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:Tc1b, Objective This systematic review evaluates the safety, feasibility, tolerability, and efficacy outcomes of intranasally administered stem cells and their derivatives (MSCs, NSCs, secretome, and EVs) for the treatment of neurological and respiratory disorders. Methods A literature search was conducted across PubMed, Google Scholar, Web of Science, Scopus, and ClinicalTrials.gov for published research from January 2011 to December 2025. A total of 19 studies were included (7 published articles, 12 registry-only or grey literature records). Risk of bias was assessed using two complementary Cochrane tools, the RoB 2 tool for all 19 studies and the ROBINS-I tool for the 6 n-RCTs. Sources of heterogeneity were systematically characterized across 5 clinical dimensions, and structural publication bias was evaluated against a 30% registry-only threshold. A random-effects model was selected for pooled analyses, with a planned subgroup analysis of treatment dosage against adverse events. Effect sizes were extracted using SMD, mean differences, risk ratios, and odds ratios as appropriate per outcome type. Results This systematic review was conducted in accordance with PRISMA 2020 guidelines. A total of 104 participants were enrolled in 7 published studies, with one completed registry trial (NCT04602104) confirming actual enrolment of an additional 18 participants. No study achieved an overall low risk of bias under either assessment tool. Under RoB 2, 1 published study was rated as having some concerns, others were rated high risk or some concerns. Under ROBINS-I, 3 n-RCT studies were rated critical overall. The remaining 3 were rated serious. Across the 7 published studies, 98 participants contributed to the analyzed outcomes. Structural publication bias was confirmed. Substantial clinical heterogeneity was identified across 9 conditions, multiple cell product categories, and mixed intranasal and intravenous delivery routes. Conclusion Although current evidence suggests that intranasal administration of stem cells, particularly MSCs and NSCs, in humans is a safe and feasible approach, with possible therapeutic improvements in CNS disorders. However, there is a serious risk of bias, critically small sample sizes, and pervasive publication bias in the available literature. Adequately powered, quadruple-blinded, placebo-controlled randomized trials need to be conducted before clinical translation can be considered. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Amyotrophic Lateral Sclerosis: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Amyotrophic Lateral Sclerosis (condition). Clinician-written summaries and actionable practice insights. Updated daily.\",\"url\":\"https://www.reachrx.ai/hub/tag/condition/Amyotrophic%20Lateral%20Sclerosis\",\"breadcrumb\":{\"@type\":\"BreadcrumbList\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https://www.reachrx.ai\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Research Hub\",\"item\":\"https://www.reachrx.ai/hub\"},{\"@type\":\"ListItem\",\"position\":3,\"name\":\"Conditions\",\"item\":\"https://www.reachrx.ai/hub/tag/condition\"},{\"@type\":\"ListItem\",\"position\":4,\"name\":\"Amyotrophic Lateral Sclerosis\",\"item\":\"https://www.reachrx.ai/hub/tag/condition/Amyotrophic%20Lateral%20Sclerosis\"}]}}"}}]],["$","$L2f",null,{"title":"Amyotrophic Lateral Sclerosis: Research & Clinical Takeaways","description":"Discover peer-reviewed research on Amyotrophic Lateral Sclerosis with concise clinician summaries and next-step guidance.","papers":[{"doi":"10.1212/wnl.0000000000218471","pmid":"42685299","title":"Repairing the Amyotrophic Lateral Sclerosis Trial Credibility Gap","journal_title":"Neurology","journal_issn":"0028-3878","published_at":"2026-09-02T00:00:00.000Z","url":"https://doi.org/10.1212/wnl.0000000000218471","source_score":18,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-09-09T06:21:11.880Z","updated_at":"2026-09-09T06:21:11.880Z","tags":[{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"brand","value":"Radicava","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"generic","value":"edaravone","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"generic","value":"neurofilament light chain","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"generic","value":"sodium phenylbutyrate-taurursodiol","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"modality","value":"Neuroprotective Agent","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"study_design","value":"Commentary / Opinion","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"warning","value":"Multiple authors report extensive pharma consulting relationships, which should be considered when weighing the perspective, even though the piece argues for greater rigor.","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"warning","value":"Neurofilament light chain is tagged as a 'generic' for indexing convenience but is a biomarker, not a drug.","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"warning","value":"Several critiqued trials are identified only indirectly or by conference abstract citation, making independent verification of specific claims difficult.","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218471","tag_type":"warning","value":"This is a perspective/commentary, not a primary research study; level of evidence is expert opinion (7).","value_numeric":null}],"summaries":{"what_studied":"This opinion/commentary piece examines why early- and mid-phase ALS clinical trial results repeatedly claim benefit but fail to replicate in phase 3 trials, cataloguing recurring scientific fallacies and the systemic incentives that drive them.","key_result":"The authors identify eight recurring fallacies in ALS trial reporting—false premise, biomarker misuse, design/objective mismatch, Texas Sharpshooter, open-label extension, data omission, data/conclusion discordance, and optimistic interpretation—each illustrated with real trial examples (e.g., AMX0035/CENTAUR OLE data claiming survival benefit later refuted by the phase 3 PHOENIX trial; edaravone approved on n=137 with baseline imbalances).","limitations":"This is a commentary without primary data; specific trials are critiqued but not always named, limiting direct verification. Authors have extensive industry consulting relationships that may introduce their own perspective bias.","practice_takeaway":"Clinicians should treat phase 2 ALS trial results—especially subgroup, post hoc, or OLE analyses—as hypothesis-generating only, not proof of efficacy. When counseling patients, clearly distinguish between preliminary signals and validated phase 3 evidence to avoid false hope and misdirected advocacy."}},{"doi":"10.1001/jamaneurol.2026.2812","pmid":"42636000","title":"TDP-43–Associated Neurodegenerative Disease Conceptualization and Integrated Staging","journal_title":"JAMA Neurology","journal_issn":"2168-6149","published_at":"2026-08-24T00:00:00.000Z","url":"https://doi.org/10.1001/jamaneurol.2026.2812","source_score":25,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-30T06:19:48.977Z","updated_at":"2026-08-30T06:19:48.977Z","tags":[{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"condition","value":"Frontotemporal Dementia","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"condition","value":"Inclusion Body Myositis","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"condition","value":"Limbic-Predominant Age-Related TDP-43 Encephalopathy","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"condition","value":"Multisystem Proteinopathy","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"condition","value":"TDP-43 Proteinopathy","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"generic","value":"TDP-43","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"modality","value":"Biomarker Development","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"study_design","value":"Expert Consensus / Conceptual Framework","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"warning","value":"The DOI year (2026) is consistent with the provided publication date; flagging in case of early-access or preprint status at time of indexing.","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"warning","value":"The 'practice_changing' impact flag reflects the proposed paradigm shift in disease classification, not a clinical trial outcome.","value_numeric":null},{"paper_doi":"10.1001/jamaneurol.2026.2812","tag_type":"warning","value":"This paper is a conceptual/opinion piece published in JAMA Neurology; no primary data, cohort, or sample size is reported — level of evidence is set to 7 (expert opinion/narrative).","value_numeric":null}],"summaries":{"what_studied":"This paper proposes a pathobiology-based framework for classifying TDP-43–associated neurodegenerative diseases — including LATE, ALS, FTD, inclusion body myositis, and multisystem proteinopathy — shifting away from clinical phenotype as the organizing principle and introducing an integrated staging system that accounts for presymptomatic disease.","key_result":"The authors argue that TDP-43 pathology underlies a spectrum of clinically distinct disorders and that recognizing this shared biology — with clinical labels like ALS, FTD, or LATE recast as phenotypic manifestations — provides a clearer road map for biomarker development and therapy targeting fundamental disease mechanisms.","limitations":"This is a conceptual/opinion paper without primary data; no clinical outcomes, biomarker validation cohorts, or staging criteria are empirically tested here.","practice_takeaway":"Clinicians should be aware that ALS, FTD, LATE, and related disorders may share a common TDP-43 pathobiology, which has direct implications for how future biomarkers and disease-modifying therapies will be developed and trialed across these conditions."}},{"doi":"10.1002/alz.71680","pmid":"42626968","title":"A combined artificial intelligence–wet lab approach identifies a pivotal role of the NAD\n ⁺\n –mitophagy axis on aging and neurodegeneration","journal_title":"Alzheimer's & Dementia","journal_issn":"1552-5260","published_at":"2026-08-21T00:00:00.000Z","url":"https://doi.org/10.1002/alz.71680","source_score":29,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-30T06:19:49.491Z","updated_at":"2026-08-30T06:19:49.491Z","tags":[{"paper_doi":"10.1002/alz.71680","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"brand","value":"PandaOmics","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"condition","value":"Alzheimer's Disease","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"condition","value":"Brain Aging","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"condition","value":"Huntington's Disease","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"generic","value":"nicotinamide mononucleotide","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"level_of_evidence","value":"4","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"modality","value":"Mitochondrial Fusion Promoter","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"modality","value":"NAD+ Pathway Modulator","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"modality","value":"RNA Interference","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"sample_size","value":"n=3489","value_numeric":3489},{"paper_doi":"10.1002/alz.71680","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"study_design","value":"Translational Study (Multi-Omics + Experimental Validation)","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"warning","value":"PandaOmics is a proprietary AI platform developed by Insilico Medicine, and several co-authors are affiliated with that company, representing a potential conflict of interest in target prioritization findings.","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"warning","value":"Sample size of n=3,489 reflects the combined transcriptomic dataset (patients + controls); the iPSC and C. elegans experiments involved much smaller groups and some endpoints had only 1–2 biological repeats.","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"warning","value":"Study design tag 'Translational Study' is used because this work combines computational transcriptomics with multi-model wet-lab validation and does not fit a single standard design label cleanly.","value_numeric":null},{"paper_doi":"10.1002/alz.71680","tag_type":"warning","value":"The study design is a hybrid of computational and preclinical experimental work; there are no human clinical intervention data. The 'level of evidence 4' reflects this preclinical/translational nature.","value_numeric":null}],"summaries":{"what_studied":"This study evaluated expression of 102 NAD⁺/mitophagy-related genes across 12 human brain regions and blood using 77 public transcriptomic datasets (1,966 neurodegenerative disease patients vs. 1,523 controls) spanning AD, PD, HD, and ALS. Key AI-prioritized targets were then validated in *C. elegans*, a HEK293 Tau-Venus cell model, and APOE4/4 iPSC-derived cortical neurons.","key_result":"The NAD⁺–mitophagy axis was more severely dysregulated in neurodegeneration than in normal brain aging, with CNS samples showing broader gene dysregulation than blood. Five AD-protective genes were prioritized: **ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1**. Knockdown of MFN1 or LAMP2 worsened Tau aggregation in the cell model; neuronal knockdown of eat-3 (OPA1) or fzo-1 (MFN1) impaired cholinergic synaptic function in *C. elegans*. Pharmacological activation of mitochondrial fusion (SML0629/OPA1 pathway) in APOE4/4 cortical neurons reduced p-Tau217 levels.","limitations":"- Experimental validation used lower-organism (*C. elegans*) and non-neuronal cell models; effects in higher organisms remain untested.\n- iPSC cortical neuron experiments were limited to short treatment windows (24 h) and single biological repeats for some endpoints, reducing statistical power.\n- The study is observational/transcriptomic for human data; causality in human brain aging and neurodegeneration cannot be established.","practice_takeaway":"The NAD⁺–mitophagy axis—particularly OPA1, MFN1, LAMP2, and ATP6V0E1—represents a promising but preclinical therapeutic target in AD; no clinical interventions are ready based on this data alone. Clinicians should watch for trials targeting mitochondrial fusion or NAD⁺ pathways as this mechanistic evidence matures."}},{"doi":"10.1136/jnnp-2026-339492","pmid":"42595353","title":"Physical activity in ALS: friend or foe?","journal_title":"Journal of Neurology, Neurosurgery & Psychiatry","journal_issn":"0022-3050","published_at":"2026-08-13T00:00:00.000Z","url":"https://doi.org/10.1136/jnnp-2026-339492","source_score":7,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-22T06:53:39.224Z","updated_at":"2026-08-22T06:53:39.224Z","tags":[{"paper_doi":"10.1136/jnnp-2026-339492","tag_type":"category","value":"Surgery","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339492","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339492","tag_type":"modality","value":"Physical Activity","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339492","tag_type":"warning","value":"Publication date (2026-08-13) is in the future relative to most training data; content has not been independently verified.","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339492","tag_type":"warning","value":"Study design, level of evidence, and specific findings are unknown and have been omitted to avoid speculation.","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339492","tag_type":"warning","value":"The full text of this paper was not provided — only the title, DOI, journal, and publication date are available. Summaries, key results, limitations, practice takeaways, study design, sample size, and most tags cannot be determined from this metadata alone.","value_numeric":null}],"summaries":{"what_studied":"The paper examines the relationship between physical activity and amyotrophic lateral sclerosis (ALS), evaluating whether physical activity acts as a beneficial or harmful factor in the context of ALS risk, progression, or management."}},{"doi":"10.1136/jnnp-2026-339165","pmid":"42595352","title":"Associations of self-reported and objectively measured physical activity and amyotrophic lateral sclerosis risk","journal_title":"Journal of Neurology, Neurosurgery & Psychiatry","journal_issn":"0022-3050","published_at":"2026-08-13T00:00:00.000Z","url":"https://doi.org/10.1136/jnnp-2026-339165","source_score":10,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-22T06:53:38.405Z","updated_at":"2026-08-22T06:53:38.405Z","tags":[{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"category","value":"Surgery","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"modality","value":"Physical Activity Intervention","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"sample_size","value":"n=384836","value_numeric":384836},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"study_design","value":"Prospective Cohort Study","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"warning","value":"Genetic subgroup analyses (especially C9ORF72 carriers, n=535) are underpowered; null findings should not be interpreted as absence of effect.","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"warning","value":"Reverse causation is a key concern — prodromal ALS-related weakness or fatigue could reduce physical activity before diagnosis, inflating the apparent protective association.","value_numeric":null},{"paper_doi":"10.1136/jnnp-2026-339165","tag_type":"warning","value":"The device-measured activity subgroup (n=96,570) is a subset of the full cohort and may not be fully representative.","value_numeric":null}],"summaries":{"what_studied":"This UK Biobank cohort study examined whether self-reported and device-measured physical activity are associated with incident ALS risk (median follow-up 14.0 years), including subgroup analyses in people with high genetic ALS risk (C9ORF72 expansion carriers and UNC13A rs12608932 C-allele homozygotes).","key_result":"Higher physical activity was linked to lower ALS risk: self-reported high vs. low activity HR=0.77 (95% CI 0.61–0.96; n=384,836; 541 ALS events); device-measured activity HR=0.75 per 1 SD (95% CI 0.58–0.97; n=96,570; 98 ALS events). The self-reported dose-response was non-linear, with lowest risk at mid-range activity levels; device-measured activity showed a linear relationship.","limitations":"- The association in C9ORF72 expansion carriers was directionally consistent but not statistically significant, likely due to small numbers (n=535, 56 events).\n- Reverse causation cannot be excluded: prodromal ALS may reduce activity before diagnosis.\n- Physical activity was self-reported at a single time point for the larger cohort, subject to recall bias.","practice_takeaway":"Regular physical activity at moderate-to-high levels is associated with meaningfully lower ALS risk, though very high activity does not appear to confer additional benefit over mid-range levels. Clinicians should not discourage activity in patients with genetic ALS risk, but should be cautious about inferring causality from observational data."}},{"doi":"10.1002/ana.78315","pmid":"42528478","title":"Toward a Behavioral Reserve Model in Amyotrophic Lateral Sclerosis","journal_title":"Annals of Neurology","journal_issn":"0364-5134","published_at":"2026-07-30T00:00:00.000Z","url":"https://doi.org/10.1002/ana.78315","source_score":11,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-06T13:22:01.912Z","updated_at":"2026-08-06T13:22:01.912Z","tags":[{"paper_doi":"10.1002/ana.78315","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"sample_size","value":"n=965","value_numeric":965},{"paper_doi":"10.1002/ana.78315","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"study_design","value":"Prospective Cohort Study","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"warning","value":"No drug or therapeutic modality is evaluated; modality and brand/generic tags are not applicable here.","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"warning","value":"The ECAS-CI analyses were conducted in a subset (n=633), which may have different characteristics from the full cohort — domain-specific ECAS-CI findings should be interpreted cautiously.","value_numeric":null},{"paper_doi":"10.1002/ana.78315","tag_type":"warning","value":"The study uses caregiver-rated (family-rated) premorbid behavioral estimates, which may introduce recall or informant bias despite sensitivity analyses. Authors acknowledge this limitation explicitly.","value_numeric":null}],"summaries":{"what_studied":"This prospective cohort study (n=965 ALS patients) examined whether premorbid behavioral regulation traits and socio-educational factors (education, occupation, Social Interaction Index) are associated with behavioral impairment in ALS, using a behavioral reserve framework. Behavioral outcomes were measured with the FrSBe (family-rated) and, in a subset (n=633), the ECAS-CI.","key_result":"Premorbid behavioral regulation was the strongest predictor of behavioral impairment across all FrSBe models. Higher combined educational attainment and social exposure were associated with lower odds of behavioral impairment, with a significant interaction across multiple behavioral domains. Reserve proxies were not significantly associated with ECAS-CI total impairment, though domain-specific effects were seen.","limitations":"Causal inference is limited by the observational design. Premorbid behavioral estimates may be subject to retrospective bias, despite sensitivity analyses. The ECAS-CI subset (n=633) may not fully represent the broader cohort.","practice_takeaway":"In ALS, patients with lower premorbid behavioral regulation or limited education and social engagement may be at higher risk for behavioral impairment — consider early behavioral risk stratification in these individuals. Clinicians should assess socio-educational history as part of non-motor profiling in ALS."}},{"doi":"10.1212/wnl.0000000000218303","pmid":"42525902","title":"Association of Military Branch and Rank With Amyotrophic Lateral Sclerosis Incidence Among United States Veterans","journal_title":"Neurology","journal_issn":"0028-3878","published_at":"2026-07-29T00:00:00.000Z","url":"https://doi.org/10.1212/wnl.0000000000218303","source_score":35,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-06T13:22:16.119Z","updated_at":"2026-08-06T13:22:16.119Z","tags":[{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"sample_size","value":"n=9942879","value_numeric":9942879},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"study_design","value":"Longitudinal Cohort Study","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"warning","value":"The 'practice_changing' impact flag reflects the large sample size and novel branch/rank findings, but causative exposures remain unidentified — clinical uptake should be tempered until specific risk factors are confirmed.","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"warning","value":"The study excludes veterans who never used the VA healthcare system, which may introduce selection bias and limit generalizability to all US veterans.","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218303","tag_type":"warning","value":"Women represented a small fraction of ALS cases (484 of 14,419 total), so female-specific hazard ratios carry wider confidence intervals and should be interpreted cautiously.","value_numeric":null}],"summaries":{"what_studied":"This longitudinal cohort study examined how US military branch, rank, and length of service relate to ALS incidence among ~9.9 million veterans with VA encounters from January 2000 through October 2024, using Cox proportional hazards models stratified by sex.","key_result":"Among men, Air Force (HR 1.29), Navy (HR 1.15), and Coast Guard (HR 1.26) service was linked to higher ALS rates vs. Army; Marine Corps was lower (HR 0.78). Officers had markedly higher rates than enlisted personnel (men HR 1.64; women HR 1.72). Longer service was associated with *lower* ALS rates. Branch differences were largest in the youngest veterans (ages 17–61).","limitations":"- Observational design cannot establish causation or identify the specific exposures driving branch/rank differences.\n- Women had far fewer cases (484 vs. 13,935 in men), limiting statistical power for female-specific findings.\n- Veterans who never used the VA were excluded, potentially introducing selection bias.","practice_takeaway":"Clinicians evaluating veterans for ALS should note that officers and those who served in the Air Force, Navy, or Coast Guard appear to carry elevated risk—heightening the index of suspicion in these groups. These findings also point toward identifying specific occupational or environmental exposures in those branches that may be modifiable."}},{"doi":"10.1212/wnl.0000000000218296","pmid":"42447421","title":"Legal Protections to Mitigate Discrimination due to Neurodegenerative Biomarker Status","journal_title":"Neurology","journal_issn":"0028-3878","published_at":"2026-07-14T00:00:00.000Z","url":"https://doi.org/10.1212/wnl.0000000000218296","source_score":19,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-23T07:33:14.580Z","updated_at":"2026-08-23T07:33:14.580Z","tags":[{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"condition","value":"Alzheimer Disease","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"condition","value":"Frontotemporal Dementia","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"condition","value":"Parkinson Disease","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"impact_flag","value":"safety_signal","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"modality","value":"Biomarker Testing","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"study_design","value":"Policy Analysis / Legal Review","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"warning","value":"No primary empirical data are presented; this is a legal/policy opinion piece, not a clinical study — sample size and statistical outcomes are not applicable.","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"warning","value":"Study design label is non-standard; the article is a legal and policy analysis published in a clinical neurology journal, which may not map cleanly onto conventional evidence hierarchies.","value_numeric":null},{"paper_doi":"10.1212/wnl.0000000000218296","tag_type":"warning","value":"The 'impact_flag' of safety_signal is applied in the context of patient legal and privacy risk, not a pharmacologic or procedural safety signal in the traditional sense.","value_numeric":null}],"summaries":{"what_studied":"This policy analysis evaluates gaps in U.S. federal legal protections (GINA, ADA, ACA, HIPAA) for individuals undergoing neurodegenerative biomarker testing (AD, PD, ALS) — particularly those in preclinical or prodromal disease stages — and proposes an evidence-informed framework for building biomarker-specific privacy and antidiscrimination policy.","key_result":"Existing federal laws leave critical gaps: GINA excludes life, long-term care, and disability insurance; the ADA requires overt symptoms to qualify as a disability; and HIPAA allows health information disclosure for treatment and payment purposes. Preclinical/prodromal individuals — who may still be employed or seeking insurance — are most exposed. A proposed 'BINA' (Biomarker Information Non-Discrimination Act) modeled on GINA is identified as a potential but imperfect solution.","limitations":"This is a legal and policy analysis with no primary empirical data; evidence on actual observed discrimination against biomarker-tested individuals is currently lacking. State-level legal variation and research-record protections are explicitly outside the article's scope.","practice_takeaway":"Until stronger protections exist, clinicians should inform patients and research participants about privacy and discrimination risks tied to biomarker testing — including the option to keep research results out of the clinical medical record. Consent documents for neurodegenerative biomarker research should explicitly address these legal gaps."}},{"doi":"10.1038/s41593-026-02348-3","pmid":"42420559","title":"Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice","journal_title":"Nature Neuroscience","journal_issn":"1097-6256","published_at":"2026-07-08T00:00:00.000Z","url":"https://doi.org/10.1038/s41593-026-02348-3","source_score":73,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-11T13:33:10.361Z","updated_at":"2026-07-11T13:33:10.361Z","tags":[{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"condition","value":"Frontotemporal Dementia","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"condition","value":"Myelin Abnormalities","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"condition","value":"TDP-43 Proteinopathy","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"generic","value":"TDP-43 (TARDBP)","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"modality","value":"Gene Knockout / Conditional Knockout","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"study_design","value":"Animal Study (Mouse Knockout Model)","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"warning","value":"Sample sizes were not statistically predetermined; breeding constraints drove group sizes, which may affect statistical power for some outcomes.","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"warning","value":"The 'practice_changing' impact flag reflects mechanistic novelty (new TREM2-DAP12-TDP-43 axis), not a clinical intervention; this is a preclinical mouse study only.","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02348-3","tag_type":"warning","value":"The study is a Nature Portfolio reporting summary (supplementary document), not the full manuscript; quantitative results cited in the summary are drawn from the abstract only, as the main figures and results sections were not included in the provided text.","value_numeric":null}],"summaries":{"what_studied":"This mouse study examined the role of microglial TDP-43 (encoded by *Tardbp*) in early postnatal brain development and adult motor function, using a conditional knockout (cKO) model (Cx3cr1-CreERT2;Tardbp-flox) assessed by MRI, confocal and electron microscopy, spatial transcriptomics, bulk RNA-seq, proteomics, and behavioral testing.","key_result":"Loss of microglial TDP-43 caused structural myelin abnormalities in the early postnatal brain, impaired microglial myelin engulfment and degradation, led to motor deficits in adult mice, and—mechanistically—produced cryptic exon inclusion in *Tyrobp* mRNA, generating a truncated DAP12 protein that disrupted TREM2 signaling. Spatial transcriptomics revealed an enriched interferon-responsive signature linked to oligodendrocyte dysfunction.","limitations":"- Study is entirely in mice; direct relevance to human TDP-43 proteinopathy (ALS, FTD) is inferential.\n- Sample sizes were not statistically predetermined; they depended on breeding capacity and litter sizes.\n- Some experiments used only one sex (electron microscopy and P12 analysis: males only; bulk RNA-seq: females only), limiting sex-generalizability.","practice_takeaway":"This is a basic science study in mice and has no immediate clinical practice implications. However, it identifies a novel TREM2-DAP12 regulatory axis controlled by TDP-43 in microglia that may inform future therapeutic targets in ALS and FTD."}},{"doi":"10.1016/j.eclinm.2026.104051","pmid":null,"title":"Neurodegenerative mortality among National Football League Players","journal_title":"eClinicalMedicine","journal_issn":"2589-5370","published_at":"2026-07-08T00:00:00.000Z","url":"https://doi.org/10.1016/j.eclinm.2026.104051","source_score":146,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-07-14T13:24:04.503Z","updated_at":"2026-07-14T13:24:04.503Z","tags":[{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"category","value":"Medicine, General & Internal","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"condition","value":"Alzheimer's Disease","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"condition","value":"Neurodegenerative Disease","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"sex","value":"male","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"study_design","value":"Cohort Study","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"warning","value":"Only bibliographic metadata was provided — no abstract, methods, results, or discussion text was available. All summary fields requiring study data (key result, sample size, practice takeaway) are null due to insufficient source content. Study design tag is an inference based on typical research of this type and may not reflect the actual methodology.","value_numeric":null},{"paper_doi":"10.1016/j.eclinm.2026.104051","tag_type":"warning","value":"The DOI references a 2026 publication date; content could not be independently verified from the snippet provided.","value_numeric":null}],"summaries":{"what_studied":"This study examined neurodegenerative disease mortality rates among National Football League (NFL) players, comparing their risk of dying from conditions such as ALS, Alzheimer's disease, and Parkinson's disease relative to the general population.","limitations":"The abstract/source text provided contains no methods, results, or discussion details — only bibliographic metadata. No specific findings, sample size, or outcomes can be extracted."}},{"doi":"10.1080/19490976.2026.2692737","pmid":"42374626","title":"Microbiome and metabolites impact enteric and central nervous systems in ALS","journal_title":"Gut Microbes","journal_issn":"1949-0976","published_at":"2026-06-29T00:00:00.000Z","url":"https://doi.org/10.1080/19490976.2026.2692737","source_score":10,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-05T13:38:40.469Z","updated_at":"2026-07-05T13:38:40.469Z","tags":[{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"category","value":"Gastroenterology & Hepatology","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"condition","value":"Gut Dysbiosis","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"generic","value":"edaravone","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"generic","value":"riluzole","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"generic","value":"sodium butyrate","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"generic","value":"tofersen","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"modality","value":"Fecal Microbiota Transplantation","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"modality","value":"Prebiotic","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"modality","value":"Probiotic","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"modality","value":"Short-Chain Fatty Acid Supplementation","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"warning","value":"Human microbiome findings are heterogeneous across cohorts — some studies found no significant microbiome difference between ALS patients and controls — so taxa-level conclusions should be interpreted cautiously.","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"warning","value":"The one randomized FMT trial cited (n=27) is small and underpowered; clinical takeaways from FMT and probiotic data are largely from case reports and mouse models.","value_numeric":null},{"paper_doi":"10.1080/19490976.2026.2692737","tag_type":"warning","value":"This is a narrative (not systematic) review; study selection was not done by formal PRISMA protocol, so there is a risk of selection bias in the literature cited.","value_numeric":null}],"summaries":{"what_studied":"This narrative review synthesizes evidence on how gut microbiota and their metabolites affect the enteric nervous system (ENS) and central nervous system (CNS) in ALS, drawing on human cohort studies, preclinical mouse models (SOD1G93A, TDP43, C9orf72), mechanistic infection/dysbiosis studies, and clinical trials of microbiome-targeted therapies (FMT, probiotics, prebiotics, dietary intervention).","key_result":"ALS patients and mouse models consistently show gut dysbiosis — including reduced butyrate-producing bacteria, altered SCFA profiles, and increased intestinal permeability — alongside ENS pathology (myenteric neuron loss, reactive enteric gliosis, slowed motility). A small randomized double-blind placebo-controlled FMT trial (n=27) found no change in ALSFRS-R, motor, or respiratory function, but reported reduced anxiety, depression, and constipation, and a microbiome shift (increased *Bifidobacterium* at week 15). In SOD1 mice, probiotic treatment and sodium butyrate supplementation reduced SOD1 aggregation, improved motor function, and prolonged survival; combining butyrate with riluzole showed additive motor benefits.","limitations":"- Most human microbiome studies are small, cross-sectional, and observational, preventing causal inference; no single ALS-specific microbial signature has been replicated across cohorts.\n- Preclinical data rely heavily on familial ALS transgenic models (SOD1G93A), which represent a minority of ALS cases and may not generalize to sporadic ALS (~90% of cases).\n- Clinical FMT trials are limited by small sample sizes and short follow-up; no active trials primarily evaluate microbiota-derived signatures as diagnostic biomarkers.","practice_takeaway":"There is not yet enough evidence to recommend microbiome-targeted therapies (FMT, probiotics) as standard ALS treatment, but clinicians should be aware that gut dysbiosis and GI symptoms are common in ALS and may influence disease trajectory. Future trials should assess how ALS drugs like riluzole interact with the gut microbiome, as microbial metabolism may alter drug bioavailability."}},{"doi":"10.1038/s41590-026-02538-y","pmid":"42373784","title":"Adaptive immunity in the pathogenesis of neurodegeneration","journal_title":"Nature Immunology","journal_issn":"1529-2908","published_at":"2026-06-29T00:00:00.000Z","url":"https://doi.org/10.1038/s41590-026-02538-y","source_score":27,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-09T13:36:02.856Z","updated_at":"2026-07-09T13:36:02.856Z","tags":[{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"category","value":"Immunology","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"condition","value":"Alzheimer's Disease","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"condition","value":"Neurodegeneration","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"modality","value":"Adaptive Immunotherapy","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"warning","value":"Candidate antigens discussed as drivers of adaptive immune responses are largely preclinical or speculative; human validation is limited.","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"warning","value":"The 'practice_changing' impact flag reflects the emerging therapeutic framing of adaptive immunity in neurodegeneration, but no clinical interventions are yet validated from this paper alone.","value_numeric":null},{"paper_doi":"10.1038/s41590-026-02538-y","tag_type":"warning","value":"This is a narrative review published in 2026; no primary experimental data are included. Level of evidence is set to 7 accordingly.","value_numeric":null}],"summaries":{"what_studied":"This review examines how adaptive immunity — including T cells, B cells, and peripheral immune cell recruitment — contributes to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and ALS, with a focus on shared mechanisms and potential therapeutic targets.","key_result":"Evidence from genetic, neuropathological, and experimental studies supports a role for adaptive immune activation in driving neurodegeneration, with cross-disease parallels identified in antigen-driven responses, CNS immune cell infiltration, and microglial/astrocyte interactions.","limitations":"As a review, no original experimental data are presented, so causal relationships are inferred from existing literature. The candidate antigens driving adaptive immune responses remain largely unconfirmed in humans.","practice_takeaway":"Clinicians should be aware that adaptive immune dysregulation is emerging as a shared mechanism across major neurodegenerative diseases. Therapeutic strategies targeting T and B cell pathways may represent a future treatment avenue worth following in clinical trial developments."}},{"doi":"10.1212/nxg.0000000000200406","pmid":null,"title":"Preparing Amyotrophic Lateral Sclerosis Clinics to Provide Longitudinal Care for Individuals Carrying ALS Risk Variants","journal_title":"Neurology Genetics","journal_issn":"2376-7839","published_at":"2026-06-24T00:00:00.000Z","url":"https://doi.org/10.1212/nxg.0000000000200406","source_score":24,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-06-27T13:27:55.087Z","updated_at":"2026-06-27T13:27:55.087Z","tags":[{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"modality","value":"Genetic Counseling","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"modality","value":"Neurological Surveillance","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"study_design","value":"Expert Opinion / Framework Paper","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"warning","value":"Full text was not available; summary is based solely on the paper's metadata and title. Specific variant types discussed, sample size, and detailed recommendations could not be verified.","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"warning","value":"No sample size tag was assigned as no patient cohort is described in the available metadata.","value_numeric":null},{"paper_doi":"10.1212/nxg.0000000000200406","tag_type":"warning","value":"Study design labeled as 'Expert Opinion / Framework Paper' based on the nature of the title and journal context — this should be confirmed against the full text.","value_numeric":null}],"summaries":{"what_studied":"This paper examines how ALS specialty clinics can prepare to provide longitudinal care for presymptomatic individuals who carry genetic variants associated with ALS risk, addressing clinical, ethical, and operational considerations.","key_result":"The authors outline a framework for ALS clinics to manage at-risk variant carriers over time, including guidance on genetic counseling, surveillance protocols, and psychosocial support — though specific outcome data or trial results are not reported.","limitations":"This appears to be a perspective or framework paper without primary outcome data; recommendations may not yet reflect evidence from prospective longitudinal cohorts of presymptomatic ALS variant carriers.","practice_takeaway":"ALS clinics should proactively develop infrastructure for presymptomatic genetic variant carriers, including standardized counseling pathways and surveillance protocols. As disease-modifying trials in prodromal ALS expand, clinics with established longitudinal care models will be better positioned to enroll and support at-risk individuals."}},{"doi":"10.1016/j.neuron.2026.04.030","pmid":"42309005","title":"Limiting neurodegeneration in ALS: A phosphatase paves the way","journal_title":"Neuron","journal_issn":"0896-6273","published_at":"2026-06-17T00:00:00.000Z","url":"https://doi.org/10.1016/j.neuron.2026.04.030","source_score":12,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-24T13:21:35.736Z","updated_at":"2026-06-24T13:21:35.736Z","tags":[{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"generic","value":"PGAM5","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"modality","value":"Phosphatase Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"study_design","value":"Basic/Preclinical Research","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"warning","value":"No sample size, sex, or human vs. model organism details are available from the abstract alone.","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"warning","value":"PGAM5 is listed as a 'generic' drug name tag for convenience, but it is a gene/protein target, not an approved therapeutic agent.","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"warning","value":"The impact_flag 'practice_changing' reflects the novelty of the mechanistic target across ALS subtypes, but no clinical data are yet available; this flag applies to the research trajectory, not current practice.","value_numeric":null},{"paper_doi":"10.1016/j.neuron.2026.04.030","tag_type":"warning","value":"This appears to be an editorial or commentary piece ('Zheng et al. identify...'), not the primary research article itself — the underlying study data are not directly accessible here.","value_numeric":null}],"summaries":{"what_studied":"This paper examines PGAM5, a mitochondrial phosphatase, as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), focusing on its role in activating the stress-regulated peptidase OMA1 and the downstream mitochondrial integrated stress response (ISR) in motor neurons.","key_result":"Zheng et al. identify that PGAM5 dephosphorylates and activates OMA1, triggering a maladaptive mitochondrial integrated stress response in motor neurons across multiple ALS subtypes — positioning PGAM5 as a novel, broadly applicable target.","limitations":"The abstract provides limited methodological detail; it is unclear whether findings are validated in human tissue or only in animal/cell models, and no clinical or functional outcome data are reported.","practice_takeaway":"No immediate clinical action is warranted, but PGAM5 inhibition represents a potentially subtype-agnostic strategy in ALS drug development worth monitoring as preclinical work matures."}},{"doi":"10.1080/21678421.2026.2677537","pmid":"42206648","title":"Air pollutants and amyotrophic lateral sclerosis in a population-based registry: investigating disease susceptibility, progression and survival","journal_title":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","journal_issn":"2167-8421","published_at":"2026-05-28T00:00:00.000Z","url":"https://doi.org/10.1080/21678421.2026.2677537","source_score":7,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-06T13:22:52.388Z","updated_at":"2026-06-06T13:22:52.388Z","tags":[{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"generic","value":"nitrogen oxides","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"generic","value":"PM2.5","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"modality","value":"Environmental Exposure","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"sample_size","value":"n=322","value_numeric":322},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"study_design","value":"Population-Based Case-Control Study with Retrospective Cohort","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"warning","value":"Sample size for the case-control arm is 161 pairs (322 total); the cohort for progression/mortality is 135 — the sample_size tag reflects the larger case-control arm as the primary analysis population.","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"warning","value":"Study design tag reflects a hybrid design (case-control for risk, retrospective cohort for progression/survival); this is somewhat atypical and may affect level-of-evidence classification.","value_numeric":null},{"paper_doi":"10.1080/21678421.2026.2677537","tag_type":"warning","value":"The NOx–mortality association (HR 1.12; 95% CI 1.00–1.26) borders on statistical non-significance; the authors themselves describe it as 'marginal.'","value_numeric":null}],"summaries":{"what_studied":"This population-based study in Lombardy, Italy examined whether long-term residential exposure to PM2.5 and NOx (averaged over 20 years before diagnosis) was associated with ALS risk, disease progression (ΔFS), and survival in 161 incident ALS cases (2011–2014) matched to 161 controls, with a retrospective cohort of 135 ALS cases for progression and mortality analyses.","key_result":"Each 5 µg/m³ increase in 20-year mean PM2.5 was linked to higher ALS risk (adjusted OR 1.19; 95% CI 1.01–1.40). NOx in the 5 years before diagnosis showed a marginal association with increased mortality (adjusted HR 1.12; 95% CI 1.00–1.26). Neither pollutant was significantly associated with disease progression rate.","limitations":"- Relatively small sample (161 cases/controls), limiting statistical power for subgroup analyses.\n- Residential address used as a proxy for exposure; actual personal exposure and mobility over 20 years were not captured.\n- Retrospective design and reliance on registry data may introduce selection or information bias.","practice_takeaway":"Chronic PM2.5 exposure may modestly increase ALS risk, supporting environmental history-taking in at-risk patients. Clinicians and public health planners should consider air pollution reduction as part of broader neurodegenerative disease prevention strategies."}},{"doi":"10.1186/s40035-026-00557-1","pmid":"42186042","title":"Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges","journal_title":"Translational Neurodegeneration","journal_issn":"2047-9158","published_at":"2026-05-25T00:00:00.000Z","url":"https://doi.org/10.1186/s40035-026-00557-1","source_score":37,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-01T13:39:40.006Z","updated_at":"2026-06-01T13:39:40.006Z","tags":[{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"condition","value":"Alzheimer's Disease","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"condition","value":"Huntington's Disease","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"condition","value":"Multiple Sclerosis","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"generic","value":"beta-hydroxybutyrate","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"generic","value":"medium-chain triglycerides","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"modality","value":"Dietary Intervention","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"modality","value":"Ketone Supplement","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"warning","value":"Clinical sample sizes are very small (many n<50 or single case studies); effect estimates should be interpreted with caution.","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"warning","value":"Most preclinical studies cited used male-only animals, limiting sex-balanced translational conclusions.","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"warning","value":"No original experimental data are presented; all conclusions are derived from cited literature.","value_numeric":null},{"paper_doi":"10.1186/s40035-026-00557-1","tag_type":"warning","value":"This is a narrative review without systematic meta-analytic methods; study selection may reflect author bias.","value_numeric":null}],"summaries":{"what_studied":"This narrative review evaluates the ketogenic diet (KD) as a therapeutic strategy across five neurodegenerative diseases — Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), ALS, and multiple sclerosis (MS) — synthesizing preclinical and clinical evidence on its effects on mitochondrial function, oxidative stress, neuroinflammation, autophagy, and gut microbiota.","key_result":"Across diseases, KD and its primary ketone body β-hydroxybutyrate (BHB) consistently reduced neuroinflammatory markers (IL-1β, TNF-α, NF-κB, NLRP3), improved energy metabolism, and showed functional benefits in small clinical trials:\n- **AD**: MCT-based KD improved working memory and episodic memory (n=20 and n=52 studies); a randomized crossover trial (n=21 completers) showed improved daily function and quality of life over two 12-week periods.\n- **PD**: A pilot RCT (n=47, 38 completers, 8 weeks) improved non-motor UPDRS scores; a 24-week longitudinal study improved motor and non-motor outcomes.\n- **HD**: One case study (48 weeks) showed 52% motor improvement and 28% gain in daily living activities.\n- **ALS**: One case study (18 months) showed 7% functional improvement and 19% quality-of-life gain.\n- **MS**: A 6-month Phase II trial (n=64) improved fatigue, depression, and reduced leptin; an 18-month RCT sustained tolerability and disability score improvements.","limitations":"- Clinical evidence is largely from small pilots and single case studies, limiting generalizability.\n- Most animal studies used only male subjects, reducing translational relevance to mixed-sex populations.\n- Long-term safety data in neurodegenerative populations are scarce; adherence to the strict regimen remains a major barrier.","practice_takeaway":"KD may offer a metabolic adjunct to standard pharmacotherapy in AD, PD, HD, ALS, and MS — particularly by improving energy metabolism and reducing neuroinflammation — but current evidence is preliminary and should not replace disease-specific treatments. Clinicians considering KD for these patients should supervise nutritional adequacy, monitor for 'keto flu,' cardiovascular risk, and micronutrient deficiencies, and pair dietary initiation with structured adherence support."}},{"doi":"10.1016/j.freeradbiomed.2026.05.285","pmid":"42156213","title":"Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications","journal_title":"Free Radical Biology and Medicine","journal_issn":"0891-5849","published_at":"2026-05-19T00:00:00.000Z","url":"https://doi.org/10.1016/j.freeradbiomed.2026.05.285","source_score":11,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-26T13:34:58.477Z","updated_at":"2026-05-26T13:34:58.477Z","tags":[{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"condition","value":"Alzheimer's Disease","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"condition","value":"Huntington's Disease","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"modality","value":"Arginase Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"warning","value":"No sample size applies — this is a review article with no primary patient cohort. Sex of subjects is not reported at the review level.","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"warning","value":"The paper was published May 19, 2026; it is very recent and may not yet have undergone broad post-publication scrutiny.","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.285","tag_type":"warning","value":"Therapeutic strategies discussed are proposed/preclinical; no approved arginase-targeted treatments for neurodegeneration are described.","value_numeric":null}],"summaries":{"what_studied":"This review evaluates evidence for dysregulation of arginase isoenzymes and arginine metabolic pathways in Alzheimer's, Parkinson's, Huntington's diseases, and ALS, drawing on patient data and experimental models to explore mechanisms and therapeutic strategies.","key_result":"Disrupted arginase activity and arginine metabolism contribute to neurodegeneration via nitrogen metabolism imbalance, oxidative/nitrosative stress, mitochondrial dysfunction, and neuroinflammation across all four diseases reviewed; therapeutic targeting of arginase-related pathways is proposed to slow disease progression.","limitations":"As a narrative review, it synthesizes existing data without systematic meta-analytic methods. Evidence is largely from experimental models, with limited direct clinical trial data. Cell-, stage-, and disease-specific roles of arginase isoenzymes remain incompletely characterized.","practice_takeaway":"No approved arginase-targeted therapies exist yet, but this review highlights arginine metabolic pathways as a potential drug target in neurodegeneration. Clinicians should watch for emerging trials focused on arginase modulation in Alzheimer's, Parkinson's, Huntington's, and ALS."}},{"doi":"10.1038/s41593-026-02300-5","pmid":"42135512","title":"Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming","journal_title":"Nature Neuroscience","journal_issn":"1097-6256","published_at":"2026-05-14T00:00:00.000Z","url":"https://doi.org/10.1038/s41593-026-02300-5","source_score":62,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-17T13:21:40.196Z","updated_at":"2026-05-17T13:21:40.196Z","tags":[{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"condition","value":"C9orf72-Associated ALS","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"level_of_evidence","value":"4","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"modality","value":"Immunomodulation","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"study_design","value":"Translational Cohort Study (Multi-Omic)","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"warning","value":"Full paper body was not accessible — only the abstract was extractable; sample sizes and statistical details are unknown.","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"warning","value":"Impact flag 'practice_changing' is based on the novelty of immune stratification findings described in the abstract; confirmatory clinical translation has not yet been demonstrated.","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"warning","value":"Publication date is May 14, 2026 — this is a very recent paper; findings have not yet undergone broad community scrutiny or replication.","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02300-5","tag_type":"warning","value":"Study design label is approximate; the paper combines multiple omic approaches (scRNA-seq, bulk RNA-seq, spatial proteogenomics) without a clear RCT or standard epidemiological design label.","value_numeric":null}],"summaries":{"what_studied":"This study used integrated single-cell RNA sequencing, bulk RNA sequencing, and spatial proteogenomics to characterize immune dynamics in peripheral blood and spinal cord tissues from patients with sporadic ALS and C9orf72-expansion ALS, examining how peripheral and central immune changes relate to motor neuron pathology and disease progression.","key_result":"The analysis uncovered broad immune remodeling specific to C9orf72 ALS, subtype-specific differences in monocyte activation, and antigen-driven clonal expansion of CD8 effector memory T cells. Spatial mapping linked complement activation and lipid-programmed myeloid states to sites of motor neuron loss and TDP-43 pathology.","limitations":"Full text beyond the abstract was not available, so sample sizes, statistical thresholds, and methodological details could not be verified. The study appears observational and cross-sectional, limiting causal inference about immune-to-motor neuron pathology directionality.","practice_takeaway":"These findings suggest that immune stratification by ALS subtype (sporadic vs. C9orf72) may be needed to guide future immunomodulatory trials. Clinicians should be aware that peripheral immune profiling could serve as a window into CNS disease activity in ALS."}},{"doi":"10.3389/fnagi.2026.1834543","pmid":null,"title":"Intranasal administration of stem cells and their derivatives for neurological and respiratory disorders: a systematic review of human clinical trials","journal_title":"Frontiers in Aging Neuroscience","journal_issn":"1663-4365","published_at":"2026-05-07T00:00:00.000Z","url":"https://doi.org/10.3389/fnagi.2026.1834543","source_score":184,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-05-10","doi":"10.3389/fnagi.2026.1834543","days":"7","issn":"1663-4365","rank":"2","field":"Clinical Medicine","score":"184","category":"Neurosciences","categories":["Neurosciences"],"_categories":["Neurosciences"]},"pubmed":null,"crossref":{"DOI":"10.3389/fnagi.2026.1834543","URL":"https://doi.org/10.3389/fnagi.2026.1834543","ISSN":["1663-4365"],"link":[{"URL":"https://www.frontiersin.org/articles/10.3389/fnagi.2026.1834543/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Intranasal administration of stem cells and their derivatives for neurological and respiratory disorders: a systematic review of human clinical trials"],"author":[{"given":"Umm E.","family":"Habiba","sequence":"first","affiliation":[{"name":"Research and Development (R&D) Department, R3 Stem Cell LLC"},{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Roshini","family":"Sathyanarayanan","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Sabiha","family":"Shamim","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Aishwarya","family":"Manian","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Ammar","family":"Haider","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Iqra","family":"Sarwar","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"David Lawrence","family":"Greene","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Stem Cell LLC"},{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]}],"issued":{"date-parts":[[2026,5,7]]},"member":"1965","prefix":"10.3389","source":"Crossref","volume":"18","created":{"date-time":"2026-05-07T05:41:35Z","timestamp":1778132495000,"date-parts":[[2026,5,7]]},"indexed":{"date-time":"2026-05-07T06:14:44Z","timestamp":1778134484033,"date-parts":[[2026,5,7]]},"license":[{"URL":"https://creativecommons.org/licenses/by/4.0/","start":{"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000,"date-parts":[[2026,5,7]]},"delay-in-days":0,"content-version":"vor"}],"subject":[],"abstract":"$30","relation":{},"resource":{"primary":{"URL":"https://www.frontiersin.org/articles/10.3389/fnagi.2026.1834543/full"}},"subtitle":[],"deposited":{"date-time":"2026-05-07T05:41:36Z","timestamp":1778132496000,"date-parts":[[2026,5,7]]},"issn-type":[{"type":"electronic","value":"1663-4365"}],"published":{"date-parts":[[2026,5,7]]},"publisher":"Frontiers Media SA","reference":[{"DOI":"10.1186/s13287-025-04254-0","key":"ref1","year":"2025","issue":null,"author":"Allouh","volume":"16","first-page":"127","unstructured":null,"article-title":"Mesenchymal stromal/stem cells from perinatal sources: biological facts, molecular biomarkers, and therapeutic promises","journal-title":"Stem Cell Res Ther","doi-asserted-by":"publisher"},{"DOI":"10.3390/pharmaceutics14020381","key":"ref2","year":"2022","issue":null,"author":"Alvites","volume":"14","first-page":"381","unstructured":null,"article-title":"Mesenchymal stem/stromal cells and their paracrine activity—immunomodulation mechanisms and how to influence the therapeutic potential","journal-title":"Pharmaceutics","doi-asserted-by":"publisher"},{"DOI":"10.25259/SNI_233_2020","key":"ref3","year":"2020","issue":null,"author":"Boika","volume":"11","first-page":"380","unstructured":null,"article-title":"Mesenchymal stem cells in Parkinson’s disease: motor and nonmotor symptoms in the early posttransplant period","journal-title":"Surg. 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Aging Neurosci."],"is-referenced-by-count":0},"unpaywall":{"doi":"10.3389/fnagi.2026.1834543","is_oa":true,"title":"Intranasal administration of stem cells and their derivatives for neurological and respiratory disorders: a systematic review of human clinical trials","updated":"2026-05-13T08:46:39+00:00","published_date":"2026-05-07","best_oa_location":{"url":"https://doi.org/10.3389/fnagi.2026.1834543","pmh_id":null,"url_for_pdf":null,"url_for_landing_page":"https://doi.org/10.3389/fnagi.2026.1834543"}}},"created_at":"2026-05-12T13:18:17.986Z","updated_at":"2026-05-14T15:13:26.918Z","tags":[{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Acute Respiratory Distress Syndrome","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Alzheimer's Disease","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Cerebral Palsy","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Neurological Disorders","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Perinatal Arterial Ischemic Stroke","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"condition","value":"Stroke","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"modality","value":"Exosome Therapy","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"modality","value":"Extracellular Vesicle Therapy","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"modality","value":"Mesenchymal Stem Cell Therapy","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"modality","value":"Neural Stem Cell Therapy","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"sample_size","value":"n=104","value_numeric":104},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"study_design","value":"Systematic Review","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"warning","value":"Level of evidence assigned as '3' reflects the systematic review of predominantly non-randomized, high-risk-of-bias studies rather than a review of RCTs; the underlying evidence base is functionally Level 4–5.","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"warning","value":"Several authors are employed by R3 Stem Cell LLC and R3 Medical Research LLC; at least one included study was conducted by a principal investigator who simultaneously served as treating physician and sole outcome assessor under a patient-funded model.","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"warning","value":"The review itself was not pre-registered in PROSPERO, introducing potential analytical flexibility bias at the review level — the authors explicitly acknowledge this.","value_numeric":null},{"paper_doi":"10.3389/fnagi.2026.1834543","tag_type":"warning","value":"The total analyzed sample is only 98 participants across 7 published studies spanning 9 distinct conditions — pooled effect size estimates have very limited interpretability.","value_numeric":null}],"summaries":{"what_studied":"This systematic review evaluated the safety, feasibility, and efficacy of intranasally administered stem cells and their derivatives (MSCs, NSCs, secretome, extracellular vesicles) for neurological and respiratory disorders across 19 studies (7 published, 12 registry-only) from January 2011 to December 2025, covering 104 enrolled participants in published studies.","key_result":"No study achieved low risk of bias under RoB 2 or ROBINS-I; 74% of the 19 studies were rated high risk overall. Structural publication bias was confirmed (63% registry-only or grey literature, exceeding the 30% threshold). Across 98 analyzed participants from 7 published studies, intranasal delivery was consistently reported as safe with no serious adverse events, and preliminary signals of benefit appeared in cerebral palsy, perinatal stroke, and Alzheimer's disease — but no efficacy conclusion is interpretable due to open-label design, absent sham controls, and unblinded outcome assessment in every published trial.","limitations":"- Every published study lacked randomization, sham/placebo intranasal control, and blinded outcome assessment, making efficacy estimates uninterpretable as biological activity.\n- Multiple studies combined intranasal and intravenous delivery, preventing route-specific attribution of any observed effect.\n- The review itself was not pre-registered in PROSPERO, and several authors have direct conflicts of interest (employment by the stem cell manufacturer whose products were evaluated).","practice_takeaway":"Do not adopt intranasal stem cell or exosome therapy for any neurological or respiratory condition based on current evidence — no adequately powered, blinded, sham-controlled trial has been completed or published. The safety signal across ~98 participants is reassuring enough to justify rigorously designed Phase 2 trials, but not clinical use."}},{"doi":"10.1016/j.freeradbiomed.2026.05.014","pmid":"42092406","title":"TRIM16 attenuates TDP43-mediated oxidative injury by coordinating Nrf2 activation and TFR1 autophagic degradation","journal_title":"Free Radical Biology and Medicine","journal_issn":"0891-5849","published_at":"2026-05-05T00:00:00.000Z","url":"https://doi.org/10.1016/j.freeradbiomed.2026.05.014","source_score":7,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-09T13:22:19.755Z","updated_at":"2026-05-09T13:22:19.755Z","tags":[{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"condition","value":"Amyotrophic Lateral Sclerosis","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"condition","value":"Ferroptosis","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"condition","value":"Oxidative Stress","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"condition","value":"TDP43 Proteinopathy","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"generic","value":"TDP43 (M337V)","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"generic","value":"TRIM16","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"modality","value":"Gene Overexpression / Ubiquitin-Proteasome Pathway Modulation","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"study_design","value":"Mechanistic Laboratory Study (In Vitro)","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"warning","value":"Age group tag is indeterminate as the study uses motor neuron-like cells (cell line model); 'mixed' was omitted and this tag was left out accordingly — no age group tag was applied.","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"warning","value":"Full text was blocked by a publisher paywall/CAPTCHA; all structured data is derived exclusively from the abstract. Key quantitative results (e.g., effect sizes, cell viability percentages, iron levels) are not available.","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"warning","value":"Study design tag 'Mechanistic Laboratory Study (In Vitro)' is inferred from abstract context; no explicit study design label is provided by the authors.","value_numeric":null},{"paper_doi":"10.1016/j.freeradbiomed.2026.05.014","tag_type":"warning","value":"The level of evidence (6) reflects basic science/in vitro work with no clinical or animal data confirmed in the abstract.","value_numeric":null}],"summaries":{"what_studied":"This study investigated the role of TRIM16 in protecting motor neuron-like cells against toxicity caused by wild-type and M337V mutant TDP43, using multi-omics analysis and functional experiments to examine oxidative stress, mitochondrial integrity, ferroptosis, and iron homeostasis.","key_result":"TRIM16 overexpression reduced TDP43-induced oxidative stress and ferroptosis via two parallel mechanisms: (1) ubiquitination and degradation of Keap1, activating Nrf2-mediated antioxidant genes; and (2) p62-dependent autophagic degradation of the iron importer TFR1, reducing iron accumulation and lipid peroxidation. The M337V TDP43 mutation worsened proteotoxicity compared to wild-type TDP43.","limitations":"Full text was inaccessible; findings are based solely on the abstract. The study used motor neuron-like cells (not primary neurons or in vivo ALS models), which may limit translational relevance. No patient-derived data or animal model validation is described in the abstract.","practice_takeaway":"While not yet clinically actionable, TRIM16 emerges as a potential therapeutic target in TDP43 proteinopathies such as ALS — particularly through its dual role in activating Nrf2 antioxidant defenses and suppressing iron-mediated ferroptosis."}}],"initialOffset":25,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Amyotrophic Lateral Sclerosis"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Amyotrophic Lateral Sclerosis"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Amyotrophic Lateral Sclerosis"}}}]]

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