JAMA neurology最新文献

{"title":"Contribution of Modifiable Midlife and Late-Life Vascular Risk Factors to Incident Dementia.","authors":"Jason R Smith, James Russell Pike, Rebecca F Gottesman, David S Knopman, Pamela L Lutsey, Priya Palta, B Gwen Windham, Elizabeth Selvin, Moyses Szklo, Karen J Bandeen-Roche, Josef Coresh, A Richey Sharrett, Alden L Gross, Jennifer A Deal","doi":"10.1001/jamaneurol.2025.1495","DOIUrl":"10.1001/jamaneurol.2025.1495","url":null,"abstract":"<p><strong>Importance: </strong>Midlife vascular risk factors are associated with an elevated risk of dementia. However, the total contribution of vascular risk factors in midlife and late life with incident dementia is uncertain.</p><p><strong>Objective: </strong>To quantify the proportion of incident dementia attributable to modifiable vascular risk factors measured in midlife and late life and to examine differences by apolipoprotein ε4 genotype, self-reported race, and sex.</p><p><strong>Design, setting, and participants: </strong>This was a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study using 33 years of follow-up (1987-2020). The setting included ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Minneapolis suburbs, Minnesota; Washington County, Maryland). Study baseline in Black and White participants with complete exposure and covariate data was set by age at risk factor measurement (45-54 years, 55-64 years, and 65-74 years). Data were analyzed from August 2023 to December 2024.</p><p><strong>Exposures: </strong>Hypertension (systolic blood pressure [BP] ≥130 mm Hg, diastolic BP ≥80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician's diagnosis, or use of any diabetes medication), and current smoking (self-reported).</p><p><strong>Main outcomes and measures: </strong>Incident dementia. Population attributable fractions were estimated by age 80 years, and separately after 80 years, from having at least 1 vascular risk factor by age at risk factor measurement.</p><p><strong>Results: </strong>A total of 7731 participants were included in analysis of risk factors measured at age 45 to 54 years (4494 female [58%]; 2207 Black [29%]; 5524 White [71%]), 12 274 contributed to analysis of risk factors measured at age 55 to 64 years (6698 female [55%]; 2886 Black [24%]; 9388 White [76%]), and 6787 contributed to analysis of risk factors measured at age 65 to 74 years (3764 female [56%], 1375 Black [20%]; 5412 White [80%]). There were 801, 995, and 422 dementia cases by 80 years, respectively. The fraction of dementia by 80 years attributable to at least 1 vascular factor at age 45 to 54 years was 21.8% (95% CI, 14.3%-29.3%), at 55 to 64 years was 26.4% (95% CI, 19.1%-33.6%), and at 65 to 74 years was 44.0% (95% CI, 30.9%-57.2%). Attributable fractions for these factors were higher in apolipoprotein ε4 noncarriers at age 55 years and older (range, 33.3%-61.4%), Black individuals at age 45 years and older (range, 25.5%-52.9%), and female individuals at age 55 years and older (range, 29.2%-51.3%). Only 2% to 8% of dementia cases after 80 years were attributable to these factors.</p><p><strong>Conclusions and relevance: </strong>Results of this cohort study suggest that between 22% and 44% of incident dementia cases by 80 years in the ARIC study were attributed to midlife and late-life vascular risk factors. Assumi","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"644-654"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolving Perspectives on α-Synuclein Testing.","authors":"Cameron Dietiker, Caroline Tanner","doi":"10.1001/jamaneurol.2024.5403","DOIUrl":"10.1001/jamaneurol.2024.5403","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"635-636"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Vascular Risk Factors to Reduce Dementia Risk.","authors":"Roch A Nianogo, Deborah E Barnes","doi":"10.1001/jamaneurol.2025.1493","DOIUrl":"10.1001/jamaneurol.2025.1493","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"641-643"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opsoclonus-Myoclonus-Ataxia Syndrome in a Patient With Subacute Sclerosing Panencephalitis.","authors":"Akhil Sahib, Arun Koul, Ashwin K Panda","doi":"10.1001/jamaneurol.2025.0899","DOIUrl":"10.1001/jamaneurol.2025.0899","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"745-746"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the Revised Criteria for Biological and Clinical Staging of Alzheimer Disease.","authors":"Alexa Pichet Binette, Ruben Smith, Gemma Salvadó, Pontus Tideman, Isabelle Glans, Danielle van Westen, Colin Groot, Rik Ossenkoppele, Erik Stomrud, Piero Parchi, Henrik Zetterberg, Kaj Blennow, Niklas Mattsson-Carlgren, Shorena Janelidze, Sebastian Palmqvist, Oskar Hansson","doi":"10.1001/jamaneurol.2025.1100","DOIUrl":"10.1001/jamaneurol.2025.1100","url":null,"abstract":"<p><strong>Importance: </strong>While clinical disease stages remained largely unchanged in the 2024 update of the Alzheimer disease (AD) criteria, tau-positron emission tomography (PET) was introduced as a core biomarker and its spatial extent was incorporated into the revised biological stages of the disease. It is important to consider both the clinical and the biological stages and understand their discrepancies.</p><p><strong>Objective: </strong>To compare individuals who have discrepant biological and clinical stages with those who have congruent stages in terms of copathologies, comorbidities, and demographics.</p><p><strong>Design, setting, and participants: </strong>Participants were from the Swedish BioFINDER-2 (inclusion from 2017 through 2023) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (inclusion from 2015 through 2024). BioFINDER-2 included a prospective population-based (cognitively normal [CN] older adults) and memory clinic-based cohort (participants with subjective cognitive impairment [SCD], mild cognitive impairment [MCI], and dementia). ADNI included a volunteer-based sample. All participants who were amyloid-β positive and had undergone tau-PET were included. In BioFINDER-2, 838 participants of a total of 1979 were included, and of 927 with tau-PET in ADNI, 380 were included.</p><p><strong>Exposures: </strong>The clinical (CN to dementia) and biological (based on PET; initial [amyloid-β-positive only] to advanced [amyloid-β-positive, elevated, and widespread tau]) stages from the revised AD criteria.</p><p><strong>Main outcomes and measures: </strong>Cross-sectional measures of neurodegeneration (cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature, neurofilament light [NfL]), α-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics.</p><p><strong>Results: </strong>There were 838 BioFINDER-2 participants (mean age, 73.9 [SD, 7.3] years; 431 women [51%]; 407 men [49%]) and 380 ADNI participants (average age, 72.9 [SD, 7.0] years; 194 women [51%]; 186 mean [49%]) included. In BioFINDER-2, 37.7% of the sample had congruent biological and clinical stages (reference group), 51.3% had more advanced clinical impairment compared with their clinical stage (clinical > biological) and 11.0% had the opposite (biological > clinical). The main differences were between the reference group and the clinical > biological group: the latter participants were more often positive for α-synuclein pathology, had higher NfL levels, greater TDP-43-like atrophy, and higher burden of cerebral small vessel disease lesions (all false discovery rate P < .05). The only difference between the biological > clinical and the reference group was that the former had less neurodegeneration (thicker cortex; all false discovery rate P < .001). The main results were replicated in the independent ADNI cohort, where congruent 56.1% of","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"666-675"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Epilepsy in Frontotemporal Dementia and Timing of Dementia Diagnosis.","authors":"Annemari Kilpeläinen, Mikko Aaltonen, Kalle Aho, Sami Heikkinen, Ave Kivisild, Adolfina Lehtonen, Laura Leppänen, Iina Rinnankoski, Helmi Soppela, Laura Tervonen, Päivi Hartikainen, Annakaisa Haapasalo, Reetta Kälviäinen, Kasper Katisko, Johanna Krüger, Eino Solje","doi":"10.1001/jamaneurol.2025.1358","DOIUrl":"10.1001/jamaneurol.2025.1358","url":null,"abstract":"<p><strong>Importance: </strong>Previous studies have described a potential association between epilepsy and frontotemporal dementia (FTD), but no systematic data are available.</p><p><strong>Objective: </strong>To determine whether epilepsy is more prevalent in patients with FTD than in healthy controls (HCs) or patients with Alzheimer disease (AD).</p><p><strong>Design, setting, and participants: </strong>In this case-control study, we compared the prevalence of epilepsy and purchases of antiseizure medicines (ASMs) among patients with FTD, matched HCs, and patients with AD from 2 early-onset dementia diagnostics centers in the same geographic regions of Finland. AD or FTD diagnoses were made between January 1, 2010, and December 31, 2021. Data were analyzed from January 26, 2024, to January 16, 2025.</p><p><strong>Main outcomes and measures: </strong>The primary outcome was to describe the prevalence of epilepsy in patients with FTD, covering the time period from 10 years before to 5 years after the FTD diagnosis. We used International Statistical Classification of Diseases, Tenth Revision codes to identify all patients with epilepsy and tracked purchases of ASMs.</p><p><strong>Results: </strong>The study cohort included 245 patients with FTD (121 female [49.4%], 124 male [50.6%]; mean [SD] age, 65.2 [8.7] years), 2416 matched HCs (1190 female [49.3%], 1226 male [50.7%]; mean [SD] age, 65.0 [8.5] years), and 1326 patients with AD (777 female [58.6%], 549 male [41.4%]; mean [SD] age, 71.7 [9.8] years). The prevalence of epilepsy was higher in the FTD group compared with the HC group (3.3% vs 0.8%, respectively; P = .002) and AD group (3.3% vs 1.4%, respectively; P = .01) 10 years before FTD diagnosis. At the year of the diagnosis, the prevalence was 6.5% in patients with FTD, 1.8% in HCs (FTD vs HC difference, 4.7 percentage points [ppt] [95% CI, 2.2-8.6 ppt]; P < .001), and 5.0% in patients with AD (FTD vs AD difference, 1.6 ppt [95% CI, -1.2 to 5.5 ppt]; P = .32); at 5 years after the diagnosis, the prevalence was 11.2% in patients with FTD, 2.2% in HCs (FTD vs HC difference, 9.0 ppt [95% CI, 5.0-14.6 ppt]; P < .001), and 6.9% in patients with AD (FTD vs AD difference, 4.2 ppt [95% CI, 0-10.0 ppt]; P = .05). ASM purchases were made significantly more often among patients with FTD (10.2%) compared with HCs (1.8%) and patients with AD (4.2%) (FTD vs HC difference, 8.4 ppt [95% CI, 5.2-12.9 ppt]; P < .001; FTD vs AD difference, 6.1 ppt [95% CI, 2.6-10.6 ppt]; P < .001) at all time points and increased during the study period.</p><p><strong>Conclusions and relevance: </strong>This case-control study found a higher prevalence of epilepsy and increased ASM use among patients with FTD compared with HCs and patients with AD , suggesting an association between epileptic abnormalities and the pathophysiology of FTD. Further studies are warranted to investigate a potential overlap in the pathophysiologic mechanisms of epilepsy and FTD.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"715-721"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Notice of Retraction and Replacement. Elser H, et al. Wildfire smoke exposure and incident dementia. JAMA Neurol. 2025;82(1):40-48.","authors":"Joan A Casey,Holly Elser","doi":"10.1001/jamaneurol.2025.2148","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2148","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"19 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Error in Figure.","authors":"","doi":"10.1001/jamaneurol.2025.2320","DOIUrl":"10.1001/jamaneurol.2025.2320","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":""},"PeriodicalIF":20.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amyloid-Beta Pathology and Cognitive Performance in Centenarians","authors":"Susan K. Rohde, Maruelle C. Luimes, Linda M. C. Lorenz, Patricia Fierro-Hernández, Annemieke J. M. Rozemuller, Marc Hulsman, Meng Zhang, Marieke J. I. Graat, Myke E. van der Hoorn, Dominique A. H. Daatselaar, Philip Scheltens, Timothy E. Richardson, Jamie M. Walker, Sietske A. M. Sikkes, Jeroen J. M. Hoozemans, Henne Holstege","doi":"10.1001/jamaneurol.2025.1734","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.1734","url":null,"abstract":"ImportanceOlder individuals without dementia often have amyloid-beta (Aβ) Thal phases similar to patients with Alzheimer disease (AD), suggesting that Aβ pathology may be a benign consequence of aging.ObjectiveTo explore whether Aβ pathology in centenarians is associated with cognitive performance.Design, Setting, and ParticipantsThis longitudinal cohort study used cross-sectional data on antemortem cognitive performance and postmortem neuropathology of participants in the Dutch 100-plus Study. Cognitive performance was measured a median of 10 (IQR, 3-13) months before postmortem brain donation. From January 2013 to July 2022, 1187 centenarians who self-reported being cognitively healthy, confirmed by proxy, were approached: 406 were included and 95 donated their brain. Centenarians were compared with patients with clinicopathologically confirmed AD from the Netherlands Brain Bank. Data were analyzed from June 2022 to October 2024.Main Outcomes and MeasuresAβ pathology was assessed with the Thal phase for Aβ progression and by determining quantitative Aβ loads (percentage positive area) in the frontal, parietal, temporal, and occipital neocortices, 3 parahippocampal, and 5 hippocampal subregions. Aβ pathology was associated with performance on 13 neuropsychological tests assessing memory, fluency, attention/processing speed, and executive functioning, as well as 4 measures of global cognition.ResultsThis study evaluated Aβ pathology in 95 centenarians (median age at brain donation, 103.5 [IQR, 102.3-104.7] years; 71 female [75%] and 24 male [25%]) and 38 patients with AD (median age, 84 [IQR, 78-90] years; 18 female [47%] and 20 male [53%]). Global cognition parameters were available for all 95 centenarians and complete cognitive assessment for 72 centenarians (76%). A fraction of the centenarians had no Aβ load (9 of 95 [9%]), most had low Aβ load (53 of 95 [56%]) and, despite high Thal phases, about one-third (33 of 95 [35%]) had high Aβ load comparable with patients with AD. Centenarians with no or low Aβ load had significantly higher cognitive performance than centenarians with high Aβ loads. Higher Aβ loads across all 4 neocortical regions, cornu ammonis 3, cornu ammonis 1/subiculum, and the entorhinal cortex specifically affected executive functioning. Interestingly, 5 resilient centenarians maintained high cognitive performance despite having high Aβ loads; they had significantly less tau pathology compared with centenarians with high Aβ loads and low cognitive performance.Conclusions and relevanceThese results indicate that Aβ pathology is not a benign consequence of aging. Even in the oldest individuals, Aβ and tau pathology interaction was consistent with the amyloid cascade hypothesis.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"36 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ambroxol as a Treatment for Parkinson Disease Dementia","authors":"Carolina R. A. Silveira, Kristy K. L. Coleman, Kathy Borron, Rommel G. Tirona, Charles A. Rupar, Guangyong Zou, Robert A. Hegele, Cheryl Wellington, Sophie Stukas, Elizabeth C. Finger, Robert Bartha, Sarah A. Morrow, Jennie L. Wells, Michael J. Borrie, Don Mahuran, Penny A. MacDonald, Mary E. Jenkins, Mandar S. Jog, George Dresser, Susan Fox, Richard Camicioli, Brian Feagan, Daniel A. Mendonça, Michael Mayich, Manas D. Sharma, Sachin K. Pandey, Stephen H. Pasternak","doi":"10.1001/jamaneurol.2025.1687","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.1687","url":null,"abstract":"ImportanceCarrying a variation in the gene for β-glucocerebrosidase is a major risk factor for Parkinson disease dementia (PDD), and raising β-glucocerebrosidase levels lowers α-synuclein in cell and animals. Ambroxol is a chaperone for β-glucocerebrosidase, which increases the levels of β-glucocerebrosidase.ObjectiveTo examine the safety and tolerability of ambroxol in PDD, test the efficacy of ambroxol in improving or slowing the progression of cognitive deficits, and acquire pharmacological data.Design, Setting, and ParticipantsThis was a 52-week, phase 2, double-blind, placebo-controlled, randomized clinical trial conducted from February 2015 to June 2023. The study took place at a single center and was referral based. Included were patients with PDD who were older than 50 years, had Parkinson disease for at least 1 year before cognitive impairment, had mild to moderate dementia, were taking stable medications, and had a study partner.InterventionsAmbroxol low dose (525 mg per day), high dose (1050 mg per day), or placebo.Main Outcomes and MeasuresSafety and tolerability outcomes were adverse events. Primary efficacy outcomes were the Alzheimer Disease Assessment Scale–cognitive subscale, version 13 (ADAS-Cog-13) and Clinician’s Global Impression of Change (CGIC).ResultsA total of 75 patients were screened, and 55 were randomized. Thirty-one individuals received ambroxol, with 8 patients (mean [SD] age, 78.8 [3.4] years, all male) in the low-dose group and 22 patients (mean [SD] age, 70.7 [7.6]; 19 male [86.4%]) in the high-dose group. One patient was excluded from the high-dose group due to a diagnosis of progressive supranuclear palsy. A total of 24 patients (mean [SD] age, 72.7 [6.3] years; 19 male [79.2%]) were included in the placebo group. Participants receiving ambroxol (23 of 193 adverse events [12%]) showed more gastrointestinal adverse events than those receiving placebo (9 of 172 adverse events [5%]). Statistical analyses compared ambroxol high dose vs placebo. There was no evidence to suggest differences between groups on primary or secondary outcomes. Mean (SD) ambroxol high-dose concentrations were 7.48μM (3.17μM; 95% CI, 6.08-8.87μM) in plasma and 0.73μM (0.07μM; 95% CI, 0.64-0.81μM) in cerebrospinal fluid at the end of titration. Mean (SD) β-glucocerebrosidase levels were higher at week 26 (ambroxol, 12.45 [1.97] nmol/h/mg; 91% CI, 11.54-13.36 nmol/h/mg); placebo, 8.50 [1.96] nmol/h/mg; 91% CI, 7.65-9.34 nmol/h/mg; <jats:italic>P</jats:italic> = .05) in the ambroxol group compared with placebo.Conclusions and RelevanceResults of this randomized clinical trial reveal that ambroxol was safe, well-tolerated, and demonstrated target engagement. However, the effect of ambroxol on cognition was not confirmed.Trial RegistrationClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://www.clinicaltrials.gov/study/NCT02914366\">NCT02914366</jats:ext-link>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"23 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}