Annals of Clinical and Translational Neurology

Uniparental isodisomy (UPiD) can cause mixed phenotypes of imprinting disorders and autosomal‐recessive diseases. We present the case of a 3‐year‐old male with a blended phenotype of TECPR2‐related hereditary sensory and autonomic neuropathy (HSAN9) and Temple syndrome (TS14) due to maternal UPiD of chromosome 14, which includes a loss‐of‐function founder variant in the TECPR2 gene [NM_014844.5: c.1319del, p.Leu440Argfs*19]. This case illustrates challenges associated with a mixed phenotype of ultra‐rare disorders and underscores the importance of investigating recessive conditions in homozygosity regions when atypical clinical features occur in patients with well‐characterized imprinting disorders.

Objective To describe peripheral neuropathy associated with familial Creutzfeldt‐Jakob disease. Methods We report two unrelated patients with genetic Creutzfeldt–Jakob disease with demyelinating peripheral neuropathy as initial presentation, with a comprehensive clinical, electrophysiological and neuropathological description. Results Both patients exhibited gait disturbance and paresthesia. Electrodiagnostic studies revealed demyelinating abnormalities with motor conduction blocks suggestive of chronic inflammatory demyelinating polyradiculoneuropathy, with abnormal plexus MRI and elevated CSF protein levels. One of them had pes cavus and a late‐onset Charcot–Marie‐Tooth (CMT) disease was also initially hypothesized. Central nervous system involvement manifested 1–2 years after the onset of peripheral symptoms. Both patients had a heterozygous E200K mutation in the PRNP gene. Postmortem neuropathological examinations showed PrPSc deposits in the peripheral nervous system, particularly in Schwann cells. Interpretation: Peripheral neuropathy in E200K genetic forms of Creutzfeldt‐Jakob disease can be inaugural and mimic chronic inflammatory demyelinating polyradiculoneuropathy.

Objective Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures. Methods This was a single‐center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes. Results Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: −57.9%; mean change CSF pNFH: −67.6%). There was apparent disease stabilization as assessed by the ALSFRS‐R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85). Interpretation This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.

Objective We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS). Methods Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n = 304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy‐free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS‐r) total score, and forced vital capacity, from baseline were included as covariates. Results Baseline higher GI and GL were associated with less decline of ALSFRS‐r total score at 3‐month follow‐up in the riluzole treatment group (RTG) but not in the no‐riluzole group (NRG). When quartile groups were used, GI second [β = −1.9, 95% CI (−4.1, −0.2), p = 0.07], third [β = −3.0, 95% CI (−5.1, −0.8), p < 0.01] and fourth [β = −2.2, 95% CI (−4.3, −0.01), p < 0.05] quartile groups were associated with less ALSFRS‐r decline at 3‐months compared to the first quartile group (GI < 47.2) among the RTG. Similarly, GL fourth quartile group (GL > 109.5) was associated with less ALSFRS‐r decline at 3 months compared to the first quartile group [β = −2.6, 95% CI (−4.7, −0.5), p < 0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS‐r decline were found among GI/GL quartile groups. Interpretation High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.

Episodic memory is a critical cognitive function that enables the encoding, storage, and retrieval of new information. Memory consolidation, a key stage of episodic memory, stabilizes this newly encoded information into long‐lasting brain “storage.” Studies using fMRI to investigate post‐encoding awake rest holds promise to shed light on early, immediate consolidation mechanisms. Here, we review fMRI studies during episodic memory to document common methods to investigate post‐encoding consolidation, such as multivoxel pattern analysis (MVPA) and functional connectivity, and the current state of the science in both healthy younger and older adults. In young adults, post‐encoding reactivation of stimuli‐specific neural patterns in the hippocampus and its connectivity with cortical and subcortical areas (e.g., visual‐temporal cortex, medial prefrontal, and medial parietal cortex) correlate with subsequent memory performance. Conversely, studies in older adults highlight the importance of large‐scale brain networks during post‐encoding rest, particularly the default mode network (DMN). Alterations in connectivity between the DMN and task‐positive networks may help older adults maintain episodic memory. Furthermore, non‐invasive brain stimulation techniques can enhance these post‐encoding consolidation processes and improve memory performance in both younger and older adults. Notably, a lack of studies has investigated post‐encoding memory consolidation in neurodegenerative disorders. This review underscores the importance of understanding how post‐encoding neural reactivation and connectivity evolve with age to partially explain age‐related declines in episodic memory performance and how such declines can be restored.

Objective Encephalitis is a serious and potentially life‐threatening condition of infectious or autoimmune cause. We aim to characterize the frequency and clinical spectrum of presenting psychiatric symptoms in encephalitis in order to inform earlier recognition and initiation of treatment. Methods This was a retrospective study of adult patients who met the 2013 International Encephalitis Consortium (IEC) and/or 2016 Graus criteria between February 2005 and February 2023. The study included two hospital systems in Houston, Texas, and Baltimore, Maryland and included a total of 642 patients. Psychiatric manifestations were grouped into five high‐level categories: behavior, psychosis, mood, sleep disturbances, and catatonia. Results In our cohort of 642 patients, 318 (49.6%) had psychiatric symptoms at the time of initial presentation, including 78.2% with autoimmune etiologies and 35.2% with viral etiologies (P < 0.001). Those with psychiatric symptoms were younger (median age 47.5 vs. 51.5; P < 0.001), and more likely to have a history of documented psychiatric disorders, as well as longer lengths of hospital stay, and poorer discharge outcomes. Of patients initially admitted to a psychiatric service (n = 28), most had autoimmune causes, although 3 out of 28 (10.7%) had herpes viral infections; admission to a psychiatric service was associated with substantially longer interval to initiation of antivirals and immunotherapy. Autoimmune and infectious etiologies differed in the spectrum and frequency of psychiatric manifestations. Interpretation Psychiatric symptoms are common across etiologies of encephalitis and are associated with longer lengths of hospital stay and worse clinical outcomes. Specific patterns and dimensionality of psychiatric symptoms distinguish autoimmune from infectious causes.

Objective Evidence for an association between psoriasis and dementia is limited and conflicting. We aimed to investigate the association using large and representative population‐based data and describe risk by dementia subtype and over time. Methods We compared dementia risk between people with and without psoriasis using an age‐, sex‐ and primary care practice‐matched cohort of adults aged ≥40 years from the Clinical Practice Research Datalink Aurum in England (1997–2021) linked to hospital admissions data, analysed with stratified Cox regression. Results Among 360,014 individuals with psoriasis and 1,799,617 without, psoriasis was associated with a small increased risk of all‐cause dementia (adjusted hazard ratio [aHR] 1.06, 95% CI 1.04–1.08; absolute rate difference 24 per 100,000 person‐years). Strength of association increased with time since psoriasis diagnosis (e.g. aHR 0.99, 0.96–1.03 within 0 to 5 years; 1.20, 1.05–1.37 within 20 to 25 years). The association was stronger for vascular dementia (aHR 1.10, 1.06–1.14) than Alzheimer's dementia (aHR 1.03, 1.00–1.06). Hazard ratios were larger for severe psoriasis (all‐cause aHR 1.32, 1.25–1.39; vascular aHR 1.58, 1.44–1.74; Alzheimer's aHR 1.11, 1.02–1.21). Interpretation Long‐term risk of all‐cause dementia and vascular dementia, but not Alzheimer's dementia, was slightly higher in people with psoriasis, but absolute risk differences were small. Risks were more substantially raised with time since psoriasis diagnosis and in severe psoriasis compared to mild to moderate psoriasis, suggesting a potential dose–response relationship.

This study evaluated disease activity in people with Multiple Sclerosis (PwMS) who received immune checkpoint inhibitors (ICIs) compared to PwMS not treated with ICIs. There were 108 PwMS included (27 PwMS+ICIs and 81 PwMS controls), matched on age, sex, disease duration, DMTs, and MS disease course. Of 27 PwMS+ICIs, one (4%) had a relapse and four (15%) developed new MRI lesions without clinical symptoms. Time to relapse and MRI activity were compared using Kaplan–Meier curves and Cox regression models. There was no significant difference for either time to relapse (p = 0.34) or MRI activity (p = 0.15) in PwMS+ICIs compared to controls.

Objectives Patients with refractory myasthenia gravis (MG) have few treatment options. Autologous hematopoietic stem cell transplantation (HSCT) has been used to treat immune diseases; however, its use in the treatment of MG is not broadly considered. Our objective is to report on the efficacy and safety of HSCT in refractory MG. Methods Twenty‐one patients who underwent HSCT for MG were retrospectively reviewed. All patients had severe MG refractory to multiple therapies. Stem cells were mobilized with cyclophosphamide and granulocyte colony‐stimulating factor. The grafts were depleted of immune cells by selecting CD34+ cells. HSCT conditioning consisted of high‐dose cytoreductive therapy and anti‐thymocyte globulin. The primary efficacy outcome was achieving clinically stable remission or minimal manifestations without treatment and remaining as such until most recent follow‐up. Results The median time from MG diagnosis to HSCT was 4.0 years. The primary outcome was reached in 16 of 18 evaluable patients (89%) at a median of 1.7 years and maintained with a median follow‐up of 6.7 years (range 1.0–21.9 years). Three patients were not evaluable for the primary outcome: one due to confounding illness and two died within 12 months of transplant. The transplant‐related mortality at 100 days was 9.5%. Two late deaths occurred, with uncertain relation to the HSCT. Interpretation After HSCT for refractory MG, most patients achieved sustained disease remission. However, HSCT‐related mortality in medically complex MG patients may be high. Prospective studies investigating the efficacy and safety of HSCT in the treatment of refractory MG are warranted.

Background Variants in the GABRA2 gene, which encodes the α2 subunit of the γ‐aminobutyric acid A receptor, have been linked to a rare form of developmental and epileptic encephalopathy (DEE) referred to as DEE78. Only eight patients have been reported globally. This study presents the clinical presentation and genetic analysis of a Chinese family with a child diagnosed with DEE78, due to a novel GABRA2 variant. Methods Genetic diagnosis was performed using trio‐whole exome sequencing, followed by bioinformatics predictions of pathogenicity. Structural modeling assessed the potential impact of the variant. A mutant plasmid was constructed and transfected into 293 T cells. Western blotting (WB) was used to evaluate mutant protein expression, while co‐immunoprecipitation (Co‐IP) analyzed interactions with GABRB3 and GABRG2 proteins. Immunofluorescence (IF) assessed the subcellular localization of the mutant protein. Results The 6‐year‐old male proband presented with seizures starting at age two, along with global developmental delay and hypotonia. Genetic testing revealed a heterozygous de novo variant in GABRA2 gene (NM_000807: c.923C>T, p.Ala308Val). Structural modeling suggested that this variant is located within the extracellular domain, which may disrupt hydrogen bonding interactions with GABRB3 and GABRG2. WB and Co‐IP showed reduced protein expression and impaired interactions, potentially destabilizing the pentamer receptor complex. If analysis revealed that the variant did not affect subcellular localization. Conclusion This study identified a novel likely pathogenic GABRA2 extracellular domain variant in a Chinese family causing the DEE phenotype. The results expand the genotypic and phenotypic spectrum of GABRA2‐related DEE.

Autosomal‐dominant variants in the CPT1C gene have been associated with hereditary spastic paraplegia type 73 (SPG73), which typically presents with slowly progressive lower limb weakness and spasticity and is therefore considered a pure form of hereditary spastic paraplegia. However, we report two unrelated males with novel CPT1C variants (NM_001199753.2: patient 1: c.2057_2061del (p.Ile686SerfsTer8) and patient 2: c.2020‐1G>C (p.?)) who presented with lower limb spasticity at 4 and 3 years old, respectively. Both patients also experienced significant cognitive impairment, seizures, or neurobehavioral symptoms. These cases illustrate a broader and more complex clinical spectrum of SPG73, extending beyond the traditionally recognized pure motor symptoms.

Objectives To explore the efficacy of ofatumumab in new onset narcolepsy type 1 following SARS‐CoV‐2 infection. Methods We present a 9‐year‐old girl who experienced new onset narcolepsy type 1 following SARS‐CoV‐2 infection. Polysomnography (PSG) followed by a daytime multiple sleep latency test (MSLT) was under taken after admission. A lumbar puncture was performed to evaluate the CSF orexin‐A level. We assessed the CSF hypocretin‐1 concentration utilizing the RIA kit from Phoenix Pharmaceuticals Inc. HLA typing was performed. Furthermore, we treated the patient with subcutaneous injections of ofatumumab, and followed her for nearly six‐month. The CSF orexin‐A level, CD19+ and total B cell population were measured before and after treatment. Results The girl had experienced SARS‐CoV‐2 infection 4 months before presentation. After that, she started to experience excessive daytime sleepiness and cataplexy. She also began to experience nightmares and violent behaviors during her nocturnal sleep, which were not present before her SARS‐CoV‐2 infection. At the same time, she developed obesity and exhibited psychiatric symptoms such as agitation, anxiety, and aggression. MSLT showed a mean sleep latency of 2.7 min, and 5 times sleep onset REM periods. The CSF orexin‐A level was pathologically low at 34.06 pg/mL, and she tested positive for HLA‐DQB1*06:02. Consequently, a diagnosis of narcolepsy type 1 was confirmed. Before and after treatment with subcutaneous injections of ofatumumab, the CD19+ and total B cell population before treatment and after 1 months showed a significant reduction from 11% and 296 cells per microliter to 0.56% and 11 cells per microliter, respectively. Within a week following ofatumumab therapy, there was a marked improvement in both excessive daytime sleepiness and cataplexy. Notably, her cataplexy was almost entirely resolved following ofatumumab therapy. Her condition remained stable throughout the 9‐month follow‐up period. She could normally attend school. Interpretation The efficacy of ofatumumab in this case provides additional support for an autoimmune etiology in narcolepsy with cataplexy, highlighting the potential involvement of B‐cells in its pathophysiology. This understanding will aid in the development of specific immunotherapeutic strategies for early implementation upon disease onset.

Objective The short‐term efficacy of red blood cell (RBC) transfusion among general traumatic brain injury (TBI) patients is unclear. Methods We used the MIMIC database to compare the efficacy of liberal (10 g/dL) versus conservative (7 g/dL) transfusion strategy in TBI patients. The outcomes were neurological progression (decrease of Glasgow coma scale (GCS) of at least 2 points) and death within 28 days of ICU admission. Each eligible individual was cloned and assigned each of the replicates to one of the treatment arm. The imbalance induced by informative censoring was adjusted by inverse probability weighting. The standardized, weighted pooled logistic regression with 500 bootstrap resampling was used to estimate the cumulative risk difference and 95% confidence interval (CI). Results Of the 1141 eligible individuals, 29.0% received RBC transfusion. Compared with the restrictive group, the liberal strategy reduced early death (3 days: 5%, 95% CI: 2%–7%; 7 days: 6%, 95% CI: 3%–11%); however, no significant difference of mortality risk at 28‐day or neurological progression risk at any time points was observed. The risk of coagulopathy at 3 days was increased by 7% (95% CI: 1%–19%) in the liberal group. The subgroup analysis indicated a beneficial effect of liberal transfusion on mortality in hemodynamically unstable patients. Interpretation Compared with the restrictive strategy, the liberal strategy does not improve the short‐term neurological prognosis and death among patients with TBI in a real‐world situation. The liberal strategy may be beneficial to survival at very early stage or in hemodynamically unstable subgroup.

Iatrogenic cerebral amyloid angiopathy, a disease caused by contact with neurosurgical material or human growth hormone contaminated by beta‐amyloid peptide (Aβ), has a prion‐like transmission mechanism. We present a series of three patients under 55 years of age who underwent cranial surgery. All of them developed multiple cerebral hemorrhages, transient focal neurological deficits, and/or cognitive impairment after 3–4 decades. MRI was compatible with CAA, and Aβ deposition was confirmed. The third patient, who had a ventriculoperitoneal valve, also showed Aβ deposition in the peritoneum and diagnostic biomarkers of Alzheimer's disease. Co‐pathology with Alzheimer disease and its iatrogenic transmission should be considered.

Objective To assess the interrelationship between cortical lesions and cortical thinning and volume loss in people with multiple sclerosis within cortical networks, and how this relates to future cognition. Methods In this longitudinal study, 230 people with multiple sclerosis and 60 healthy controls underwent 3 Tesla MRI at baseline and neuropsychological assessment at baseline and 5‐year follow‐up. Cortical regions (N = 212) were divided into seven functional networks. Regions were defined as either lesional or normal‐appearing cortex based on presence of a cortical lesion on artificial intelligence‐generated double inversion‐recovery scans. Cortical volume and thickness were determined within lesional or normal‐appearing cortex. Results Prevalence of at least one cortical lesion was highest in the limbic (73%) followed by the default mode network (70.9%). Multiple sclerosis‐related cortical thinning was more pronounced in lesional (mean Z‐score = 0.70 ± 0.84) compared to normal‐appearing cortex (−0.45 ± 0.60; P < 0.001) in all, except sensorimotor, networks. Cognitive dysfunction, particularly of verbal memory, visuospatial memory, and inhibition, at follow‐up was best predicted by baseline network volume of normal‐appearing cortex of the default mode network [B (95% CI) = 0.31 (0.18; 0.43), P < 0.001]. Mediation analysis showed that the effect of cortical lesions on future cognition was mediated by volume loss of the normal‐appearing instead of lesional cortex, independent of white matter lesion volume. Interpretation Multiple sclerosis‐related cortical thinning was worse in lesional compared to normal‐appearing cortex, while volume loss of normal‐appearing cortex was most predictive of subsequent cognitive decline, particularly in the default mode network. Mediation analyses indicate that cortical lesions impact cognitive decline plausibly by inducing atrophy, rather than through a direct effect.

Objective We describe neurologic phenotype, clinical associations, and outcomes in autoimmune brainstem encephalitis. Methods Medical records of neural‐IgG positive autoimmune brainstem encephalitis patients diagnosed at Mayo Clinic (January 1, 2006–December 31, 2022) were reviewed. Results Ninety‐eight patients (57 male) were included. Median age of symptom onset was 51 years (range, 8 months‐85 years). Frequent presenting features were ≥1: diplopia (80%), ataxia (78%), dysarthria (68%), vestibulocochlear symptoms (67%), dysphagia (61%), nausea/vomiting (42%), and facial weakness (32%). Altered mental status (11%) was uncommon. Neural antibodies detected were as follows: KLHL‐11 (26 patients), GAD65 (high titer, 12), ANNA‐1 (anti‐Hu, 8), ANNA‐2 (anti‐Ri, 8), Ma2 (7), IgLON‐5 (6), AQP4 (6), MOG (4), glycine receptor (4), GQ1B (4), PCA‐1 (anti‐Yo, 4), DPPX (2), neurochondrin (2), neurofilament (2), NMDA‐R (2), AGNA‐1 (SOX‐1, 1), ANNA‐3 (DACH1, 1), amphiphysin (1), CRMP‐5 (1), ITPR‐1 (1), PCA‐Tr (DNER, 1), and PDE10A (1). Cancer was identified in 55 patients: germ cell (23 patients; 3 extra‐testicular), ductal breast adenocarcinoma (8), small cell carcinoma (6, lung 4), adenocarcinomas (6), neuroendocrine carcinoma (3), hematologic (2), squamous cell (2), and other (7). Median modified Ranking score (mRS) at last follow‐up was 3 (range, 0–6). Factors associated with poor outcome included abnormal brain MRI, bulbar symptoms, and elevated CSF IgG index. Kaplan–Meier analysis revealed faster progression to wheelchair in patients who were immunotherapy refractory and with elevated CSF IgG index. Diagnostic criteria for autoimmune brainstem encephalitis (definite and probable) are proposed. Interpretation Autoimmune brainstem encephalitis is a distinct clinical subphenotype of autoimmune encephalitis. Abnormal brain MRI, bulbar symptoms, and elevated CSF‐IgG index associate with poor outcome.

In this study, we compared the value of pathological alpha‐synuclein (αSyn) seed amplification assay (SAA) in gastric and duodenal biopsies with skin biopsies in Parkinson disease (PD) patients with different disease duration. The accuracy of αSyn SAA was 87.7% in skin, 67.4% in duodenum, and 80.0% in gastric biopsies, with significantly higher sensitivity in advanced PD (skin: 81.8%; gastric: 88.9%; duodenal 58.8%). Misfolded αSyn was detected with higher sensitivity in advanced PD across all matrices, likely reflecting the progression of αSyn pathology. The seeding activity was lower in the duodenal than in the gastric wall, indicating differences in αSyn burden.

Objective Epilepsy is associated with progressive cortical atrophy exceeding normal aging. We aimed to explore longitudinal cortical alterations in patients with temporal lobe epilepsy (TLE) and distinct surgery outcomes. Methods We obtained longitudinal T1‐weighted MRI data in a well‐designed cohort, including 53 operative TLE patients, 23 nonoperative TLE patients, and 23 healthy controls. According to seizure outcomes at 24 months after surgery, operative patients were divided into seizure‐free (SF) and nonseizure‐free (NSF) group. Operative patients were scanned before and after surgery, while nonoperative patients and healthy controls were rescanned with similar interval times. We measured gray matter volume (GMV) in all participants and compared longitudinal cortical alterations among groups. Results In nonoperative group, statistically significant GMV decrease was observed in ipsilateral median cingulate and paracingulate gyri and cerebellum crus I when compared with healthy controls. In operative group, postoperative GMV increase was discovered in many regions involving bilateral hemispheres, especially in the frontal lobe, without differences between SF and NSF group. Postoperative GMV decrease was found in ipsilateral inferior frontal gyrus, putamen, thalamus, and insula. GMV decrease in ipsilateral inferior frontal gyrus, putamen, and insula was more significant in SF group. Interpretation Progressive cortical atrophy existed in nonoperative TLE patients. Cortical remodeling indicated by postoperative GMV increase may arise mostly from the surgery itself, rather than postsurgical seizure outcomes. More significant GMV decrease in ipsilateral inferior frontal gyrus, putamen, and insula may imply their closer connections with resected regions in seizure‐free patients.

Objective To define the epidemiology and clinical presentation of seropositive neuromyelitis optica spectrum disorder (NMOSD) in a large US health system. Methods We completed a retrospective observational study of adult patients in the University of Colorado Health System from 1 January 2011 to 31 December 2020, using Health Data Compass (HDC), a data warehouse that combines electronic health information with claims and public health data in Colorado. We screened HDC for patients with either (1) an abnormal aquaporin‐4 IgG test or (2) any G36 ICD‐10 code. We extracted key clinical elements by chart review and confirmed diagnosis by the 2015 International Panel for NMO Diagnosis criteria. Annual incidence and prevalence rates were calculated. Results Our population consisted of 2,475,591 individuals contributing 11,103,522.72 person‐years of observation. In total, 115 seropositive NMOSD patients were identified. The average yearly incidence was 0.22 per 100,000 person‐years. Age and sex‐adjusted prevalence (per 100,000) was 4.33, and highest among those identifying as Asian or Pacific Islander (17.72), and Black (14.74), as separately by Hispanic ethnicity (8.02). Prevalence was higher in women (6.20:1 female:male ratio). Transverse myelitis (45%) and optic neuritis (43%) were the most common presenting clinical syndromes. In total, 6% of initial presentations were characterized by short‐segment transverse myelitis without other features. Interpretation Seropositive NMOSD incidence is higher in our cohort than many contemporary studies. Women and those identifying as Asian or Pacific Islander, Black, and Hispanic shoulder the highest burden of disease. Clinical onset with short‐segment myelitis underscores the need for serum aquaporin‐4 IgG testing in acute myelitis presentations.

Objective Recent work has bolstered the possibility that peripheral changes may be relevant to Alzheimer's disease pathogenesis in the brain. While age‐associated blood‐borne proteins have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here, we investigate whether APOE allelic variation or presence of brain amyloid are associated with plasma proteomic changes and the molecular processes associated with these changes. Methods Using the SOMAscan assay, we measured 1305 plasma proteins from 53 homozygous, APOE3 and APOE4 subjects without dementia. We investigated the relationship of either the APOE‐ε4 allele or amyloid positivity with plasma proteome changes by linear mixed effects modeling and ontology‐based pathway and module–trait correlation analyses. Results APOE4 is associated with plasma protein differences linked to atherosclerosis, tyrosine kinase activity, cholesterol transport, extracellular matrix, and synaptogenesis pathways. Independent of APOE4, we found that subjects likely harboring brain amyloid exhibit plasma proteome signatures associated with AD‐linked pathways, including neurovascular dysfunction. Interpretation Our results indicate that APOE4 status or presence of brain amyloid are associated with plasma proteomic shifts prior to the onset of symptoms, suggesting that systemic pathways in certain risk contexts may be plausible targets for disease modification.

Objective The objective of this work was to evaluate if task‐specific training (TST) preceded by bilateral upper limb motor priming (BUMP) reduces upper limb impairment more than TST preceded by control priming ([CP], sham electrical stimulation) in people with chronic stroke. Methods In this single‐blind, randomized controlled trial, 76 adults with moderate to severe upper limb hemiparesis ≥6 months post‐stroke were stratified by baseline impairment and randomized to receive either BUMP or CP prior to receiving the same TST protocol. Participants completed 30 h of treatment in 15 days over 6 weeks. The primary outcome was change in Fugl‐Meyer upper extremity (FMUE) from baseline to 8‐week follow‐up. We also report clinically meaningful response rates defined as a change in FMUE score of 6 points or greater. Results In response to treatment, both groups improved to a significant extent at follow‐up, exceeding the FMUE minimum clinically important difference. Those in BUMP and CP saw a mean change of 5.68 (SE 0.76, p < 0.001) and 5.87 (SE 0.76, p < 0.001) respectively. There was no significant difference between treatment arms (mean difference of −0.20 (95% CI = [−2.37, 1.97], SE = 1.08, p = 0.86)). A response of ≥6 points was observed in 46% in BUMP and 50% in CP. Interpretation There was no beneficial effect of BUMP. The magnitude of change seen in both groups reflects the largest improvement achieved with just 22.5 h of TST in this population, matching or out‐performing more invasive, time‐intensive, and costly interventions proposed in recent years.

Objective To investigate retinal layer thinning as a biomarker of disease‐modifying treatment (DMT) effects in relapsing multiple sclerosis (RMS). Methods From an ongoing prospective observational study, we included patients with RMS, who (i) had an optical coherence tomography (OCT) scan within 6 to 12 months after DMT start (rebaseline) and ≥1 follow‐up OCT ≥12 months after rebaseline and (ii) adhered to DMT during follow‐up. Differences between DMT in thinning of peripapillary‐retinal‐nerve‐fiber‐layer (pRNFL) and macular ganglion cell‐plus‐inner plexiform‐layer (GCIPL) were analyzed using mixed‐effects linear regression. Eyes suffering optic neuritis during follow‐up were excluded. Results We included 291 RMS patients (mean age 30.8 years [SD 7.9], 72.9% female, median disease duration 9 months [range 6–94], median rebaseline‐to‐last‐follow‐up‐interval 32 months [12–82]). Mean annualized rates of retinal layer thinning (%/year) in reference to DMF (n = 84, GCIPL 0.28, pRNFL 0.53) were similar under TERI (n = 18, GCIPL 0.34, pRNFL 0.59), GLAT (n = 24, GCIPL 0.32, pRNFL 0.56), and IFNb (n = 13, GCIPL 0.33, pRNFL 0.60) were slightly lower under S1PM (n = 27, GCIPL 0.19, pRNFL 0.42) and CLA (n = 23, GCIPL 0.20, pRNFL 0.42), and were significantly lower under NTZ (n = 47, GCIPL 0.09, pRNFL 0.24; both p < 0.001) and antiCD20 (n = 55, GCIPL 0.10, pRNFL 0.23; both p < 0.001). In patients achieving NEDA‐2, observed thinning rates were lower overall, but still significantly lower under NTZ and antiCD20. Interpretation Applying a rebaselining concept, retinal layer thinning differentiates DMT effects even in clinically stable patients and, thus, might be a useful biomarker to monitor DMT efficacy on subclinical neuroaxonal degeneration—at least on a group level.

Objective Limb‐girdle muscular dystrophy R9 (LGMDR9, formerly known as LGMD2I), caused by variants in the fukutin‐related protein (FKRP) gene leads to progressive muscle weakness of the shoulder and pelvic limb‐girdles and loss of motor function over time. Clinical management and future trial design are improved by determining which standardized clinical outcome assessments (COA) of function are most appropriate to capture disease presentation and progression, informing endpoint selection and enrollment criteria. The purpose of our study was to evaluate the cross‐sectional validity and reliability of clinical outcome assessments in patients with FKRP‐related LGMDR9 participating in the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP) natural history study. Methods Enrolled patients completed a battery of COA on two consecutive days, including the North Star Assessment for limb girdle‐type dystrophies (NSAD), the 100‐m timed test (100 m), and the Performance of Upper Limb 2.0 (PUL). Results A total of 101 patients with FKRP‐related LGMDR9 completed COA evaluations. All functional COA were highly and significantly correlated even across constructs, except for the 9‐hole peg test. Similarly, all tests demonstrated excellent test–retest reliability across 2‐day visits. The NSAD and PUL demonstrate robust psychometrics with good targeting, ordered response thresholds, fit and stability, and limited dependency of items across the scales. Conclusions This study has determined the suitability of several functional COA, cross‐sectionally, in LGMDR9 to inform future trial design and clinical care.

Objective Motor recovery is challenging for spinal cord injury (SCI), especially in low‐level SCI. Methods A 16‐year‐old patient with complete SCI at T12 presented flaccid paralysis and inability to control defecation and was scored as ASIA A at admission. The patient underwent spinal cord stimulation (SCS) implantation at the T11‐L1, followed by an innovative algorithm combining spatiotemporal SCS with real‐time triggered exoskeleton training (EXS‐SCS). Results After 1 month of treatment, she gained substantial improvement in her iliopsoas and quadriceps femoris muscle strength to grade 3–4 as well as percutaneous EMG, allowing for assisted standing and walking, and was reassessed as ASIA C. Interpretation This case reveals the potential of SCS‐EXS regimen in restoring walking capability of SCI patients.