Annals of Clinical and Translational Neurology最新文献

Objectives: Psychological stress has been suggested as a contributory factor in the onset and progression of multiple sclerosis (MS). The 7 October 2023 terrorist attacks in Israel caused significant psychological stress, providing a unique context to study its impact on MS activity. This study aims to assess the impact of war-related psychological stress on MS activity using magnetic resonance imaging (MRI) scans and clinical follow-up.

Methods: This observational retrospective case-control study includes 93 patients with MS (pwMS) who had routine annual MRI scans from three periods (7 October 2021 to 7 January 2022; 7 October 2022 to 7 January 2023; and 7 October 2023 to 7 January 2024). Data were collected from medical records and MRI scans at Hadassah Medical Center. MRI scans were classified as active if new or enlarging T2 lesions and/or enhancing T1 lesions were present.

Results: MRI activity significantly increased among pwMS during the first 3 months of the war compared to the corresponding period in the preceding year (11/93 vs. 23/93, P = 0.0139), with an OR of 4.0 (95% confidence interval: 1.29-16.442). pwMS with an EDSS score ≥4 showed a significant increase in MRI activity (P = 0.045), whereas no significant increase was observed in patients with an EDSS score ≤3.5 (P = 0.23). Additionally, MRI activity increased later during the war compared to the previous year (P < 0.0001).

Interpretation: This study provides evidence of increased MRI-detected disease activity in pwMS during periods of war-related psychological stress. Our findings highlight the importance of considering psychological stress in MS management. Healthcare providers should be aware of the potential for increased disease activity in pwMS during extreme stress and may consider more frequent monitoring, including MRI scans, or treatment adjustments during such periods.

Objective: Krabbe disease is due to deficiency of galactocerebrosidase, resulting in progressive neurodegeneration due to demyelination. The purpose of this study is to document disease progression in the newly classified infantile-onset (0-12 months). We evaluated the outcomes of hematopoietic stem cell transplantation (HSCT) and described meaningful clinical endpoints.

Methods: Patients with infantile Krabbe disease were prospectively evaluated between 2000 and 2022. All patients underwent comprehensive and standardized protocols. Descriptive statistics and Kaplan-Meier survival curves were used for analysis.

Results: One hundred and thirty-seven children with infantile Krabbe disease were included (68 males and 69 females). Of the 137, 96 were not treated and 41 underwent hematopoietic stem cell transplantation. Twenty-three were asymptomatic and 18 symptomatic. Initial symptoms included irritability, developmental delay or loss of milestones, feeding difficulties, spasticity, and reflux with an average survival of 2.2. Abnormalities in nerve conduction studies, auditory brainstem responses, and brain MRIs were evident in both groups of patients. Age at transplantation and signs and symptoms determined functional outcomes. Symptomatic and asymptomatic transplanted patients showed an increase in galactocerebrosidase and a decrease in psychosine, but did not reach the normal range. The median survival for transplanted symptomatic patients was 5 years while asymptomatic was extended to 15.5 years.

Interpretation: Infantile Krabbe disease with onset before 12 months is rapidly progressive. Irreversible brain damage occurs unless timely HSCT is performed. HSCT does not prevent the progression of peripheral nerve disease. This study can be used to monitor patients and evaluate the effects of future therapies.

Background: Medial intracranial carotid artery calcifications (ICAC) are associated with impaired vascular physiology, increased arterial stiffness and pulse pressure. Their presence might therefore be associated with increased risk of intracerebral hemorrhage (ICH) expansion, according to the avalanche model. We explored the association between ICAC presence and pattern and hematoma expansion (HE).

Methods: Retrospective analysis of a monocentric, prospectively collected cohort of ICH patients admitted between June 2017 and October 2023. ICAC pattern was determined by Kockelkoren's rating scale on admission CT; medial ICAC were defined with a >6 points cutoff. A follow-up CT scan was performed within 72 h. HE was analyzed as a dichotomous (≥6 mL and/or ≥33%) and as a categorical (none/mild/moderate/severe) variable, and its predictors were explored with logistic and ordinal regression respectively, accounting for baseline volume, onset-to-CT time, and anticoagulation. All the analyses were stratified by ICH location (supratentorial deep vs lobar ICH).

Results: A total of 201 patients were included (median age 78, 42% females, 59% deep ICH). Medial ICAC were significantly more common in deep ICH with HE compared with non-expanders (72% vs 49%, p = 0.03), whereas there was no association between ICAC and HE in lobar ICH (53% vs 52%, p = 0.85). This association between medial ICAC and HE in deep ICH remained significant in logistic (aOR 3.11, 95% CI [1.19-9.06], p = 0.03) and ordinal regression (acOR 2.42, 95% CI [1.19-4.99], p = 0.01).

Interpretation: Ipsilateral medial ICAC are associated with higher odds of HE in deep ICH. Our findings are best interpreted as hypothesis generating, requiring prospective validation and further research to characterize the underlying biological mechanisms.

In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA.

Objective: There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs.

Methods: We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland-II) motor standard scores, motor milestones and tone abnormalities.

Results: In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland-II motor standard score <56 included GRIN2B-related disorder (mean standard score = 53.5), HNRNPH2-related disorder (mean standard score = 55.8) and SCN2A-related disorder (mean standard score = 49.9). The only genetic condition with a mean age of sitting unsupported ≥18 months was GRIN1-related disorder (mean age = 26.3 months). Genetic conditions with a mean age of walking independently ≥36 months included CTNNB1-related disorder (mean age = 37.4 months) and HNRNPH2-related disorder (mean age = 41.9 months). Tone abnormalities included hypotonia in 83% (577/696), hypertonia in 16% (112/696), a diagnosis of cerebral palsy (CP) in 10% (73/696) and a diagnosis specifically of spastic CP in 3% (23/696).

Interpretation: Patients with genetic NDDs have a spectrum of motor impairment, which warrant further characterization.

Twin girls born at 30 weeks' gestation with spinal muscular atrophy (SMA) received onsasemnogene-abeparvovec (OA) at 3.5 weeks of life. They had no treatment-related adverse events, normal acquisition of motor milestones, and normal neurological examination at 19 months. Genotyping revealed 0 copies of SMN1 and a single, hybrid SMN2 gene containing the positive genetic modifier c.835-44A>G. This was associated with full-length SMN2 blood mRNA expression levels similar to a 2 copy SMA infant. The observed favorable outcomes are likely due to the genetic modifier combined with early drug administration enabled by prematurity.

Objective: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes.

Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review.

Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease-modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving "drops," but should incorporate additional patient-centered outcomes, using emerging measures adapted to people with LGS.

Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient-centered clinical trials that are tailored to LGS pathophysiology and natural history.

Objective: To assess the prevalence, timing, and functional impact of neuropsychiatric symptoms in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to assess whether these neuropsychiatric symptoms are associated with magnetic resonance imaging (MRI) features of the patients.

Methods: Our study included a total of 78 patients with CADASIL. To assess neuropsychiatric symptoms, we evaluated the caregivers using the Neuropsychiatric Inventory (NPI). Patients were considered to have an irritability, depression, apathy, aggression, or anxiety disorder if they scored ≥1 in the NPI. Subsequently, we conducted a more detailed assessment of irritability, depression, apathy, aggression, and anxiety. Multivariate logistic regression was employed to analyze the relationships between neuropsychiatric symptoms and clinical/MRI features in the patients.

Results: Overall, 57.69% of patients with CADASIL experienced neuropsychiatric symptoms. Among these symptoms, irritability was the most prevalent (52.56%), followed by depression (19.23%), apathy (17.95%), aggression (7.69%), and anxiety (6.41%). The mean age of onset for irritability was the youngest, followed by anxiety, apathy, aggression, and depression. Among patients with both stroke/TIA and neuropsychiatric symptoms, 31.03% reported experiencing neuropsychiatric symptoms prior to stroke/TIA. Furthermore, both irritability and apathy had a negative impact on the patients' daily functioning. Additionally, there was a correlation between the presence of neuropsychiatric symptoms and the patients' MRI lesion burden.

Interpretation: Our study has discovered that neuropsychiatric symptoms are highly prevalent in patients with CADASIL and may occur before cerebrovascular events, suggesting that neuropsychiatric symptoms of CADASIL deserve more attention and earlier exploration.

Objective: To describe patient clinical characteristics associated with matched oligoclonal bands (OCB).

Methods: A retrospective review at the University of Utah examined patients with matched OCB from 2015 to 2020. Clinical data, diagnosis, and outcomes were collected. Patients were classified with either multiple sclerosis (MS), other inflammatory neurologic disorder (other-IND), or noninflammatory neurologic disorder (NIND).

Results: Of 539 identified patients, 436 (53.4% female) were matched-only, while 103 (43.7% female) were matched + unique. Patients with matched-only bands were older (57.4 ± 16 vs. 52 ± 14.2, p < 0.001) and more likely to have a history of autoimmune disease (40.1% vs. 28.2%, p = 0.024) and/or cancer (28.7% vs. 16.5%, p = 0.012). Patients with matched + unique bands were more likely to have CSF pleocytosis (52.4% vs. 25.9%, p < 0.001), high IgG index (52.2% vs. 7.6%, p < 0.001), and an abnormal MRI (86.9% vs. 63.1%, p < 0.001). More than two-thirds of matched-only patients had NIND, while 33% and 41.7% of matched + unique patients had MS and other-IND, respectively. Patients exhibiting matched-only bands and a high IgG index demonstrated a significantly higher incidence of other-IND compared to those with matched-only bands and a normal IgG index (55.6% vs. 30.4%, p = 0.013). While Kaplan-Meier survival curves demonstrated higher mortality in the matched-only cohort compared to the matched + unique cohort (p = 0.02), multivariable Cox regression analysis showed this difference was not statistically significant when adjusting for various factors. A history of cancer was the significant predictor of increased mortality risk (Hazard ratio = 3.147, 95% CI [2.196, 4.51]).

Interpretation: Patients with matched only versus matched + unique OCB have distinct clinical profiles.

Objective: This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non-demented older adults.

Methods: Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow-up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers.

Results: In main effect models, higher SCD was associated with more amyloidosis (p-values <0.004). SCD was not associated with tau, p-tau, or neurofilament light (NFL) levels (p-values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p-values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p-values <0.003), men (p = 0.0003), and higher education. No SCD score × reading-level interaction was found (p-values >0.51) though SCD related to amyloid markers in the higher reading-level group (p-values <0.004).

Interpretation: Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors.