NPJ dementia最新文献_第2页

Progranulin deficiency does not exacerbate TDP-43 pathology in TDP-43 transgenic mouse models. 在TDP-43转基因小鼠模型中，原颗粒蛋白缺乏不会加重TDP-43的病理。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-07-21 DOI: 10.1038/s44400-025-00020-4

Cha Yang, Tuancheng Feng, Fenghua Hu

{"title":"Progranulin deficiency does not exacerbate TDP-43 pathology in TDP-43 transgenic mouse models.","authors":"Cha Yang, Tuancheng Feng, Fenghua Hu","doi":"10.1038/s44400-025-00020-4","DOIUrl":"10.1038/s44400-025-00020-4","url":null,"abstract":"The progranulin (PGRN) protein is tightly linked with TDP-43 proteinopathy in neurodegenerative diseases. However, how PGRN regulates TDP-43 proteinopathy remains unclear. In this study, we investigated the effect of PGRN loss on TDP-43 pathology in the TDP-43Q331K knock-in mice expressing an ALS-linked TDP-43 mutation at the endogenous level, and in the transgenic mice overexpressing human TDP-43 in neurons. We found that PGRN deficiency leads to mild glial activation and behavioral deficits in TDP-43Q331K mice without inducing typical TDP-43 pathology. RNA-seq analysis reveals upregulation of immune pathways and downregulation of myelination-related pathways in PGRN-deficient TDP-43Q331K mice. In addition, we observed myelination defects in human TDP-43 transgenic mice, but PGRN loss does not exacerbate TDP-43 pathology, myelination defects, and motor deficits in this mouse strain. Our studies demonstrated that PGRN deficiency exacerbates behavioral deficits and glial pathology caused by TDP-43 Q331K mutation but has minimal effect on TDP-43 pathology in mouse models.","PeriodicalId":520469,"journal":{"name":"NPJ dementia","volume":"1 1","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Post-symptomatic NLRP3 inhibition rescues cognitive impairment and mitigates amyloid and tau driven neurodegeneration. 症状后NLRP3抑制挽救认知障碍，减轻淀粉样蛋白和tau驱动的神经变性。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-05-06 DOI: 10.1038/s44400-025-00011-5

Anick Auger, Rania Faidi, Alexis D Rickman, Carolina Pena Martinez, Austin Fajfer, Jeremy Carling, Addison Hilyard, Mubashshir Ali, Ryosuke Ono, Connor Cleveland, Ria Seliniotakis, Nhi Truong, Amandine Chefson, Marianne Raymond, Marie-Anne Germain, Michael A Crackower, Bradlee L Heckmann

{"title":"Post-symptomatic NLRP3 inhibition rescues cognitive impairment and mitigates amyloid and tau driven neurodegeneration.","authors":"Anick Auger, Rania Faidi, Alexis D Rickman, Carolina Pena Martinez, Austin Fajfer, Jeremy Carling, Addison Hilyard, Mubashshir Ali, Ryosuke Ono, Connor Cleveland, Ria Seliniotakis, Nhi Truong, Amandine Chefson, Marianne Raymond, Marie-Anne Germain, Michael A Crackower, Bradlee L Heckmann","doi":"10.1038/s44400-025-00011-5","DOIUrl":"https://doi.org/10.1038/s44400-025-00011-5","url":null,"abstract":"Emerging evidence has established neuroinflammation as a primary driver of progressive neuronal loss observed across neurodegenerative diseases (NDDs). The NLRP3 inflammasome is a cytosolic immunoprotective danger sensing complex, which when aberrantly activated drives neuroinflammation, propagates amyloid deposition, and neurodegeneration. Herein, we report the therapeutic benefit of NLRP3 inflammasome inhibition in Alzheimer's disease (AD), using a novel and selective brain-penetrant small molecule NLRP3 inhibitor, VEN-02XX, which we profiled in the 5XFAD/Rubicon KO AD model. We demonstrate for the first time that targeting NLRP3, post-symptomatic establishment, rescues cognitive deficits, mitigates neuronal loss, and is sufficient to significantly reduce reactive microgliosis, neuroinflammation and tau pathology. Our data further suggest that pharmacological inhibition of NLRP3, after disease onset, has the potential to reduce cortical and hippocampal amyloid burden. Together, these results highlight the potential for NLRP3 inhibition as a symptomatic and disease modifying therapeutic target for AD pathology and more broadly NDDs.","PeriodicalId":520469,"journal":{"name":"NPJ dementia","volume":"1 1","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12055592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNA methylation age from peripheral blood predicts progression to Alzheimer's disease, white matter disease burden, and cortical atrophy. 外周血DNA甲基化年龄预测阿尔茨海默病的进展、白质疾病负担和皮质萎缩。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-05-27 DOI: 10.1038/s44400-025-00007-1

Luke W Bonham, Daniel W Sirkis, Alina P S Pang, Leo P Sugrue, Hernando Santamaría-García, Agustín M Ibáñez, Bruce L Miller, Jennifer S Yokoyama, Michael J Corley

{"title":"DNA methylation age from peripheral blood predicts progression to Alzheimer's disease, white matter disease burden, and cortical atrophy.","authors":"Luke W Bonham, Daniel W Sirkis, Alina P S Pang, Leo P Sugrue, Hernando Santamaría-García, Agustín M Ibáñez, Bruce L Miller, Jennifer S Yokoyama, Michael J Corley","doi":"10.1038/s44400-025-00007-1","DOIUrl":"10.1038/s44400-025-00007-1","url":null,"abstract":"Cross-sectional studies suggest a limited relationship between accelerated epigenetic aging derived from epigenetic clocks, and Alzheimer's disease (AD) pathophysiology or risk. However, most prior analyses have not utilized longitudinal analyses or whole-brain neuroimaging biomarkers of AD. Herein, we employed longitudinal modeling and structural neuroimaging analyses to test the hypothesis that accelerated epigenetic aging would predict AD progression. Using survival analyses, we found that two second-generation epigenetic clocks, DNAmPhenoAge and DNAmGrimAge, predicted progression from cognitively normal aging to mild cognitive impairment or AD and worse longitudinal cognitive outcomes. Epigenetic age was also strongly associated with cortical thinning in AD-relevant regions and white matter disease burden. Thus, in contrast to earlier work suggesting limited applicability of blood-based epigenetic clocks in AD, our novel analytic framework suggests that second-generation epigenetic clocks have broad utility and may represent promising predictors of AD risk and pathophysiology.","PeriodicalId":520469,"journal":{"name":"NPJ dementia","volume":"1 1","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Infecting human brain organoids with FFI or sCJD preserves prion traits regardless of host genotype. 无论宿主基因型如何，用FFI或sCJD感染人脑类器官均可保留朊病毒特征。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-09-16 DOI: 10.1038/s44400-025-00029-9

B R Groveman, S T Foliaki, K Williams, C D Orrù, B Race, G Zanusso, C L Haigh

引用次数: 0

Previous parity differentially influences cognition in later life depending on dementia status. 根据痴呆状态，以前的胎次对晚年认知的影响是不同的。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-10-10 DOI: 10.1038/s44400-025-00035-x

Bonnie H Lee, Cindy K Barha, Jessica Chaiton, Stephanie E Lieblich, Sarah Wong, Travis E Hodges, Tallinn F L Splinter, Ging-Yuek R Hsiung, Kelly J Murphy, Sherri Hayden, Liisa A M Galea

{"title":"Previous parity differentially influences cognition in later life depending on dementia status.","authors":"Bonnie H Lee, Cindy K Barha, Jessica Chaiton, Stephanie E Lieblich, Sarah Wong, Travis E Hodges, Tallinn F L Splinter, Ging-Yuek R Hsiung, Kelly J Murphy, Sherri Hayden, Liisa A M Galea","doi":"10.1038/s44400-025-00035-x","DOIUrl":"10.1038/s44400-025-00035-x","url":null,"abstract":"Sex influences cognitive aging and dementia, yet research on the impact of female-specific factors, such as parity and fetal sex, on later-life cognition remains limited and equivocal. Inconsistencies in the literature may reflect varying effects across cognitive domains and dementia status. This study reviewed data from female participants of the University of British Columbia Hospital Clinic for Alzheimer and Related Dementias (UBCH CARD) to examine how parity and son-to-daughter ratio affect performance on medial temporal lobe-dependent (episodic memory) and prefrontal lobe-dependent (executive function) tasks depending on dementia status. Among females with dementia, higher parity was associated with reduced episodic memory but enhanced executive function performance, whereas a greater son-to-daughter ratio was associated with reduced executive function performance. These relationships were not observed in cognitively normal females or those diagnosed with mild cognitive impairment. These results emphasize the importance of integrating sex-specific factors into research and the development of precision therapeutics.","PeriodicalId":520469,"journal":{"name":"NPJ dementia","volume":"1 1","pages":"29"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex/gender differences in lifetime dementia risk among Asian American and White older adults. 亚裔美国人和白人老年人终生痴呆风险的性别差异。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-10-13 DOI: 10.1038/s44400-025-00038-8

L Paloma Rojas-Saunero, Yingyan Wu, Yixuan Zhou, Eleanor Hayes-Larson, Gilbert C Gee, Ron Brookmeyer, Holly Elser, Alexander Ivan B Posis, Alka M Kanaya, Rachel A Whitmer, Paola Gilsanz, Elizabeth Rose Mayeda

{"title":"Sex/gender differences in lifetime dementia risk among Asian American and White older adults.","authors":"L Paloma Rojas-Saunero, Yingyan Wu, Yixuan Zhou, Eleanor Hayes-Larson, Gilbert C Gee, Ron Brookmeyer, Holly Elser, Alexander Ivan B Posis, Alka M Kanaya, Rachel A Whitmer, Paola Gilsanz, Elizabeth Rose Mayeda","doi":"10.1038/s44400-025-00038-8","DOIUrl":"10.1038/s44400-025-00038-8","url":null,"abstract":"Evidence on differences in dementia risk by sex and gender is mixed. We aimed to compare lifetime dementia risk by sex/gender among Asian American and non-Latino White adults aged 60 and older. We included Chinese (n = 6415), Filipino (n = 5020), Japanese (n = 3314), South Asian (n = 1061), and non-Latino White (n = 143,667) Kaiser Permanente Northern California members aged ≥60 years who completed health surveys (2002-2020) and were dementia-free at baseline. We estimated cause-specific cumulative dementia incidence from age 60 to 95 years (i.e., lifetime dementia risk, treating death as a competing event) and evaluated sex/gender differences. Lifetime dementia risk was higher among women in all groups, ranging from 7 (95% CI: 2-13) percentage points higher for Japanese women vs. men to 21 (8-38) percentage points higher for South Asian women vs. men. Variations of sex/gender differences across racial and ethnic groups are potentially driven by dementia-free mortality and social and structural factors.","PeriodicalId":520469,"journal":{"name":"NPJ dementia","volume":"1 1","pages":"32"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12518132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Smoking predicts brain atrophy in 10,134 healthy individuals and is potentially influenced by body mass index. 吸烟可以预测10134名健康人的脑萎缩，并可能受到体重指数的影响。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-07-23 DOI: 10.1038/s44400-025-00024-0

Somayeh Meysami, Saurabh Garg, Sam Hashemi, Nasrin Akbari, Ahmed Gouda, Yosef Gavriel Chodakiewitz, Thanh Duc Nguyen, Rajpaul Attariwala, Kellyann Niotis, David A Merrill, Cyrus A Raji

{"title":"Smoking predicts brain atrophy in 10,134 healthy individuals and is potentially influenced by body mass index.","authors":"Somayeh Meysami, Saurabh Garg, Sam Hashemi, Nasrin Akbari, Ahmed Gouda, Yosef Gavriel Chodakiewitz, Thanh Duc Nguyen, Rajpaul Attariwala, Kellyann Niotis, David A Merrill, Cyrus A Raji","doi":"10.1038/s44400-025-00024-0","DOIUrl":"10.1038/s44400-025-00024-0","url":null,"abstract":"Cigarette smoking is a risk factor for Alzheimer's and vascular dementia, but its impact on brain volume loss, a neurodegeneration biomarker on MRI, is unclear. In total, 10,134 participants from 4 sites were scanned with a whole-body 1.5 T MRI protocol with separate dedicated structural neuroimaging with 3D T1 MPRAGE sequences. Smokers versus non-smokers were compared by gray and white matter volumes normalized to total intracranial volume using a two-tailed t-test. Smokers had lower normalized gray (t = -7.806e+00, p = 6.508e-15) and white matter volumes (t = -7.374e + 00, p = 1.791e-13) compared to non-smokers. Adjusting for age, sex, study site, BMI, and multiple comparisons, higher pack years of smoking predicted volume loss in such regions as total gray matter volume, total white matter volume, temporal lobe, parietal lobe, hippocampus, precuneus, and posterior cingulate. The inclusion and exclusion of BMI from the model suggested an influence of this variable.","PeriodicalId":520469,"journal":{"name":"NPJ dementia","volume":"1 1","pages":"17"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12286857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Independent validation of the PrecivityAD2™ blood test to identify presence or absence of brain amyloid pathology in individuals with cognitive impairment. 独立验证precvityad2™血液检测在认知障碍患者中是否存在脑淀粉样蛋白病理。

NPJ dementia Pub Date : 2025-01-01 Epub Date: 2025-09-04 DOI: 10.1038/s44400-025-00026-y

Justine Coppinger, Tim West, Kris M Kirmess, Ilana Fogelman, Sutapa Ray, Philip B Verghese, Joel B Braunstein, Kevin E Yarasheski

{"title":"Independent validation of the PrecivityAD2™ blood test to identify presence or absence of brain amyloid pathology in individuals with cognitive impairment.","authors":"Justine Coppinger, Tim West, Kris M Kirmess, Ilana Fogelman, Sutapa Ray, Philip B Verghese, Joel B Braunstein, Kevin E Yarasheski","doi":"10.1038/s44400-025-00026-y","DOIUrl":"10.1038/s44400-025-00026-y","url":null,"abstract":"The diagnostic performance of the Amyloid Probability Score 2 (APS2; the algorithmic result of the PrecivityAD2™ blood test) was originally trained and validated in two cohorts of cognitively impaired (CI) individuals and is in clinical use. Here, we further test the repeatability and reliability of the prespecified APS2 algorithm and cut point in an independent cohort. APS2 diagnostic performance was determined using amyloid positron emission tomography (PET) as the reference standard. Concordance with amyloid PET was high (AUC-ROC 0.95 (95% CI): 0.93-0.98); 54% of participants had a positive APS2. The previously validated APS2 cut point yielded an overall accuracy of 91% (95% CI: 86-94%), sensitivity 90% (95% CI: 83-94%) and specificity 92% (95% CI: 84-96%). Our findings demonstrate that the prespecified APS2 algorithm and cut point are repeatable, reliable, robust, accurate, and generalizable for identifying brain beta-amyloid pathology in patients with cognitive impairment and being evaluated in a clinical care setting.","PeriodicalId":520469,"journal":{"name":"NPJ dementia","volume":"1 1","pages":"23"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0