Journal of Neurology最新文献

{"title":"Richard B. Stein (1940-2020).","authors":"Alberto Arturo Vergani","doi":"10.1007/s00415-025-13392-7","DOIUrl":"https://doi.org/10.1007/s00415-025-13392-7","url":null,"abstract":"","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"674"},"PeriodicalIF":4.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered gut microbiota mediates the association between APOE genotype and amyloid-β accumulation in middle-aged adults.","authors":"Yannick N Wadop, Rebecca Bernal, Wepnyu Y Njamnshi, Claudia L Satizabal, Alexa Beiser, Agustin Ruiz, Alfred K Njamnshi, Ramachandran S Vasan, Sudha Seshadri, Jayandra Jung Himali, Bernard Fongang","doi":"10.1007/s00415-025-13412-6","DOIUrl":"10.1007/s00415-025-13412-6","url":null,"abstract":"<p><strong>Background: </strong>The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer's disease, yet the mechanisms linking APOE to amyloid-β (Aβ) pathology remain incompletely understood. Emerging evidence suggests that the gut microbiome may modulate neurodegeneration; however, its role as a mediator in the APOE-Aβ relationship remains unclear.</p><p><strong>Objective: </strong>Evaluate whether specific microbial taxa mediate APOE-related effects on brain Aβ burden in a population-based study.</p><p><strong>Methods: </strong>This study involved 227 participants from the Framingham Heart Study with stool 16S rRNA sequencing and carbon-11 Pittsburgh Compound-B imaging for Aβ collected at the third examination (2016-2019). Associations between gut microbiota and global/regional Aβ deposition were assessed using multivariable models. We stratified participants by APOE ε4 status and conducted mediation analysis to evaluate whether specific taxa mediated APOE-related effects on Aβ. Microbial functional potential was inferred to examine enrichment of metabolic pathways.</p><p><strong>Results: </strong>Higher Aβ burden was significantly associated with the depletion of protective genera (e.g., Faecalibacterium, Ruminococcus, Butyricicoccus) and the enrichment of pro-inflammatory taxa (e.g., Alistipes, Bacteroides) and Barnesiella. These associations were more pronounced in APOE ε4 carriers, who exhibited a broader spectrum of microbial dysbiosis. Mediation analysis showed that Ruminococcus, Butyricicoccus, Clostridium, and Christensenellaceae collectively mediated ~ 0.3-0.4% of the effect of APOE ε4 on global Aβ burden. Functional profiling revealed a reduced abundance of microbial genes involved in key metabolic pathways among individuals with higher Aβ levels.</p><p><strong>Conclusion: </strong>Gut microbiome composition mediates the deleterious effect of APOE ε4 on cerebral amyloid deposition, suggesting that microbiome-targeted interventions may mitigate APOE-related risk.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"670"},"PeriodicalIF":4.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12491116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Idiopathic intracranial hypertension and Ehlers-Danlos syndrome: a case series.","authors":"Isha V Ingle, David F Santos Malave, Gabrielle Bonhomme","doi":"10.1007/s00415-025-13416-2","DOIUrl":"https://doi.org/10.1007/s00415-025-13416-2","url":null,"abstract":"<p><strong>Background: </strong>Ehlers Danlos syndrome (EDS) is a group of 13 heritable connective tissue disorders with various ophthalmic manifestations. Idiopathic intracranial hypertension (IIH) is the presence of raised intracranial pressure (ICP) without specific neurological disease and deficits along with normal neuroimaging. The relationship between EDS and IIH has not been evaluated. In this report, we present a series of three confirmed cases of EDS with features of IIH.</p><p><strong>Case series: </strong>Case 1 was a 23 year old female patient with EDS who presented with intractable headaches. Her lumbar puncture (LP) had an elevated opening pressure of 53 cm H₂0 and an MRI showed signs of raised ICP. Similarly, Case 2 was a 38 year old female who presented with worsening headaches in the setting of clinically proven EDS. LP had an elevated opening pressure of 37 cm H₂0 and an MRI showed signs of raised ICP. Optical coherence tomography (OCT) showed ganglion cell loss. Case 3 was a 55 year old female with EDS who presented with diplopia and pituitary microadenoma in the setting of chronic IIH. OCT showed nerve fiber layer and ganglion cell loss. We did not observe papilledema in any of the cases.</p><p><strong>Conclusion: </strong>This is the largest series of cases linking IIH to EDS. Hyperextensibility may make meninges more pliable and tolerant to raised ICP. There may be a potential association between IIH and EDS, and IIH may be considered as one of the rare manifestations of EDS.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"673"},"PeriodicalIF":4.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain age as an accurate biomarker of preclinical cognitive decline: evidence from a 12-year longitudinal study.","authors":"Odelia Elkana, Iman Beheshti","doi":"10.1007/s00415-025-13414-4","DOIUrl":"https://doi.org/10.1007/s00415-025-13414-4","url":null,"abstract":"<p><p>Cognitive decline in older adults, particularly during the preclinical stages of Alzheimer's disease (AD), presents a critical opportunity for early detection and intervention. While T1-weighted MRI is widely used in AD research, its capacity to identify early vulnerability and monitor longitudinal progression remains incompletely characterized. We analyzed longitudinal T1-weighted MRI data from 224 cognitively unimpaired older adults followed for up to 12 years. Participants were stratified by clinical outcome into converters to mild cognitive impairment (HC-converters, n = 112) and stable controls (HC-stable, n = 112). Groups were matched at baseline for age (mean ~ 74-75 years), education (~ 16.4 years), and cognitive scores (MMSE ≈ 29; CDR-SB ≈ 0.04). Four MRI-derived biomarkers were examined: brain-predicted age difference (brain-PAD), mean cortical thickness, AD-cortical signature, and hippocampal volume. Brain-PAD showed the strongest baseline association with future conversion (β = 1.25, t = 3.52, p = 0.0009) and highest classification accuracy (AUC = 0.66; sensitivity = 62%, and specificity = 67%). Longitudinal mixed-effects models focusing on the group × time interaction revealed a significant positive slope in brain-PAD for converters (β = 0.0079, p = 0.003) and a non-significant trend in stable controls (β = 0.0047, p = 0.075), indicating incipient divergence in brain aging trajectories during the preclinical window. Hippocampal volume and AD-cortical signature declined similarly in both groups. The mean cortical thickness had limited discriminative or dynamic utility. These findings support brain-PAD, derived from routine T1-weighted MRI using machine learning, as a sensitive, performance-independent biomarker for early risk stratification and monitoring of cognitive aging trajectories.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"672"},"PeriodicalIF":4.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGCR genetic variability in Parkinson's disease in a Spanish cohort: associations with lipid metabolism and early onset.","authors":"Rafael Díaz-Belloso, Miguel Martín-Bornez, Daniel Macías-García, Sergio García-Díaz, Marta Bonilla-Toribio, Dolores Buiza-Rueda, Rocío Pineda Sánchez, Laura Muñoz-Delgado, Elena Ojeda, Silvia Jesús, Astrid Adarmes-Gómez, Fátima Carrillo, Pablo Mir, Pilar Gómez-Garre","doi":"10.1007/s00415-025-13404-6","DOIUrl":"10.1007/s00415-025-13404-6","url":null,"abstract":"<p><p>Lipid metabolism has emerged as a key factor in the pathophysiology of Parkinson's disease (PD). While 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis, has been implicated in neurodegenerative disorders, such as Alzheimer disease, its role in PD remains unexplored. Given the shared pathological features between these neurodegenerative disorders (such as lysosomal dysfunction and lipid dysregulation) we hypothesized that HMGCR genetic variability could influence PD susceptibility and/or phenotypic expression, particularly in early-onset cases (EOPD). Therefore, we performed targeted sequencing of HMGCR in 1162 Spanish PD patients and analyzed associations with PD risk or age at onset. Replication was attempted in 436 PD cases from Parkinson's Progression Markers Initiative (PPMI). We identified 21 HMGCR variants, including a likely pathogenic variant affecting the splice site of exon 4 (c.278-1G > A) in a patient with early-onset PD (EOPD), rapid progression, and severe dyslipidemia. The rs5908 variant was significantly associated with EOPD in our cohort (OR = 2.22, p = 0.025). Further analysis revealed rs5908 is in linkage disequilibrium with rs115169875, an intronic variant with putative regulatory impact. Our findings nominate HMGCR as a candidate gene for PD development, particularly in early-onset cases. The metabolic profile of the c.278-1G > A carrier parallels GBA-associated PD, suggesting convergent lipid-lysosomal pathways in neurodegeneration. While cohort differences highlight population-specific genetic effects, these findings underscore the importance of lipid pathways in PD and the need to explore HMGCR's role in PD subtypes with metabolic comorbidity.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"671"},"PeriodicalIF":4.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12491363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-driven subtypes of subjective cognitive decline: neuropsychological profiles, Alzheimer's disease biomarkers, and clinical trajectories.","authors":"Salvatore Mazzeo, Sara Boveri, Elisa Bortolin, Giulia Bruschi, Emanuele Girani, Alessandro Bombaci, Federico Emanuele Pozzi, Maria Vittoria Corbari, Federico Ambrogi, Federica Agosta, Massimo Filippi, Maria Salsone","doi":"10.1007/s00415-025-13418-0","DOIUrl":"https://doi.org/10.1007/s00415-025-13418-0","url":null,"abstract":"<p><strong>Objectives: </strong>Subjective Cognitive Decline (SCD) is a heterogeneous condition recognized as the earliest manifestation of Alzheimer's disease (AD). We hypothesized that the heterogeneity of SCD may be synthesized in distinct subtypes.</p><p><strong>Methods: </strong>We analyzed data from the AD Neuroimaging Initiative (ADNI) database. For all participants, demographic variables, cognitive measures, APOE genotype, CSF biomarkers, brain MRI, and FDG-PET data were available. Participants underwent follow-up visits every 6 or 12 months.</p><p><strong>Results: </strong>542 cognitively normal (CN), 346 SCD, and 423 early mild cognitive impairment (E-MCI) individuals were included. A data-driven approach based on cognitive measures identified three SCD clusters (k1, k2, k3) that performed differently in verbal memory (k2 outperformed all the groups and k3 showed the poorest performance, p < 0.001) and in executive function (k1 had the lowest scores, p = 0.006). Regarding CSF biomarkers, k2 exhibited lower p-tau (20.6 ± 9.2 vs. 24.2 ± 13.6, p = 0.03) and k3 had higher Aβ₄₂ levels (1131.3 ± 379.8 vs. 942.87 ± 355.3, p = 0.01) compared to the E-MCI group, while there were no differences between k1 and E-MCI. Regarding brain FDG-PET, k1 demonstrated reduced uptake compared to CN, k2, and k3 (p < 0.001). During follow-up, k1 exhibited a higher rate of progression to MCI or dementia compared to k2 and k3 (Log-rank χ² = 18.18, p = 0.0002) and a steeper decline in general cognition and long-term verbal memory compared to k2.</p><p><strong>Interpretation: </strong>We proposed a three-subgroup system classification for SCD, reflecting different cognitive profiles and longitudinal trajectories. Classifying individuals with SCD may enhance diagnostic pathways and inform personalized interventions.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"669"},"PeriodicalIF":4.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ataxia with oculomotor apraxia type 2: two pedigree studies and a comprehensive review.","authors":"Lang Yang, Sushuang Yang, Jianfei Liu, Xiaoyang Lei, Dian He","doi":"10.1007/s00415-025-13277-9","DOIUrl":"https://doi.org/10.1007/s00415-025-13277-9","url":null,"abstract":"<p><strong>Background: </strong>Ataxia with oculomotor apraxia type 2 (AOA2), a rare autosomal recessive neurodegenerative disorder, exhibits marked clinical heterogeneity, thereby presenting substantial diagnostic challenges. This study conducts an investigation of two pedigrees with SETX gene mutation-associated AOA2, coupled with a review of the clinical manifestations and genetic characteristics documented in previously reported study.</p><p><strong>Methods: </strong>Clinical data were collected from probands and their respective family members. A systematic literature review of AOA2 cases was conducted utilizing the PubMed, Google Scholar, and Web of Science databases to analyze the clinical and genetic characteristics.</p><p><strong>Results: </strong>Both pedigrees exhibited progressive gait instability, dysarthria, peripheral neuropathy, cerebellar atrophy, and elevated α-fetoprotein (AFP). Genetic testing identified a homozygous c.7034_7036delTAA mutation in Pedigree A and compound heterozygous mutations (c.6812A > G and exon7-10 deletion) in Pedigree B. Literature review of 216 patients revealed median onset age of 15 years old (interquartile range: 13-18), with 77.1% developing symptoms between 10 and 20 years. Key clinical features included ataxia (100%), dysarthria (99.2%), cerebellar atrophy (99.4%), and elevated AFP (97.6%). Oculomotor apraxia was observed in 34.2% of cases. Disease progression to wheelchair dependence averaged 15.9 ± 8.6 years, with no significant differences observed in gender or adult onset and juvenile onset.</p><p><strong>Conclusions: </strong>We identified novel SETX mutations in patients with AOA2. Notably, oculomotor apraxia is not always a clinical manifestation of AOA2 at diagnosis. Mild elevation of AFP could serve as a valuable diagnostic indicator in people with hereditary ataxia. Disease progression to wheelchair dependence may not be correlated with gender and age of onset.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"668"},"PeriodicalIF":4.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wilhelm Waldeyer (1836-1921).","authors":"Lazaros C Triarhou","doi":"10.1007/s00415-025-13399-0","DOIUrl":"https://doi.org/10.1007/s00415-025-13399-0","url":null,"abstract":"","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"663"},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Max Isserlin (1879-1941).","authors":"Lazaros C Triarhou","doi":"10.1007/s00415-025-13377-6","DOIUrl":"https://doi.org/10.1007/s00415-025-13377-6","url":null,"abstract":"","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"661"},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A spatial covariance ¹²³I-5IA-85380 SPECT study of α4β2 nicotinic receptors in dementia with Lewy bodies.","authors":"Judith R Harrison, Sean J Colloby, John T O'Brien, John-Paul Taylor","doi":"10.1007/s00415-025-13332-5","DOIUrl":"10.1007/s00415-025-13332-5","url":null,"abstract":"<p><strong>Background: </strong>Cholinergic dysfunction, particularly involving nicotinic acetylcholine receptors (nAChRs), contributes to cognitive and psychiatric symptoms in dementia with Lewy bodies (DLB), yet spatial covariance patterns remain unexplored. We aimed to characterise these patterns using ¹²³I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) SPECT (α4β2 nAChR assessment) and examine their association with cognitive function.</p><p><strong>Methods: </strong>Fifteen DLB and 16 healthy controls underwent ¹²³5IA-85380 and rCBF ^99mTc-exametazime SPECT scanning. Voxel principal components analysis (PCA), generated PC images representing common intercorrelated voxels across subjects. Linear regression identified α4β2 nAChR and rCBF patterns distinguishing DLB from controls.</p><p><strong>Results: </strong>A distinct α4β2 nAChR pattern differentiated DLB from controls (F_1,29 = 165.1, p < 0.001), that was dissimilar to rCBF changes. This pattern was characterised by decreased uptake in temporal pole, inferior frontal cortex, amygdala, olfactory cortex, insula, anterior/mid cingulate, and putamen, alongside preserved/increased uptake in sensorimotor cortex, fusiform and occipital lobe. These regions mapped onto default, salience, limbic, frontostriatal, sensorimotor and visual hubs. We then derived from patients, α4β2 nAChR patterns that correlated with CAMCOG_total (r =  - 0.52, p = 0.04), MMSE (r =  - 0.68, p = 0.01) and CAMCOG_memory (r =  - 0.70, p = 0.01), demonstrating a common topography of relative decreased binding in lateral/medial prefrontal, lateral temporal, fusiform, inferior parietal and thalamus along with relative preserved/increased binding in cingulate, insula, occipital and medial temporal regions: structures within a range of networks supporting executive, language, attention, motor and visual processing.</p><p><strong>Conclusion: </strong>These findings provide novel insights into the pathophysiology of DLB and may inform future therapeutic strategies targeting nAChRs.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"660"},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}