Annals of Clinical and Translational Neurology最新文献

Objective: Freezing of gait (FOG) in people with Parkinson's disease (PwPD) is debilitating and has limited treatments. Modafinil modulates beta/gamma band activity in the pedunculopontine nucleus (PPN), like PPN deep brain stimulation. We therefore tested the hypothesis that Modafinil would improve FOG in PwPD.

Methods: PwPD with FOG were randomized to early-start (24 weeks modafinil) or delayed-start (12 weeks each, placebo then modafinil) of oral modafinil 50 mg, followed by a 2-week washout for both arms. Primary outcomes were change in OFF-levodopa stride length and FOG questionnaire scores; secondary outcomes were change in motor Unified Parkinson's Disease Rating Scale (UPDRS), sleep and quality-of-life scores, and post hoc outcome was change in percent freezing time (%FT).

Results: Early- (n = 12) and delayed-start (n = 9) group participants were well matched for age, OFF-levodopa motor UPDRS and FOG-Q scores. Primary and secondary outcomes did not reach statistical significance. Limiting the analysis to study completers with quantifiable visualized freezing at the initial visit and collapsing the two study arms (n = 11), %FT trended to improvement with 50 mg modafinil in 8/11 participants (p = 0.15) and worsening after 2 weeks washout in 9/11 participants (p = 0.09). A future cross-over study with 50 participants would have 0.80 power to detect a 0.5 standard-deviation improvement in %FT.

Interpretation: For future therapeutic trials, selecting PwPD with moderate, quantifiable FOG and utilizing appropriate outcome measures like %FT will improve the ability to identify intervention effects. Even for short trials, analyses must account for gait decline. An FOG outcome measure that requires less analysis time burden than video quantification, and the ability for at-home monitoring is needed.

Objective: Patients with minor stroke exhibit slowed processing speed and generalized alterations in functional connectivity involving frontoparietal cortex (FPC). The pattern of connectivity evolves over time. In this study, we examine the relationship of functional connectivity patterns to cognitive performance, to determine neurophysiological underpinnings of improvement, and whether connectivity profiles may be useful in evaluating and predicting longer-term cognitive outcomes.

Methods: Patients hospitalized with a minor ischemic stroke (NIH Stroke Scale < 10) were neurologically evaluated approximately 1 month following discharge. A battery of neuropsychological tests was administered to assess performance across multiple cognitive domains. Functional connectivity was evaluated using resting state magnetoencephalography (MEG). Repeat evaluations were performed 3-6 months later. The Network Localized Granger Causality framework was used to estimate functional connectivity at each visit. Relationships between functional connectivity and cognitive performance at each visit were assessed using cluster-based permutation tests and mixed effects modeling.

Results: Forty-nine patients had available data for both follow-up visits. The average age was 62.4 years; 57% were female; 39% were Black. Mixed effects models indicated significant increases in contralesional frontoparietal beta-band connectivity across visits that corresponded to improved behavioral performance. Early reliance on the contralesional hemisphere was associated with better scores at visit 1, and continued reliance on areas within the ipsilesional hemisphere was associated with poorer performance at visit 2.

Discussion: Specific connectivity profiles are associated with better acute and longer-term cognitive performance and may indicate greater potential for recovery. Further studies are needed to determine if patterns are modifiable.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a chronic autoimmune neuroinflammatory disease, typically characterized by antibodies against aquaporin 4 (AQP4-IgG) or myelin oligodendrocyte glycoprotein (MOG-IgG). Simultaneous seropositivity for both antibodies in a single patient is exceedingly rare. We present a dual AQP4-IgG/MOG-IgG seropositivity case who was treated with satralizumab throughout the whole preconception-to-postpartum course, to evaluate the effectiveness and safety of satralizumab, especially during the perinatal period. A 34 year-old female, initially presenting with decreased visual acuity in the left eye, was diagnosed with NMOSD as both AQP4-IgG and MOG-IgG seropositive. With traditional treatment of corticosteroids and mycophenolate mofetil, her vision gradually recovered and overall condition stabilized. Due to the desire for conception, her treatment regimen was transitioned to satralizumab monotherapy. Three months later with five doses of satralizumab, she successfully conceived and delivered a healthy female infant at 38 weeks' gestation. Satralizumab treatment was continued throughout the preconception-to-postpartum course. All routine and perinatal assessments were within normal limits, and 4 months postpartum, the condition of both mother and child remained stable, further supporting the favorable effectiveness and safety of satralizumab in this case. The coexistence of AQP4-IgG and MOG-IgG in an NMOSD patient represents an extremely rare and complex clinical scenario. When fertility is desired, the selection of disease-modifying therapy must carefully balance effectiveness and safety. In such cases, satralizumab may serve as a viable option, supported by promising real-world data.

New-onset refractory status epilepticus (NORSE) arises without an identifiable cause or prior epilepsy history, with a 16%-27% mortality rate and significant long-term neurological sequelae. Neuromodulation such as deep brain stimulation (DBS) targeting the anterior and centromedian thalamic nuclei has shown promise when the traditional approach of anti-seizure medications (ASMs), anesthetics, and immunomodulation fails. We present a case of cryptogenic NORSE in a 30-year-old male with autism and developmental delay, with refractory seizures localized to bilateral posterior quadrants. Sensing-enabled DBS targeting the pulvinar thalami led to decreased seizure burden and clinical improvement, highlighting the importance of tailoring neuromodulatory targets to seizure localization.

Objectives: We describe the clinical manifestations and developmental abilities of individuals with SYT1-associated neurodevelopmental disorder (Baker-Gordon syndrome) from infancy to adulthood. We further describe the neuroradiological and electrophysiological characteristics of the condition at different ages, and explore the associations between these characteristics and clinical symptoms.

Methods: Participants were recruited to the UK-based Brain and Behavior in Neurodevelopmental Disorders of Genetic Origin project. Caregivers completed a medical history questionnaire and a battery of standardized neurodevelopmental measures. MRI and EEG records were obtained with consent from treating clinicians. Age-related clinical manifestations and neuroimaging records were systematically analyzed. Balanced accuracy testing was used to explore brain-symptom associations.

Results: This study describes 40 individuals with 30 distinct de novo SYT1 variants, including 10 novel variants. Qualitative age-related clinical trends included the resolution of hypotonia and worsening of movement disorders, sleep difficulties, and self-injurious behaviors. Social-communicative impairments were prominent, with evidence of progression with age. MRI abnormalities were identified in 45% of individuals, while EEG abnormalities were present in 93%. Epileptiform activity frequently co-occurred with movement disorders, while irregular sleep EEG coincided with sleep difficulties and respiratory problems.

Interpretation: This study characterizes the broad spectrum and age-related progression of clinical symptoms and brain-related findings in individuals with SYT1-associated neurodevelopmental disorder. Further research is needed to understand factors contributing to within-individual change, and to develop targeted interventions aimed at improving outcomes and quality of life for affected individuals and their families.

Objective: To examine the risk of hospital readmission after an index hospitalization for TBI in older adults.

Methods: Using data from the Atherosclerosis Risk in Communities (ARIC) study, we used propensity score matching of individuals with an index TBI-related hospitalization to individuals with (1) non-TBI hospitalizations (primary analysis) and (2) orthopedic injury hospitalizations (secondary analysis). The rate of all-cause hospital readmission was estimated using adjusted Fine-Gray proportional hazards regression models within strata defined by time since hospitalization. Follow-up extended from the date of index hospitalization after study enrollment (1987-1989) through December 31, 2019.

Results: Six hundred sixty-seven participants with an index TBI-related hospitalization were matched using propensity scores with replacement with a ratio of 1:4-2668 participants with non-TBI-related hospitalizations and 1:3 with 2001 participants with orthopedic injury-related hospitalizations. Median age was 68 years (IQR = 46-95) at index hospitalization. Compared to participants with an index non-TBI-related hospitalization, readmission rates were lower among participants with an index TBI-related hospitalization (HR = 0.80, 95% CI = 0.74, 0.87) over a median follow-up of 2.7 years, although similar readmission rates were observed within the first year of follow-up (HR = 1.03, 95% CI = 0.88, 1.21). Rates of hospital readmission among persons with an index TBI-related hospitalization were similarly decreased compared with persons with an orthopedic injury-related hospitalization (HR = 0.78, 95% CI = 0.72, 0.85) over a median follow-up of 3.1 years.

Interpretation: Among community-dwelling older adults with a TBI-related hospitalization, rates of hospital readmission were similar to individuals hospitalized for a non-TBI cause in the first year, but lower subsequently. Targeted interventions in the first year post-hospitalization may be most beneficial for reducing readmissions among individuals with TBI.

RETRACTION: B. Spencer, S. Williams, E. Rockenstein, E. Valera, W. Xin, M. Mante, J. Florio, A. Adame, E. Masliah, and M.R. Sierks, “ α-Synuclein Conformational Antibodies Fused to Penetratin are Effective in Models of Lewy Body Disease,” Annals of Clinical and Translational Neurology 3, no. 8 (2016): 588–606, https://doi.org/10.1002/acn3.321.

The above article, published online on 16 June 2016, in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, Ahmet Hoke; the American Neurological Association; and Wiley Periodicals LLC. Following publication, a third party contacted the publisher with concerns about duplications in Figures 1A, 3A, 3C, and 4A. Additionally, duplicated panels were discovered for Figure 5 with an earlier publication by some of the same authors (Fields et al., 2016 [https://doi.org/10.1186/s12974-016-0585-8]). The retraction has been agreed to because of evidence that significant portions of multiple figures were duplicated, affecting the interpretation of the data and results presented. Author Eliezer Masliah did not indicate his agreement with the retraction. The other authors did not respond to communications from the Publisher regarding the retraction.

Objective: Spinocerebellar ataxias (SCA) are hereditary cerebellar degenerative disorders with a common feature of dysarthria, involving impaired phonatory and articulatory control of speech, thereby affecting social communication. In this study, we investigated whether acoustic measures could objectively measure speech dysfunction and identify common indicators across SCA types 1, 2, and 3.

Methods: We recorded speech from 24 SCA patients and 24 age-matched controls during connected speech and sustained vowel tasks. Speech was assessed using the Acoustic Voice Quality Index (AVQI) and sub-metrics (cepstral peak prominence smoothed [CPPS], harmonics-to-noise ratio [HNR], and shimmer). Jitter was used to quantify dysfunction in sustained vowels, and formant analysis was used to examine articulatory control. We also evaluated whether these measures capture speech dysfunction severity.

Results: AVQI was the most consistent indicator of speech dysfunction across SCA subgroups, showing a significant increase compared to controls. SCA patients exhibited abnormalities in AVQI sub-metrics (CPPS, HNR, and shimmer) and increased jitter during sustained vowels. Furthermore, formant analysis revealed articulation differences linked to changes in F2, F3, and F4 during connected speech, and F2 and F4 during sustained vowels. Additionally, AVQI correlates with the Scale for Assessment and Rating of Ataxia (SARA) speech sub-scores, whereas CPPS and jitter can differentiate between mild and moderate stages of ataxic speech.

Conclusion: Our findings show that SCA patients exhibit speech dysfunction across both connected speech and sustained vowel tasks, as AVQI stands out as a key indicator, whereas CPPS and jitter track ataxic speech severity. Our findings support using acoustic measures for objectively assessing speech dysfunction and thereby informing disease monitoring and guiding future targeted therapies.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy featuring progressive weakness, sensory deficits, and areflexia. While corticosteroids, intravenous immunoglobulin, and plasmapheresis are effective first-line immunotherapies, a subset of patients remains treatment-refractory. Daratumumab, an anti-CD38 monoclonal antibody approved for multiple myeloma, demonstrates immunomodulatory effects suggesting utility in refractory neuroimmune disorders. However, evidence for its efficacy in CIDP remains limited. We report a case study of treatment-refractory CIDP successfully managed with daratumumab, including 1 year follow-up data.

Objective: This study aimed to systematically observe the clinical manifestations, immune cell subsets, and dynamic changes in serological indicators in patients with myasthenia gravis (MG) before and after efgartigimod (EFG) treatment.

Methods: We analyzed the baseline data, laboratory parameters, and lymphocyte subset proportions in MG patients before and after EFG treatment. Serum levels of 92 inflammation-related proteins were measured using Olink Target 96 proteomics in MG patients before and after EFG treatment. Validation was performed by enzyme-linked immunosorbent assay in an expanded cohort and followed by in vitro experiments to evaluate the effects of novel biomarkers on peripheral blood mononuclear cells from MG patients.

Results: Following EFG treatment, patients showed significant reductions in MG Activities of Daily Living (MG-ADL) scores and serum IgG levels, along with remodeling of immunocyte subset distribution. Olink proteomics analysis identified six differentially expressed inflammatory cytokines, among which fibroblast growth factor-19 (FGF-19) exhibited the most notable downregulation. Validation in an independent cohort demonstrated that serum FGF-19 levels were elevated and positively correlated with disease severity in MG patients. Furthermore, in EFG responders, the expression level of FGF-19 decreased after treatment. In vitro experiments demonstrated that FGF-19 promotes B-cell to plasma cell differentiation in MG patients.

Interpretation: EFG treatment can alleviate the clinical symptoms and decrease IgG levels in patients with MG. The downregulated expression following EFG treatment, along with the findings of in vitro experiments, indicates that FGF-19 may not only act as a biomarker for the efficacy of EFG, but also play a role in promoting the differentiation of B cells into plasma cells, thereby offering a novel target for therapeutic interventions.