Journal of Neurology最新文献

Spinal muscular atrophy (SMA) is a rare neuromuscular disease caused by biallelic mutations in the SMN1 gene, leading to progressive muscle weakness due to degeneration of the anterior horn cells. Since 2017, SMA patients can be treated with the anti-sense oligonucleotide Nusinersen, which promotes alternative splicing of the SMN2 gene, by regular intrathecal injections. In this prospective study, we applied metabolomic, lipidomic, and proteomic analysis to examine sequential CSF samples from 13 SMA patients and controls. This multi-omic approach identified over 800 proteins and 400 small molecules including lipids. Multivariate analysis of multi-omic data successfully discriminated between the CSF derived from SMA patients and control subjects. Lipidomic analysis revealed increased levels of cholesteryl esters and lyso-phospholipids, along with reduced levels of cholesterol and phospholipids in the CSF of SMA patients as compared to healthy controls. These data, combined with results from functional assays, led us to conclude that SMA patients exhibit altered levels and function of high-density-lipoprotein (HDL)-like particles in the CSF. Notably, Nusinersen therapy was observed to reverse disease-specific profile changes toward a physiological state, potentially explicable by restoring HDL function.

The classification of multiple sclerosis (MS) into the two distinct phases of relapsing-remitting and progressive, including primary progressive and secondary progressive phenotypes (PPMS and SPMS, respectively) has long been accepted; however, there are several unmet needs associated with this particular model. The observation that both inflammation and neurodegeneration are present from the onset of MS has resulted in a paradigm shift towards MS as a disease continuum driven by pathological mechanisms underlying clinical progression. Here we report the results from a meeting of Italian MS specialists, exploring the evolving perception of MS pathobiology and its implications for diagnosis and treatment. Insights garnered from the expert panel advocate for a redefined understanding of MS. This expert opinion paper reviews the disease continuum and the intertwined nature of inflammatory and neurodegenerative processes. Also, the need for changes in diagnostic criteria and treatment strategies, including the development of novel biomarkers and new therapies targeting smouldering disease, is discussed.

Background: Risk stratification based on intracranial plaque characteristics is crucial for patients with intracranial atherosclerosis (ICAS). Nonetheless, there remains a significant deficit of validated imaging markers capable of predicting recurrent strokes. Consequently, we conducted a systematic review and meta-analysis to investigate the prognostic significance of high-risk plaque characteristics (HPCs) in relation to recurrent stroke.

Methods: The systematic review was registered in PROSPERO (CRD420245820945). We systematically searched PubMed, Ovid Medline, and Web of Science for studies evaluating the association between HPCs and risk of stroke recurrence. Data were aggregated and pooled using a random-effects meta-analysis. Heterogenicity and publication bias were assessed, with subgroup and sensitivity analyses performed where appropriate.

Results: Eighteen studies, comprising 13 prospective and 5 retrospective, involving a total of 4967 patients (3594 symptomatic, and 1373 asymptomatic), were included in the analysis. Among symptomatic patients, those with HPCs exhibited a higher incidence of stroke recurrence compared to those without HPCs (adjusted HR, 3.90 ([95% CI, 2.15-7.08]). ICAS patients with baseline plaque enhancement (adjusted HR, 5.20 [95% CI, 3.12-8.66]), calcification (adjusted HR, 2.92 [95% CI, 1.32-6.45]), high plaque steepness (adjusted HR, 110.27 [95% CI, 4.75-2559.74]), and progression in plaque burden (adjusted HR, 6.29 [95% CI, 1.62-24.45]) were identified as being at an increased risk of stroke recurrence. Subgroup analyses revealed that traditional cerebrovascular risk factors, including increasing age, hypertension, diabetes mellitus, and smoking, further elevated the risk of HPC-related stroke recurrence in ICAS patients.

Conclusion: The identification of HPCs confers independent prognostic value for the prediction of stroke recurrence in ICAS patients, which could be instrumental for patients risk stratification.

Background: Neuromuscular diseases (NMDs) and mitochondriopathies are rare and heterogeneous disorders. Diagnosis is often difficult and delayed, partly due to the lack of reliable biomarkers. Chitotriosidase (CHIT1) as a candidate marker for lysosomal storage diseases is elevated in Niemann pick disease type C as a prototype of this group of diseases. Most recently, a relevant role of the lysosomal pathway in mitochondriopathies has been discussed, but markers of lysosomal involvement have not been investigated. Therefore, the aim of this study was to evaluate CHIT1 concentrations in a broad spectrum of NMDs and mitochondriopathies.

Methods: CHIT1 serum concentration of 151 patients with NMD or primary mitochondriopathy was determined by enzyme-linked immunosorbent assay, and compared to 38 healthy controls and 8 patients with Niemann pick disease type C. Results were controlled for age, sex, CRP and CHIT1 polymorphism, and compared to several established markers (CK, FGF21, GDF15).

Results: CHIT1 levels were not altered in NMDs, but significantly increased in mitochondriopathies, within the range of Niemann-Pick patients. Compared to the established biomarkers, CHIT1 and FGF21 showed a similar diagnostic performance, while better results were found for GDF15. However, there was a tendency for higher CHIT1 concentrations in patients with central nervous system involvement (MELAS syndrome), while FGF21 and GDF15 were not relevantly altered in these patients. Consequently, a combination of biomarkers including CHIT1 provided the best overall diagnostic performance.

Conclusions: Serum CHIT1 concentration is significantly elevated in mitochondriopathies compared to healthy controls and other NMD, identifying CHIT1 as potential complementary biomarker in mitochondriopathies.

Background: Comprehensive neurocognitive function analyses of autoimmune encephalitis (AE) patients, especially long-term ones, are rare. This study aims to measure cognitive function in patients diagnosed with AE.

Methods: This case-control study included AE patients (n = 11) with antibodies against NMDA receptor (NMDAR) (n = 4), VGKC (n = 3), GAD (3), and one antibody-negative patient. The control group contained 12 pneumococcal meningo-encephalitis patients (PC). Subgroup analyses compared AE patients with and without NMDAR antibodies. Neurocognitive tests were performed to evaluate verbal and visual memory, face recognition, attentional capacity, incidental learning capacity, and overall cognitive function (Montreal cognitive assessment, MoCA). Limbic structural involvement was assessed through magnetic resonance imaging (MRI). Statistical analyses investigated correlations between antibody status, results of neurocognitive tests, and MRI findings.

Results: Follow-up (AE vs. PC) was 33 (11-95) vs. 96 (26-132) months after diagnosis. Neurocognitive functions were normal in both AE and PC groups in all tests except face recognition, which was pathological in both groups. The overall/recognition/long-delay visual memory (p = 0.009/0.008/0.005) and incidental learning (p = 0.017) scores were significantly higher in NMDAR patients compared to non-NMDAR patients. Non-NMDAR patients with right-sided limbic MRI pathologies had significantly lower overall/recognition/long-delay visual memory (p = 0.006/0.044/0.024) and incidental learning (p = 0.009) scores compared to NMDAR patients.

Conclusions: We observed mainly normal neurocognitive functions after autoimmune and bacterial encephalitis. However, compared to NMDAR patients, patients with non-NMDAR autoimmune encephalitis showed a significant and material-specific association between a right-sided hippocampal lesion and limitations in figural-mnestic and incidental learning capacities. Neurocognitive functions in AE patients should be further evaluated prospectively and in more detail.