Ning Hua, Olga Minaeva, Douglas Parsons, Juliet A Moncaster, Elijah Demb, Lee E Goldstein
Background Traumatic brain injury (TBI) is a risk factor for the earlier onset of Alzheimer's disease (AD), and the more severe the injury, the greater the risk of developing AD. Given the prevalence of AD in modern society, the possibility that TBI may predispose individuals to develop AD has significant social and economic implications. Therefore, it is important to understand how TBI triggers accelerated AD progression. In this study, we explored how neurotrauma accelerates hippocampal degeneration in a transgenic mouse model of AD using high‐resolution ex vivo diffusion‐MRI. Method Unanesthetized 3xTg‐AD mice ( n = 4) were pretreated with a non‐sedating dose of the analgesic buprenorphine and then subjected to left‐lateral closed‐head impact injury (Figure 1) at 10‐12 weeks of age. At 6‐months post‐TBI, the mice were sacrificed via transcardial perfusion. The harvested brains were submerged in 10% formalin for 24 hours and then stored in Gadavist‐doped PBS (1:400 dilution) until MRI. MRI data were acquired using a 9.4T Bruker scanner and a cryoprobe. Key parameters were TR=300ms, TE=27.7ms, b=3000 (48 directions), and 5000s/mm 2 (80 directions), FOV=14.30x10.66x7.02mm 3 , Matrix=220x164x108, resolution=65mm 3 . Diffusion MRI was analyzed in DSI Studio and NODDI toolbox. T1‐weighted (T1W) images (resolution=32.5 µm 3 ) were also acquired (FLASH) for structural reference. Age‐, gender‐matched 3xTg‐AD mice ( n = 4) without TBI were used as controls. Result Figure 2 shows a representative T1W image and corresponding diffusion‐derived hippocampal maps from a TBI mouse. Compared to the contralateral side, the ipsilateral radiatum of CA1 and CA3 showed decreased quantitative anisotropy (QA) values and increased orientation dispersion index (ODI), the ipsilateral stratum pyramidale showed decreased QA and axial diffusivity (AxD), and the ipsilateral alveus showed decreased AxD. Statistical analysis revealed that the average fractional anisotropy (FA) values in radiatum were lower (CA3, significant; CA1, trend) in the ipsilateral hippocampus compared to the contralateral side of TBI mice or the bilateral sides of control mice (Figure 3). Conclusion Our results demonstrate that the hippocampal CA1/CA3 subregions are more vulnerable to neurotrauma. This finding may help clarify the mechanisms underlying trauma‐accelerated AD and suggest that advanced diffusion‐MRI is a potential tool for the early diagnosis of trauma patients at risk of developing AD.
{"title":"High‐Resolution Diffusion‐MRI Detects Degeneration in Hippocampal Subregions after Neurotrauma in 3xTg‐AD Mice","authors":"Ning Hua, Olga Minaeva, Douglas Parsons, Juliet A Moncaster, Elijah Demb, Lee E Goldstein","doi":"10.1002/alz70856_107226","DOIUrl":"https://doi.org/10.1002/alz70856_107226","url":null,"abstract":"Background Traumatic brain injury (TBI) is a risk factor for the earlier onset of Alzheimer's disease (AD), and the more severe the injury, the greater the risk of developing AD. Given the prevalence of AD in modern society, the possibility that TBI may predispose individuals to develop AD has significant social and economic implications. Therefore, it is important to understand how TBI triggers accelerated AD progression. In this study, we explored how neurotrauma accelerates hippocampal degeneration in a transgenic mouse model of AD using high‐resolution ex vivo diffusion‐MRI. Method Unanesthetized 3xTg‐AD mice ( <jats:italic>n</jats:italic> = 4) were pretreated with a non‐sedating dose of the analgesic buprenorphine and then subjected to left‐lateral closed‐head impact injury (Figure 1) at 10‐12 weeks of age. At 6‐months post‐TBI, the mice were sacrificed via transcardial perfusion. The harvested brains were submerged in 10% formalin for 24 hours and then stored in Gadavist‐doped PBS (1:400 dilution) until MRI. MRI data were acquired using a 9.4T Bruker scanner and a cryoprobe. Key parameters were TR=300ms, TE=27.7ms, b=3000 (48 directions), and 5000s/mm <jats:sup>2</jats:sup> (80 directions), FOV=14.30x10.66x7.02mm <jats:sup>3</jats:sup> , Matrix=220x164x108, resolution=65mm <jats:sup>3</jats:sup> . Diffusion MRI was analyzed in DSI Studio and NODDI toolbox. T1‐weighted (T1W) images (resolution=32.5 µm <jats:sup>3</jats:sup> ) were also acquired (FLASH) for structural reference. Age‐, gender‐matched 3xTg‐AD mice ( <jats:italic>n</jats:italic> = 4) without TBI were used as controls. Result Figure 2 shows a representative T1W image and corresponding diffusion‐derived hippocampal maps from a TBI mouse. Compared to the contralateral side, the ipsilateral radiatum of CA1 and CA3 showed decreased quantitative anisotropy (QA) values and increased orientation dispersion index (ODI), the ipsilateral stratum pyramidale showed decreased QA and axial diffusivity (AxD), and the ipsilateral alveus showed decreased AxD. Statistical analysis revealed that the average fractional anisotropy (FA) values in radiatum were lower (CA3, significant; CA1, trend) in the ipsilateral hippocampus compared to the contralateral side of TBI mice or the bilateral sides of control mice (Figure 3). Conclusion Our results demonstrate that the hippocampal CA1/CA3 subregions are more vulnerable to neurotrauma. This finding may help clarify the mechanisms underlying trauma‐accelerated AD and suggest that advanced diffusion‐MRI is a potential tool for the early diagnosis of trauma patients at risk of developing AD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"84 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955177","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}
Fabricio Nery Garrafiel, Ricardo Benardi Soder, Ricardo Pessini Paganin, Maria Rosa Alves da Silva, Andrei Bieger, Vitor Verlindo Vidaletti, Cristiano Aguzzoli, Lucas Porcello Schilling
Background Magnetic resonance imaging (MRI) is a tool used in the evaluation of patients with cognitive deficits, capable of identifying characteristic changes of neurodegenerative processes, such as hippocampal atrophy. The most common assessment methods include scoring systems using the Fazekas and MTA scales. The present study aims to evaluate the relationship between the classification data from the MTA scale, obtained through the analysis of MRI images by two experienced neuroradiologists, and the data obtained from hippocampal volumetry of the same image sample. Method 677 MRI images were collected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and the hippocampal volume quantification values were extracted using Freesurfer. The degree of atrophy, according to the MTA scale, on both sides of the hippocampus were classified by two independent specialized radiologists. Result The correlation between MTA classifications was 0.85, and a negative correlation (‐0.64) was found between volumetry and atrophy grade (fgure 1). Despite these results correlating the MTA grade with automatic volumetry, approximately 10% of the individuals were classified as outliers, being determined to be outside 2 standard deviations from the mean volume of each atrophy grade (Figure 2). Conclusion The results showed a strong correlation between the MTA scale and volumetry, as well as a consistent correlation between the radiologists' MTA classification. Albeit we identified 10% of individuals classified as outliers, highlighting the existence of specific cases that should be better investigated in order to understand the efficiency of the qualitative method and the accuracy of its classifications.
{"title":"Analysis of the relationship between volumetry and visual classification of hippocampal atrophy on magnetic ressonance image","authors":"Fabricio Nery Garrafiel, Ricardo Benardi Soder, Ricardo Pessini Paganin, Maria Rosa Alves da Silva, Andrei Bieger, Vitor Verlindo Vidaletti, Cristiano Aguzzoli, Lucas Porcello Schilling","doi":"10.1002/alz70856_106082","DOIUrl":"https://doi.org/10.1002/alz70856_106082","url":null,"abstract":"Background Magnetic resonance imaging (MRI) is a tool used in the evaluation of patients with cognitive deficits, capable of identifying characteristic changes of neurodegenerative processes, such as hippocampal atrophy. The most common assessment methods include scoring systems using the Fazekas and MTA scales. The present study aims to evaluate the relationship between the classification data from the MTA scale, obtained through the analysis of MRI images by two experienced neuroradiologists, and the data obtained from hippocampal volumetry of the same image sample. Method 677 MRI images were collected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and the hippocampal volume quantification values were extracted using Freesurfer. The degree of atrophy, according to the MTA scale, on both sides of the hippocampus were classified by two independent specialized radiologists. Result The correlation between MTA classifications was 0.85, and a negative correlation (‐0.64) was found between volumetry and atrophy grade (fgure 1). Despite these results correlating the MTA grade with automatic volumetry, approximately 10% of the individuals were classified as outliers, being determined to be outside 2 standard deviations from the mean volume of each atrophy grade (Figure 2). Conclusion The results showed a strong correlation between the MTA scale and volumetry, as well as a consistent correlation between the radiologists' MTA classification. Albeit we identified 10% of individuals classified as outliers, highlighting the existence of specific cases that should be better investigated in order to understand the efficiency of the qualitative method and the accuracy of its classifications.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"93 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955175","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}
Tsz Wing Fan, WonHee Kim, Corinne Thomas, Jeremy Tan, Wenjing Jiang, Feng Xuan
Background Alzheimer's disease misdiagnosis in specialized clinics and primary care often delays confirmatory testing and treatment windows for anti‐amyloid therapies. Plasma pTau‐217 assays offer a minimally invasive, scalable alternative for detecting amyloid pathology, yet their cost‐effectiveness in reducing confirmatory testing remains uncertain. Many current assays fail to surpass 90% sensitivity and specificity with a single cutoff, relying instead on a tiered double‐cutoff approach that inflates accuracy by discounting the intermediate zone (>20%). Stricter thresholds further expand this gray zone, leaving a substantial number of patients with delayed treatment decisions. To improve diagnostic accuracy, normalization strategies incorporating non‐phosphorylated tau or amyloid‐beta ratios were explored to mitigate false positives from commodities like CKD beyond pTau‐217 alone. Method We present the SPEAR UltraDetect™ pTau‐217 immunoassay, which employs a unique two‐factor authentication mechanism and a homogenous assay format, allowing free analyte‐binder interaction for maximized specificity. The test is semi‐automated (20 min hands‐on time) and achieves >90% clinical accuracy for amyloid pathology using a single cutoff. The assay requires only 1 µL of diluted plasma per measurement and operates on a wash‐free workflow with qPCR readout. A GAP (Global Alzheimer's Platform) cohort diagnosed with MCI ( n = 67) or mild dementia ( n = 34) with amyloid PET‐confirmed status (44 negative, 57 positive) was evaluated. Assay performance was compared to the MSD assay with Eli Lilly antibody, assessing specificity and fold‐change using single and double‐cutoff strategies. Result The SPEAR pTau‐217 assay demonstrated a 4.9‐fold increase in pTau‐217 levels in PET‐positive cases, nearly doubling the 2.5‐fold seen with the MSD assay with Eli Lilly antibody. Using a single cutoff, SPEAR achieved 91.2% sensitivity, 93.2% specificity, 94.6% PPV, and 89.1% NPV, with 92.1% overall accuracy. When optimizing for ≥95% specificity and sensitivity, the indeterminate range was reduced from 24.8% (MSD Eli Lilly antibody) to 13.9%. The assay exhibited robust inter‐day precision (5% CV) and 99% concordance across runs. Conclusion The SPEAR UltraDetect™ pTau‐217 assay offers improved clinical differentiation of amyloid PET status with > 90% accuracy using a single cutoff. Its minimal sample requirement, wash‐free workflow, and qPCR compatibility make it potentially a scalable, cost‐effective test for determining amyloid pathology of AD.
{"title":"SPEAR UltraDetect™ pTau‐217: A High‐Accuracy, Scalable Plasma Biomarker for PET Confirmed Cognitively Impaired Patients Using a Single Cutoff","authors":"Tsz Wing Fan, WonHee Kim, Corinne Thomas, Jeremy Tan, Wenjing Jiang, Feng Xuan","doi":"10.1002/alz70856_106293","DOIUrl":"https://doi.org/10.1002/alz70856_106293","url":null,"abstract":"Background Alzheimer's disease misdiagnosis in specialized clinics and primary care often delays confirmatory testing and treatment windows for anti‐amyloid therapies. Plasma pTau‐217 assays offer a minimally invasive, scalable alternative for detecting amyloid pathology, yet their cost‐effectiveness in reducing confirmatory testing remains uncertain. Many current assays fail to surpass 90% sensitivity and specificity with a single cutoff, relying instead on a tiered double‐cutoff approach that inflates accuracy by discounting the intermediate zone (>20%). Stricter thresholds further expand this gray zone, leaving a substantial number of patients with delayed treatment decisions. To improve diagnostic accuracy, normalization strategies incorporating non‐phosphorylated tau or amyloid‐beta ratios were explored to mitigate false positives from commodities like CKD beyond pTau‐217 alone. Method We present the SPEAR UltraDetect™ pTau‐217 immunoassay, which employs a unique two‐factor authentication mechanism and a homogenous assay format, allowing free analyte‐binder interaction for maximized specificity. The test is semi‐automated (20 min hands‐on time) and achieves >90% clinical accuracy for amyloid pathology using a single cutoff. The assay requires only 1 µL of diluted plasma per measurement and operates on a wash‐free workflow with qPCR readout. A GAP (Global Alzheimer's Platform) cohort diagnosed with MCI ( <jats:italic>n</jats:italic> = 67) or mild dementia ( <jats:italic>n</jats:italic> = 34) with amyloid PET‐confirmed status (44 negative, 57 positive) was evaluated. Assay performance was compared to the MSD assay with Eli Lilly antibody, assessing specificity and fold‐change using single and double‐cutoff strategies. Result The SPEAR pTau‐217 assay demonstrated a 4.9‐fold increase in pTau‐217 levels in PET‐positive cases, nearly doubling the 2.5‐fold seen with the MSD assay with Eli Lilly antibody. Using a single cutoff, SPEAR achieved 91.2% sensitivity, 93.2% specificity, 94.6% PPV, and 89.1% NPV, with 92.1% overall accuracy. When optimizing for ≥95% specificity and sensitivity, the indeterminate range was reduced from 24.8% (MSD Eli Lilly antibody) to 13.9%. The assay exhibited robust inter‐day precision (5% CV) and 99% concordance across runs. Conclusion The SPEAR UltraDetect™ pTau‐217 assay offers improved clinical differentiation of amyloid PET status with > 90% accuracy using a single cutoff. Its minimal sample requirement, wash‐free workflow, and qPCR compatibility make it potentially a scalable, cost‐effective test for determining amyloid pathology of AD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"243 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955176","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}
Agneta K Nordberg, Marco Bucci, Mariola Zapater‐Fajari, Konstantinos Chiotis, Anders Wall, Jonas Eriksson, Gunnar Antoni, Ilaria Pola, Kübra Tan, Wiebke Traichel, Andrea L. Benedet, Nicholas Ashton, Kaj Blennow, Henrik Zetterberg, Nenad Bogdanovic
Background Although the diagnosis of Alzheimer´s disease (AD) dominates in the tertiary memory clinic setting, there are also patients which show no sign for presence of amyloid in brain when assessed for CSF biomarkers after lumbar puncture (LP) or amyloid PET. Since these amyloid negative (A‐) patients can clinically mimic symptomatic AD patients, it is important to obtain further insight into the in vivo pathology of these patients. This study therefore aimed to perform tau PET imaging with the tracer [18F]RO948 and measure plasma biomarkers in patients clinically diagnosed as primary age‐related tauopathy (PART) and limbic dominant TDP‐43 age‐related encephalopathy (LATE) at the clinic for cognitive disorders at Karolinska University Hospital. Method Four patients diagnosed with PART (mean age 76 years) and four with LATE (mean age 79 years) were included in the study. Clinical characteristics and biomarkers are reported in Table 1. The ATN classification for PART patients was A‐T+N+ and for LATE patients A‐T‐N+. On the same day, all participants underwent [18F]RO948 tau PET and MRI scans, and blood sampling for plasma biomarker analysis using the NuLISAseq (Alamarbio) CNS panel. The obtained data was compared with 27 amyloid positive MCI and AD patients from Karolinska as well as 10 cognitive healthy controls. Result Low uptake of [18F]RO948 was observed in PART and LATE brains compared to MCI A+ as shown in Figure 1, including also Radar plots of different brain regions. Box plot data (Figure 2) showed low [18F]RO948 regional uptake except for a higher uptake ( p <0.05) in the putamen in PART and LATE compared to controls. Higher plasma levels of ptau217, ptau181, ptau231 were observed in PART patients ( p <0.05) but not in LATE compared to cognitively healthy controls. Plasma ptau217 levels were however higher in LOAD ( p <0.05) compared to PART. Higher plasma Aß42 values were observed both in LATE and PART compared to LOAD. Conclusion PART and LATE patients exhibit Tau PET uptake similar to that of controls, except in the putamen. Additionally, PART patients show elevated plasma levels of p ‐tau 217, p ‐tau 181, and p ‐tau 231, whereas LATE patients do not.
虽然阿尔茨海默病（AD）的诊断在三级记忆临床环境中占主导地位，但也有患者在腰椎穿刺（LP）或淀粉样蛋白PET后评估脑脊液生物标志物时未显示出脑内淀粉样蛋白存在的迹象。由于这些淀粉样蛋白阴性（A‐）患者可以在临床上模拟症状性AD患者，因此进一步了解这些患者的体内病理非常重要。因此，本研究旨在使用示踪剂[18F]RO948进行tau PET成像，并在卡罗林斯卡大学医院的认知障碍临床诊断为原发性年龄相关脑病（PART）和边缘显性TDP - 43年龄相关脑病（LATE）的患者中测量血浆生物标志物。方法选取4例确诊为PART的患者（平均年龄76岁）和4例确诊为LATE的患者（平均年龄79岁）。临床特征和生物标志物见表1。PART患者的ATN分类为A‐T+N+， LATE患者的ATN分类为A‐T‐N+。同一天，所有参与者进行[18F]RO948 tau PET和MRI扫描，并使用NuLISAseq (Alamarbio) CNS面板采血进行血浆生物标志物分析。将获得的数据与来自卡罗林斯卡的27名淀粉样蛋白阳性MCI和AD患者以及10名认知健康对照进行比较。结果与MCI A+相比，PART和LATE脑对[18F]RO948的摄取较低，如图1所示，包括不同脑区的Radar图。箱形图数据（图2）显示，与对照组相比，局部区域RO948摄取较低[18F]，但部分和晚期组壳核的RO948摄取较高（p <0.05）。与认知健康对照组相比，PART患者血浆中ptau217、ptau181、ptau231水平升高（p <0.05），而LATE患者血浆中ptau217、ptau181、ptau231水平升高。然而，与PART相比，LOAD组血浆ptau217水平更高（p <0.05）。LATE和PART组血浆Aß42值均高于LOAD组。结论部分和晚期患者的Tau PET摄取与对照组相似，但壳核除外。此外，PART患者显示p - tau 217、p - tau 181和p - tau 231的血浆水平升高，而LATE患者则没有。
{"title":"[18F] RO948 Tau PET imaging and plasma biomarkers in PART and LATE patients compared with sporadic Alzheimer's Disease","authors":"Agneta K Nordberg, Marco Bucci, Mariola Zapater‐Fajari, Konstantinos Chiotis, Anders Wall, Jonas Eriksson, Gunnar Antoni, Ilaria Pola, Kübra Tan, Wiebke Traichel, Andrea L. Benedet, Nicholas Ashton, Kaj Blennow, Henrik Zetterberg, Nenad Bogdanovic","doi":"10.1002/alz70856_107395","DOIUrl":"https://doi.org/10.1002/alz70856_107395","url":null,"abstract":"Background Although the diagnosis of Alzheimer´s disease (AD) dominates in the tertiary memory clinic setting, there are also patients which show no sign for presence of amyloid in brain when assessed for CSF biomarkers after lumbar puncture (LP) or amyloid PET. Since these amyloid negative (A‐) patients can clinically mimic symptomatic AD patients, it is important to obtain further insight into the in vivo pathology of these patients. This study therefore aimed to perform tau PET imaging with the tracer [18F]RO948 and measure plasma biomarkers in patients clinically diagnosed as primary age‐related tauopathy (PART) and limbic dominant TDP‐43 age‐related encephalopathy (LATE) at the clinic for cognitive disorders at Karolinska University Hospital. Method Four patients diagnosed with PART (mean age 76 years) and four with LATE (mean age 79 years) were included in the study. Clinical characteristics and biomarkers are reported in Table 1. The ATN classification for PART patients was A‐T+N+ and for LATE patients A‐T‐N+. On the same day, all participants underwent [18F]RO948 tau PET and MRI scans, and blood sampling for plasma biomarker analysis using the NuLISAseq (Alamarbio) CNS panel. The obtained data was compared with 27 amyloid positive MCI and AD patients from Karolinska as well as 10 cognitive healthy controls. Result Low uptake of [18F]RO948 was observed in PART and LATE brains compared to MCI A+ as shown in Figure 1, including also Radar plots of different brain regions. Box plot data (Figure 2) showed low [18F]RO948 regional uptake except for a higher uptake ( <jats:italic>p</jats:italic> <0.05) in the putamen in PART and LATE compared to controls. Higher plasma levels of ptau217, ptau181, ptau231 were observed in PART patients ( <jats:italic>p</jats:italic> <0.05) but not in LATE compared to cognitively healthy controls. Plasma ptau217 levels were however higher in LOAD ( <jats:italic>p</jats:italic> <0.05) compared to PART. Higher plasma Aß42 values were observed both in LATE and PART compared to LOAD. Conclusion PART and LATE patients exhibit Tau PET uptake similar to that of controls, except in the putamen. Additionally, PART patients show elevated plasma levels of <jats:italic>p</jats:italic> ‐tau 217, <jats:italic>p</jats:italic> ‐tau 181, and <jats:italic>p</jats:italic> ‐tau 231, whereas LATE patients do not.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"265 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955160","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}
Julie E. Oomens, Theresa M. Harrison, Jeffrey L. Dage, Kristen A. Russ, Henrik Zetterberg, William J. Jagust, Tatiana M. Foroud, Sarah Biber, Elizabeth C. Mormino, Sterling C Johnson
Background Data accessibility and interoperability across the U.S. Alzheimer's Disease Research Centers (ADRCs) provides necessary resources and data access to enable novel hypothesis testing without additional data collection and will allow end users to rapidly advance our understanding of multiple pathologies or multiple chronic conditions on disease progression within Alzheimer's disease and related diseases. The aim of the current study was to integrate plasma data from the National Centralized Repository for Alzheimer's Disease and Related Dementia's (NCRAD) with ADRC neuroimaging data from the SCAN initiative and National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS) demographic data, all publicly available through the NACC Data Platform and Data Front Door. We provide sample descriptives and present the results of initial data explorations. Method The NACC and NCRAD data request procedures were completed to gain access to the data. We focused on the subset of participants for whom Quanterix Simoa HD‐X Alzpath plasma pTau217 data was available (NCRAD). Amyloid pathology was defined based on centiloid values (cut‐off >= 20; SCAN initiative). Demographic information was available for all participants (NACC UDS). We integrated data using the NACC identifier and visit age where available. We used Spearman correlations to assess the association between plasma pTau217 and centiloid values and we used ROC analyses to assess amyloid classification performance. Result Plasma pTau217 data was available for 927 participants (sample descriptives in Table 1). Figure 1 shows the distribution of plasma pTau217 levels across diagnostic groups. In the subset of participants for whom amyloid PET was available ( n = 170, Table 1), the Spearman correlation between plasma pTau217 levels and centiloid values was 0.59. Quanterix pTau217 accurately classified amyloid status with a ROC AUC of .92 (95%CI 0.89–0.97; accuracy 85%; Figure 2). Tau PET was available for 135 participants with plasma pTau217 data and 114 participants with both plasma pTau217 and amyloid PET data. Conclusion Combining the SCAN PET and NCRAD plasma results in a promising resource, already with 36% demographic diversity. Sample sizes will increase through ongoing efforts as part of the SCAN initiative and the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI).
美国阿尔茨海默病研究中心（adrc）的数据可访问性和互操作性提供了必要的资源和数据访问，使新的假设检验无需额外的数据收集，并将允许最终用户快速推进我们对阿尔茨海默病和相关疾病的多种病理或多种慢性疾病进展的理解。当前研究的目的是将来自国家阿尔茨海默病和相关痴呆症中央存储库（NCRAD）的血浆数据与来自SCAN计划和国家阿尔茨海默病协调中心统一数据集（NACC UDS）人口统计数据的ADRC神经成像数据整合起来，所有这些数据都可以通过NACC数据平台和数据前门公开获得。我们提供了样本描述并展示了初始数据探索的结果。方法完成NACC和NCRAD数据请求程序，获取数据。我们重点研究了Quanterix Simoa HD - X Alzpath血浆pTau217数据可用的参与者子集（NCRAD）。淀粉样蛋白病理根据厘体值定义（cut - off >= 20； SCAN初始值）。所有参与者的人口统计信息均可获得（NACC UDS）。在可用的情况下，我们使用NACC标识符和访问年龄来整合数据。我们使用Spearman相关性来评估血浆pTau217与centiloid值之间的关系，并使用ROC分析来评估淀粉样蛋白分类的表现。结果927名参与者获得了血浆pTau217数据（样本描述见表1）。图1显示了诊断组血浆pTau217水平的分布。在可获得淀粉样蛋白PET的参与者子集中（n = 170，表1），血浆pTau217水平与centiloid值之间的Spearman相关性为0.59。Quanterix pTau217准确分类淀粉样蛋白状态，ROC AUC为。92 （95%CI 0.89-0.97；准确率85%；图2）。Tau PET可用于135名血浆pTau217数据的参与者和114名血浆pTau217和淀粉样蛋白PET数据的参与者。结论结合SCAN PET和NCRAD血浆是一个很有前途的资源，已经有36%的人口多样性。通过SCAN计划和通过成像研究ADRD清晰度的ADRC联盟（CLARiTI）的持续努力，样本量将增加。
{"title":"Integration of plasma and imaging data within the ADRC biofluid and imaging ecosystems","authors":"Julie E. Oomens, Theresa M. Harrison, Jeffrey L. Dage, Kristen A. Russ, Henrik Zetterberg, William J. Jagust, Tatiana M. Foroud, Sarah Biber, Elizabeth C. Mormino, Sterling C Johnson","doi":"10.1002/alz70856_104199","DOIUrl":"https://doi.org/10.1002/alz70856_104199","url":null,"abstract":"Background Data accessibility and interoperability across the U.S. Alzheimer's Disease Research Centers (ADRCs) provides necessary resources and data access to enable novel hypothesis testing without additional data collection and will allow end users to rapidly advance our understanding of multiple pathologies or multiple chronic conditions on disease progression within Alzheimer's disease and related diseases. The aim of the current study was to integrate plasma data from the National Centralized Repository for Alzheimer's Disease and Related Dementia's (NCRAD) with ADRC neuroimaging data from the SCAN initiative and National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS) demographic data, all publicly available through the NACC Data Platform and Data Front Door. We provide sample descriptives and present the results of initial data explorations. Method The NACC and NCRAD data request procedures were completed to gain access to the data. We focused on the subset of participants for whom Quanterix Simoa HD‐X Alzpath plasma pTau217 data was available (NCRAD). Amyloid pathology was defined based on centiloid values (cut‐off >= 20; SCAN initiative). Demographic information was available for all participants (NACC UDS). We integrated data using the NACC identifier and visit age where available. We used Spearman correlations to assess the association between plasma pTau217 and centiloid values and we used ROC analyses to assess amyloid classification performance. Result Plasma pTau217 data was available for 927 participants (sample descriptives in Table 1). Figure 1 shows the distribution of plasma pTau217 levels across diagnostic groups. In the subset of participants for whom amyloid PET was available ( <jats:italic>n</jats:italic> = 170, Table 1), the Spearman correlation between plasma pTau217 levels and centiloid values was 0.59. Quanterix pTau217 accurately classified amyloid status with a ROC AUC of .92 (95%CI 0.89–0.97; accuracy 85%; Figure 2). Tau PET was available for 135 participants with plasma pTau217 data and 114 participants with both plasma pTau217 and amyloid PET data. Conclusion Combining the SCAN PET and NCRAD plasma results in a promising resource, already with 36% demographic diversity. Sample sizes will increase through ongoing efforts as part of the SCAN initiative and the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI).","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"15 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955172","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}
Timothy Lawn, Ibai Diez, Elisenda Bueichekú2, Maxime Van Egroo, Gillian T Coughlan, Rachel F. Buckley, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Jorge Sepulcre, Heidi I.L. Jacobs
Background Brainstem nuclei such as the locus coeruleus (LC) are amongst the earliest regions affected by tau pathology in Alzheimer's disease (AD). The LC's extensive noradrenergic projections shape brain network architecture and its structural integrity is associated with resilience against cognitive decline. However, the role of LC network connectivity in cognitive resilience remains unclear, as does its potential differential impact across distinct population subgroups who might specifically benefit from its augmentation. Methods We included 393 cognitively unimpaired Aβ+ individuals (centiloid > 19) from the A4 study who underwent baseline resting‐state fMRI and florbetapir Aβ‐PET as well as longitudinal Preclinical Alzheimer's Cognitive Composite (PACC) assessment. Pearsons's correlation coefficient was used to create maps of LC functional connectivity (LC‐FC) to 454 parcels of the Schaefer‐Tian parcellation which were harmonised across scanners using NeuroCombat. Mixed‐effects models with natural cubic splines (2 DOF) were used to test whether global, Yeo17 network, and individual parcel level LC‐FC moderated PACC decline over time as well as in interaction with centiloid, sex, and APOΕ4 status, controlling for age, education, framewise displacement, treatment, and sex (when not interacted). Analyses were deemed significant following Benjamini‐Hochberg false‐discovery rate correction for multiple comparisons. Results The LC showed widespread connectivity that was strongest within the limbic regions, hippocampus, and thalamus (Figure 1a). Greater global LC‐FC was associated with attenuated cognitive decline (Figure 1b, p = 0.014), especially at higher levels of Aβ (Figure 1c, p <0.001). At the network level, LC‐FC resilience was predominantly related to task‐positive (control and dorsal/ventral attentional) networks, whilst in the default mode network greater LC‐FC was associated with reduced cognitive decline at lower Aβ (Figure 1b/c). The effect of LC‐FC on PACC decline was particularly pronounced in females at high Aβ levels (Figure 2b) and APOE‐e4 carriers (Figure 2c), demonstrating a synergistic effect of sex and genetic risk on LC‐mediated cognitive resilience (Figure 2d). Conclusions Our findings further support the role of the LC in cognitive resilience and suggest this particularly manifests from modulation of task‐positive attentional and frontoparietal control networks. Moreover, female e4‐carriers exhibit more pronounced attenuation of cognitive decline, suggesting they may especially benefit from augmentation of noradrenergic function.
{"title":"Sex and APOE status moderate locus coeruleus network related resilience in preclinical Alzheimer's disease","authors":"Timothy Lawn, Ibai Diez, Elisenda Bueichekú2, Maxime Van Egroo, Gillian T Coughlan, Rachel F. Buckley, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Jorge Sepulcre, Heidi I.L. Jacobs","doi":"10.1002/alz70856_107257","DOIUrl":"https://doi.org/10.1002/alz70856_107257","url":null,"abstract":"Background Brainstem nuclei such as the locus coeruleus (LC) are amongst the earliest regions affected by tau pathology in Alzheimer's disease (AD). The LC's extensive noradrenergic projections shape brain network architecture and its structural integrity is associated with resilience against cognitive decline. However, the role of LC network connectivity in cognitive resilience remains unclear, as does its potential differential impact across distinct population subgroups who might specifically benefit from its augmentation. Methods We included 393 cognitively unimpaired Aβ+ individuals (centiloid > 19) from the A4 study who underwent baseline resting‐state fMRI and florbetapir Aβ‐PET as well as longitudinal Preclinical Alzheimer's Cognitive Composite (PACC) assessment. Pearsons's correlation coefficient was used to create maps of LC functional connectivity (LC‐FC) to 454 parcels of the Schaefer‐Tian parcellation which were harmonised across scanners using NeuroCombat. Mixed‐effects models with natural cubic splines (2 DOF) were used to test whether global, Yeo17 network, and individual parcel level LC‐FC moderated PACC decline over time as well as in interaction with centiloid, sex, and APOΕ4 status, controlling for age, education, framewise displacement, treatment, and sex (when not interacted). Analyses were deemed significant following Benjamini‐Hochberg false‐discovery rate correction for multiple comparisons. Results The LC showed widespread connectivity that was strongest within the limbic regions, hippocampus, and thalamus (Figure 1a). Greater global LC‐FC was associated with attenuated cognitive decline (Figure 1b, <jats:italic>p</jats:italic> = 0.014), especially at higher levels of Aβ (Figure 1c, <jats:italic>p</jats:italic> <0.001). At the network level, LC‐FC resilience was predominantly related to task‐positive (control and dorsal/ventral attentional) networks, whilst in the default mode network greater LC‐FC was associated with reduced cognitive decline at lower Aβ (Figure 1b/c). The effect of LC‐FC on PACC decline was particularly pronounced in females at high Aβ levels (Figure 2b) and APOE‐e4 carriers (Figure 2c), demonstrating a synergistic effect of sex and genetic risk on LC‐mediated cognitive resilience (Figure 2d). Conclusions Our findings further support the role of the LC in cognitive resilience and suggest this particularly manifests from modulation of task‐positive attentional and frontoparietal control networks. Moreover, female e4‐carriers exhibit more pronounced attenuation of cognitive decline, suggesting they may especially benefit from augmentation of noradrenergic function.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"18 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955173","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}
Simona Merlini, Roberta Diaz Brinton, Francesca Vitali
Background Age, sex, and APOE4 genotype are key non‐modifiable risk factors for Alzheimer's disease (AD), with APOE4 significantly increasing risk, especially in women. The APOE‐sex (APOE‐SX) interaction underscores the need for personalized AD treatments. We analyzed plasma blood proteomic data from the UK Biobank to identify sex and APOE‐specific protein and pathway signatures. Method Plasma samples were analyzed for AD‐diagnosed participants and controls. After propensity‐score matching on age and education level, 199 AD cases (133 F) and 199 controls (104 F) from APOE3/3, 3/4 and 4/4 individuals were retained. Protein levels were normalized using z‐scores and a two‐step approach of within‐batch and across‐batches intensity normalization. For each APOE‐SX condition, differentially expressed proteins (DEPs, p ‐value < 0.05) between AD and controls were identified using linear regression with empirical Bayes estimators to calibrate per‐protein variance using information from all proteins. Gene Set Enrichment Analysis (GSEA) was subsequently conducted using Gene Ontology Biological Processes (GO‐BP) accounting for DEP fold change. Redundant GO‐BP terms (adjusted p ‐values<0.05) were removed (GO‐BP semantic similarity cut‐off of 0.6). Comparison analyses were then conducted to identify common and unique DEPs and enriched GO‐BPs across APOE‐SX conditions. To achieve this, heatmaps were generated to visualize the overlap and differences in protein expression and pathway enrichment across groups, enabling systematic between‐group comparisons. Result Differential expression analysis identified 95 common DEPs in females and 7 DEPs among APOE4 carriers, while no GO‐BPs were shared across all sex‐genotype subgroups. Female APOE4 carriers exhibited the highest number of DEPs (F4/4: n = 759; F3/4: n = 698) while male APOE3 carriers had the lowest ( n = 102), but the number of enriched GO‐BPs was comparable to across APOE‐SX conditions, suggesting that a greater number of dysregulated proteins are involved in a limited set of biological processes. GO‐BPs were predominantly downregulated in females and upregulated in males. Notably, humoral immune response mediated by circulating immunoglobulin was uniquely upregulated in F4/4, whereas interferon‐gamma response was a shared pathway in males across APOE genotypes. Conclusion These findings suggest APOE‐SX specific proteomic signatures and altered biological processes in AD, highlight strong sex differences in AD plasma proteomics and support the development of personalized therapeutics considering APOE‐SX interaction.
{"title":"Large‐scale proteomics analysis of Alzheimer's Disease plasma blood reveals sex and APOE specific signatures","authors":"Simona Merlini, Roberta Diaz Brinton, Francesca Vitali","doi":"10.1002/alz70856_106951","DOIUrl":"https://doi.org/10.1002/alz70856_106951","url":null,"abstract":"Background Age, sex, and APOE4 genotype are key non‐modifiable risk factors for Alzheimer's disease (AD), with APOE4 significantly increasing risk, especially in women. The APOE‐sex (APOE‐SX) interaction underscores the need for personalized AD treatments. We analyzed plasma blood proteomic data from the UK Biobank to identify sex and APOE‐specific protein and pathway signatures. Method Plasma samples were analyzed for AD‐diagnosed participants and controls. After propensity‐score matching on age and education level, 199 AD cases (133 F) and 199 controls (104 F) from APOE3/3, 3/4 and 4/4 individuals were retained. Protein levels were normalized using z‐scores and a two‐step approach of within‐batch and across‐batches intensity normalization. For each APOE‐SX condition, differentially expressed proteins (DEPs, <jats:italic>p</jats:italic> ‐value < 0.05) between AD and controls were identified using linear regression with empirical Bayes estimators to calibrate per‐protein variance using information from all proteins. Gene Set Enrichment Analysis (GSEA) was subsequently conducted using Gene Ontology Biological Processes (GO‐BP) accounting for DEP fold change. Redundant GO‐BP terms (adjusted <jats:italic>p</jats:italic> ‐values<0.05) were removed (GO‐BP semantic similarity cut‐off of 0.6). Comparison analyses were then conducted to identify common and unique DEPs and enriched GO‐BPs across APOE‐SX conditions. To achieve this, heatmaps were generated to visualize the overlap and differences in protein expression and pathway enrichment across groups, enabling systematic between‐group comparisons. Result Differential expression analysis identified 95 common DEPs in females and 7 DEPs among APOE4 carriers, while no GO‐BPs were shared across all sex‐genotype subgroups. Female APOE4 carriers exhibited the highest number of DEPs (F4/4: <jats:italic>n</jats:italic> = 759; F3/4: <jats:italic>n</jats:italic> = 698) while male APOE3 carriers had the lowest ( <jats:italic>n</jats:italic> = 102), but the number of enriched GO‐BPs was comparable to across APOE‐SX conditions, suggesting that a greater number of dysregulated proteins are involved in a limited set of biological processes. GO‐BPs were predominantly downregulated in females and upregulated in males. Notably, humoral immune response mediated by circulating immunoglobulin was uniquely upregulated in F4/4, whereas interferon‐gamma response was a shared pathway in males across APOE genotypes. Conclusion These findings suggest APOE‐SX specific proteomic signatures and altered biological processes in AD, highlight strong sex differences in AD plasma proteomics and support the development of personalized therapeutics considering APOE‐SX interaction.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"31 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955158","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}
Jeremy A. Tanner, Sophia Lu, Hugo J. Aparicio, Sara Doyle, Mitzi M. Gonzales, Jayandra Jung Himali, Tiffany F. Kautz, Terrie‐Jeanne Liu, Pauline Maillard, Emer McGrath, Jaime Ramos‐Cejudo, Claudia L Satizabal, Russell P. Tracy, Mohamad Habes, Suzanne E. Schindler, Charles Decarli, Alexa S Beiser, Sudha Seshadri
Background Plasma ADRD biomarkers are emerging as accessible and cost‐effective diagnostic tools, but data on their relevance in the general population is needed prior to widespread use. Plasma Ptau shows potential for AD screening, yet its association with structural brain changes in community‐based populations remains unclear. Similarly, it is unclear if plasma NfL and GFAP more closely reflect vascular disease or neurodegeneration, and whether this differs in those with, versus without, AD. This study assesses:(1) the association between plasma Ptau181 and brain MRI outcomes and(2) whether elevated Ptau181 modifies the relationship between NfL, GFAP, and brain MRI features in the Framingham Heart Study(FHS), a flagship population‐based cohort. Method FHS Offspring and Omni 1 Cohort participants (Exam 9;2011‐2014) with available plasma biomarkers, brain MRI, and no confounding neurologic disorders were included. Plasma Ptau181, GFAP, and NfL were measured using Quanterix Simoa. MRI outcomes included measures of vascular disease, neurodegeneration, AD‐pattern atrophy, and white matter disease. Plasma Ptau181 was analyzed as a continuous and binary predictor (highest quintile vs remainder) using multivariate linear regressions adjusted for age, age 2 , sex, eGFR, and MRI‐plasma collection interval, with FDR correction. Additional models assessed GFAP and NfL as continuous predictors, stratified by Ptau181 level (highest quintile vs remainder). Sensitivity analyses excluded participants with dementia and/or stroke. Result 1183 participants were included (mean age 69±8, 56%Female, mean MMSE 29±1.6). Elevated Ptau181 was associated with AD‐pattern cortical thickness in primary and all sensitivity analyses, and with cortical atrophy in primary though not all sensitivity analyses (Table 1). Elevated GFAP was most strongly associated with worsened AD‐pattern atrophy and cortical atrophy in individuals with elevated Ptau181, and with periventricular white matter hyperintensities(WMH) in those with low Ptau181(Table 2). Elevated NfL was associated with AD‐pattern and cortical atrophy in those with/without elevated Ptau181, and additionally with extensive WMH in those with elevated PTau181(Table 3). Conclusion The combination of plasma Ptau181, GFAP, and NfL provide information on the etiology and severity of brain disease in the community. In AD, each are associated with worsening neurodegeneration severity, and NfL is also associated with vascular disease. In individuals with low Ptau181, GFAP is associated with vascular disease.
{"title":"Plasma Ptau as a Biomarker of Structural Brain Health in the Community","authors":"Jeremy A. Tanner, Sophia Lu, Hugo J. Aparicio, Sara Doyle, Mitzi M. Gonzales, Jayandra Jung Himali, Tiffany F. Kautz, Terrie‐Jeanne Liu, Pauline Maillard, Emer McGrath, Jaime Ramos‐Cejudo, Claudia L Satizabal, Russell P. Tracy, Mohamad Habes, Suzanne E. Schindler, Charles Decarli, Alexa S Beiser, Sudha Seshadri","doi":"10.1002/alz70856_106409","DOIUrl":"https://doi.org/10.1002/alz70856_106409","url":null,"abstract":"Background Plasma ADRD biomarkers are emerging as accessible and cost‐effective diagnostic tools, but data on their relevance in the general population is needed prior to widespread use. Plasma Ptau shows potential for AD screening, yet its association with structural brain changes in community‐based populations remains unclear. Similarly, it is unclear if plasma NfL and GFAP more closely reflect vascular disease or neurodegeneration, and whether this differs in those with, versus without, AD. This study assesses:(1) the association between plasma Ptau181 and brain MRI outcomes and(2) whether elevated Ptau181 modifies the relationship between NfL, GFAP, and brain MRI features in the Framingham Heart Study(FHS), a flagship population‐based cohort. Method FHS Offspring and Omni 1 Cohort participants (Exam 9;2011‐2014) with available plasma biomarkers, brain MRI, and no confounding neurologic disorders were included. Plasma Ptau181, GFAP, and NfL were measured using Quanterix Simoa. MRI outcomes included measures of vascular disease, neurodegeneration, AD‐pattern atrophy, and white matter disease. Plasma Ptau181 was analyzed as a continuous and binary predictor (highest quintile vs remainder) using multivariate linear regressions adjusted for age, age <jats:sup>2</jats:sup> , sex, eGFR, and MRI‐plasma collection interval, with FDR correction. Additional models assessed GFAP and NfL as continuous predictors, stratified by Ptau181 level (highest quintile vs remainder). Sensitivity analyses excluded participants with dementia and/or stroke. Result 1183 participants were included (mean age 69±8, 56%Female, mean MMSE 29±1.6). Elevated Ptau181 was associated with AD‐pattern cortical thickness in primary and all sensitivity analyses, and with cortical atrophy in primary though not all sensitivity analyses (Table 1). Elevated GFAP was most strongly associated with worsened AD‐pattern atrophy and cortical atrophy in individuals with elevated Ptau181, and with periventricular white matter hyperintensities(WMH) in those with low Ptau181(Table 2). Elevated NfL was associated with AD‐pattern and cortical atrophy in those with/without elevated Ptau181, and additionally with extensive WMH in those with elevated PTau181(Table 3). Conclusion The combination of plasma Ptau181, GFAP, and NfL provide information on the etiology and severity of brain disease in the community. In AD, each are associated with worsening neurodegeneration severity, and NfL is also associated with vascular disease. In individuals with low Ptau181, GFAP is associated with vascular disease.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"57 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955161","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}
José Enrique Arriola-Infante, Alejandra O. Morcillo-Nieto, Maria Franquesa-Mullerat, Sara E Zsadanyi, Lídia Vaqué-Alcázar, Mateus Rozalem Aranha, José Allende Parra, Zili Zhao, Javier Arranz, Íñigo Rodríguez-Baz, Lucía Maure-Blesa, Laura Videla, Isabel Barroeta, Laura Del Hoyo, Bessy Benejam, Susana Fernandez, Aida Sanjuan Hernandez, Sandra Giménez, Daniel Alcolea, Olivia Belbin, Albert Flotats, Valle Camacho, Alberto Lleó, Maria Carmona-Iragui, Juan Fortea, Alexandre Bejanin
Background
To date, limited evidence exists on the different sensitivity of MRI versus [18F]FDG-PET to detect early cerebral changes along the Alzheimer's disease (AD) continuum in Down syndrome (DS). Therefore, we aimed to characterize volume and metabolism alterations in adults with DS and compare their performance in detecting AD clinical stages.
Method
Cross-sectional study, including 92 adults with DS from the Down-Alzheimer Barcelona Neuroimaging Initiative (34 asymptomatic without amyloid pathology [aDS A−], 20 asymptomatic with amyloid pathology [aDS A+], 12 with prodromal AD [pDS], and 26 with AD dementia [dDS]; Table 1), who underwent 3T-MRI and [18F]FDG-PET. Amyloid status in the aDS group was determined using amyloid-PET (>20 centiloids, n = 29) or CSF Aβ42/Aβ40 ratio (<0.062, Lumipulse, n = 25). Brain volume and metabolism values were extracted using the Hammers atlas, normalizing MRI volumes by total intracranial volume and PET images using the pons as reference region. We calculated standardized-β coefficients, adjusted for sex and scanner, to assess the effectiveness of MRI and PET scans in identifying stages of AD (aDS A− vs. aDS A+; aDS vs. symptomatic DS [sDS=pDS + dDS]).
Result
Progressive brain volume loss and metabolic decline were observed along the AD continuum in DS. Compared to aDS A−, aDS A+ exhibited lower volume in multiple regions, particularly in the frontal lobe. sDS individuals showed widespread atrophy, predominantly in temporal areas (Figure 1). In contrast, no significant hypometabolism was detected in aDS A+ compared to aDS A−, but sDS individuals exhibited global hypometabolism, primarily in temporo-parietal regions (Figure 2).
Conclusion
Amyloid pathology in aDS individuals is linked to frontal-predominant atrophy without clear hypometabolism. In symptomatic stages, both MRI and [18F]FDG-PET revealed widespread involvement, with atrophy predominating in temporal regions and hypometabolism in temporo-parietal areas. Unlike in sporadic AD, no brain region showed greater hypometabolism than atrophy, suggesting alternative contributing factors in the general population. Our findings also suggest that MRI outperforms [18F]FDG-PET in identifying brain changes associated with AD clinical stages in DS, which has implications for early diagnosis and clinical trials.
迄今为止，关于MRI与[18 F]FDG‐PET在检测唐氏综合征（DS）患者阿尔茨海默病（AD）连续体早期大脑变化的不同敏感性的证据有限。因此，我们的目的是表征成人DS患者的体积和代谢变化，并比较它们在检测AD临床分期方面的表现。方法横断面研究，包括来自唐氏阿尔茨海默氏巴塞罗那神经影像学倡议的92名成人退行性痴呆患者（34名无淀粉样蛋白病理[aDS A−]，20名无淀粉样蛋白病理[aDS A+]， 12名前驱AD [pDS]， 26名AD痴呆[dDS]；表1），接受3T‐MRI和[18f]FDG‐PET检查。采用淀粉样蛋白- PET（20个厘体，n = 29）或CSF a - β42/ a - β40比值（0.062,Lumipulse, n = 25）测定ad组的淀粉样蛋白状态。使用Hammers图谱提取脑容量和代谢值，通过总颅内容量和PET图像将脑桥作为参考区域归一化MRI体积。我们计算了标准化β系数，并根据性别和扫描仪进行了调整，以评估MRI和PET扫描在识别AD分期（aDS A - vs. aDS A+; aDS vs.症状性DS [sDS=pDS + dDS]）方面的有效性。结果退行性痴呆患者在AD连续过程中出现进行性脑容量减少和代谢下降。与ad A−相比，ad A+在多个区域表现出更低的体积，尤其是在额叶。sDS个体表现出广泛的萎缩，主要在颞区（图1）。相比之下，与aDS A -相比，aDS A+中未检测到明显的低代谢，但sDS个体表现出全面的低代谢，主要是在颞顶叶区域（图2）。结论ad个体的淀粉样蛋白病理与额叶显性萎缩有关，但无明显的低代谢。在症状阶段，MRI和[18 F]FDG - PET均显示广泛受累，萎缩主要发生在颞区，颞顶区代谢低下。与散发性阿尔茨海默病不同，没有大脑区域表现出比萎缩更严重的代谢低下，这表明在一般人群中有其他因素。我们的研究结果还表明，MRI在识别与退行性痴呆临床阶段相关的大脑变化方面优于FDG‐PET [18 F]，这对早期诊断和临床试验具有重要意义。
{"title":"Distinct Sensitivity of MRI Versus [18F]FDG-PET To Detect Cerebral Changes Across the Alzheimer's Continuum in Down Syndrome: A Multimodal Imaging Study","authors":"José Enrique Arriola-Infante, Alejandra O. Morcillo-Nieto, Maria Franquesa-Mullerat, Sara E Zsadanyi, Lídia Vaqué-Alcázar, Mateus Rozalem Aranha, José Allende Parra, Zili Zhao, Javier Arranz, Íñigo Rodríguez-Baz, Lucía Maure-Blesa, Laura Videla, Isabel Barroeta, Laura Del Hoyo, Bessy Benejam, Susana Fernandez, Aida Sanjuan Hernandez, Sandra Giménez, Daniel Alcolea, Olivia Belbin, Albert Flotats, Valle Camacho, Alberto Lleó, Maria Carmona-Iragui, Juan Fortea, Alexandre Bejanin","doi":"10.1002/alz70856_107114","DOIUrl":"10.1002/alz70856_107114","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>To date, limited evidence exists on the different sensitivity of MRI versus [<sup>18</sup>F]FDG-PET to detect early cerebral changes along the Alzheimer's disease (AD) continuum in Down syndrome (DS). Therefore, we aimed to characterize volume and metabolism alterations in adults with DS and compare their performance in detecting AD clinical stages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Cross-sectional study, including 92 adults with DS from the Down-Alzheimer Barcelona Neuroimaging Initiative (34 asymptomatic without amyloid pathology [aDS A−], 20 asymptomatic with amyloid pathology [aDS A+], 12 with prodromal AD [pDS], and 26 with AD dementia [dDS]; Table 1), who underwent 3T-MRI and [<sup>18</sup>F]FDG-PET. Amyloid status in the aDS group was determined using amyloid-PET (>20 centiloids, <i>n</i> = 29) or CSF Aβ42/Aβ40 ratio (<0.062, Lumipulse, <i>n</i> = 25). Brain volume and metabolism values were extracted using the Hammers atlas, normalizing MRI volumes by total intracranial volume and PET images using the pons as reference region. We calculated standardized-β coefficients, adjusted for sex and scanner, to assess the effectiveness of MRI and PET scans in identifying stages of AD (aDS A− vs. aDS A+; aDS vs. symptomatic DS [sDS=pDS + dDS]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Progressive brain volume loss and metabolic decline were observed along the AD continuum in DS. Compared to aDS A−, aDS A+ exhibited lower volume in multiple regions, particularly in the frontal lobe. sDS individuals showed widespread atrophy, predominantly in temporal areas (Figure 1). In contrast, no significant hypometabolism was detected in aDS A+ compared to aDS A−, but sDS individuals exhibited global hypometabolism, primarily in temporo-parietal regions (Figure 2).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Amyloid pathology in aDS individuals is linked to frontal-predominant atrophy without clear hypometabolism. In symptomatic stages, both MRI and [<sup>18</sup>F]FDG-PET revealed widespread involvement, with atrophy predominating in temporal regions and hypometabolism in temporo-parietal areas. Unlike in sporadic AD, no brain region showed greater hypometabolism than atrophy, suggesting alternative contributing factors in the general population. Our findings also suggest that MRI outperforms [<sup>18</sup>F]FDG-PET in identifying brain changes associated with AD clinical stages in DS, which has implications for early diagnosis and clinical trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 S2","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz70856_107114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955244","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}
Ismael Luis Calandri, Laura E. Jonkman, Sophie E. Mastenbroek, Alex J. Wesseling, Colin Groot, Frederik Barkhof, Yolande A.L. Pijnenburg, Rik Ossenkoppele
<div> <section> <h3> Background</h3> <p>Alzheimer's disease (AD) exhibits diverse neurodegeneration patterns, highlighting the need for detailed atrophy mapping to improve early diagnosis and monitoring. Although MRI scans are commonly used for <i>in vivo</i> brain assessment, the interpretation of atrophy patterns in the context of neuropathological findings has been limited. This study aims to address this gap by combining structural MRI with postmortem pathological data to assess howdata-driven atrophy subtypes correlate with underlying AD pathology, axonal degeneration and myelin integrity.</p> </section> <section> <h3> Method</h3> <p>We analyzed 2,029 MRI scans from cognitively impaired individuals with positive AD biomarkers. Cortical volumes and thicknesses were computed using FreeSurfer and harmonized across MRI scanners with NeuroCombat. Measurements were normalized using data from 620 cognitively unimpaired individuals with negative AD biomarkers. A SuStaIn (Subtype and staging inference) model was trained with detection thresholds of 0.5, 1, and 2 SDs. To validate, the trained model was used to classify and stage a subset with available postmortem MRI and neuropathological data (<i>n</i> = 34 AD, <i>n</i> = 16 controls). We quantified amyloid (4G8), pTau (AT8), NfL, myelin (PLP), and microglia (IBA1) in the fusiform gyrus, superior parietal lobule, precuneus, middle temporal gyrus, middle frontal gyrus, posterior cingulate gyrus, parahippocampal gyrus, occipital cortex and right hippocampus. A linear mixed-effects model tested regional neuropathological differences across subtypes, adjusting for stage.</p> </section> <section> <h3> Result</h3> <p>We found three subtypes: Subtype-1,(limbic) initially hippocampal involvement, accounting for 55.8% of cases; subtype-2 (posterior), initial involvement of the parietal lobes, (29.4%); and subtype-3 (hippocampal sparing), relative preserved hippocampi until advanced stages (14.7%, Figures 1 and 2). Subtypes 1 and 2 showed significantly greater pTau deposition in middle frontal gyrus and temporal (fusiform gyrus, medial and parahippocampal) regions compared to subtype 3 (<i>p</i> <0.01, Figure 3). Subtype-2 exhibited higher Tau burden than subtype-1 in parietal regions (<i>p</i> <0.01). Additionally, subtype 1 had higher NfL levels in the superior parietal lobule (<i>p</i> = 0.02) than subtype-2. No significant differences were found in amyloid and microglia distribution.</p> </section> <section> <h3> Conclusion</h3> <p>We identified three subtypes of atrophy progression that resemble clini
{"title":"Characterization of MRI-derived atrophy subtypes using post-mortem MRI and neuropathological markers in Alzheimer's disease","authors":"Ismael Luis Calandri, Laura E. Jonkman, Sophie E. Mastenbroek, Alex J. Wesseling, Colin Groot, Frederik Barkhof, Yolande A.L. Pijnenburg, Rik Ossenkoppele","doi":"10.1002/alz70856_106454","DOIUrl":"10.1002/alz70856_106454","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) exhibits diverse neurodegeneration patterns, highlighting the need for detailed atrophy mapping to improve early diagnosis and monitoring. Although MRI scans are commonly used for <i>in vivo</i> brain assessment, the interpretation of atrophy patterns in the context of neuropathological findings has been limited. This study aims to address this gap by combining structural MRI with postmortem pathological data to assess howdata-driven atrophy subtypes correlate with underlying AD pathology, axonal degeneration and myelin integrity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>We analyzed 2,029 MRI scans from cognitively impaired individuals with positive AD biomarkers. Cortical volumes and thicknesses were computed using FreeSurfer and harmonized across MRI scanners with NeuroCombat. Measurements were normalized using data from 620 cognitively unimpaired individuals with negative AD biomarkers. A SuStaIn (Subtype and staging inference) model was trained with detection thresholds of 0.5, 1, and 2 SDs. To validate, the trained model was used to classify and stage a subset with available postmortem MRI and neuropathological data (<i>n</i> = 34 AD, <i>n</i> = 16 controls). We quantified amyloid (4G8), pTau (AT8), NfL, myelin (PLP), and microglia (IBA1) in the fusiform gyrus, superior parietal lobule, precuneus, middle temporal gyrus, middle frontal gyrus, posterior cingulate gyrus, parahippocampal gyrus, occipital cortex and right hippocampus. A linear mixed-effects model tested regional neuropathological differences across subtypes, adjusting for stage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>We found three subtypes: Subtype-1,(limbic) initially hippocampal involvement, accounting for 55.8% of cases; subtype-2 (posterior), initial involvement of the parietal lobes, (29.4%); and subtype-3 (hippocampal sparing), relative preserved hippocampi until advanced stages (14.7%, Figures 1 and 2). Subtypes 1 and 2 showed significantly greater pTau deposition in middle frontal gyrus and temporal (fusiform gyrus, medial and parahippocampal) regions compared to subtype 3 (<i>p</i> <0.01, Figure 3). Subtype-2 exhibited higher Tau burden than subtype-1 in parietal regions (<i>p</i> <0.01). Additionally, subtype 1 had higher NfL levels in the superior parietal lobule (<i>p</i> = 0.02) than subtype-2. No significant differences were found in amyloid and microglia distribution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We identified three subtypes of atrophy progression that resemble clini","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 S2","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz70856_106454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955844","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}
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