Annals of Clinical and Translational Neurology最新文献

{"title":"Targeted Long-Read Sequencing as a Single Assay Improves the Diagnosis of Spastic-Ataxia Disorders.","authors":"Laura Ivete Rudaks, Igor Stevanovski, Dennis Yeow, Andre L M Reis, Sanjog R Chintalaphani, Pak Leng Cheong, Hasindu Gamaarachchi, Lisa Worgan, Kate Ahmad, Michael Hayes, Andrew Hannaford, Samuel Kim, Victor S C Fung, Gabor M Halmagyi, Andrew Martin, David Manser, Michel Tchan, Karl Ng, Marina L Kennerson, Ira W Deveson, Kishore Raj Kumar","doi":"10.1002/acn3.70008","DOIUrl":"https://doi.org/10.1002/acn3.70008","url":null,"abstract":"<p><strong>Objective: </strong>The hereditary spastic-ataxia spectrum disorders are a group of disabling neurological diseases. The traditional genetic testing pathway is complex, multistep and leaves many cases unsolved. We aim to streamline and improve this process using long-read sequencing.</p><p><strong>Methods: </strong>We developed a targeted long-read sequencing strategy with the capacity to characterise the genetic variation of all types and sizes within 469 disease-associated genes, in a single assay. We applied this to a cohort of 34 individuals with unsolved spastic-ataxia. An additional five individuals with a known genetic diagnosis were included as positive controls.</p><p><strong>Results: </strong>We identified causative pathogenic variants that would be sufficient for genetic diagnosis in 14/34 (41%) unsolved participants. The success rate was 5/11 (45%) in those who were naïve to genetic testing and 9/23 (39%) in those who were undiagnosed after prior genetic testing, completed on a clinical basis. Short tandem repeat expansions in FGF14 were the most common (7/34, 21%). Two individuals (2/34, 6%) had biallelic pathogenic expansions in RFC1 and one individual had a monoallelic pathogenic expansion in ATXN8OS/ATXN8. Causative pathogenic sequence variants other than short tandem repeat expansions were found in four individuals, including in VCP, STUB1, ANO10 and SPG7. Furthermore, all five positive controls were identified.</p><p><strong>Interpretation: </strong>Our results demonstrate the utility of targeted long-read sequencing in the genetic evaluation of patients with spastic-ataxia spectrum disorders, highlighting both the capacity to increase overall diagnostic yield and to streamline the testing pathway by capturing all known genetic causes in a single assay.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497761","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":"Evidence of blood-brain barrier dysfunction and CSF immunoglobulin synthesis in Down Syndrome Regression Disorder.","authors":"Jonathan D Santoro, Neetha Paul Eduthan, Mellad M Khoshnood, Saba Jafarpour, Natalie K Boyd, Benjamin N Vogel, Lina Nguyen, Lilia Kazerooni, Eleanor Britton, Hannah R Lyford, Matthew D Galbraith, Angela L Rachubinski, Joaquin M Espinosa","doi":"10.1002/acn3.52299","DOIUrl":"https://doi.org/10.1002/acn3.52299","url":null,"abstract":"<p><strong>Objectives: </strong>This study sought to evaluate proteomic, metabolomic, and immune signatures in the cerebrospinal fluid of individuals with Down Syndrome Regression Disorder (DSRD).</p><p><strong>Methods: </strong>A prospective case-control study comparing proteomic, metabolomic, and immune profiles in individuals with DSRD was performed. Samples were obtained from a biorepository of affected individuals and compared to clinically available data and previously obtained neurodiagnostic studies. Individuals with DSRD were compared to individuals with established neuroinflammatory conditions (e.g., multiple sclerosis), and neurotypical controls undergoing a lumbar puncture for headaches. Samples underwent high-throughput proteomic, metabolomic, and immune marker profiling. Data was compared across groups and clinical phenotypes. Gene set enrichment analysis and pathway analyses were utilized to analyze the data.</p><p><strong>Results: </strong>In total, 34 individuals with DSRD, 22 neuroinflammatory controls, and 27 neurotypical controls were enrolled in the study. We observed a highly significant concordance in dysregulated proteomics signatures in DSRD and neuroinflammatory controls versus healthy controls, most prominently upregulation of many immunoglobulin sequences. In addition, individuals with DSRD displayed strong upregulation of liver-derived plasma proteins and erythrocyte proteins in the CSF, indicating poor blood-brain barrier integrity. The immune marker profile of DSRD is clearly similar to other neuroimmunological conditions, including strong elevation of MIP3-α, eotaxin, and IFN-γ.</p><p><strong>Interpretation: </strong>Individuals with DSRD have unique CSF proteomic and metabolomic signatures consistent with neuroinflammation and increased blood-brain barrier permeability. The CSF of individuals with DSRD was more comparable to individuals with neuroinflammatory disorders than neurotypical controls, indicating the potential for an immune etiology of disease.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490142","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":"Capturing what matters: Patient-reported LGI1-ANTibody encephalitis outcome RatiNg scale (LANTERN).","authors":"Mark J Kelly, Barbara Wagner, Bryan Ceronie, Christine Strippel, Ann Yee Lin, Adam Handel, John Soltys, Sophie Binks, Philip A Powell, Sarosh R Irani","doi":"10.1002/acn3.70006","DOIUrl":"https://doi.org/10.1002/acn3.70006","url":null,"abstract":"<p><strong>Background: </strong>LGI1-antibody encephalitis (LGI1-Ab-E) is a common form of autoimmune encephalitis where most patients demonstrate 'good' clinician-rated outcomes. However, more targeted questionnaires reveal numerous debilitating symptoms for many years. To better quantify these persistent features, we designed the LGI1-Antibody Encephalitis Rating (LANTERN) scale, a quantified, disease-specific patient-reported outcome measure (PROM), adhering to FDA guidelines.</p><p><strong>Methods: </strong>A participant-driven mixed-methods approach to develop a clinically valid questionnaire over three stages: (1) Item generation through semi-structured interviews; (2) Repeated cognitive debriefing rounds to advance comprehensibility, relevance and comprehensiveness; (3) Psychometric survey to condense the most sensitive and valid questions. Analyses incorporated sensitivity testing with multiple internal and external validations.</p><p><strong>Results: </strong>From 73 items across six domains (Stage 1; n = 18), a questionnaire assessing the frequency and severity of 43 symptoms (80 questions), plus nine activities of daily living (ADL), was developed through cognitive debriefing (Stage 2; n = 15). This 89-question survey was completed (Stage 3; n = 66 patients and 32 relatives) and distilled, using exploratory factor analyses, to a three-factor symptom-burden questionnaire comprising 41 questions (19 symptoms and 6 ADL), separated into physical, cognitive/behavioural and ADL domains. These factors demonstrated strong internal reliability (Cronbach alpha: 0.85-0.91), correlations with relative-completed questionnaires (R = 0.73-0.85; p < 0.001), good-to-excellent intraclass re-testing correlations (0.81-0.98; n = 19) and strong associations with numerous predefined external measures.</p><p><strong>Discussion: </strong>LANTERN represents a PROM for LGI1-Ab-E, with initial content, structural and construct validity and test-retest reliability. It can be used as a reliable, tailored, efficient and sensitive method to establish symptom burden in people with LGI1-Ab-E, both in clinical practice and trials.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490119","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":"Longitudinal Trajectories of Digital Cognitive Biomarkers for Multiple Sclerosis.","authors":"Yi Chao Foong, Daniel Merlo, Melissa Gresle, Chao Zhu, Katherine Buzzard, Jeannette Lechner-Scott, Michael Barnett, Chenyu Wang, Bruce V Taylor, Tomas Kalincik, Trevor Kilpatrick, David Darby, Pamela Dobay, Johan van Beek, Robert Hyde, Steve Simpson-Yap, Helmut Butzkueven, Anneke van der Walt","doi":"10.1002/acn3.70015","DOIUrl":"https://doi.org/10.1002/acn3.70015","url":null,"abstract":"<p><strong>Background: </strong>Cognitive impairment is one of the most common and debilitating symptoms of relapsing-remitting multiple sclerosis (RRMS). Digital cognitive biomarkers require less time and resources and are rapidly gaining popularity in clinical settings. We examined the longitudinal trajectory of the iPad-based Processing Speed Test (PST) and predictors of PST scores.</p><p><strong>Methods: </strong>We prospectively enrolled RRMS patients between 2017 and 2021 across six Australian MS centres. Longitudinal data was analysed with mixed effect modelling and latent class mixed models. We then examined whether latent class group membership predicted confirmed decrease in correct PST responses.</p><p><strong>Results: </strong>We recruited a total of 1093 participants, of which 724 had complete baseline data with a median follow up duration of 2 years. At a population level, PST trajectory was stable. A small practice effect was present up to the 4th visit. Age, baseline disability, T2 lesion volume, male sex and depression were associated with lower correct PST responses, whilst years of education and full/part-time employment were associated with more correct PST responses. We identified four latent class trajectories of PST. The worst latent class was typified by low baseline PST and lack of a practice effect. Being in the worst latent class was associated with a greater hazard of time to sustained 5% decrease in PST (HR 2.84, 95% CI 1.16-6.94, p = 0.02).</p><p><strong>Conclusion: </strong>Worse baseline cognitive performance and lack of a practice effect predicted future cognitive decline in RRMS.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497759","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":"High-Fat and Low-Carbohydrate Dietary Environments Are Linked to Reduced Idiopathic Epilepsy Incidence and Prevalence.","authors":"Duan Ni, Alistair Senior, David Raubenheimer, Stephen J Simpson, Ralph Nanan","doi":"10.1002/acn3.70017","DOIUrl":"https://doi.org/10.1002/acn3.70017","url":null,"abstract":"<p><p>Dietary manipulations like ketogenic diets are established interventions for recalcitrant epilepsy. However, it remains unknown whether specific macronutrient exposure through dietary environments could possibly extend to primary preventive qualities, associated with changes in epilepsy disease burden (prevalence and incidence). Here, macronutrient supply, GDP, and idiopathic epilepsy disease burden data were collated from more than 150 countries from 1990 to 2018. Nutritional geometry generalized additive mixed models (GAMMs) modeling unraveled that dietary environments with high-fat and low-carbohydrate supplies were linked to lower epilepsy incidence and prevalence. Our analyses suggested a plausible primary preventive role of dietary manipulations for epilepsy.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497757","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":"Clinical impact and safety of brain biopsy in unexplained central nervous system disorders: a real-world cohort study.","authors":"Robin W van Steenhoven, Saan Salih, Juna M de Vries, Ide Smets, Rob M Verdijk, Mayke Gardeniers, Jeroen Kerstens, Juliette Brenner, Yvette S Crijnen, Marjolein Geurts, Jacoline E C Bromberg, Corine H GeurtsvanKessel, Peter A E Sillevis Smitt, Rutger K Balvers, Maarten J Titulaer","doi":"10.1002/acn3.70000","DOIUrl":"https://doi.org/10.1002/acn3.70000","url":null,"abstract":"<p><strong>Objective: </strong>A substantial part of central nervous system (CNS) disorders remains unexplained, despite various new and minimally invasive diagnostic techniques. Within this rapidly developing diagnostic field, the precise role of brain biopsy is unknown. We aimed to study the clinical impact and safety of brain biopsies in unexplained CNS disorders.</p><p><strong>Methods: </strong>In this retrospective cohort study, we included all adult patients who were referred for a diagnostic work-up to our academic center with neuro-inflammatory, neuro-oncological, and neuro-infectious expertise and underwent a brain biopsy between January 2010 and December 2023. Typical cases of CNS neoplasms and infections were not analyzed. Brain biopsies were evaluated with respect to diagnostic and therapeutic impact and complication risk.</p><p><strong>Results: </strong>Brain biopsy was performed in 587 patients. Ninety-four patients with a CNS disorder of unknown cause, with 107 biopsies, were analyzed (44% female, median age 58 years). Postoperative diagnoses included brain tumors/lymphomas (37/94, 39%), inflammatory disorders (11/94, 12%), infections (8/94, 9%), autoimmune encephalitis (8/94, 9%), and primary angiitis of the CNS (4/94, 4%). Diagnostic yield of brain biopsy was 62%, increasing up to 72% after repeat biopsies, as 10 additional patients were diagnosed with a brain tumor. In 77% of patients, brain biopsy changed the treatment strategy. Symptomatic intracranial hemorrhage occurred in 4 of 107 brain biopsies (4%).</p><p><strong>Interpretation: </strong>In a selected population of patients with unexplained CNS disorders, clinical impact of brain biopsies is high, while being relatively safe. A multidisciplinary team approach is fundamental in establishing optimal indication for brain biopsy and subsequent treatment decisions.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466682","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":"High-Throughput Immunoassays for Cavin-4 IgG: A Diagnostic Tool for Immune-Mediated Rippling Muscle Disease.","authors":"Reghann G LaFrance-Corey, Haidara Kherbek, Nimalan Harinesan, Margherita Milone, Naveen K Paramasivan, Pallab Sarker, Andrew M Knight, Carley Karsten, Surendra Dasari, Teerin Liewluck, William J Litchy, Sean J Pittock, John R Mills, Divyanshu Dubey","doi":"10.1002/acn3.70012","DOIUrl":"https://doi.org/10.1002/acn3.70012","url":null,"abstract":"<p><p>Cavin-4 was identified as a potential autoantigen for immune-mediated rippling muscle disease (iRMD). To validate this, we developed and tested various immunoassays, including a cell-based assay (CBA), cavin-4 recombinant protein ELISA, and multi-peptide ELISA. Among 19 iRMD patients, all exhibited muscle rippling, and 13 had percussion-induced mounding. All immunoassays demonstrated clinical and analytical specificities greater than 95%. The protein ELISA had the highest sensitivity (94.7%) and specificity (99.9%), outperforming CBA (sensitivity 89.5%, specificity 99.6%) and the multi-peptide ELISA (sensitivity 79.0%, specificity 97.2%). Our results suggest that the cavin-4 protein ELISA is a promising tool for high-throughput clinical testing in iRMD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432120","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":"Amygdala Neurodegeneration: A Key Driver of Visual Dysfunction in Parkinson's Disease.","authors":"Asier Erramuzpe, Ane Murueta-Goyena, Antonio Jimenez-Marin, Marian Acera, Sara Teijeira-Portas, Rocío Del Pino, Tamara Fernández-Valle, Ibai Diez, Unai Sainz-Lugarezaresti, Naroa Ibarretxe-Bilbao, Unai Ayala, Maitane Barrenechea, Alberto Cabrera-Zubizarreta, Jesús Cortés, Juan Carlos Gómez-Esteban, Iñigo Gabilondo","doi":"10.1002/acn3.70007","DOIUrl":"https://doi.org/10.1002/acn3.70007","url":null,"abstract":"<p><strong>Objective: </strong>Visual disability in Parkinson's disease (PD) is not fully explained by retinal neurodegeneration. We aimed to delineate the brain substrate of visual dysfunction in PD and its association with retinal thickness.</p><p><strong>Methods: </strong>Forty-two PD patients and 29 controls underwent 3-Tesla MRI, retinal spectral-domain optical coherence tomography, and visual testing across four domains. Voxel-level associations between gray matter volume and visual outcomes were used to define a visual impairment region (visualROI). Functional connectivity of the visualROI with brain networks was analyzed. Covariance analysis of brain regions associated with retinal thinning (retinalROI) was conducted using hierarchical clustering to develop a model of retinal and brain neurodegeneration linked to disease progression.</p><p><strong>Results: </strong>The amygdala was the primary component of the visualROI, comprising 32.3% and 14.6% of its left and right volumes. Functional connectivity analysis revealed significant disruptions between the visualROI and medial/lateral visual networks in PD. Covariance analysis identified three clusters within retinalROI: (1) the thalamic nucleus, (2) the amygdala and lateral/occipital visual regions, and (3) frontal regions, including the anterior cingulate cortex and frontal attention networks. Hierarchical clustering suggested a two-phase progression: early amygdala damage (Braak 1-3) disrupting visual network connections, followed by retinal and frontal atrophy (Braak 4-5) exacerbating visual dysfunction.</p><p><strong>Interpretation: </strong>Our findings support a novel, amygdala-centric two-phase model of visual dysfunction in PD. Early amygdala degeneration disrupts visual pathways, while advanced-stage disconnection between the amygdala and frontal regions and retinal neurodegeneration contributes to further visual disability.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432114","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":"Ethnoracial disparities in gray matter atrophy are mediated by structural disconnectivity in multiple sclerosis.","authors":"Ahmed Bayoumi, Joseph A Thomas, Breanna R Alonzo, Juan Jimenez, Christopher M Orlando, Carlos A Pérez, Khader M Hasan, Jerry S Wolinsky, John A Lincoln","doi":"10.1002/acn3.52311","DOIUrl":"https://doi.org/10.1002/acn3.52311","url":null,"abstract":"<p><strong>Objective: </strong>To investigate ethnoracial disparities in gray matter (GM) atrophy, the contribution of white matter lesions and consequent structural disconnectivity among patients with multiple sclerosis (MS).</p><p><strong>Methods: </strong>This retrospective study included 297 patients with MS (pwMS), 98 Hispanic/Latinx (H-MS), 82 non-Hispanic Black (B-MS), and 117 non-Hispanic White (W-MS). GM atrophy was assessed using univariate, voxel-based morphometry, and multivariate techniques, source-based morphometry. Structural disconnectivity secondary to white matter lesions was evaluated using the network modification tool. Mediation analyses explored relationships between ethnoracial groups, white matter lesions, structural disconnectivity, and gray matter atrophy.</p><p><strong>Results: </strong>B-MS and H-MS generally exhibited greater gray matter atrophy compared to W-MS, particularly in temporal, parahippocampal, precuneus, and cuneus GM. Structural disconnectivity differences were most prominent in the hippocampal, cingulate, precuneus, and deep gray matter regions. Mediation analyses revealed that lesion load significantly mediated group differences in global GM atrophy (percent mediated = 52.4%), while structural disconnectivity mediated some differences in specific gray matter components, notably in deep gray matter, insular, and anterior cingulate regions.</p><p><strong>Interpretation: </strong>Significant ethnoracial disparities exist in GM atrophy and its patterns among diverse MS patients, partially mediated by white matter lesions and consequent structural disconnectivity. These findings underscore the importance of considering ethnoracial factors in MS research and clinical practice, potentially informing personalized treatment strategies and emphasizing the need for diverse representation in clinical trials.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432118","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":"Associations of Cerebrospinal Fluid Orexin-A, Alzheimer Disease Biomarkers, and Cognitive Performance.","authors":"Ruijin Lu, Krish Shah, Cristina D Toedebusch, Ashley Hess, Rachel Richardson, Emmanuel Mignot, Suzanne E Schindler, Tammie L S Benzinger, Shaney Flores, Jason Hassenstab, Chengjie Xiong, John C Morris, David M Holtzman, Brendan P Lucey","doi":"10.1002/acn3.70009","DOIUrl":"https://doi.org/10.1002/acn3.70009","url":null,"abstract":"<p><strong>Objective: </strong>Cerebrospinal fluid (CSF) orexin-A has been suggested to be a biomarker of Alzheimer disease (AD). In both cognitively unimpaired healthy older adults and individuals with symptomatic AD, CSF orexin-A is positively associated with CSF Aβ42, p-tau181, and total tau (t-tau) concentrations. However, a recent systematic review and meta-analysis did not support differences in orexin-A between AD and controls. In this study, we tested the association between CSF orexin-A concentrations, AD biomarkers, and cognitive performance in older adults with and without symptomatic AD.</p><p><strong>Methods: </strong>Two hundred and seventy community-dwelling older adults underwent standardized cognitive assessments, sleep monitoring with a single-channel electroencephalography test, one night of home sleep apnea testing, biofluid and imaging AD biomarker measurement within 1 year of sleep monitoring, and APOE genotyping. Plasma and CSF AD biomarkers were measured by immunoassay or mass spectrometry. CSF orexin-A was measured by radioimmunoassay.</p><p><strong>Results: </strong>CSF orexin-A levels did not differ by amyloid positivity, cognitive status, or AD stage. However, CSF AD biomarkers (Aβ40, Aβ42, and t-tau) were positively associated with CSF orexin-A levels even after correction for multiple comparisons. CSF orexin-A was not associated with any measure of cognitive performance.</p><p><strong>Interpretation: </strong>This study showed that CSF orexin-A is associated with multiple CSF AD biomarkers, but not with AD pathology or cognitive performance. We hypothesize that this is due to similar mechanisms of production/release of these proteins with sleep-wake activity. Future studies measuring other forms of orexin peptides, such as orexin-B, may provide evidence for orexin as a marker for AD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432116","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}