Alzheimer's Research & Therapy最新文献

{"title":"Longitudinal evaluation of common and unique brain-networks in variants of primary progressive aphasia.","authors":"Rajan Kashyap, Rose Dawn Bharath, Changsong Zhou, Kyrana Tsapkini, John E Desmond, S H Annabel Chen, Kaviraja Udupa, P T Sivakumar, Sagarika Bhattacharjee","doi":"10.1186/s13195-025-01800-z","DOIUrl":"10.1186/s13195-025-01800-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>The two variants of primary progressive aphasia (PPA) with Frontotemporal dementia pathology- semantic (svPPA) and non-fluent (nfvPPA) exhibit both shared and distinct features. The phenotypic heterogeneity stems from alterations in underlying brain networks. Investigating the common network (CN) and variant-specific unique network (UN) is critical to understanding the pathology of these conditions. Additionally, examining the evolution of these networks is key to elucidating disease progression.</p><p><strong>Method: </strong>We applied algebraic-topology to explore the CN and UN using individualised resting-state fMRI data from 31 patients with nfvPPA, 32 with svPPA, and 38 age- and sex-matched controls (scanned at first visit). Using persistent homology, we identified the networks that differentiated (p < 0.01) each patient group from healthy controls. Since the subset of these subjects was scanned at the 6th and 12th months, the longitudinal changes in the rsfMRI networks were evaluated at each interval. Network features were correlated with clinical behaviours, and the longitudinal impact of the changes in these networks on behaviours was evaluated over the 12-month period. To validate the rsfMRI networks and the longitudinal changes, we evaluated the grey matter (GM) volume, GM atrophy and the rate-of-atrophy of the brain areas. To corroborate the findings, we applied persistent homology on the structural networks derived from diffusion tensor images.</p><p><strong>Result: </strong>We found the existence of a left lateralised functional network identical in both PPA groups. This CN, comprising regions associated with language and cognition, remained stable over time (12 months period) and was associated with the severity of dementia. Conversely, the right-dominant UN in both variants showed progressive disintegration annually. In svPPA, cerebellar disassociation led to a decline in daily life activities, while parietal lobe degradation in nfvPPA impaired naming abilities. The CN and UN with similar regions were also found in the structural connectivity and the longitudinal changes in UN aligned with accelerated GM atrophy in the affected regions.</p><p><strong>Discussion: </strong>Given the limited availability of pharmacological treatments, rehabilitation in PPA has primarily focused on modulating the left hemisphere using brain stimulation techniques. However, our findings indicate that while the disintegrated left hemispheric CN remained relatively stable, dysconnectivity progressed in the right hemisphere. These observations, along with the phylogenetic organization of brain networks and the variant-specific patterns of progression, highlight the need to incorporate right hemispheric rehabilitation strategies alongside the conventional left-hemispheric approaches in PPA.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"192"},"PeriodicalIF":7.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation and interpretation of DTI-ALPS, a proposed surrogate marker for glymphatic clearance, in a large population-based sample.","authors":"Siddhartha Satpathi, Robert I Reid, Scott A Przybelski, Sheelakumari Raghavan, Petrice M Cogswell, Nolan K Meyer, Val J Lowe, Jeffrey L Gunter, Ronald C Petersen, Clifford R Jack, Jonathan Graff-Radford, Prashanthi Vemuri","doi":"10.1186/s13195-025-01842-3","DOIUrl":"10.1186/s13195-025-01842-3","url":null,"abstract":"<p><strong>Background: </strong>The diffusion tensor imaging along perivascular spaces index (DTI-ALPS), which measures diffusivity in the perivascular spaces along the medullary veins, has gained popularity and controversy as a surrogate marker of glymphatic clearance. The goal of this work is to automatically estimate DTI-ALPS in a large population-based sample, evaluate the correlates of the signal observed in the context of aging and dementia biomarkers, and evaluate its clinical usefulness.</p><p><strong>Methods: </strong>We identified 2715 participants aged 30 + years in the population-based Mayo Clinic Study of Aging with diffusion MRI. We calculated DTI-ALPS through a modified pipeline of previously published methods. We evaluated DTI-ALPS using different protocols and scanners and reported ICC for agreement. We examined the predictors of longitudinal DTI-ALPS with demographics (age, sex), vascular risk, clinical data (diagnosis, global cognition), and imaging markers (white matter hyperintensity (WMH), global amyloid load from PIB-PET, and temporal meta-ROI Tau-PET SUVR) in a subset of participants aged 50 + years using Pearson correlations, ANCOVA with adjustments for age and sex, and linear mixed effect models. We also compared the utility of DTI-ALPS with WMH for prediction of cognitive decline.</p><p><strong>Results: </strong>With modifications to the automated DTI-ALPS pipeline, consistent measurements can be made from data obtained with different protocols on different scanners. DTI-ALPS was negatively correlated with age, vascular risk, and WMH burden and was positively correlated with cognitive scores and higher in females. In the longitudinal models, WMH explained the greatest variability in decline of DTI-ALPS. The age and sex adjusted associations with AD biomarkers (amyloid and tau) were minimal. DTI-ALPS had a significant interaction with WMH on the rate of cognitive decline.</p><p><strong>Conclusions: </strong>DTI-ALPS can be reliably automated in large samples. The computed DTI-ALPS was associated with vascular dysfunction (vascular risk and WMH) and may provide additional complementary information about cognitive decline. The low associations with AD biomarkers suggest that DTI-ALPS may be a poor surrogate of AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"191"},"PeriodicalIF":7.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel miR-4536-3p inhibition ameliorates Alzheimer's disease by reducing Aβ accumulation and tau phosphorylation.","authors":"Jiyun Choi, Dohee Kim, Haewon Jeong, Jinsu Hwang, Mahesh Ramalingam, Sujin Han, Hyong-Ho Cho, Byeong C Kim, Han-Seong Jeong, Sujeong Jang","doi":"10.1186/s13195-025-01834-3","DOIUrl":"10.1186/s13195-025-01834-3","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by cognitive decline, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. Effective therapies remain limited; therefore, recent studies have explored microRNAs as potential therapeutic targets.</p><p><strong>Methods: </strong>miR-4536-3p inhibition was investigated using in vitro (SH-SY5Y cells) and in vivo (5xFAD mouse) AD models. Apoptosis, neuronal markers, and signaling pathways were assessed through functional assays. Cognitive effects were evaluated via the Morris water maze.</p><p><strong>Results: </strong>miR-4536-3p inhibition increased an expression of Drebrin1 (DBN1), a key regulator of synaptic plasticity, but it reduced Aβ deposition, tau phosphorylation, and apoptosis. The treatment improved neuronal marker levels and significantly enhanced the spatial learning and memory of 5xFAD mice. Mechanistically, miR-4536-3p inhibition activated the PI3K/Akt/GSK3β signaling pathway, suppressing apoptosis and mitigating AD pathology.</p><p><strong>Conclusion: </strong>miR-4536-3p inhibition offers a promising therapeutic strategy for AD by restoring the DBN1 expression, reducing neurodegeneration, and improving cognitive outcomes through PI3K/Akt pathway modulation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"189"},"PeriodicalIF":7.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"White matter hyperintensities and their impact in brain structure and function in alzheimer's disease and behavioral variant frontotemporal dementia across Latin America and the United States: a cross-sectional study.","authors":"Florencia Altschuler, Verónica Canziani, Matías Fraile-Vázquez, Raul Gonzalez-Gomez, Hernán Hernández, Sandra Baez, Joaquín Migeot, Sol Fittipaldi, Marcelo Adrian Maito, Agustina Legaz, Maria Eugenia Godoy, Sebastián Moguilner, Josephine Cruzat, Carlos Coronel-Oliveros, Enzo Tagliazucchi, Hernando Santamaria Garcia, Pablo Reyes, Diana L Matallana, José Alberto Avila-Funes, Andrea Slachevsky, María I Behrens, Nilton Custodio, Juan Felipe Cardona, Luis Ignacio Brusco, Martin A Bruno, Ana L Sosa Ortiz, Stefanie D Pina-Escudero, Leonel T Takada, Elisa de Paula Franca Resende, Katherine L Possin, Maira Okada de Oliveira, Kun Hu, Brian Lawlor, Jennifer S Yokoyama, Bruce Miller, Francisco Lopera, Adolfo Martin Garcia, Vicente Medel, Agustin Ibañez, Cecilia Gonzalez Campo","doi":"10.1186/s13195-025-01832-5","DOIUrl":"10.1186/s13195-025-01832-5","url":null,"abstract":"<p><strong>Background: </strong>White matter hyperintensities (WMHs) are a core manifestation of normal and pathological aging and are potentially linked to geographical differences in social and physical exposomes. Previous studies have not examined the impact of WMHs burden on neurodegeneration and cognition in healthy controls (HCs) and patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) across geographic regions. This study addressed this gap by assessing the impact of WMHs burden on participants with and without dementia from Latin America (LA) and the United States (US).</p><p><strong>Methods: </strong>The study comprised 994 participants, including HCs (n = 402), AD (n = 359), and bvFTD subjects (n = 233) from LA and the US. WMHs and their association with grey matter (GM) atrophy, assessed through GM volume and cortical thickness, were evaluated and compared among groups (HCs, AD, and bvFTD) in LA and the US using a voxel-wise brain imaging approach (p < 0.05 family-wise error-corrected for multiple comparisons, minimum cluster size = 50 voxels). Multiple regressions analysis were employed to examine geographic differences in WMHs burden, WMHs-GM associations, and the effect of WMHs on cognitive performance, as assessed by the Mini-Mental State examination.</p><p><strong>Results: </strong>In the LA cohort only, higher WMHs load was associated with greater GM atrophy across all groups (HCs, AD, bvFTD), with a specific neurodegenerative pattern involving orbitofrontal, cingulate, and temporal areas. HCs from LA showed a greater WMHs load than their US counterparts, and this effect was dependent on GM atrophy. Finally, WMHs burden negatively impacted cognitive performance in dementia subjects, with a greater effect observed in bvFTD subjects from the US.</p><p><strong>Conclusion: </strong>WMHs have a more pronounced impact on neurodegeneration across the LA cohort, with a worse impact on HCs, which also show higher WMHs burden than their US counterparts. This could increase the risk of developing dementia. Moreover, WMHs burden differentially impacts cognition, with a greater negative effect observed in bvFTD subjects from the US. These findings highlight geographic variations in WMHs-related conditions, offering valuable insights for tailored future research.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"188"},"PeriodicalIF":7.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analyses of NOTCH3 variants in Chinese patients with clinically diagnosed Alzheimer's disease and frontotemporal dementia.","authors":"Haitian Nan, Min Chu, Ailing Yue, Qianqian He, Jieying Li, Yanchen Liu, Lijun Chi, Xiaoyan Liu, Guoping Peng, Liyong Wu","doi":"10.1186/s13195-025-01836-1","DOIUrl":"10.1186/s13195-025-01836-1","url":null,"abstract":"<p><strong>Background: </strong>A pathogenic variant in the NOTCH3 gene has been identified as the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Studies focusing on variants in NOTCH3 in Alzheimer's disease (AD) and frontotemporal dementia (FTD) cohorts have been limited. We aim to screen clinically diagnosed AD and FTD patients with unknown etiology for pathogenic variants in NOTCH3 in the Chinese population.</p><p><strong>Methods: </strong>This study included early-onset AD and FTD patients consecutively recruited from Xuanwu Hospital. We performed the whole exome sequencing of genomic DNA from the patients screened for rare, nonsynonymous, predicted deleterious NOTCH3 variants. The clinical characteristics of dementia patients with likely pathogenic NOTCH3 variants were described in detail.</p><p><strong>Results: </strong>Three hundred four AD and 261 FTD patients were screened for variants in the NOTCH3 gene. Four cysteine-altering NOTCH3 variants-c.1630C > T,p.(R544C); c.1672C > T,p.(R558C); c.1759C > T,p.(R587C); and c.1918C > T,p.(R640C)-were identified as likely pathogenic variants according to ACMG guidelines. All four patients with cysteine-altering variants were clinically diagnosed with AD or FTD and presented with characteristic clinical manifestations and neuroimaging profiles. Notably, they also showed mild periventricular and deep white matter signal changes on neuroimaging. Our study showed a 0.7% (4/565) occurrence of NOTCH3 pathogenic variants in Chinese early-onset dementia patients.</p><p><strong>Conclusions: </strong>Our findings expand the mutational and phenotypic spectrum associated with NOTCH3. NOTCH3 pathogenic variants are present in clinically diagnosed AD and FTD patients. However, the absence of biomarkers to confirm AD or FTD diagnoses limits the interpretation of whether these cases represent comorbid conditions or phenotypic overlaps with CADASIL. Clinical identification of dementia patients with these variants at an early stage is challenging.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"186"},"PeriodicalIF":7.6,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct gut microbiota profiles and network properties in older Korean individuals with subjective cognitive decline, mild cognitive impairment, and Alzheimer's disease.","authors":"Sang Joon Son, Xuanga Wu, Hyun Woong Roh, Yong Hyuk Cho, Sunhwa Hong, You Jin Nam, Chang Hyung Hong, Sunmin Park","doi":"10.1186/s13195-025-01820-9","DOIUrl":"10.1186/s13195-025-01820-9","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"187"},"PeriodicalIF":7.6,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma phosphorylated tau 217 and amyloid‑β 42/40 for amyloid risk in subgroups.","authors":"Heekyoung Kang, Heejin Yoo, Jungah Lee, Soyeon Yoon, Henrik Zetterberg, Kaj Blennow, Fernando Gonzalez-Ortiz, Nicholas J Ashton, Theresa A Day, Sung Hoon Kang, Jihwan Yun, Min Young Chun, Eun Hye Lee, Jun Pyo Kim, Hee Jin Kim, Duk L Na, Hyemin Jang, Daeun Shin, Sang Won Seo","doi":"10.1186/s13195-025-01826-3","DOIUrl":"10.1186/s13195-025-01826-3","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) pathology. Recently, plasma biomarkers, particularly p-tau217, have emerged as promising tools for early diagnosis and risk stratification. In this retrospective study, we evaluated the diagnostic performance of p-tau217 combined with other plasma biomarkers in distinguishing Aβ Positron emission tomography (PET) positivity in cognitively unimpaired (CU) and cognitively impaired (CI) individuals across diverse clinical subgroups.</p><p><strong>Methods: </strong>We analyzed 2,497 participants from the Korea-Registries to Overcome dementia and Accelerate Dementia (K-ROAD) cohort, including 636 CU and 1,971 CI individuals. Plasma p-tau217 was measured using both SIngle MOlecule Array (SIMOA) and Meso Scale Discovery (MSD) assays, alongside Aβ42/40, Glial fibrillary acidic protein (GFAP), and Neurofilament light chain (NfL). We assessed the diagnostic performance of biomarker combinations for Aβ PET positivity through the area under the receiver operating characteristic curve (AUC), Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), and performed subgroup analyses based on age, sex, body mass index (BMI), and Apolipoprotein E (APOE) ε4 status. To assess applicability, we stratified the cohort by recruitment site into a development set (Samsung Medical Center, n = 1,545) and a validation set (other centers, n = 952).</p><p><strong>Results: </strong>In CU individuals from the development cohort, the combination of p-tau217 and Aβ42/40 significantly improved diagnostic accuracy (AUC: ALZpath 0.937 vs. 0.905, MSD 0.901 vs. 0.861; p < 0.05, DeLong test; 95% CIs) and model fit (AIC /BIC, p < 0.001) compared to p-tau217 alone. In contrast, in CI individuals, the combination provided only modest improvements in model fit without significantly enhancing AUC. GFAP and NfL did not contribute significantly to amyloid detection in either group. These findings were successfully validated in an independent cohort from other centers. Subgroup analyses in CU individuals showed the greatest improvements in older adults, females, and APOE4 non-carriers, regardless of obesity status. In CI individuals, the combination had no significant impact on AUC except in males, where a small but significant increase was observed (p = 0.002).</p><p><strong>Conclusion: </strong>Combining p-tau217 with Aβ42/40 enhances amyloid detection in CU individuals, improving both diagnostic accuracy and model fit, whereas its impact in CI individuals is limited. These results highlight the potential of plasma biomarker combinations for refining early AD diagnostics and individualized risk assessment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"184"},"PeriodicalIF":7.6,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal structural MRI-based deep learning and radiomics features for predicting Alzheimer's disease progression.","authors":"Sepehr Aghajanian, Fateme Mohammadifard, Ida Mohammadi, Shahryar Rajai Firouzabadi, Ali Baradaran Bagheri, Elham Moases Ghaffary, Omid Mirmosayyeb","doi":"10.1186/s13195-025-01827-2","DOIUrl":"10.1186/s13195-025-01827-2","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the principal cause of dementia and requires the early diagnosis of people with mild cognitive impairment (MCI) who are at high risk of progressing. Early diagnosis is imperative for optimizing clinical management and selecting proper therapeutic interventions. Structural magnetic resonance imaging (MRI) markers have been widely investigated for predicting the conversion of MCI to AD, and recent advances in deep learning (DL) methods offer enhanced capabilities for identifying subtle neurodegenerative changes over time.</p><p><strong>Methods: </strong>We selected 228 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had at least three T1-weighted MRI scans within 18 months of baseline. MRI volumes underwent bias correction, segmentation, and radiomics feature extraction. A 3D residual network (ResNet3D) was trained using a pairwise ranking loss to capture single-timepoint risk scores. Longitudinal analyses were performed by extracting deep convolutional neural network (CNN) embeddings and gray matter radiomics for each scan, which were put into a time-aware long short-term memory (LSTM) model with an attention mechanism.</p><p><strong>Results: </strong>A single-timepoint ResNet3D model achieved modest performance (c-index ~ 0.70). Incorporating longitudinal MRI files or downstream survival models led to a pronounced prognostic improvement (c-index:0.80-0.90), but was not further improved by longitudinal radiomics data. Time-specific classification within two- and three-year and five-year windows after the last MRI acquisition showed high accuracy (AUC > 0.85). Several radiomics, including gray matter surface to volume and elongation, emerged as the most predictive features. Each SD change in the gray matter surface to volume change within the last visit was associated with an increased risk of developing AD (HR: 1.50; 95% CI: 1.25-1.79).</p><p><strong>Conclusions: </strong>These findings emphasize the value of structural MRI within the advanced DL architectures for predicting MCI-to-AD conversion. The approach may enable earlier risk stratification and targeted interventions for individuals most likely to progress. limitations in sample size and computational resources warrant larger, more diverse studies to confirm these observations and explore additional improvements.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"182"},"PeriodicalIF":7.6,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-human study of neuron regenerative therapy NNI-362 to evaluate the safety, pharmacokinetics, and pharmacodynamics in healthy aged population.","authors":"Judith Kelleher-Andersson, Esther Yoon, Carol Green, Claire McFarlane, Donya Bagheri, Lynn Parker Thomas, R Scott Turner","doi":"10.1186/s13195-025-01837-0","DOIUrl":"10.1186/s13195-025-01837-0","url":null,"abstract":"<p><strong>Background: </strong>A placebo-controlled, double-blind Phase 1a trial examined the safety, tolerability, and pharmacokinetics of NNI-362 as well as the pharmacodynamic outcome of plasma phosphorylated tau¹⁸¹ (p-tau¹⁸¹).</p><p><strong>Methods: </strong>Oral NNI-362 and placebo were randomized in healthy, cognitively-unimpaired individuals (ages 50-72) at a 3:1 ratio, with sponsor, principal investigator, and subjects all blinded. Plasma levels of p-tau¹⁸¹ were determined in the placebo and the two highest arms of 120 and 240 mg NNI-362. Plasma biomarker was examined for statistical change from baseline.</p><p><strong>Results: </strong>NNI-362 treatment was safe and well tolerated in older individuals. NNI-362, at the two highest multiple doses, significantly reduced plasma p-tau¹⁸¹ levels compared to pretreatment levels (P < 0.0012 to P < 0.0009), while no change occurred in placebo groups.</p><p><strong>Conclusions: </strong>These findings suggest in older subjects, oral NNI-362 appeared safe, well tolerated and reduced plasma p-tau¹⁸¹. Phase 2 studies of NNI-362 are warranted for Alzheimer's disease and age-related degenerative disorders.</p><p><strong>Trial registry number: </strong>NCT04074837. First registered: 2019-08-27.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"185"},"PeriodicalIF":7.6,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning applications in vascular neuroimaging for the diagnosis and prognosis of cognitive impairment and dementia: a systematic review and meta-analysis.","authors":"Valerie Lohner, Amanpreet Badhwar, Flavie E Detcheverry, Cindy L García, Helena M Gellersen, Zahra Khodakarami, René Lattmann, Rui Li, Audrey Low, Claudia Mazo, Amelie Metz, Olivier Parent, Veronica Phillips, Usman Saeed, Sean Y W Tan, Stefano Tamburin, David J Llewellyn, Timothy Rittman, Sheena Waters, Jose Bernal","doi":"10.1186/s13195-025-01815-6","DOIUrl":"10.1186/s13195-025-01815-6","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"183"},"PeriodicalIF":7.6,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}