Annals of Clinical and Translational Neurology最新文献

The timing for initiating immunotherapy in patients with glutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy is a challenge. We used the translocator protein radioligand [¹⁸F]DPA-714 and PET to evaluate brain microglial activation. [¹⁸F]DPA-714 PET brain images of 11 patients with GAD65 antibody-associated epilepsy and seven controls were analyzed. Patients with acute symptomatic seizures presented higher [¹⁸F]DPA-714 SUVR in the hippocampus than did controls and patients with chronic temporal lobe epilepsy. Our findings highlight that [¹⁸F]DPA-714 PET/MRI represents a useful tool to assess neuroinflammation in patients with GAD65 antibody-associated epilepsy.

Adrenoleukodystrophy is a rare inherited peroxisomal disease caused by pathogenic variants in the ABCD1 gene located on the X chromosome. Although the most severe central nervous system and adrenal complications typically affect only men with adrenoleukodystrophy, the majority of women develop myeloneuropathy symptoms in adulthood. In observational studies of women with adrenoleukodystrophy, several clinical rating scales have been used to assess disease manifestations and capture differences between asymptomatic and symptomatic women. To facilitate development of treatments to address symptoms in women, there is a need to identify clinical outcome measures that can sensitively assess disease progression and treatment responses. The goals of this scoping review were to: (1) identify and review clinically relevant assessment scales that have been utilized to capture disease manifestations in women with adrenoleukodystrophy, and (2) provide recommendations on key objectives for further research.

Diffuse axonal injury (DAI) is caused by acceleration-deceleration forces during trauma that shear white matter tracts. Susceptibility-weighted MRI (SWI) identifies microbleeds that are considered the radiologic hallmark of DAI and are used in clinical prognostication. However, this assumption is limited by a lack of systematic radiologic-pathologic correlation studies. Here, we performed ex vivo SWI on three brains from patients who died after severe TBI and assessed axonal injury around SWI microbleeds using immunohistochemistry to the amyloid-beta precursor protein. Axonal injury was present in 64% of microbleeds, indicating a heterogeneous injury response in the white matter.

Introduction: Progressive Supranuclear Palsy (PSP) is a neurodegenerative 'tauopathy' with predominating pathology in the basal ganglia and midbrain. Caudal tau spread frequently implicates the cerebellum; however, the pattern of atrophy remains equivocal. We hypothesise that volume loss is appreciable in the cerebellum and brainstem regions-beyond the midbrain-in individuals with PSP and linked to motor and non-motor clinical features.

Methods: In this cross-sectional observational study, volumetric brainstem and cerebellar subsegmentation of T1-weighted magnetic resonance imaging (MRI) was performed in 37 adults with PSP. Group-level comparisons were made with 38 adults with Parkinson's disease (PD) and 35 healthy control (HC) subjects. Regional volumes in the PSP cohort were correlated against disease severity and cognition.

Results: Compared with HC, the midbrain, corpus medullare, and flocculonodular lobe were smaller in PSP (d = 0.90-1.2). Compared with PD, the midbrain, pons, and superior cerebellar peduncle (SCP) were smaller in PSP (d = 0.82-1.9). There was a positive correlation between the frontal assessment battery (FAB) and volume of the superior (r = 0.50) and inferior (r = 0.48) cerebellar posterior lobes. The PSP rating scale also correlated with SCP (r = -0.58) and midbrain (r = -0.52) volume.

Conclusion: Additional regions of brainstem and cerebellar volume loss, alongside midbrain atrophy, were observed in PSP. The reported clinico-radiologic correlations suggest a role of the cerebellum in cognitive dysfunction. These findings indicate that the cerebellum is not spared and support further work to understand the temporal course of cerebellar and cerebellar connectivity changes relative to other brain regions.

Background: Endovascular treatment (EVT) achieves high rates of recanalization in acute large-vessel occlusion (LVO) stroke, but functional recovery remains heterogeneous. While symptomatic intracranial hemorrhage (sICH) has been well studied, the prognostic impact of asymptomatic intracranial hemorrhage (aICH) after EVT is less certain.

Methods: We performed a pooled analysis of individual patient data from three randomized clinical trials (DEVT, RESCUE BT, MARVEL). Patients with anterior circulation LVO treated with EVT within 24 h were included. Hemorrhagic events were adjudicated by a blinded core laboratory using the modified Heidelberg Bleeding Classification. The primary outcome was 90-day modified Rankin Scale (mRS) distribution. Analyses included multivariable ordinal logistic regression, propensity score matching (PSM), and inverse probability of treatment weighting (IPTW). Exploratory analyses used LASSO-based selection to develop a risk model for a composite endpoint of aICH with poor outcome (mRS ≥ 4).

Results: Among 2562 eligible patients, 721 (28.1%) developed aICH, the median age was 68 years (IQR, 58-76), and 57% were women. aICH was significantly associated with worse functional outcomes (adjusted odds ratio, 0.51; 95% CI, 0.44-0.60) and higher mortality (adjusted odds ratio, 1.64; 95% CI, 1.28-2.0). These associations were consistent across analytic methods and subgroups. Parenchymal hematoma carried the greatest prognostic burden. Older age, higher baseline NIHSS scores, lower baseline ASPECTS, elevated admission glucose, and unsuccessful reperfusion are independently associated with aICH combined with poor prognosis.

Conclusions: AICH after EVT is independently associated with poorer functional recovery and higher mortality, highlighting its clinical significance beyond radiological detection.

Trial registration: ChiCTR.org.cn Identifier: ChiCTR-IOR-17013568; ChiCTR-IOR-17014167; ChiCTR2100051729.

Backgrounds: Alzheimer's disease (AD) is characterized by amyloid-beta plaques, tau tangles, and neuroinflammation. C-X3-C motif chemokine ligand 1 (CX3CL1, also known as fractalkine), a neuroimmune chemokine implicated in AD pathogenesis, shows inconsistent alterations in plasma/serum across studies. Specifically examining age-dependency and diagnostic utility, we investigated plasma CX3CL1 levels across the cognitive continuum (cognitively normal [CN], amnestic mild cognitive impairment [aMCI], AD) in a Chinese cohort.

Methods: A total of 443 participants, including 130 patients with AD, 72 patients with aMCI, and 99 age-and sex-matched CN controls, as well as a cohort of 142 CN subjects of different ages, were enrolled from Chongqing General Hospital. Plasma CX3CL1 levels were determined using Enzyme-Linked Immunosorbent Assay (ELISA). Apolipoprotein E genotypes (APOE) were performed. The correlations between Plasma CX3CL1 levels and cognition test scores or age were analyzed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis.

Results: Plasma CX3CL1 levels significantly increased with age in CN individuals. No significant sex difference was found. Plasma CX3CL1 levels did not differ significantly between APOE ε4 carriers and non-carriers. Stepwise elevation across continuum: CX3CL1 levels showed a significant stepwise increase: CN controls (1.73 ± 0.51 ng/mL) < aMCI (2.40 ± 1.06 ng/mL) < AD (4.15 ± 1.24 ng/mL) (p < 0.001 between all groups). This pattern persisted in both male and female subgroups, between the AD group and the aMCI group, between the AD group and the CN control group (p < 0.001), between the aMCI group and the CN control group, and between the male and female subgroups (p < 0.05). CX3CL1 levels negatively correlated with Mini-Mental State Examination (MMSE) scores and positively correlated with age.

Conclusions: Plasma CX3CL1 levels exhibit a significant age-dependent increase in cognitively normal individuals, peak in midlife (40-49 years), and demonstrate a stepwise elevation across the AD continuum (CN → aMCI → AD). Strong inverse correlations with cognitive scores in disease groups and high diagnostic accuracy for AD, particularly against CN, support its role as a biomarker reflecting both physiological aging and AD-related pathological decline. Its regulation appears independent of APOE ε4 status. The midlife peak suggests potential relevance for preclinical processes, warranting further investigation of CX3CL1 as a biomarker and therapeutic target.

Objective: Epidemiologic studies have reported inconsistent altered cancer risk in individuals with multiple sclerosis (MS). Factors such as immune dysregulation, comorbidities, and disease-modifying therapies may contribute to this variability. This study aimed to assess the potential causal effects and shared genetic risk between MS and 12 common cancers.

Methods: We used large-scale genetic studies for MS (47,429 cases, 68,374 controls) and 12 cancers (sample size 85,716 to 417,127). Two-sample Mendelian randomization (MR) was performed to estimate the causal effect of genetic liability to MS on cancer risk. Colocalization analysis was employed to identify shared genetic loci between MS and cancers. Tissue enrichment analyses for prioritized genes and directionality tests were performed.

Results: MR analyses found no evidence for a causal effect of MS liability on cancer risk after correcting for multiple testing. Colocalization analysis revealed 12 MS-cancer pairs across nine loci, implicating shared genetic mechanisms in six cancers. Ten out of the 12 colocalization pairs demonstrated antagonistic pleiotropy (p = 0.019). For example, variants in the BACH2 locus were associated with opposing risks for MS and non-melanoma skin cancers (posterior probability > 0.99). Fine mapping identified the rs72928038 variant as likely causal, its minor allele reducing BACH2 expression and increasing MS risk but decreasing skin cancer risk.

Interpretation: While no causal relationship between MS liability and cancer risk was identified, shared genetic effects highlight potential biological mechanisms linking immune regulation in MS and cancer risk. The observed antagonistic pleiotropy, where genetic variants increase MS risk but decrease cancer susceptibility, mirrors patterns seen in autoimmunity and infection.

Objectives: WHO grade 4 astrocytomas are associated with poor prognosis, and their prognostic factors remain controversial. This study aimed to identify the prognostic factors and develop a management algorithm for these patients.

Methods: This study retrospectively included 151 CNS5 adult grade 4 astrocytomas from two medical centers. The tumors were classified as histologic grade 2/3 astrocytomas with CDKN2A/B homozygous deletion (molecular grade 4 astrocytoma, MA4), histologic grade 4 astrocytomas with CDKN2A/B homozygous deletion (molecular and histologic grade 4 astrocytoma, MHA4), and histologic grade 4 astrocytomas without CDKN2A/B homozygous deletion (histologic grade 4 astrocytoma, HA4). Prognostic factors were identified and incorporated into recursive partitioning analysis (RPA) for survival risk stratification.

Results: Histologic grade 4 astrocytomas with CDKN2A/B homozygous deletion, postoperative tumor volume (TV), and chemoradiotherapy were associated with patient survival. RPA identified three groups with distinct prognoses (p = 0.001). Group 1 had a median overall survival (OS) of 77.8 months, consisting of MA4 and HA4 with postoperative TV on FLAIR ≤ 28.5 mL. Group 2 had a median OS of 32.2 months, including MA4 and HA4 with postoperative TV on FLAIR > 28.5 mL receiving chemoradiotherapy, or MHA4 with postoperative TV on FLAIR ≤ 28.5 mL. Group 3 had a median OS of 14.9 months, including MA4 and HA4 with postoperative TV on FLAIR > 28.5 mL without chemoradiotherapy, or MHA4 with postoperative TV on FLAIR > 28.5 mL receiving chemoradiotherapy.

Conclusion: Histologic grade 4 astrocytomas with CDKN2A/B homozygous deletion confer the worst survival. Maximal or complete resection, as assessed on FLAIR images, is critical to improving outcomes.

The role of inflammation in cortical superficial siderosis (cSS), a marker of cerebral amyloid angiopathy (CAA) linked to high hemorrhage risk, is unclear. We examined 15 patients with cSS using 3 T post-contrast vessel wall MRI (VWI) and CSF analysis. Although only 27% met current CAA-ri criteria, 93% showed vessel wall enhancement or sulcal hyperintensities near cSS, frequently extending beyond. Seven patients with follow-up VWI demonstrated corticosteroid-responsive regression of inflammation. CSF albumin quotients, indicating blood-brain barrier dysfunction, correlated with MRI inflammation scores. These findings reveal subclinical meningovascular inflammation in cSS and support VWI for detecting a broader CAA-related inflammation spectrum.

Objective: Cerebrospinal fluid (CSF) analysis is a key diagnostic tool for neurological diseases. To date, only a few studies have investigated in larger cohorts the effect of age and biological sex on diagnostic markers extracted from CSF.

Methods: For this retrospective observational study, 4163 CSF findings (2012-2020) were evaluated. After exclusion of pathogenic CSF findings above or below the locally established reference ranges that are routinely applied in the CSF laboratory for clinical reporting, 1270 findings were included for statistical analysis. Using regression analysis, the relationship between age and CSF markers was illustrated, and regression equations were created.

Results: A significant effect of sex was shown for CSF albumin (p < 0.001; ΔM 29.34), CSF protein (p < 0.001; ΔM 39.38) and CSF glucose (p < 0.001; ΔM 3.63) as well as CSF/serum albumin quotient (Q Alb) (p < 0.001; ΔM 0.57), for Immunoglobulin G in CSF (IgG CSF) (p < 0.001; ΔM 2.48), CSF/serum IgG quotient (Q IgG) (p < 0.001; ΔM 0.27), Immunoglobulin A in CSF (IgA CSF) (p < 0.001; ΔM 0.52), CSF/serum IgA quotient (Q IgA) (p < 0.001; ΔM 0.15) and CSF/serum IgM quotient (Q IgM) (p < 0.001; ΔM 0.09). Age showed a significant effect throughout most CSF markers, most strongly for CSF protein (p < 0.001; η² = 0.16) and Q Alb (p < 0.001; η² = 0.23). Both parameters increased significantly with age, leading to higher mean values in older individuals.

Interpretation: For almost all markers in CSF, a significant effect of age alone on the markers or a significant effect of sex and age on the markers could be detected. Our study underscores the importance of age- and sex-adjusted reference values for the interpretation of CSF markers in clinical practice.