Journal of Neurology最新文献

{"title":"Co-occurring functional neurological disorder and autism: an exploratory study of comorbidities in a retrospective cohort study using TriNetX.","authors":"Lily Smythe, Livia Asan, Timothy R Nicholson, Francesca Happé, Mark J Edwards","doi":"10.1007/s00415-025-13385-6","DOIUrl":"10.1007/s00415-025-13385-6","url":null,"abstract":"<p><strong>Background: </strong>Functional Neurological Disorder (FND) encompasses motor, cognitive, and sensory symptoms resulting from disruptions in brain-body communication. Emerging research suggests a higher-than-expected occurrence of autism in FND, potentially due to shared cognitive mechanisms and overlapping comorbidities. However, large-scale characterisation of this dual-diagnosis is lacking.</p><p><strong>Methods: </strong>Using de-identified health records from the TriNetX research network, we identified children and adults with both FND and autism ('FND + Autism'), comparing them to individuals with FND only ('FND-only') and autism only ('Autism-only'). We examined psychiatric comorbidities (e.g. mood, anxiety, post-traumatic stress disorder, personality disorders, obsessive-compulsive disorder), intellectual disability and ADHD.</p><p><strong>Results: </strong>Of 220,312 individuals with an FND diagnosis, and 674,971 individuals with an autism diagnosis, 5,152 (2.3% of FND, 0.76% of autism) had both FND and autism. The rates of autism were therefore 6 times higher in FND compared to the base rates of the TriNetX population. Most were diagnosed with autism before FND, with over one-third diagnosed in childhood. Functional seizures were the most common FND subtype, and were more frequent in FND + Autism than FND-only (adults: 52% vs. 44%; children: 47% vs. 42%). Comorbidity across all psychiatric conditions was significantly higher in FND + Autism compared to both comparison groups. ADHD was particularly elevated in FND + Autism (adults: 50% vs. 13% FND-only, 36% Autism-only; children: 64% vs. 21% FND-only, 41% Autism-only).</p><p><strong>Conclusions: </strong>This study presents the largest dataset to date characterising individuals with co-occurring FND and autism. Findings are consistent with previous findings of higher rates of autism in people with FND and reveal a potentially distinct clinical profile, marked by elevated rates of ADHD and psychiatric comorbidities, and increased occurrence of functional seizures compared to FND- or Autism-only groups. Recognising this overlap may improve diagnosis, clinical care, and understanding of mechanisms underlying the co-occurrence of FND and autism.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"653"},"PeriodicalIF":4.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12464146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149447","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":"Apraxic deficits predict general cognitive impairment in patients with biomarker-verified Alzheimer's pathology.","authors":"Claudia C Schmidt, Michella M Bardakan, Elena Jaeger, Nils Richter, Gérard N Bischof, Kathrin Giehl, Oezguer A Onur, Frank Jessen, Gereon R Fink, Alexander Drzezga, Peter H Weiss","doi":"10.1007/s00415-025-13401-9","DOIUrl":"10.1007/s00415-025-13401-9","url":null,"abstract":"<p><p>Apraxia represents a core feature of Alzheimer's disease (AD), a neurodegenerative disorder characterised by the accumulation of β-amyloid plaques and tau deposition. However, systematic descriptions of apraxic deficits in AD patients remain scarce. Here, we comprehensively investigate apraxia profiles and their link with cognitive impairment in patients with biomarker-verified Alzheimer's pathology. We characterised the frequency and patterns of apraxic deficits in patients with biomarker-verified Alzheimer's pathology using a battery of standardised apraxia tests. Demographic variables and apraxia scores were related to patients' general cognitive impairment using hierarchical regression analysis. Apraxic deficits were found in 67% of patients with biomarker-verified Alzheimer's pathology (n = 63). Patients with Alzheimer's pathology were more impaired in imitating finger gestures (than hand gestures: 89.2% vs. 80.0%, p < 0.001) and imitating complex hand movements (than single hand movements: 97.4% vs. 78.5%, p < 0.001), even when controlling for general cognitive impairment. Apraxia assessments explained about 60% of the variance in dementia severity, with performance in the KAS subtest of pantomiming object use (beta coefficient: 0.47, p = 0.001) and the DATE subtest for limb apraxia (beta coefficient: 0.37, p = 0.005) constituting significant predictors of general cognitive impairment. These findings emphasise the relevance of apraxia in patients with biomarker-verified Alzheimer's pathology, revealing that praxis deficits predict general cognitive impairment in AD. Further research is warranted into the role of apraxia as a potential early diagnostic criterion in AD.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"654"},"PeriodicalIF":4.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12464036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149515","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":"The impact of CGRP monoclonal antibodies on cytokine expression in chronic migraine: a cohort study.","authors":"Jason C Ray, Stuart McDonald, Marian Todaro, Josephine Baker, Wei Zhen Yeh, Elspeth J Hutton, Manjit Matharu, Helmut Butzkueven","doi":"10.1007/s00415-025-13400-w","DOIUrl":"10.1007/s00415-025-13400-w","url":null,"abstract":"<p><strong>Background: </strong>Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are an effective preventative therapy for migraine; however, there have been rare reports of possible inflammatory complications. The primary objective of this study was to examine the impact of CGRP mAbs on immune system activation by evaluating the plasma cytokine profile of a cohort of patients pre- and post-CGRP mAb.</p><p><strong>Methodology: </strong>A prospective cohort study was undertaken at a tertiary headache service. Following informed consent and screening, the plasma cytokine profile of participants was determined using a Simoa CorPlex human cytokine 10-plex with ten targets: interferon gamma, interleukin-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-22, and TNF⍺ prior to initiation of CGRP mAb and following 3 months of therapy. A comparator group of healthy controls at a single time point was also included.</p><p><strong>Results: </strong>A total of 22 patients with chronic migraine and 10 healthy controls were included in the study. Administration of CGRP mAb was not associated with a significant change in cytokine expression (Wilk's lambda 0.528, p = 0.448). On post-hoc analysis, there was a significant reduction in IL-5 levels (z = - 2.321, p = 0.020) following CGRP mAb therapy.</p><p><strong>Conclusion: </strong>In this study of patients with chronic migraine, we found no evidence that treatment with CGRP mABs is associated with a significant alteration in plasma cytokine levels or shift to a Th1 phenotype.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"649"},"PeriodicalIF":4.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131023","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":"[¹⁸F]THK5351 uptake in multiple system atrophy compared with other parkinsonian disorders.","authors":"Yoshihiko Horimoto, Emi Hayashi, Yoshihiro Ito, Nobuyuki Okamura, Noriyuki Matsukawa","doi":"10.1007/s00415-025-13389-2","DOIUrl":"https://doi.org/10.1007/s00415-025-13389-2","url":null,"abstract":"<p><strong>Background: </strong>The pathological processes in the early stages of multiple system atrophy (MSA) are still incompletely understood. Moreover, early-stage MSA is difficult to diagnose.</p><p><strong>Objectives: </strong>We investigated the monoamine oxidase-B positron emission tomography findings with an aim to characterize degeneration in the early stages of MSA.</p><p><strong>Methods: </strong>Positron emission tomography using [¹⁸F]THK5351 was performed on three patients with relatively early stages of MSA: two with cerebellar-type MSA and one with parkinsonian-type MSA. The findings were compared with nine patients with other parkinsonian disorders (Lewy body disease, progressive supranuclear palsy, or spinocerebellar ataxia type 31) and six control subjects (Alzheimer disease or normal aging).</p><p><strong>Results: </strong>Uptake of [¹⁸F]THK5351 in the middle cerebellar peduncles was distinctly higher in all three patients with MSA than in patients with other parkinsonian disorders or control subjects (both p < 0.001; unpaired t-tests).</p><p><strong>Conclusions: </strong>The results of the presented patients suggest the potential diagnostic utility of [¹⁸F]THK5351 imaging and may help to clarify the preclinical pathology of the middle cerebellar peduncle in MSA.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"650"},"PeriodicalIF":4.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130848","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":"Effect of aging on biomarkers and clinical profile in Parkinson's disease.","authors":"Giulia Di Lazzaro, Federico Paolini Paoletti, Giovanni Bellomo, Tommaso Schirinzi, Piergiorgio Grillo, Guido Maria Giuffrè, Martina Petracca, Anna Picca, Nicola Biagio Mercuri, Lucilla Parnetti, Paolo Calabresi, Anna Rita Bentivoglio","doi":"10.1007/s00415-025-13384-7","DOIUrl":"10.1007/s00415-025-13384-7","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) has different progression rates and disease characteristics according to age of onset, the younger being less cognitively affected and experiencing more motor fluctuations. We explored different pathophysiologic mechanisms underlying PD in patients of different ages independently from disease duration, through CSF biomarkers.</p><p><strong>Methods: </strong>Patients with clinically established diagnosis of PD underwent clinical evaluation through validated clinical scales (MDS-UPDRS, NMSS, MoCA, WOQ, QUIP, UDysRS). CSF inflammatory (YKL-40, TREM-2) and neurodegeneration (A-Beta42 and 40, t-Tau, p-Tau, NfL, Neurogranin, alpha-synuclein) biomarkers were analyzed.</p><p><strong>Results: </strong>95 PD patients were recruited, among whom 43 were younger than 66 years old, and 52 older. Age strongly correlated with neurofilament CSF levels, both light and heavy chain, with YKL-40 and with tau species. Younger and older patients showed different biomarker profiles. Younger patients showed significantly lower levels of inflammatory molecules (YKL-40), of degeneration biomarkers (tau species, neurofilament light and heavy chains), independently from disease duration. Clinically, younger patients had better scores at MDS-UPDRS parts I and III and were more prone to develop motor fluctuations and impulse control disorders.</p><p><strong>Conclusions: </strong>Our data support the hypothesis that PD has different underlying biological features in younger and older subjects. Older subjects may have a broader spectrum of disease mechanisms, reflected in the higher prevalence of amyloid pathology and neurodegeneration, which could underlie the worse cognitive performances and lower dyskinesia burden. They could therefore necessitate a wider array of treatment strategies along with dopaminergic supplementation. Consequently, some of these biomarkers hold promise in refining treatment approaches in PD.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"651"},"PeriodicalIF":4.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131002","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":"Temporal trends indicate an epidemiological shift in the pathology of mesial temporal lobe epilepsy.","authors":"Christoph Helmstaedter, Sarah Al-Haj Mustafa, Juri-Alexander Witt","doi":"10.1007/s00415-025-13398-1","DOIUrl":"10.1007/s00415-025-13398-1","url":null,"abstract":"<p><strong>Background: </strong>Recent multicenter studies suggest a temporal trend of a decreasing number of patients with classic early-onset mesial temporal lobe epilepsy (mTLE) with ammon's horn sclerosis (mTLE-AHS). In parallel, the awareness of late-onset mTLE patients with suspected limbic encephalitis (sLE) is increasing. To evaluate a potential epidemiological shift, a large cohort of mTLE patients collected over 4 decades was analyzed.</p><p><strong>Methods: </strong>Anonymized data sets of a monocentric cohort of 1,556 patients with the diagnosis of mTLE, who underwent their very first neuropsychological assessment between 1986 and 2024 in the Department of Epileptology at the University Hospital Bonn in Germany, were retrospectively evaluated in regard to temporal trends of age, age at epilepsy onset, neuropsychological performance, and MRI pathology. Five-year intervals were evaluated.</p><p><strong>Results: </strong>Most significant was a trend of an increasing age at epilepsy onset over time (from 12 to 36 years), education and IQ increased over time, impairments became less global, and verbal/figural memory impairments became less marked and discriminative over time. While the number of patients with mTLE remained quite stable since 1996 (50-60% of all TLE patients seen), patients with early-onset mTLE-AHS (n = 1079, average age at epilepsy onset: 16 years) faded over time (from 100 to 32%), while the patients with late-onset mTLE suspicious of limbic encephalitis (N = 477, average age at epilepsy onset: 40 years) became increasingly prevalent (from 0 to 68%).</p><p><strong>Conclusions: </strong>Trends of changing etiologies as well as altering clinical and neuropsychological features of patients with mTLE suggest an epidemiological shift over the past decades. Overlapping distributions of fading early-onset classic mTLE-AHS and an increasing influx of late-onset sLE fit the clinical observations and demand retrospective follow-up studies in other countries/regions to disentangle triggering factors. Prospective studies should investigate temporal trends in autoantibody subgroups of patients with sLE.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"652"},"PeriodicalIF":4.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137847","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":"Letter to editors regarding \"Serological analysis of gluten‑related antibodies in idiopathic neuropathies and cerebellar ataxia\".","authors":"Iain D Croall, Nigel Hoggard, Richard A Grunewald, Marios Hadjivassiliou","doi":"10.1007/s00415-025-13376-7","DOIUrl":"https://doi.org/10.1007/s00415-025-13376-7","url":null,"abstract":"","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"647"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124824","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":"Kappa free light chain index as a diagnostic and prognostic biomarker in multiple sclerosis.","authors":"Luis Moreno-Navarro, Sergio Mora-Diaz, Lourdes Ruiz-Escribano-Menchen, Angel P Sempere","doi":"10.1007/s00415-025-13381-w","DOIUrl":"10.1007/s00415-025-13381-w","url":null,"abstract":"<p><strong>Background: </strong>The proposed 2024 McDonald criteria incorporate the kappa free light chain (KFLC) index as an additional biomarker in multiple sclerosis (MS) diagnosis. Emerging evidence suggests that a high KFLC index may relate to worse outcomes in people with MS (pwMS). This study had two main objectives: to evaluate the diagnostic performance of the KFLC index against the 2017 and proposed 2024 clinico-radiological McDonald criteria, and to explore its prognostic significance.</p><p><strong>Methods: </strong>We performed a retrospective cohort study of adults with a first episode suggestive of MS (2019-2024). All underwent lumbar puncture with simultaneous determination of the KFLC index and oligoclonal bands (OCB).</p><p><strong>Results: </strong>Among 150 participants, OCB showed sensitivities of 85.9% (2017) and 86.6% (2024) with specificities of 79.7% and 81.9%. A KFLC index cut-off of 12.0 yielded sensitivities of 87.5% (2017) and 88.1% (2024) with specificities of 79.2% and 81.4%, comparable to OCB. In pwMS, KFLC index ≥ 100 was associated with younger age (OR 1.53, p = 0.048), women (OR 1.53, p = 0.037), relapses (OR 2.30, p = 0.029) and new infratentorial or spinal cord (SC) lesions (OR 6.90, p = 0.003). In multivariable analysis, KFLC index ≥ 100 remained associated with new infratentorial or SC lesions (aOR 8.07, p = 0.019).</p><p><strong>Conclusion: </strong>The KFLC index shows diagnostic utility comparable to OCB; however, it is an adjunctive biomarker that complements clinical and MRI findings and should not be used as a standalone diagnostic test. An elevated KFLC index was associated with short-term accrual of infratentorial or SC lesions; these exploratory findings require validation in larger, longer-term cohorts.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"646"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124785","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":"Widespread and progressive brain atrophy is a common feature in patients with mitochondrial disease.","authors":"Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen","doi":"10.1007/s00415-025-13354-z","DOIUrl":"10.1007/s00415-025-13354-z","url":null,"abstract":"<p><strong>Background: </strong>Primary mitochondrial diseases comprise a group of inherited disorders that frequently affect the central nervous system. Previous studies have reported brain imaging findings commonly associated with mitochondrial disease. However, longitudinal data on volumetric brain abnormalities, their progression in time, and associations with clinical features of the disease remain limited.</p><p><strong>Methods: </strong>We conducted a retrospective observational study of 36 patients with genetically confirmed mitochondrial disease at Turku University Hospital (Turku, Finland). A total of 73 brain magnetic resonance scans (1-8 per patient) were analysed using the cNeuro® image quantification tool to assess lobar and regional cortical atrophy. Associations with clinical features, including stroke-like episodes (SLEs), sex, and genetic subtype, were investigated.</p><p><strong>Results: </strong>Cerebral atrophy was present in all patients and was most pronounced in the temporal and occipital lobes. Patients with a history of SLEs exhibited significantly greater atrophy in both temporal lobes and the right occipital and parietal lobes. Follow-up imaging (available for 15 patients) revealed progressive atrophy, particularly in the occipital lobes, in patients with SLEs. No significant differences in atrophy severity or progression were found between patients with the m.3243A > G variant and those with other genetic causes.</p><p><strong>Conclusions: </strong>Cerebral atrophy is a common and often progressive feature of mitochondrial disease, even in patients without clinical brain symptoms. Atrophy predominantly affects posterior brain regions, and its progression is particularly evident in patients with SLEs. These findings underline the neurodegenerative nature of mitochondrial disease and highlight the need to develop neuroprotective therapies.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"648"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124874","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":"Neuroanatomical normative modelling in frontotemporal lobar degeneration: higher heterogeneity in the behavioural variant.","authors":"Srijan Konwar, Nikolett Hunyadvari, Annalena Venneri, James H Cole, Martina Bocchetta","doi":"10.1007/s00415-025-13378-5","DOIUrl":"10.1007/s00415-025-13378-5","url":null,"abstract":"<p><strong>Introduction: </strong>Frontotemporal lobar degeneration (FTLD) includes heterogenous diseases: behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasias (PPA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We applied neuroanatomical normative modelling to quantify individual atrophy patterns and heterogeneity within and between FTLD forms.</p><p><strong>Methods: </strong>We included 160 participants across FTLDNI and 4RTNI studies: controls (n = 15), bvFTD (n = 22), nfvPPA (n = 14), svPPA (n = 21), CBS (n = 43) and PSP (n = 45). Using cortical thickness and subcortical volumes from 3T MRIs, we applied normative modelling with a large healthy reference dataset (n = 58,836), further accounting for age, sex, and scanner. Outlier regions (z < - 1.96) were used to compute total outlier counts (tOC) and Hamming distances, capturing individual atrophy patterns and inter-subject dissimilarity.</p><p><strong>Results: </strong>bvFTD, svPPA, CBS and PSP showed significantly higher cortical tOC than controls, with all groups showing higher subcortical tOC than controls, especially svPPA and PSP. bvFTD, svPPA, CBS and PSP had significantly higher cortical Hamming distance scores than controls, with higher scores in bvFTD and svPPA than nfvPPA and PSP. svPPA and PSP had significantly higher subcortical scores than controls and CBS. Greater disease severity (measured using the Clinical Dementia Rating-CDR for PSP and CBS, and the CDR® plus NACC-FTLD global scores for FTD variants) was associated with increased tOC and dissimilarity, highlighting the link between clinical progression and neuroanatomical heterogeneity.</p><p><strong>Conclusions: </strong>The pronounced heterogeneity within and between FTLD subtypes (particularly in bvFTD) increases with disease progression and may reflect distinct underlying pathologies. This supports the development of subtype-specific biomarkers and emphasize the need for personalized diagnostic and therapeutic strategies.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 10","pages":"642"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124830","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}