Annals of Clinical and Translational Neurology最新文献

Objective: Posterior Cortical Atrophy (PCA) is a distinct dementia syndrome primarily affecting spatial abilities and visual processing. It is associated with degeneration in the posterior part of the brain. PCA is subclassified into PCA-pure and PCA-plus syndromes based on consensus criteria. To address this, the PCA Asia Workgroup was established to study PCA in Asian countries.

Methods: The Asia PCA Workgroup collected demographic and clinical data, including symptoms and signs, from PCA patients. Patients were classified into PCA-pure (solely meeting PCA criteria) and PCA-plus (additional features of other neurodegenerative syndromes). The frequency of clinical presentations, symptoms, and signs was compared to the consensus classification estimation and the meta-analysis of published data.

Results: PCA-pure (76.2%) was the most common subtype, with earlier onset (80.95%) and distinct early prominent deficit of executive/memory > visual disturbances which is different from the consensus study has estimated and the meta-analysis of published data. PCA-Lewy body disease (PCA-DLB) exhibited higher frequencies of attention deficits, visual hallucinations, cognitive fluctuations, and rigidity compared to PCA-pure.

Interpretation: This study reveals the real-world clinical presentation of PCA syndrome in an Asian population, emphasizing the differences from consensus estimations and the meta-analysis of published data. Further research is needed to validate these findings and compare them with real clinical data from PCA patients of other ethnicities, in order to gain a comprehensive understanding of PCA worldwide.

Objective: Hereditary spastic paraplegia (HSP) is a group of disorders characterized by progressive spasticity and lower limb weakness, with mutations in SPG4/SPAST being the most common cause. Detailed studies and clinical and molecular comparisons across different populations are missing. We examined the clinical, pathological, and genetic spectrum of the SPG4/SPAST gene in patients with HSP.

Methods: The study involved 726 HSP patients recruited from Italy, Brazil, and Japan between 2001 and 2025, with analysis conducted in collaborative centers. SPG4/SPAST variants were identified using direct and next-generation sequencing. The pathogenicity of novel variants was confirmed through familial segregation and in silico analysis.

Results: Clinical and epidemiological differences were observed across populations, particularly in phenotype, age at onset, and disability, expanding the SPG4 clinical spectrum. Genetic analysis identified 52 pathogenic SPG4/SPAST mutations in 284 patients, including four novel variants. Several mutations were population-specific, and a possible founder effect was suggested for a recurrent variant in Italy. Dementia occurred in 44 HSP-SPG4 patients and was neuropathologically confirmed in four unrelated autopsied cases from four families comprising 28 individuals; atypical pathological features were observed in all four autopsied cases. Additionally, 18 patients with SPG4/SPAST mutations presented with thin corpus callosum and intellectual disability.

Interpretation: In this study, we investigated pathogenic SPG4/SPAST variants in an international cohort of HSP patients from three continents. Our findings expand the clinical spectrum of HSP-SPG4, identifying a new type complicated by an atypical pathological form of dementia. Careful assessment of genotype-phenotype relationships offers insights into patient counseling and future research planning.

Objective: Considerable efforts have been dedicated to developing effective treatments for post-stroke executive impairment (PSEI), among which repetitive transcranial magnetic stimulation (rTMS) has shown great potential. This study aimed to investigate the therapeutic effects of high-frequency rTMS on working memory (WM) and response inhibition (RI) of executive functions in PSEI patients and the potential neural mechanisms.

Methods: In a randomized, double-blind trial, 10 Hz rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) in 32 PSEI patients for 10 days, who were divided into real and sham rTMS groups. The Stroop color-word test (SCWT), digit span test (DST), and functional near-infrared spectroscopy (fNIRS) were used for assessment before and after the intervention. Resting-state functional connectivity (rsFC) and graph theory methods were used to analyze changes in brain function.

Results: Compared to the sham rTMS group, the real rTMS group showed significant reductions in SCWT response time (F = 4.223, p = 0.049) and improvements in DST forward scores (F = 4.739, p = 0.037) after the intervention. Moreover, the real rTMS group demonstrated significant enhancements in rsFC from left DLPFC to the right DLPFC (F = 8.538, p = 0.007) and the right posterior parietal cortex (F = 9.905, p = 0.004), as well as in the Degree Centrality of the left DLPFC (F = 7.144, p = 0.012), which were respectively significantly correlated with reduced SCWT response time and increased DST forward scores.

Conclusions: High-frequency rTMS effectively improves WM and RI performance in patients with PSEI, which may be attributed to the remodeling of specific connectivity patterns and enhancement of local communication efficiency within the frontoparietal network.

Objective: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration. Glycolytic dysregulation is implicated in disease progression, yet the underlying mechanisms remain unclear. This study investigates how Aldolase A (ALDOA) drives ALS progression through glycolysis-mediated motor neuron pyroptosis.

Methods: In vivo, tamoxifen-induced TDP-43 cKO mice were assessed for motor function (rotarod/suspension tests), motor cortex L-lactic acid, and ALDOA/NLRP3/GSDMD expression. The ALDOA inhibitor Aldometanib was administered. In vitro, TDP-43 KO NSC34 cells were used to measure viability, glucose uptake, and L-lactic acid.

Results: ALS model mice exhibited significant motor deficits, progressive weight loss, and reduced survival. Their motor cortex showed elevated ALDOA expression, L-lactic acid accumulation, and NLRP3/GSDMD inflammasome activation. Aldometanib treatment suppressed glycolysis, prolonged survival, and slowed disease progression by inhibiting NLRP3/GSDMD-mediated pyroptosis. In vitro, TDP-43-deficient NSC34 cells displayed increased ALDOA levels, enhanced glycolytic flux, NLRP3/GSDMD pathway activation, and impaired proliferation.

Conclusion: We show that ALDOA-mediated glycolytic dysregulation activates the NLRP3/GSDMD inflammasome, leading to pyroptosis in motor neurons. Pharmacological inhibition of ALDOA alleviates glycolytic dysregulation and extends survival, identifying ALDOA as a potential therapeutic target.

Objective: Although hippocampal sclerosis (TLE-HS) represents the most frequent cause of temporal lobe epilepsy (TLE), up to 30% of patients show no lesion on visual MRI inspection (TLE-MRIneg). These cases pose diagnostic and therapeutic challenges and are underrepresented in surgical series. We investigated whether TLE-MRIneg constitutes a distinct clinical and neuroanatomical entity compared to TLE-HS and aimed to identify subtypes within the TLE-MRIneg group.

Methods: We analyzed MRI and clinical data from 209 patients with TLE and 102 healthy controls from the multicenter "3TLE project". Based on expert radiological review, 96 patients were classified as TLE-MRIneg and 76 as TLE-HS; the remaining 37 were excluded due to other focal lesions. We compared clinical characteristics and brain morphometry between TLE-MRIneg and TLE-HS and applied clustering techniques to detect TLE-MRIneg subtypes.

Results: Compared with TLE-HS, TLE-MRIneg was associated with later onset, shorter disease duration, and milder clinical presentation. TLE-HS patients exhibited widespread cortical and subcortical atrophy, while TLE-MRIneg showed only subtle cortical thinning. Cluster analysis revealed two subtypes of TLE-MRIneg: one characterized by ipsilateral amygdala enlargement (AE) and the other by diffuse cortical atrophy.

Interpretation: These findings demonstrate that TLE-MRIneg represents a distinct clinical-imaging entity from TLE-HS. The identification of morphologically defined subtypes, particularly AE, highlights the heterogeneity of TLE-MRIneg and its potential clinical relevance. This work supports the use of advanced imaging and data-driven methods to improve diagnosis and guide individualized management in non-lesional epilepsies.

Objective: Intravenous thrombolysis (IVT) before thrombectomy for ischemic stroke may alter clot structure and procedural performance. We investigated how IVT relates to thrombectomy metrics across stroke etiologies.

Methods: We performed a time-to-event analysis of consecutive patients with anterior circulation large vessel occlusion (acLVO) stroke from a prospective thrombectomy registry at a German tertiary stroke center (January 2017-January 2023). The associations between IVT and groin-to-recanalization time and number of aspiration attempts were assessed using multivariable stratified Cox regression adjusted for demographic, cardiovascular, and stroke-related variables.

Results: Of 1702 patients screened, 798 (413 female [51.8%], median age 77 years [66, 84; IQR]) underwent thrombectomy. IVT was administered to 395 (49.5%) patients, and successful reperfusion (mTICI ≥ 2b) was achieved in 680 (85.2%) patients. In non-cardioembolic stroke, IVT facilitated clot removal, yielding a 40% higher likelihood of successful reperfusion at any time point compared with direct thrombectomy (aHR 1.40; 95% CI [1.08, 1.81]; p = 0.01) and a 36% reduction of aspiration attempts (IRR = 0.64, 95% CI [0.50-0.84], p = 0.001). In cardioembolic stroke, IVT did not alter the incidence of successful reperfusion during thrombectomy (aHR 1.13; 95% CI [0.92, 1.39]; p = 0.26) or the number of aspiration attempts (combined IRR ≈ 1.00, 95% CI [0.82-1.22]) but was associated with a 43% lower likelihood of successful reperfusion throughout the intervention if distal thrombus migration occurred (aHR 0.57; 95% CI [0.33, 0.96]; p = 0.03).

Interpretation: IVT was associated with faster reperfusion during thrombectomy in non-cardioembolic acLVO, whereas in cardioembolic stroke with distal clot migration it was associated with delayed reperfusion.

Objective: To evaluate [¹⁸F]fluorodeprenyl-D2 ([¹⁸F]F-DED) positron-emission tomography (PET) imaging as a biomarker of disease activity in autoimmune encephalitis (AIE) associated with glutamic acid decarboxylase 65 (GAD65) antibodies.

Methods: [¹⁸F]F-DED PET was performed in 25 GAD65-AIE patients and 8 controls using dynamic (0-60 min) and static (30-60 min) acquisitions. Global astrogliosis was assessed by volumes of distribution (VT; 1-tissue-compartment model with carotid input) and standardized uptake values (SUV). Regional cerebellar and mesiotemporal (MT) uptake was normalized to global uptake (SUVr). PET measures were correlated with clinical phenotypes, MRI findings, and serum biomarkers (neurofilament light chain [sNfL], GAD65-Ab titers, and glial fibrillary acidic protein [sGFAP]).

Results: Clinical phenotypes included limbic encephalitis/temporal lobe epilepsy (LE/TLE; n = 17), stiff-person syndrome (n = 4), and cerebellar ataxia (CA; n = 4), with overlap in nine patients. Global [¹⁸F]F-DED uptake was higher in patients than controls. VT analysis showed increased cortical and MT uptake, while SUVr analysis demonstrated elevated MT uptake across the cohort. LE/TLE patients exhibited increased MT uptake, and CA patients showed higher cerebellar uptake. [¹⁸F]F-DED uptake did not correlate with sNfL or GAD65-Ab titers, but sGFAP showed associations with cerebellar and white-matter uptake. Regional uptake correlated with clinical severity in LE/TLE (MT lobe) and CA (cerebellar white matter).

Interpretation: [¹⁸F]F-DED PET reveals region-specific astrogliosis corresponding to clinical manifestations and disease severity in GAD65-AIE, supporting its potential as a monitoring tool for disease activity.

Objective: Sarcoglycanopathies are among the most severe limb-girdle muscular dystrophies (LGMD), though milder presentations have been described. These diseases are primarily caused by missense variants, but the limited predictability of their effect on protein maturation, complex formation, and transport has hindered reliable genotype-phenotype correlations. This study aimed to establish accurate genotype-phenotype correlations for LGMDR3, LGMDR4, and LGMDR5.

Methods: We analyzed the largest sarcoglycanopathy cohort to date (n = 541). Clinical data, including age at symptom onset and loss of ambulation, were collected and used to define phenotype severity. Predictive models were developed considering the impact of non-truncating variants on secondary structure, functional domains, evolutionary conservation, and intra-complex protein-protein interactions. Patients carrying two variants predicted to disrupt membrane trafficking were expected to present with severe phenotypes.

Results: For LGMDR3, the best-performing model classified variants affecting β-sheets, cadherin-like, and ATP-binding domains as disruptive to membrane translocation, achieving 89% predictive power, 0.867 balanced accuracy, and 2.4% false-negative rate (clinically severe patients who were wrongly classified by the model as mild). For LGMDR4 and LGMDR5, the best-performing model involved conserved residues, β-sheets, EGF-like domain, and protein-protein interactions-reaching 80% predictive power, 0.689 balanced accuracy, and 3.1% false-negative rate (LGMDR4), and 90% predictive power, 0.536 balanced accuracy, with no false negatives (LGMDR5). Additionally, we developed an open-access predictive tool for clinical and research application.

Interpretation: This study provides a robust genotype-phenotype correlation for sarcoglycanopathies, improving prognosis, patient management, and clinical trial recruitment.