2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T789,Neurodegenerative disorders are characterized by progressive, irreversible neuronal loss that often advances silently for years before symptoms appear. Disease-modifying therapies are generally less effective once symptoms emerge, as substantial neuronal damage has already occurred. Consequently, there is an urgent need for accessible biomarkers that can predict disease well in advance and serve as reliable target-engagement measures in prevention trials. We analysed archival gastrointestinal (GI) biopsies from 196 individuals with unexplained GI symptoms and 13-15 years of follow-up. Using sensitive histopathologic staining, we assessed misfolded TDP-43, tau, and α-synuclein to test whether peripheral proteinopathies can serve as predictive biomarkers for neurodegeneration. Protein misfolding enteropathy was identified in 60% of cases. Individuals with GI proteinopathy were significantly more likely to develop non-Alzheimer's dementia or α-synucleinopathies, demonstrating >80% sensitivity; however, this performance should be balanced against a low specificity. The presence of 2 or more proteinopathy markers was associated with a dose-dependent reduction in survival, establishing GI proteinopathy as an independent, life-limiting prognostic factor. Importantly, these pathologic changes were present 6.9 years before neurologic symptoms emerged. Our findings reveal that neurodegeneration-associated proteinopathies are not confined to the central nervous system but can be detected in routine GI biopsies years before clinical onset. This discovery provides a practical and scalable biomarker platform that could transform early diagnosis, risk stratification, and target-engagement monitoring in clinical trials. Protein misfolding enteropathy represents a new frontier for disease interception in neurodegenerative disorders, enabling intervention at a stage when neuronal damage may still be preventable.31:T72b,The socioeconomic burden of early onset dementia (EOD) defined as disease onset before the age of 65 years, is substantial due to its widespread disabling effects in relatively young individuals. While dementia is widely recognised as a major contributor to mortality among the elderly, only a limited number of studies have assessed survival and factors associated with prognosis specifically in EOD. A population-based cohort study, encompassing all incident EOD cases from two defined regions in Finland. The survival and all-cause mortality rates in EOD and its subtypes were evaluated from January 2010 to December 2021. All visits at the dementia outpatient clinics were reviewed and manually re-assessed (n=12 490), resulting in 794 validated EOD cases of Alzheimer's disease (AD), frontotemporal dementia (FTD), alpha-synucleinopathy (α-SYNU) and other EOD spectra. Region-, age- and sex-matched control groups without neurodegenerative diseases were created from nonselective general population data registers (1:10 case to control ratio, 7930 controls in total). The median survival for EOD was 8.7 years, with the shortest survival in the FTD (6.9 years) and α-SYNU groups (7.0 years), followed by the AD group (9.9 years). Compared with controls, mortality was significantly higher in the total EOD group (HR=6.56, 95% CI=5.56-7.74, p<0.001). Among the dementia subtypes, FTD spectrum patients had the highest all-cause mortality risk compared with controls (HR=13.75, 95% CI=10.25-18.43, p<0.001). Male sex, older age, several comorbidities and lower level of education were associated with increased mortality, but these were not EOD-specific. EOD diagnosis significantly deteriorates patients' survival, with significant variation between different diagnostic groups and in relation to patients' demographic factors.32:T983, Background The socioeconomic burden of early onset dementia (EOD) defined as disease onset before the age of 65 years, is substantial due to its widespread disabling effects in relatively young individuals. While dementia is widely recognised as a major contributor to mortality among the elderly, only a limited number of studies have assessed survival and factors associated with prognosis specifically in EOD. Methods A population-based cohort study, encompassing all incident EOD cases from two defined regions in Finland. The survival and all-cause mortality rates in EOD and its subtypes were evaluated from January 2010 to December 2021. All visits at the dementia outpatient clinics were reviewed and manually re-assessed (n=12 490), resulting in 794 validated EOD cases of Alzheimer’s disease (AD), frontotemporal dementia (FTD), alpha-synucleinopathy (α-SYNU) and other EOD spectra. Region-, age- and sex-matched control groups without neurodegenerative diseases were created from nonselective general population data registers (1:10 case to control ratio, 7930 controls in total). Results The median survival for EOD was 8.7 years, with the shortest survival in the FTD (6.9 years) and α-SYNU groups (7.0 years), followed by the AD group (9.9 years). Compared with controls, mortality was significantly higher in the total EOD group (HR=6.56, 95% CI=5.56–7.74, p<0.001). Among the dementia subtypes, FTD spectrum patients had the highest all-cause mortality risk compared with controls (HR=13.75, 95% CI=10.25–18.43, p<0.001). Male sex, older age, several comorbidities and lower level of education were associated with increased mortality, but these were not EOD-specific. Conclusion EOD diagnosis significantly deteriorates patients’ survival, with significant variation between different diagnostic groups and in relation to patients’ demographic factors. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Alpha-Synucleinopathy: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Alpha-Synucleinopathy (condition). Clinician-written summaries and actionable practice insights. 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Loss was detectable 15 years before diagnosis (€2,774/year; p=0.008) and averaged €12,021/year at diagnosis. By subtype: FTD showed loss from 11 years pre-diagnosis (€4,799/year) rising to €16,116/year at diagnosis; AD from 6 years pre-diagnosis (€2,767/year) rising to €11,431/year; α-synucleinopathies only at diagnosis (€11,284/year); and the vascular/mixed \"other EOD\" group had consistently high losses throughout (€8,322–€8,744/year).","limitations":"- Residual confounding from unmeasured baseline socioeconomic status, occupation type, and psychiatric comorbidity cannot be excluded.\n- The α-synucleinopathy subgroup (n=46) is small, limiting statistical power.\n- HCA captures only wage-based productivity loss, excluding unpaid caregiving and housework; findings may not generalize beyond Finland's universal health care and social security context.","practice_takeaway":"Clinicians should be aware that EOD — especially FTD — causes measurable income and work-capacity decline up to a decade before diagnosis, which can help frame discussions with patients and families about early financial and workplace planning. Earlier diagnostic pathways and workplace support systems are warranted to reduce the substantial socioeconomic burden on individuals and society."}},{"doi":"10.1016/j.neuron.2026.04.033","pmid":"42127911","title":"Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies","journal_title":"Neuron","journal_issn":"0896-6273","published_at":"2026-05-12T00:00:00.000Z","url":"https://doi.org/10.1016/j.neuron.2026.04.033","source_score":64,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-17T13:21:36.757Z","updated_at":"2026-05-17T13:21:36.757Z","tags":[{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"condition","value":"Alpha-Synucleinopathy","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"generic","value":"anti-GPNMB antibody","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"level_of_evidence","value":"4","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"modality","value":"Monoclonal Antibody","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"sample_size","value":"n=1675","value_numeric":1675},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"study_design","value":"Translational Laboratory Study with Human Postmortem Cohort","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.033","tag_type":"warning","value":"The study is primarily preclinical (iPSC-derived cells, fibril-seeding model); the postmortem cohort provides human genetic support but cannot confirm causality. The 'practice_changing' flag reflects the novel therapeutic target identification, not clinical trial data. The DOI domain suggests 2026 publication — verified against the provided date.","value_numeric":null}],"summaries":{"what_studied":"This study examined whether secreted (non-membrane-anchored) GPNMB can enhance neuronal uptake of fibrillar alpha-synuclein (aSyn) in a non-cell-autonomous manner, using iPSC-derived microglia, GPNMB knockout neurons, an aSyn fibril-seeded Parkinson's disease model, and 1,675 human postmortem brain cases.","key_result":"Microglia-derived secreted GPNMB increased neuronal aSyn uptake and pathology—even in GPNMB knockout neurons—while anti-GPNMB antibodies rescued neurons from developing aSyn pathology; human postmortem data (n=1,675) showed GPNMB genotypes linked to higher expression were associated with more widespread aSyn pathology.","limitations":"Findings rely partly on iPSC-derived cell models and a fibril-seeding model, which may not fully recapitulate in vivo Parkinson's disease; the postmortem genetic association is correlational and cannot establish causality; therapeutic efficacy of anti-GPNMB antibodies is not yet tested in living humans or animal models.","practice_takeaway":"GPNMB secreted by microglia may drive a feed-forward cycle of aSyn spread in Parkinson's disease, and anti-GPNMB antibodies show early preclinical promise as a strategy to interrupt this cycle. Clinicians should watch for clinical trials targeting GPNMB in Parkinson's disease."}},{"doi":"10.1001/jamaneurol.2026.0989","pmid":"42081229","title":"Phenoconversion in Pure Autonomic Failure","journal_title":"JAMA Neurology","journal_issn":"2168-6149","published_at":"2026-05-04T00:00:00.000Z","url":"https://doi.org/10.1001/jamaneurol.2026.0989","source_score":27,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-07T22:49:12.024Z","updated_at":"2026-05-07T22:49:12.024Z","tags":[{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"condition","value":"Alpha-Synucleinopathy","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"condition","value":"Dementia With Lewy Bodies","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"condition","value":"Multiple System Atrophy","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"condition","value":"Parkinson Disease","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"condition","value":"Pure Autonomic Failure","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"sample_size","value":"n=900","value_numeric":900},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"study_design","value":"Systematic Review and Meta-Analysis","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"warning","value":"Mean age at onset (63.1 years) and 63.8% male composition may limit generalizability to all PAF populations.","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"warning","value":"Only 9 studies met inclusion criteria, limiting subgroup precision, especially for PD-specific conversion rates (wide CIs: 0.75–2.41).","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.0989","tag_type":"warning","value":"The 'practice_changing' impact flag is applied cautiously — while conversion rates are well-quantified, no disease-modifying therapies for PAF phenoconversion currently exist; the clinical value lies primarily in prognostication and trial enrollment.","value_numeric":null}],"summaries":{"what_studied":"This systematic review and meta-analysis evaluated phenoconversion rates from pure autonomic failure (PAF) to central α-synucleinopathies (PD, DLB, MSA) and identified clinical predictors of phenoconversion across 9 longitudinal studies (n=900; mean follow-up 6.4 years).","key_result":"30% of PAF patients converted to a central α-synucleinopathy (~5.09 per 100 person-years; 95% CI 3.79–6.85): 12% to MSA, 11% to DLB, and 7% to PD. MSA conversion was frontloaded (IR 1.96), while Lewy body disorders converted at steadier rates. RBD and subtle motor signs predicted conversion to any synucleinopathy; hyposmia distinguished PD/DLB from MSA (pooled RR 1.88; 95% CI 1.26–2.97).","limitations":"Only 9 studies with 900 participants were included; heterogeneity was partly explained by follow-up duration, suggesting variability in cohort design. No biomarker data were available for pooled analysis.","practice_takeaway":"Clinicians should monitor PAF patients closely for RBD, subtle motor signs, and hyposmia—each raises the likelihood of phenoconversion to a specific synucleinopathy at a rate comparable to isolated RBD. Early identification of these features may allow timely referral and enrollment in neuroprotective trials."}},{"doi":"10.1053/j.gastro.2026.04.003","pmid":"42013966","title":"Protein Misfolding Enteropathy Predicts and Prognosticates Neurodegenerative Disease Years Before Symptom Onset","journal_title":"Gastroenterology","journal_issn":"0016-5085","published_at":"2026-04-22T00:00:00.000Z","url":"https://doi.org/10.1053/j.gastro.2026.04.003","source_score":65,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-04-20","doi":"10.1053/j.gastro.2026.04.003","days":"30","issn":"0016-5085","rank":"7","field":"Clinical Medicine","score":"65","category":"Gastroenterology & Hepatology","categories":["Gastroenterology & Hepatology"],"_categories":["Gastroenterology & Hepatology"]},"pubmed":{"doi":"10.1053/j.gastro.2026.04.003","title":"Protein Misfolding Enteropathy Predicts and Prognosticates Neurodegenerative Disease Years Before Symptom Onset.","journal":"Gastroenterology","methods":"","results":"Protein misfolding enteropathy was identified in 60% of cases. Individuals with GI proteinopathy were significantly more likely to develop non-Alzheimer's dementia or α-synucleinopathies, demonstrating >80% sensitivity; however, this performance should be balanced against a low specificity. The presence of 2 or more proteinopathy markers was associated with a dose-dependent reduction in survival, establishing GI proteinopathy as an independent, life-limiting prognostic factor. Importantly, these pathologic changes were present 6.9 years before neurologic symptoms emerged.","abstract":"$30","keywords":["A-synuclein","Biomarker","Gastrointestinal Tract","Neurodegeneration","Proteinopathy","TDP-43","Tau"],"pubmed_id":"42013966","conclusions":"","publication_date":"2026-04-22T00:00:00"},"crossref":{"DOI":"10.1053/j.gastro.2026.04.003","URL":"https://doi.org/10.1053/j.gastro.2026.04.003","ISSN":["0016-5085"],"link":[{"URL":"https://api.elsevier.com/content/article/PII:S0016508526003574?httpAccept=text/xml","content-type":"text/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https://api.elsevier.com/content/article/PII:S0016508526003574?httpAccept=text/plain","content-type":"text/plain","content-version":"vor","intended-application":"text-mining"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Protein Misfolding Enteropathy Predicts and Prognosticates Neurodegenerative Disease Years Before Symptom Onset"],"author":[{"given":"Tatiana","family":"Langerová","sequence":"first","affiliation":[]},{"given":"Emma","family":"MacVicar","sequence":"additional","affiliation":[]},{"given":"Rollo","family":"Press","sequence":"additional","affiliation":[]},{"given":"Fiona L.","family":"Read","sequence":"additional","affiliation":[]},{"given":"Mattia","family":"Piana","sequence":"additional","affiliation":[]},{"given":"Sarah","family":"Murdoch","sequence":"additional","affiliation":[]},{"given":"Jayne","family":"Innes","sequence":"additional","affiliation":[]},{"given":"Joan","family":"Wilson","sequence":"additional","affiliation":[]},{"given":"Angus J.M.","family":"Watson","sequence":"additional","affiliation":[]},{"given":"Fergal M.","family":"Waldron","sequence":"additional","affiliation":[]},{"given":"George","family":"Ramsay","sequence":"additional","affiliation":[]},{"given":"Jenna M.","family":"Gregory","sequence":"additional","affiliation":[]}],"funder":[{"id":[{"id":"10.13039/100012357","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100012357","name":"LifeArc","doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/100013013","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100013013","name":"Target ALS Foundation Inc","doi-asserted-by":"publisher"},{"id":[{"id":"10.13039/501100023968","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/501100023968","name":"NHS Grampian","doi-asserted-by":"publisher"}],"issued":{"date-parts":[[2026,4]]},"member":"78","prefix":"10.1053","source":"Crossref","volume":null,"created":{"date-time":"2026-04-19T23:19:19Z","timestamp":1776640759000,"date-parts":[[2026,4,19]]},"indexed":{"date-time":"2026-05-14T04:13:04Z","timestamp":1778731984051,"date-parts":[[2026,5,14]]},"license":[{"URL":"https://www.elsevier.com/tdm/userlicense/1.0/","start":{"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000,"date-parts":[[2026,4,1]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"https://www.elsevier.com/legal/tdmrep-license","start":{"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000,"date-parts":[[2026,4,1]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"http://creativecommons.org/licenses/by/4.0/","start":{"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000,"date-parts":[[2026,4,15]]},"delay-in-days":14,"content-version":"vor"}],"subject":[],"abstract":null,"language":"en","relation":{},"resource":{"primary":{"URL":"https://linkinghub.elsevier.com/retrieve/pii/S0016508526003574"}},"subtitle":[],"assertion":[{"name":"publisher","label":"This article is maintained by","value":"Elsevier"},{"name":"articletitle","label":"Article Title","value":"Protein Misfolding Enteropathy Predicts and Prognosticates Neurodegenerative Disease Years Before Symptom Onset"},{"name":"journaltitle","label":"Journal Title","value":"Gastroenterology"},{"name":"articlelink","label":"CrossRef DOI link to publisher maintained version","value":"https://doi.org/10.1053/j.gastro.2026.04.003"},{"name":"content_type","label":"Content Type","value":"article"},{"name":"copyright","label":"Copyright","value":"© 2026 The Author(s). Published by Elsevier Inc. on behalf of American Gastroenterological Association Institute."}],"deposited":{"date-time":"2026-05-14T03:46:00Z","timestamp":1778730360000,"date-parts":[[2026,5,14]]},"issn-type":[{"type":"print","value":"0016-5085"}],"published":{"date-parts":[[2026,4]]},"publisher":"Elsevier BV","reference":[{"DOI":"10.3389/fnmol.2023.1242925","key":"10.1053/j.gastro.2026.04.003_bib1","year":"2023","issue":null,"author":"Naskar","volume":"16","first-page":null,"unstructured":null,"article-title":"Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders","journal-title":"Front Molec Neurosci","doi-asserted-by":"crossref"},{"DOI":null,"key":"10.1053/j.gastro.2026.04.003_bib2","year":"2018","issue":null,"author":"Katsuno","volume":"80","first-page":"289","unstructured":null,"article-title":"Preclinical progression of neurodegenerative 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Mortality was higher than controls in all EOD (HR 6.56, 95% CI 5.56–7.74), with the highest risk in frontotemporal dementia (HR 13.75, 95% CI 10.25–18.43); male sex, older age, comorbidities, and lower education were linked to higher mortality.","limitations":"Data come from only two regions in Finland, which may limit generalizability. The abstract does not give absolute death counts or detail the composition of the “other EOD” subgroup.","practice_takeaway":"Expect shorter survival in EOD (about 9 years), with frontotemporal and alpha‑synucleinopathy subtypes faring worst; Alzheimer’s disease has longer survival among EOD. Discuss prognosis and planning with patients and families, noting higher mortality with male sex, older age, comorbidity burden, and lower education."}}],"initialOffset":5,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Alpha-Synucleinopathy"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Alpha-Synucleinopathy"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Alpha-Synucleinopathy"}}}]]

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