Pub Date : 2025-04-01DOI: 10.1038/s41591-025-03589-8
Carlos Maluquer de Motes, David O. Ulaeto
The human interaction with mpox has changed across its entire endemic range, revealing the endemic and pandemic risk of monkeypox virus and the current knowledge gaps on its biology that hamper virus control.
{"title":"Mpox poses an ever-increasing epidemic and pandemic risk","authors":"Carlos Maluquer de Motes, David O. Ulaeto","doi":"10.1038/s41591-025-03589-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03589-8","url":null,"abstract":"The human interaction with mpox has changed across its entire endemic range, revealing the endemic and pandemic risk of monkeypox virus and the current knowledge gaps on its biology that hamper virus control.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"18 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1038/s41591-025-03627-5
Frank J. Lowery, Stephanie L. Goff, Billel Gasmi, Maria R. Parkhurst, Nivedita M. Ratnam, Hyunmi K. Halas, Thomas E. Shelton, Michelle M. Langhan, Aarushi Bhasin, Aaron J. Dinerman, Victoria Dulemba, Ian S. Goldlust, Alexandra M. Gustafson, Abraham A. Hakim, Kyle J. Hitscherich, Lisa M. Kenney, Lior Levy, Juliette G. Rault-Wang, Alakesh Bera, Satyajit Ray, Courtney D. Seavey, Chuong D. Hoang, Jonathan M. Hernandez, Jared J. Gartner, Sivasish Sindiri, Todd D. Prickett, Lori S. McIntyre, Sri Krishna, Paul F. Robbins, Nicholas D. Klemen, Mei Li M. Kwong, James C. Yang, Steven A. Rosenberg
Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7–20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4–40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4+ neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: NCT01174121.
{"title":"Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial","authors":"Frank J. Lowery, Stephanie L. Goff, Billel Gasmi, Maria R. Parkhurst, Nivedita M. Ratnam, Hyunmi K. Halas, Thomas E. Shelton, Michelle M. Langhan, Aarushi Bhasin, Aaron J. Dinerman, Victoria Dulemba, Ian S. Goldlust, Alexandra M. Gustafson, Abraham A. Hakim, Kyle J. Hitscherich, Lisa M. Kenney, Lior Levy, Juliette G. Rault-Wang, Alakesh Bera, Satyajit Ray, Courtney D. Seavey, Chuong D. Hoang, Jonathan M. Hernandez, Jared J. Gartner, Sivasish Sindiri, Todd D. Prickett, Lori S. McIntyre, Sri Krishna, Paul F. Robbins, Nicholas D. Klemen, Mei Li M. Kwong, James C. Yang, Steven A. Rosenberg","doi":"10.1038/s41591-025-03627-5","DOIUrl":"https://doi.org/10.1038/s41591-025-03627-5","url":null,"abstract":"<p>Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7–20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4–40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4<sup>+</sup> neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: NCT01174121.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"33 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1038/s41591-025-03632-8
Sandrine Andrieu, Randall J. Bateman, Erika Bereczki, Niranjan Bose, Anthony J. Brookes, P. Murali Doraiswamy, Miia Kivipelto, Susan Kohlhaas, Lampros Kourtis, Lefkos T. Middleton, Gregory J. Moore, Jeffrey R. Petrella, Neil Postlethwaite, Ricardo Sainz-Fuertes
Alzheimer’s disease remains one of the most formidable challenges in contemporary medicine, necessitating innovative strategies to expedite the development of effective diagnostics and therapeutics1,2. As leaders spanning academia, industry and healthcare, we recognize the profound potential of artificial intelligence (AI) to surmount crucial obstacles in Alzheimer’s research.
{"title":"Harnessing artificial intelligence to transform Alzheimer’s disease research","authors":"Sandrine Andrieu, Randall J. Bateman, Erika Bereczki, Niranjan Bose, Anthony J. Brookes, P. Murali Doraiswamy, Miia Kivipelto, Susan Kohlhaas, Lampros Kourtis, Lefkos T. Middleton, Gregory J. Moore, Jeffrey R. Petrella, Neil Postlethwaite, Ricardo Sainz-Fuertes","doi":"10.1038/s41591-025-03632-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03632-8","url":null,"abstract":"<p>Alzheimer’s disease remains one of the most formidable challenges in contemporary medicine, necessitating innovative strategies to expedite the development of effective diagnostics and therapeutics<sup>1,2</sup>. As leaders spanning academia, industry and healthcare, we recognize the profound potential of artificial intelligence (AI) to surmount crucial obstacles in Alzheimer’s research.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1038/s41591-025-03532-x
Sandeep S. Raj, Teng Fei, Shalev Fried, Andrew Ip, Joshua A. Fein, Lori A. Leslie, Ana Alarcon Tomas, Doris Leithner, Jonathan U. Peled, Magdalena Corona, Parastoo B. Dahi, Ivetta Danylesko, Zachary Epstein-Peterson, Tyler Funnell, Sergio A. Giralt, Elad Jacoby, Meirav Kedmi, Ivan Landego, Richard J. Lin, Allison Parascondola, Lauren Pascual, Natali Orozco, Jae H. Park, M. Lia Palomba, Gilles Salles, Amethyst Saldia, Heiko Schöder, Inbal Sdayoor, Gunjan L. Shah, Michael Scordo, Noga Shem-Tov, Avichai Shimoni, John Slingerland, Ronit Yerushalmi, Arnon Nagler, Benjamin D. Greenbaum, Andrew J. Vickers, Hyung C. Suh, Abraham Avigdor, Miguel-Angel Perales, Marcel R. M. van den Brink, Roni Shouval
Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60–4.91; P < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy.
{"title":"An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma","authors":"Sandeep S. Raj, Teng Fei, Shalev Fried, Andrew Ip, Joshua A. Fein, Lori A. Leslie, Ana Alarcon Tomas, Doris Leithner, Jonathan U. Peled, Magdalena Corona, Parastoo B. Dahi, Ivetta Danylesko, Zachary Epstein-Peterson, Tyler Funnell, Sergio A. Giralt, Elad Jacoby, Meirav Kedmi, Ivan Landego, Richard J. Lin, Allison Parascondola, Lauren Pascual, Natali Orozco, Jae H. Park, M. Lia Palomba, Gilles Salles, Amethyst Saldia, Heiko Schöder, Inbal Sdayoor, Gunjan L. Shah, Michael Scordo, Noga Shem-Tov, Avichai Shimoni, John Slingerland, Ronit Yerushalmi, Arnon Nagler, Benjamin D. Greenbaum, Andrew J. Vickers, Hyung C. Suh, Abraham Avigdor, Miguel-Angel Perales, Marcel R. M. van den Brink, Roni Shouval","doi":"10.1038/s41591-025-03532-x","DOIUrl":"https://doi.org/10.1038/s41591-025-03532-x","url":null,"abstract":"<p>Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60–4.91; <i>P</i> < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"42 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-31DOI: 10.1038/s41591-025-03593-y
Jiali Duan, John S. Ji, Rong Chen, Martha Hickey, Lan Zhu
<p>Female sexual dysfunction (FSD) has historically received less attention than male sexual dysfunction, in terms of research, diagnosis and treatment, for various reasons, including culturally specific societal stigma, lack of awareness and diagnostic complexities. Sex-hormone insufficiency has long been considered a primary cause of FSD<sup>1</sup>, particularly during menopause. Menopause marks the end of reproductive capabilities, but it is also widely perceived as a period of sexual function decline<sup>2</sup>. However, although menopause undeniably brings hormonal adjustments, the link with FSD is complex. For example, we conducted a narrative review of over 200 studies on changes in sexual function during the perimenopausal period (stage –2 to stage +1 according to The Stages of Reproductive Aging Workshop + 10 staging system) and found that postmenopausal status alone does not associate with FSD (as summarized in Table 1), particularly when a diagnosis of distress was incorporated into the survey. Other psychological and relational factors influence the sexual health of middle-aged women and might exert a greater effect than the hormonal changes associated with menopause<sup>3</sup>.</p><figure><figcaption><b data-test="table-caption">Table 1 Studies investigating the relationship between menopause and female sexual dysfunction</b></figcaption><span>Full size table</span><svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-chevron-right-small" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></figure><p>Research has consistently shown a decline in sexual function during the postmenopausal period, which can be evaluated through the use of tools such as the Female Sexual Function Index (FSFI) and the Short Personal Experiences Questionnaire (SPEQ). The Melbourne Women’s Midlife Health Project, a longitudinal cohort study conducted in Australia, observed over 400 premenopausal women 45–55 years of age at baseline. This study measured sexual function and hormone levels annually with SPEQ for 8 years, showing that as menopause progressed, the proportion of women with low sexual function (SPEQ ≤ 7) increased from 42% to 88%. Alongside this, there was a substantial decline in desire, arousal, orgasm, lubrication and frequency of sexual activity, accompanied by an increase in dyspareunia<sup>4</sup>. In further support of these results, a prospective cohort study of 1,525 British women followed annually from 47 to 54 years of age showed that compared with remaining premenopausal, becoming postmenopausal independently decreased sexual satisfaction and increased intercourse difficulties<sup>5</sup>. Similarly, The Penn Ovarian Aging Study, which included 218 African American and 218 white women and used the FSFI scale, identified postmenopausal status as a risk factor for low sexual function (FSFI < 20). The Seattle Midlife Women’s Health Study noted a decrease in desire with menopause
{"title":"The role of distress in female sexual dysfunction during menopause","authors":"Jiali Duan, John S. Ji, Rong Chen, Martha Hickey, Lan Zhu","doi":"10.1038/s41591-025-03593-y","DOIUrl":"https://doi.org/10.1038/s41591-025-03593-y","url":null,"abstract":"<p>Female sexual dysfunction (FSD) has historically received less attention than male sexual dysfunction, in terms of research, diagnosis and treatment, for various reasons, including culturally specific societal stigma, lack of awareness and diagnostic complexities. Sex-hormone insufficiency has long been considered a primary cause of FSD<sup>1</sup>, particularly during menopause. Menopause marks the end of reproductive capabilities, but it is also widely perceived as a period of sexual function decline<sup>2</sup>. However, although menopause undeniably brings hormonal adjustments, the link with FSD is complex. For example, we conducted a narrative review of over 200 studies on changes in sexual function during the perimenopausal period (stage –2 to stage +1 according to The Stages of Reproductive Aging Workshop + 10 staging system) and found that postmenopausal status alone does not associate with FSD (as summarized in Table 1), particularly when a diagnosis of distress was incorporated into the survey. Other psychological and relational factors influence the sexual health of middle-aged women and might exert a greater effect than the hormonal changes associated with menopause<sup>3</sup>.</p><figure><figcaption><b data-test=\"table-caption\">Table 1 Studies investigating the relationship between menopause and female sexual dysfunction</b></figcaption><span>Full size table</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><p>Research has consistently shown a decline in sexual function during the postmenopausal period, which can be evaluated through the use of tools such as the Female Sexual Function Index (FSFI) and the Short Personal Experiences Questionnaire (SPEQ). The Melbourne Women’s Midlife Health Project, a longitudinal cohort study conducted in Australia, observed over 400 premenopausal women 45–55 years of age at baseline. This study measured sexual function and hormone levels annually with SPEQ for 8 years, showing that as menopause progressed, the proportion of women with low sexual function (SPEQ ≤ 7) increased from 42% to 88%. Alongside this, there was a substantial decline in desire, arousal, orgasm, lubrication and frequency of sexual activity, accompanied by an increase in dyspareunia<sup>4</sup>. In further support of these results, a prospective cohort study of 1,525 British women followed annually from 47 to 54 years of age showed that compared with remaining premenopausal, becoming postmenopausal independently decreased sexual satisfaction and increased intercourse difficulties<sup>5</sup>. Similarly, The Penn Ovarian Aging Study, which included 218 African American and 218 white women and used the FSFI scale, identified postmenopausal status as a risk factor for low sexual function (FSFI < 20). The Seattle Midlife Women’s Health Study noted a decrease in desire with menopause ","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"36 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-31DOI: 10.1038/s41591-025-03565-2
Hamilton Se-Hwee Oh, Deniz Yagmur Urey, Linda Karlsson, Zeyu Zhu, Yuanyuan Shen, Amelia Farinas, Jigyasha Timsina, Michael R. Duggan, Jingsha Chen, Ian H. Guldner, Nader Morshed, Chengran Yang, Daniel Western, Muhammad Ali, Yann Le Guen, Alexandra Trelle, Sanna-Kaisa Herukka, Tuomas Rauramaa, Mikko Hiltunen, Anssi Lipponen, Antti J. Luikku, Kathleen L. Poston, Elizabeth Mormino, Anthony D. Wagner, Edward N. Wilson, Divya Channappa, Ville Leinonen, Beth Stevens, Alexander J. Ehrenberg, Rebecca F. Gottesman, Josef Coresh, Keenan A. Walker, Henrik Zetterberg, David A. Bennett, Nicolai Franzmeier, Oskar Hansson, Carlos Cruchaga, Tony Wyss-Coray
Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20–40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case–control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10–4) and A+T1+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10–16) over a 15-year follow-up, adjusting for CSF pTau181:Aβ42, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.
阿尔茨海默病(AD)的认知能力下降率差异极大。虽然淀粉样蛋白-β(Aβ)和 tau 蛋白的生物标记物(阿氏痴呆症的标志性病理特征)改善了基于病理学的诊断,但它们只能解释阿氏痴呆症相关认知障碍(CI)差异的 20-40%。为了发现 AD 中 CI 的新型生物标志物,我们对来自六个主要前瞻性 AD 病例对照队列的 3,397 人进行了脑脊液(CSF)蛋白质组学研究。突触蛋白与 CI 的相关性最强,与 Aβ 和 tau 无关。通过机器学习,我们得出了 CSF YWHAG:NPTX2 突触蛋白比值,该比值对 Aβ+ 和磷酸化 tau+ (A+T1+)个体 CI 变异的解释率为 27%,高于 CSF pTau181:Aβ42;对 tau 正电子发射断层扫描的解释率为 11%,高于 CSF 神经丝蛋白、生长相关蛋白 43 和神经粒蛋白;对 Aβ+ 和磷酸化 tau+ (A+T1+)个体 CI 变异的解释率为 28%。CSF YWHAG:NPTX2 也随着正常衰老和常染色体显性 AD 突变携带者估计症状出现前 20 年而增加。在认知预后方面,CSF YWHAG:NPTX2 预测了从 A+T1+ 认知正常到轻度认知障碍的转变(标准偏差增加危险比 = 3.0,P = 7.0 × 10-4)和 A+T1+ 轻度认知障碍转为痴呆(标准差增加危险比 = 2.2,P = 8.2 × 10-16),随访 15 年,调整 CSF pTau181:Aβ42、CSF neurofilament、CSF neurogranin、CSF 生长相关蛋白 43、年龄、APOE4 和性别。我们还建立了 CI 的血浆蛋白质组特征,并对 13,401 份样本进行了评估,结果部分再现了 CSF YWHAG:NPTX2 的特征。总之,我们的研究结果表明,CSF YWHAG:NPTX2 是认知恢复能力相对于 AD 发病和进展的可靠预后生物标志物,突出了血浆蛋白质组学取代 CSF 测量的潜力,并进一步表明突触功能障碍是 AD 痴呆症的核心驱动因素。
{"title":"A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease","authors":"Hamilton Se-Hwee Oh, Deniz Yagmur Urey, Linda Karlsson, Zeyu Zhu, Yuanyuan Shen, Amelia Farinas, Jigyasha Timsina, Michael R. Duggan, Jingsha Chen, Ian H. Guldner, Nader Morshed, Chengran Yang, Daniel Western, Muhammad Ali, Yann Le Guen, Alexandra Trelle, Sanna-Kaisa Herukka, Tuomas Rauramaa, Mikko Hiltunen, Anssi Lipponen, Antti J. Luikku, Kathleen L. Poston, Elizabeth Mormino, Anthony D. Wagner, Edward N. Wilson, Divya Channappa, Ville Leinonen, Beth Stevens, Alexander J. Ehrenberg, Rebecca F. Gottesman, Josef Coresh, Keenan A. Walker, Henrik Zetterberg, David A. Bennett, Nicolai Franzmeier, Oskar Hansson, Carlos Cruchaga, Tony Wyss-Coray","doi":"10.1038/s41591-025-03565-2","DOIUrl":"https://doi.org/10.1038/s41591-025-03565-2","url":null,"abstract":"<p>Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20–40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case–control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau<sub>181</sub>:Aβ<sub>42</sub>, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ<sup>+</sup> and phosphorylated tau<sup>+</sup> (A+T<sub>1</sub>+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T<sub>1</sub>+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, <i>P</i> = 7.0 × 10<sup>–4</sup>) and A+T<sub>1</sub>+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, <i>P</i> = 8.2 × 10<sup>–16</sup>) over a 15-year follow-up, adjusting for CSF pTau<sub>181</sub>:Aβ<sub>42</sub>, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, <i>APOE4</i> and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"87 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-31DOI: 10.1038/s41591-025-03617-7
Kanta Horie, Gemma Salvadó, Rama K. Koppisetti, Shorena Janelidze, Nicolas R. Barthélemy, Yingxin He, Chihiro Sato, Brian A. Gordon, Hong Jiang, Tammie L. S. Benzinger, Erik Stomrud, David M. Holtzman, Niklas Mattsson-Carlgren, John C. Morris, Sebastian Palmqvist, Rik Ossenkoppele, Suzanne E. Schindler, Oskar Hansson, Randall J. Bateman
Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer’s disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (n = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding (β = 0.72, R2 = 0.56) and cognitive performance (β = 0.60, R2 = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials.
{"title":"Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease","authors":"Kanta Horie, Gemma Salvadó, Rama K. Koppisetti, Shorena Janelidze, Nicolas R. Barthélemy, Yingxin He, Chihiro Sato, Brian A. Gordon, Hong Jiang, Tammie L. S. Benzinger, Erik Stomrud, David M. Holtzman, Niklas Mattsson-Carlgren, John C. Morris, Sebastian Palmqvist, Rik Ossenkoppele, Suzanne E. Schindler, Oskar Hansson, Randall J. Bateman","doi":"10.1038/s41591-025-03617-7","DOIUrl":"https://doi.org/10.1038/s41591-025-03617-7","url":null,"abstract":"<p>Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer’s disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (<i>n</i> = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding (<i>β</i> = 0.72, <i>R</i><sup>2</sup> = 0.56) and cognitive performance (<i>β</i> = 0.60, <i>R</i><sup>2</sup> = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"38 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-31DOI: 10.1038/s41591-025-03607-9
Yosef Ellenbogen, Gelareh Zadeh
A detailed case report shows that neoadjuvant combination immunotherapy can activate antitumor immunity and drive clinical benefit in newly diagnosed glioblastoma, revealing avenues for further research that could shift the treatment landscape to improve survival.
{"title":"A new paradigm for immunotherapy in glioblastoma","authors":"Yosef Ellenbogen, Gelareh Zadeh","doi":"10.1038/s41591-025-03607-9","DOIUrl":"https://doi.org/10.1038/s41591-025-03607-9","url":null,"abstract":"A detailed case report shows that neoadjuvant combination immunotherapy can activate antitumor immunity and drive clinical benefit in newly diagnosed glioblastoma, revealing avenues for further research that could shift the treatment landscape to improve survival.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"183 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-31DOI: 10.1038/s41591-025-03675-x
Alexander J. Nihart, Marcus A. Garcia, Eliane El Hayek, Rui Liu, Marian Olewine, Josiah D. Kingston, Eliseo F. Castillo, Rama R. Gullapalli, Tamara Howard, Barry Bleske, Justin Scott, Jorge Gonzalez-Estrella, Jessica M. Gross, Michael Spilde, Natalie L. Adolphi, Daniel F. Gallego, Heather S. Jarrell, Gabrielle Dvorscak, Maria E. Zuluaga-Ruiz, Andrew B. West, Matthew J. Campen
Correction to: Nature Medicine https://doi.org/10.1038/s41591-024-03453-1, published online 3 February 2025.
{"title":"Author Correction: Bioaccumulation of microplastics in decedent human brains","authors":"Alexander J. Nihart, Marcus A. Garcia, Eliane El Hayek, Rui Liu, Marian Olewine, Josiah D. Kingston, Eliseo F. Castillo, Rama R. Gullapalli, Tamara Howard, Barry Bleske, Justin Scott, Jorge Gonzalez-Estrella, Jessica M. Gross, Michael Spilde, Natalie L. Adolphi, Daniel F. Gallego, Heather S. Jarrell, Gabrielle Dvorscak, Maria E. Zuluaga-Ruiz, Andrew B. West, Matthew J. Campen","doi":"10.1038/s41591-025-03675-x","DOIUrl":"https://doi.org/10.1038/s41591-025-03675-x","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-024-03453-1, published online 3 February 2025.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"25 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-30DOI: 10.1038/s41591-025-03671-1
Stefan D. Anker, Mahir Karakas, Robert J. Mentz, Piotr Ponikowski, Javed Butler, Muhammad Shahzeb Khan, Khawaja M. Talha, Paul R. Kalra, Adrian F. Hernandez, Hillary Mulder, Frank W. Rockhold, Marius Placzek, Christian Röver, John G. F. Cleland, Tim Friede
Uncertainty remains about the effect of intravenous (IV) iron on outcomes for heart failure (HF) with iron deficiency. Here, we summarize the efficacy and safety of IV iron from six trials (FAIR-HF, CONFIRM-HF, AFFIRM-AHF, IRONMAN, HEART-FID, and FAIR-HF2) including 7,175 patients. In comparison to prior analyses, this meta-analysis adds new data from FAIR-HF2, uses a harmonized and robust Bayesian approach, and includes individual participant data from 5 trials. Patients assigned to IV iron, as compared to those assigned to placebo, had lower rates for the composite endpoint of recurrent HF hospitalizations and cardiovascular mortality at 12 months (RR 0.72 [95% CI 0.55–0.89]) and for the complete length of follow up (RR 0.81 [95% CI 0.63–0.97]). Each component of the primary endpoint contributed to the beneficial effect of IV iron at both 12 months and for the complete length of follow up: recurrent HF hospitalizations (RR 0.69 [95% CI 0.48–0.88] and RR 0.78 [95% CI 0.55–0.98], respectively) and cardiovascular mortality (HR 0.80 [95% CI 0.61–1.03] and HR 0.87 [95% CI 0.73–1.04], respectively). All-cause mortality at 12 months and for the complete length of follow up (HR: 0.82 [95% CI 0.65–1.03]) and 0.92 [95% CI 0.80–1.07], respectively) indicated the overall safety of IV iron treatment. Treatment effects were greatest in the first year after randomization when doses of IV iron provided are highest. These findings suggest that treating iron deficiency in patients with HF significantly reduces cardiovascular events and suggests further investigation of optimal dosing of IV iron.
静脉注射(IV)铁剂对缺铁性心力衰竭(HF)预后的影响仍不确定。在此,我们总结了六项试验(FAIR-HF、CONFIRM-HF、AFFIRM-AHF、IRONMAN、HEART-FID 和 FAIR-HF2)中静脉注射铁剂的疗效和安全性,其中包括 7175 名患者。与之前的分析相比,本荟萃分析增加了来自 FAIR-HF2 的新数据,采用了统一、稳健的贝叶斯方法,并包含了来自 5 项试验的个体参与者数据。与服用安慰剂的患者相比,接受静脉注射铁剂治疗的患者在 12 个月内复发心房颤动住院和心血管死亡的复合终点(RR 0.72 [95% CI 0.55-0.89])和整个随访时间(RR 0.81 [95% CI 0.63-0.97])的发生率较低。在 12 个月和整个随访期间,主要终点的每个组成部分都对静脉注射铁剂的有益效果做出了贡献:复发性高血压住院率(RR 分别为 0.69 [95% CI 0.48-0.88] 和 RR 0.78 [95% CI 0.55-0.98])和心血管死亡率(HR 分别为 0.80 [95% CI 0.61-1.03] 和 HR 0.87 [95% CI 0.73-1.04])。12 个月和整个随访期间的全因死亡率(HR:分别为 0.82 [95% CI 0.65-1.03]) 和 0.92 [95% CI 0.80-1.07])表明静脉注射铁剂治疗总体上是安全的。随机分组后第一年的治疗效果最好,因为此时静脉注射铁剂的剂量最大。这些研究结果表明,治疗高血压患者的铁缺乏症可显著减少心血管事件的发生,并建议进一步研究静脉注射铁剂的最佳剂量。
{"title":"Systematic review and meta-analysis of intravenous iron therapy for patients with heart failure and iron deficiency","authors":"Stefan D. Anker, Mahir Karakas, Robert J. Mentz, Piotr Ponikowski, Javed Butler, Muhammad Shahzeb Khan, Khawaja M. Talha, Paul R. Kalra, Adrian F. Hernandez, Hillary Mulder, Frank W. Rockhold, Marius Placzek, Christian Röver, John G. F. Cleland, Tim Friede","doi":"10.1038/s41591-025-03671-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03671-1","url":null,"abstract":"<p>Uncertainty remains about the effect of intravenous (IV) iron on outcomes for heart failure (HF) with iron deficiency. Here, we summarize the efficacy and safety of IV iron from six trials (FAIR-HF, CONFIRM-HF, AFFIRM-AHF, IRONMAN, HEART-FID, and FAIR-HF2) including 7,175 patients. In comparison to prior analyses, this meta-analysis adds new data from FAIR-HF2, uses a harmonized and robust Bayesian approach, and includes individual participant data from 5 trials. Patients assigned to IV iron, as compared to those assigned to placebo, had lower rates for the composite endpoint of recurrent HF hospitalizations and cardiovascular mortality at 12 months (RR 0.72 [95% CI 0.55–0.89]) and for the complete length of follow up (RR 0.81 [95% CI 0.63–0.97]). Each component of the primary endpoint contributed to the beneficial effect of IV iron at both 12 months and for the complete length of follow up: recurrent HF hospitalizations (RR 0.69 [95% CI 0.48–0.88] and RR 0.78 [95% CI 0.55–0.98], respectively) and cardiovascular mortality (HR 0.80 [95% CI 0.61–1.03] and HR 0.87 [95% CI 0.73–1.04], respectively). All-cause mortality at 12 months and for the complete length of follow up (HR: 0.82 [95% CI 0.65–1.03]) and 0.92 [95% CI 0.80–1.07], respectively) indicated the overall safety of IV iron treatment. Treatment effects were greatest in the first year after randomization when doses of IV iron provided are highest. These findings suggest that treating iron deficiency in patients with HF significantly reduces cardiovascular events and suggests further investigation of optimal dosing of IV iron.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"70 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}