.

ImportancePrognosticating functional independence after an acute stroke is critical for anticipatory guidance and rehabilitation planning. Here we demonstrate that poor brain health at the time of incident stroke is linked to worse functional outcomes for women compared to men. ObjectiveTo determine if brain health at time of stroke presentation has a differential effect on functional outcomes between men and women. DesignRetrospective cross-sectional study. SettingAnalysis conducted in 2025 with multi-center patient data that included participants from two large acute ischemic stroke cohorts; local (GASROS) and multinational (MRI-GENIE) between the years 2003 and 2011. ParticipantsClinical data collected for enrolled study participants included demographic data, medical history of hypertension, diabetes mellitus, hyperlipidemia, smoking status, acute stroke severity as measured by National Institutes of Health Stroke Scale (NIHSS), stroke etiology, and modified Rankin Scale (mRS) score at 90 days post-stroke. Brain health was quantified as effective reserve derived from acute neuroimaging data. Exposure(s)designated sex, retrieved from registration records. Main OutcomeFunctional outcome was measured by mRS scores at 90 days post-stroke, in men and women with poor, moderate, or good brain health at time of stroke injury. ResultsA total of 1039 patients were included in the analysis, 37.8 % women, median age 67 [interquartile range 56-77]. Women with poor brain health (i.e. lowest quartile of effective reserve) had worse functional outcomes at 90 days (55.6% with mRS>2) compared to men with poor brain health (31.2% with mRS>2: p < 0.001). This difference between men and women was not observed in categories of moderate or good brain health. There was no observed significant difference in stroke severity, volume of acute lesion, burden of white matter hyperintensities, or stroke etiology between men and women with poor brain health. Conclusions and RelevanceBrain health at the time of incident stroke has a differential effect on functional outcomes at 90 days between men and women. Women with poor brain health endure disproportionately worse outcomes compared to men. This highlights an important step in understanding sex-specific vulnerability in early recovery post-stroke, and can inform disposition, rehabilitation services, and resource allocation planning.

BackgroundDopa-responsive dystonia is caused by pathogenic variants in the GCH1 gene. Although its clinical features and reduced penetrance are known, in vivo metabolic and structural alterations in symptomatic (sMC) and asymptomatic mutation carriers (aMC) remain poorly understood. ObjectivesTo characterize volumetric and neurometabolic brain changes of GCH1 mutation carriers and explore their relationship with clinical severity. MethodsWe studied 20 sMC, 5 aMC, and 25 mutation-free healthy controls (HC) using volumetric MRI combined with 31phosphorus magnetic resonance spectroscopy imaging (31P-MRSI) of the basal ganglia and cerebellum. ANCOVA was used for group comparisons, and correlations were assessed with clinical symptom severity rating scales. ResultsVolumetric analyses revealed enlarged globus pallidus (+16.6%, p = 0.001) and putamen (+7.2%, p = 0.031) volumes in carriers and increased cerebellar gray matter in aMC (+8.0%, p = 0.050). NAD levels were significantly reduced in the basal ganglia of carriers (NAD/Pi: -14.7%, p = 0.046; NAD/ATP-: -15.5%, p = 0.018). In the cerebellum, aMC demonstrated elevated high-energy phosphate ratios ((ATP-+PCr)/Pi: +23.7%, p = 0.017; ATP-/Pi: +21.3%, p = 0.046; PCr/Pi: +25.2%, p = 0.009) compared with sMC and HC. Smaller cerebellar volumes correlated with greater dystonia severity (BFMDRS, {rho} = -0.475, p = 0.019) while lower basal ganglia NAD ratios correlated with higher MDS-UPDRS-III ({rho} = -0.472, p=0.041) and TWSTRS scores ({rho} = -0.477, p = 0.039). Conclusions31P-MRSI and volumetric MRI reveal region- and subgroup-specific metabolic and structural alterations in GCH1 mutation carriers, linking basal ganglia vulnerability and cerebellar adaptation to clinical severity.

BackgroundHuntingtons disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they compare with expected natural-history trajectories remains unknown. MethodsWe evaluated outcomes through Week 104 from baseline in participants who received continuous pridopidine (45 mg twice daily) and remained off-ADMs throughout the double-blind and open-label extension period (n=90). External comparators from ENROLL-HD and TRACK-HD were constructed using propensity-score weighting methods. Least-squares mean changes from baseline to Week 104 were estimated using mixed-effects models for repeated measures across outcomes. ResultsAt two-years, pridopidine treatment was associated with benefits versus propensity-score weighted natural-history comparators across multiple outcomes. Relative to ENROLL-HD, participants receiving pridopidine showed slowing of progression over 104 weeks, expressed as percent slowing across cUHDRS, TFC, SWR, SDMT, and TMS outcomes (39.5-88.3% slowing). Similar patterns were observed relative to TRACK-HD across the same measures (48.5 - 81.5% slowing), including quantitative motor performance assessed by Q-Motor FT-IOI (77.8% slowing). Exploratory analyses including participants receiving concomitant ADMs showed similar directional patterns as the primary analyses. ConclusionsIn a two-year follow-up, continuous pridopidine treatment in participants remaining off-ADMs was associated with slower clinical progression relative to expected natural-history trajectories. (Clinical Trials Identifier: NCT04556656)

BackgroundFunctional neurological disorder (FND) is one of the most common, but least researched, conditions in neurology. Debate exists as to whether the clinical entity referred to as FND is truly a single disorder or is in fact multiple entities which have been erroneously amalgamated into the same condition. We sought to provide empirical evidence on this question by treating it as a problem of model comparison. MethodsWe formulated statistical models equivalent to: (1) FND being a single entity with variation in phenotype, represented by latent trait (binary factor/item response theory) models, and (2) FND being multiple discrete entities, represented by latent class analysis (LCA) models. We fitted these models to data on the symptoms experienced by 697 people with FND from the FND Research Connect database (fnd-research.org) and used Bayesian model comparison methods to compare them. ResultsAll but one of the latent trait models, representing FND as a single entity with heterogeneous phenotype, fit the data better than all the LCA models. Secondary analysis of the LCA models showed results compatible with the models capturing discretisation of continuous variation rather than true discrete categories. DiscussionOur results suggest that the symptom structure of FND is the result of a single pathophysiological process, either as a single entity, or a common pathway preceded by multiple causative processes where the common pathway is solely responsible for the phenotype of the condition.

IntroductionNeurodegenerative dementia syndromes are severely debilitating, progressive and increasing in incidence with an ageing population. A treatable differential diagnosis to neurodegenerative dementia is autoimmune encephalitis (AE), but AE patients are often misdiagnosed, delaying treatment. Previous work in the Netherlands has shown that 0.8% of patients with suspected neurodegenerative dementia suffer from AE. In Sweden, there is considerable variability in the prevalence of AE, possibly indicating under-diagnosis. We hypothesized that some Swedish individuals seeking care for memory impairment might suffer from an undetected AE and that these would show aberrances in available markers of neuroinflammation. MethodsWe retrospectively screened frozen sera from 1041 individuals seen between 2019 and 2023 at the Karolinska University hospital memory clinics in Stockholm for autoantibodies to contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), gamma-aminobutyric acid receptor B (GABABR), the n-methyl-d-aspartate receptor (NMDA-R) and Immunoglobulin superfamily containing LAMP, OBCAM, and Neurotrimin family member 5 (IgLON5) using live cell-based assays (CBAs) and scored them by microscopy. Serum and CSF from suspected positive patient samples were re-tested and titrated by live CBA, commercial fixed CBAs and tissue based assays. Results8 of the 1021 individuals, or 0.8% of the cohort, tested positive in at least three different tests for antibodies to CASPR2 (n=3), GABABR (n=2), LGI1 (n=1) and NMDAR (n=2). Seven of these patients had not been previously diagnosed with AE. Apart from two CASPR2-antibody positive patients showing neuropathic pain and seizures and neuromyotonia, respectively, the patients lacked clinical signs of encephalitis aside from memory impairment and affect lability. The antibody-positive patients did not differ significantly from autoantibody-negative patients in any available clinical parameter. None showed signs of inflammation on brain magnetic resonance tomography, and 2/7 lacked any sign of neuroinflammation in the CSF with available tests, which is commonly seen in later-onset AE. ConclusionOur work identifies undiagnosed AE patients with subtle symptomatology among Swedish memory clinic visitors, that cannot be sensitively separated from antibody-negative patients with current diagnostic tests. Our results suggest the need for the introduction of more sensitive markers of neuroinflammation to the memory clinic to identify and treat individuals with AE among sufferers of memory impairment.

Objective: Spinocerebellar ataxia type 1 (SCA1) is a rare, inherited neurodegenerative disease characterised by progressive deterioration of motor and cognitive function. Here, we illustrate the pattern and evolution of brain atrophy in people with SCA1 using a large multisite dataset. Methods: Structural magnetic resonance imaging data from SCA1 (n=152) and healthy control (n=131) participants from seven sites and two consortia were analyzed using voxel-based morphometry. Cross-sectional stratification and correlations were undertaken with ataxia severity and duration to profile disease evolution. Cerebrocerebellar structural covariance analysis was used to understand the relationship between cerebral and cerebellar tissue atrophy. Results: Atrophy in SCA1 first manifests in the lower brainstem and cerebellar white matter (WM), before progressing to the pons, anterior cerebellum, and cerebellar lobule IX. The midbrain and peri-thalamic WM and the remainder of the cerebellar cortex are then affected, with preferential involvement of specific motor and cognitive areas. Finally, degeneration in the striatum and cerebral WM corresponding to the corticospinal tract become apparent. Atrophy and correlations with ataxia severity are most pronounced in the cerebellar WM and pons. Structural covariance analysis showed reduced correlations between cerebellar and cerebral WM volume in SCA1 participants. Interpretation: Cross-sectional stratification of a large SCA1 cohort by ataxia severity indicates a pattern of atrophy spread across the brainstem, cerebellum, and subcortical grey and white matter. Ongoing volume loss throughout the disease course is most evident in a core set of infra-tentorial brain regions. Atrophy of cerebellum spans both motor and cognitive functional zones. Cerebellar degeneration is not directly mirrored by downstream effects in the cerebrum.

Objective: Migraine attacks are frequently accompanied by patient-reported subjective cognitive symptoms, but objective findings have been inconsistent. We used high-frequency, smartphone-based cognitive testing to assess within-person changes in subjective and objective cognition across migraine phases using daily diaries. Methods: Adults with migraine were recruited through social media. Eligible participants met ICHD-3 migraine criteria and had 3 to 22 monthly headache days. For 30 days, they completed daily smartphone-based reports on headache features, cognitive symptoms, and three smartphone-based objective cognitive tasks. Objective tests included Symbol Search (processing speed/visual search), Color Dots (visual working memory/attention), and Grid Memory (visuospatial working memory). Primary analyses contrasted assessments on current headache days (ictal) versus days with no headache (nonictal). When possible, non-ictal days were subclassified using information from adjacent days as pre-ictal, post-ictal, and interictal days. Outcomes included subjective cognition, reaction time (mean across correctly scored trials), accuracy, and a speed-accuracy composite (Reaction Time/Accuracy). Mixed-effects models adjusted for age, sex, and practice effects. Results: The 139 eligible participants (84.9% female; mean age 38.2 years) contributed 3,014 person-days for ictal versus nonictal comparisons (2,097 nonictal; 917 ictal); for 1,828 person-days precise phase classification was possible. Subjective cognitive symptoms were worse on ictal days, with higher odds of more severe brain fog (OR=3.39, 95% CI 2.70-4.27) and task forgetting (OR=2.82, 95% CI 2.29-3.49). In adjusted models, reaction times were slower on ictal days for Symbol Search (reaction time ratio =1.043, 95% CI 1.028-1.059) and Color Dots (ratio=1.015, 95% CI 1.003-1.026) but not Grid Memory (reaction time ratio =1.006, 95% CI 0.985-1.028). Grid Memory accuracy was lower on ictal days (OR=0.867, 95% CI 0.823-0.914). In analyses based on phase, most nonictal phases showed faster reaction time and lower subjective symptom burden relative to ictal days, with limited differentiation among preictal, postictal, and interictal periods. Conclusions: In persons with migraine, daily smartphone assessments revealed subjective cognitive impairment on ictal vs nonictal days in brain fog and forgetfulness. Objective testing revealed slowing in processing speed and attention and modest differences in the accuracy of working-memory. High-frequency digital cognition appears feasible and may provide scalable functional endpoints for real-world monitoring and treatment evaluation.