Objectives
Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian ...populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian‐specific NOTCH3 p.R75P mutation.
Methods
This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi‐Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations.
Results
Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45–37.31), multiple CMB (3.00, 1.34–6.71), and absence of temporopolar lesions (4.91, 2.29–10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83–35.89), multiple CMB (1.90, 1.01–3.56), and absence of temporopolar lesions (2.32, 1.08–4.97). Structural analysis revealed solvent‐exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations.
Interpretation
NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040–1054
Characteristics of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cysteine-sparing NOTCH3 mutations are relatively unknown. ...This study compared clinical and imaging characteristics between patients with CADASIL and cysteine-sparing NOTCH3 mutations and those with CADASIL and cysteine-involving NOTCH3 mutations. We retrospectively reviewed medical records of patients with CADASIL admitted to the Asan Medical Center between September 1999 and September 2017. We compared clinical and brain magnetic resonance imaging (MRI) characteristics based on the presence or absence of cysteine-involving NOTCH3 gene mutations. We compared white matter change frequencies and grades in specific spatial regions between the groups according to age-related white matter change (ARWMC) scores. We evaluated the presence, number, and anatomical distributions of cerebral microbleeds according to the microbleed anatomical rating scale. We reviewed data from 79 patients (55 cysteine-involving, 24 cysteine-sparing NOTCH3 mutations). Clinical symptoms and signs did not differ significantly between the groups. The white matter change frequency and ARWMC scores (adjusted for age and stroke risk factors) in the anterior temporal lobes were lower in cysteine-sparing patients than in cysteine-involving patients. Frequencies and grades of the other brain region's white matter changes and cerebral microbleeds were similar between the groups.
ABSTRACT
Introduction: Although thymectomy is an important therapeutic option for myasthenia gravis (MG), factors predicting remission after thymectomy are not well known. Methods: We retrospectively ...reviewed patients with acetylcholine receptor antibody (AChR‐Ab)‐positive MG who had undergone thymectomy. Prognostic factors predicting remission were investigated. Changes in AChR‐Ab titer before and after thymectomy were also evaluated. Results: Among the 179 patients, 52.5% achieved complete stable or pharmacologic remission. Nonthymomatous pathology and mild preoperative status were favorable predictors of remission. The decrease in AChR‐Ab titer after thymectomy was significant in nonthymomatous MG but not in thymomatous MG. Discussion: Nonthymomatous pathology and mild preoperative status are prognostic factors that may predict remission after thymectomy. The decrease in AChR‐Ab titer after thymectomy was significant in nonthymomatous MG but not in thymomatous MG, suggesting that the pathogenic role of the thymus differs according to pathology. Muscle Nerve 58:796–800, 2018
To investigate alterations in the choroid plexus in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) using brain magnetic resonance imaging (MRI).
We prospectively recruited ...consecutive patients with MS or NMOSD from July 2018 to February 2019. The inclusion criterion was brain MRI within three months from onset of acute neurological symptoms. The thickness and enhancement ratio of the choroid plexus on gadolinium-enhanced T1-weighted images of patients with MS (n = 51), patients with NMOSD (n = 32), and healthy controls (HCs, n = 28) were compared.
MRI in patients with MS or NMOSD showed a comparably thick but more enhanced choroid plexus compared with that of HCs. In the axial view, enhancement ratios of the lateral ventricle of MS and NMOSD patients and HCs were 1.64 ± 0.34, 1.65 ± 0.25, and 1.39 ± 0.17, respectively (P > .999 for MS vs. NMOSD; P = .001 for MS vs. HCs; P = .001 for NMOSD vs. HCs).
The choroid plexus was significantly more enhanced on brain MRI of patients with MS or NMOSD than on that of HCs, suggesting the involvement of the choroid plexus in the autoimmune inflammatory processes in MS and NMOSD.
•We investigated alterations of choroid plexus in MS and NMOSD using brain MRI.•MRI in patients with MS or NMOSD showed significantly enhanced choroid plexus.•Choroid plexus may be involved in the inflammatory process of MS and NMOSD.
Acquired myasthenia gravis (MG) is a prototype autoimmune disease of the neuromuscular junction, caused in most patients by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). There ...seem to be ethnic and regional differences in the frequency and clinical features of MG seronegative for the AChR antibody. This study aimed to describe the autoantibody profiles and clinical features of Korean patients with generalized MG seronegative for the AChR antibody. A total of 62 patients with a high index of clinical suspicion of seronegative generalized MG were identified from 18 centers, and we examined their sera for antibodies to clustered AChR, muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) by cell-based assays (CBA) and to MuSK by radioimmunoprecipitation assay (RIPA). We also included 8 patients with ocular MG, 3 with Lambert-Eaton myasthenic syndrome, 5 with motor neuron disease, and 9 with other diagnoses as comparators for the serological testing. Antibodies were identified in 25/62 (40.3%) patients: 7 had antibodies to clustered AChR, 17 to MuSK, and 2 to LRP4. Three patients were double seropositive: 1 for MuSK and LRP4, and 2 for MuSK and clustered AChR. The patients with MuSK antibodies were mostly female (88.2%) and characterized by predominantly bulbar involvement (70%) and frequent myasthenic crises (58.3%). The patients with antibodies to clustered AChR, including 2 with ocular MG, tended to have a mild phenotype and good prognosis.
It is unclear whether serum proteins can serve as biomarkers to reflect pathological changes and predict recovery in inflammation of optic nerve. We evaluated whether serum proteins could monitor and ...prognosticate optic neuritis (ON). We prospectively recruited consecutive patients with recent ON, classified as ON with anti-aquaporin-4 antibody (AQP4-ON), ON with anti-myelin oligodendrocyte glycoprotein antibody (MOG-ON), and double-seronegative ON (DSN-ON). Using ultrasensitive single-molecule array assays, we measured serum neurofilament light chain and glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF). We analyzed the markers according to disease group, state, severity, and prognosis. We enrolled 60 patients with recent ON (15 AQP4-ON; 14 MOG-ON; 31 DSN-ON). At baseline, AQP4-ON group had significantly higher serum GFAP levels than did other groups. In AQP4-ON group, serum GFAP levels were significantly higher in the attack state than in the remission state and correlated with poor visual acuity. As a prognostic indicator, serum BDNF levels were positively correlated with follow-up visual function in the AQP4-ON group (r = 0.726, p = 0.027). Serum GFAP reflected disease status and severity, while serum BDNF was identified as a prognostic biomarker in AQP4-ON. Serum biomarkers are potentially helpful for patients with ON, particularly those with AQP4-ON.
Despite its close association with CNS inflammatory demyelinating disorders (CIDDs), pathogenic characteristics of idiopathic transverse myelitis (ITM) remain largely unknown. Here, we investigated ...serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) in patients with ITM to unravel the disease characteristics of ITM. We prospectively recruited 70 patients with ITM, 62 with AQP4 + NMOSD and 85 with RRMS-including 31 patients with acute TM attacks-along with 30 HCs. We measured sNfL and sGFAP levels using single-molecular arrays and compared these levels per lesion volume between the disease groups during attacks. Compared to HCs, ITM patients showed higher sNfL and sGFAP during acute attacks (sNfL: p < 0.001, sGFAP: p = 0.024), while those in remission (sNfL: p = 0.944, sGFAP: p > 0.999) did not, regardless of lesion extents and presence of multiple attacks. ITM patients demonstrated lower sGFAP/volume (p = 0.011) during acute attacks and lower sGFAP (p < 0.001) in remission compared to AQP4 + NMOSD patients. These findings suggest that both neuronal and astroglial damages occur in patients with acute ITM attacks at a similar level to those with RRMS, distinct from AQP4 + NMOSD. However, active neuroinflammatory process was not remarkable during remission in this cohort.
Glial fibrillary acidic protein (GFAP) is a type III intermediate filament protein found in astrocytes in the brain. Damaged astrocytes release GFAP into cerebrospinal fluid and blood. Thus, GFAP ...levels in these body fluids may reflect the disease state of neuromyelitis optica spectrum disorder (NMOSD), which includes astrocytopathy, characterized by pathogenic antibodies against aquaporin 4 located on astrocytes. Recently, single-molecule array technology that can detect these synaptic proteins in blood, even in the subfemtomolar range, has been developed. Emerging evidence suggests that GFAP protein is a strong biomarker candidate for NMOSD. This mini-review provides basic information about GFAP protein and innovative clinical data that show the potential clinical value of blood GFAP levels as a biomarker for NMOSD.
Amphiphysin‐IgG was identified in 71 patients among 120,000 evaluated serologically for paraneoplastic autoantibodies. Clinical information was available for 63 patients. Cancer was detected in 50 ...(mostly limited), proven histologically in 46, and was imaged intrathoracically in 4 patients (lung, small–cell 27 and non–small cell 1), breast 16 and melanoma 2). Neurological accompaniments included (decreasing frequency): neuropathy, encephalopathy, myelopathy, stiff‐man phenomena, and cerebellar syndrome. In a case examined neuropathologically, parenchymal T‐lymphocyte infiltration (predominantly CD8+) was prominent in lower brainstem, spinal cord, and dorsal root ganglion. Coexisting paraneoplastic autoantibodies, identified in 74% of patients, predicted a common neoplasm and indicated other neuronal autoantigen targets that plausibly explained several neurological manifestations; for example, P/Q‐type Ca2+‐channel antibody with Lambert–Eaton syndrome (n = 5), anti‐neuronal nuclear antibody type 1 with sensory neuronopathy (n = 7), K+‐channel antibody with limbic encephalitis (n = 1) or neuromyotonia (n = 1), and collapsin response‐mediator protein‐5‐IgG with optic neuritis (n = 3). Patients with isolated amphiphysin‐IgG (n = 19) were more likely to be women (with breast cancer, p < 0.05) and to have myelopathy or stiff‐man phenomena (p < 0.01). Overall, a minority of women (39%) and men (12%) had stiff‐man phenomena. Only 10% of women (some with lung carcinoma) and 4% of men fulfilled diagnostic criteria for stiff‐man syndrome. Ann Neurol 2005;58:96–107
ABSTRACT
Introduction
Spinal and bulbar muscular atrophy (SBMA) is caused by the expansion of a CAG repeat in the androgen receptor gene. The relationship between the CAG repeat size and ...electrophysiological findings is not completely understood.
Methods
We retrospectively analyzed 62 SBMA patients to assess the correlation between their CAG repeat size and electrophysiological findings.
Results
In multiple regression analysis including age at examination and disease duration, we identified a negative correlation between the CAG repeat size and the compound muscle action potential (CMAP) amplitude. No significant correlation was found between the CAG repeat size and sensory nerve action potential (SNAP) amplitude.
Discussion
Contrary to previous reports of motor‐ and sensory‐dominant phenotypes correlating with CAG repeat sizes, the CAG repeat size was negatively correlated only with CMAP amplitude, and not with SNAP amplitude. Muscle Nerve 57: 683–686, 2018
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