Pub Date : 2026-03-01Epub Date: 2025-12-13DOI: 10.1016/j.neurobiolaging.2025.12.003
Soo-Jin Song, Jung-A Shin
Aging is a natural physiological process that may be accompanied by pathological changes, particularly in the brain. Iron is an essential trace element supporting various physiological functions and maintaining cellular homeostasis. However, iron levels tend to increase in certain brain regions of older adults and are associated with the development of neurodegenerative diseases. Despite this association, the causal relationship between aging, iron accumulation, and neurodegenerative diseases remains unknown. This study aimed to elucidate the potential contribution of systemic iron overload (IO) to brain pathology during aging. An IO model was established by intraperitoneal iron dextran (0.5 g/kg), 5 days/week for 4 weeks into C57BL/6 mice. Animals were divided into control and IO groups and further categorized into younger and older mice. No parenchymal iron accumulation was observed in any group; however, ferritin expression increased with IO and showed as plaques in older mice regardless of IO. Amyloid beta (Aβ) aggregation was observed in the entorhinal cortex and hippocampus, with higher burden in the older IO group. Ferritin plaques localized to the same regions as Aβ aggregation, and both showed a marked increase in older IO mice. The hippocampal Aβ 42/40 ratio was also increased in this group. Additionally, excessive iron was associated with reduced exploratory activity and showed trends toward impaired spatial working memory in older mice. These findings suggest that while aging is not pathological, IO may accelerate Aβ pathology during aging, although the presence of such pathology does not necessarily indicate neurodegeneration or cognitive impairment.
{"title":"Excess iron may accelerate amyloid beta accumulation in the brains of older mice","authors":"Soo-Jin Song, Jung-A Shin","doi":"10.1016/j.neurobiolaging.2025.12.003","DOIUrl":"10.1016/j.neurobiolaging.2025.12.003","url":null,"abstract":"<div><div>Aging is a natural physiological process that may be accompanied by pathological changes, particularly in the brain. Iron is an essential trace element supporting various physiological functions and maintaining cellular homeostasis. However, iron levels tend to increase in certain brain regions of older adults and are associated with the development of neurodegenerative diseases. Despite this association, the causal relationship between aging, iron accumulation, and neurodegenerative diseases remains unknown. This study aimed to elucidate the potential contribution of systemic iron overload (IO) to brain pathology during aging. An IO model was established by intraperitoneal iron dextran (0.5 g/kg), 5 days/week for 4 weeks into C57BL/6 mice. Animals were divided into control and IO groups and further categorized into younger and older mice. No parenchymal iron accumulation was observed in any group; however, ferritin expression increased with IO and showed as plaques in older mice regardless of IO. Amyloid beta (Aβ) aggregation was observed in the entorhinal cortex and hippocampus, with higher burden in the older IO group. Ferritin plaques localized to the same regions as Aβ aggregation, and both showed a marked increase in older IO mice. The hippocampal Aβ 42/40 ratio was also increased in this group. Additionally, excessive iron was associated with reduced exploratory activity and showed trends toward impaired spatial working memory in older mice. These findings suggest that while aging is not pathological, IO may accelerate Aβ pathology during aging, although the presence of such pathology does not necessarily indicate neurodegeneration or cognitive impairment.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 47-59"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-18DOI: 10.1016/j.neurobiolaging.2025.12.005
Alberto Benussi , Marco Michelutti , Tiziana Maria Isabella Lombardo , Barbara Toffoletto , Federica Palacino , Valentina Cenacchi , Luca Pelusi , Francesco Capacchione , Alina Menichelli , Alberto Perego , Francesca Sirianni , Tatiana Cattaruzza , Paolo Manganotti
Early and accurate diagnosis of Alzheimer’s disease (AD) typically relies on invasive or expensive methods like cerebrospinal fluid (CSF) biomarkers and amyloid PET imaging. Blood-based biomarkers, particularly plasma phosphorylated tau (pTau181, pTau217) and amyloid-beta ratios (Aβ42/40), offer a more accessible diagnostic alternative. This study assessed the diagnostic accuracy of plasma biomarkers and developed a three-zone classification model to reduce reliance on invasive confirmatory tests. We retrospectively evaluated 109 participants referred to a tertiary memory clinic. Participants underwent cognitive assessments, brain MRI, CSF biomarker analyses (pTau181, Aβ42/40), and plasma biomarker measurements (pTau181, pTau217, Aβ42/40, pTau217/Aβ42 ratio). Diagnostic performance was evaluated using ROC analyses, and thresholds achieving ≥ 95 % sensitivity and specificity were used to define low, intermediate and high-risk zones. Plasma biomarkers correlated significantly with CSF biomarkers. For identifying AD pathology (A+/T + vs. others), plasma pTau217 and the pTau217/Aβ42 ratio demonstrated the highest accuracy (both AUC=0.95), outperforming plasma pTau181 (AUC=0.88) and Aβ42/40 ratio (AUC=0.73). At optimal thresholds, plasma pTau217 showed 87.5 % sensitivity and 93.4 % specificity, whereas the pTau217/Aβ42 ratio showed higher sensitivity (95.8 %) but lower specificity (85.2 %). Using the three-zone model, plasma pTau217 enabled definitive classification in 80.7 % of patients, increasing to 84.4 % with the pTau217/Aβ42 ratio. Among patients with mild cognitive impairment, plasma pTau217 achieved excellent accuracy (AUC=0.98). Plasma pTau217, alone or combined with Aβ42, provides highly accurate and scalable identification of AD pathology, substantially reducing the need for invasive diagnostic procedures.
阿尔茨海默病（AD）的早期和准确诊断通常依赖于侵入性或昂贵的方法，如脑脊液（CSF）生物标志物和淀粉样蛋白PET成像。基于血液的生物标志物，特别是血浆磷酸化tau蛋白（pTau181, pTau217）和淀粉样蛋白- β比率（a - β42/40），提供了更容易获得的诊断选择。本研究评估了血浆生物标志物的诊断准确性，并建立了一个三区分类模型，以减少对侵入性确证试验的依赖。我们回顾性地评估了109名转诊至第三记忆诊所的参与者。参与者接受认知评估、脑MRI、CSF生物标志物分析（pTau181、a - β42/40）和血浆生物标志物测量（pTau181、pTau217、a - β42/40、pTau217/ a - β42比值）。采用ROC分析评估诊断效果，并采用≥ 95 %的敏感性和特异性阈值来定义低、中、高风险区域。血浆生物标志物与脑脊液生物标志物显著相关。鉴别AD病理(A+/T + vs.；血浆pTau217和pTau217/ a - β42比值的准确度最高（AUC均为0.95），优于血浆pTau181 （AUC=0.88）和a - β42/40比值（AUC=0.73）。在最佳阈值下，血浆pTau217的敏感性为87.5 %，特异性为93.4 %，而pTau217/ a - β42的敏感性较高（95.8% %），特异性较低（85.2% %）。使用三区模型，血浆pTau217使80.7% %的患者能够明确分类，随着pTau217/ a - β42的比例增加到84.4 %。在轻度认知障碍患者中，血浆pTau217的准确性非常好（AUC=0.98）。血浆pTau217，单独或联合Aβ42，提供了高度准确和可扩展的阿尔茨海默病病理鉴定，大大减少了侵入性诊断程序的需要。
{"title":"Diagnostic performance of plasma pTau217/Aβ42 ratio and a three-zone threshold model for Alzheimer’s disease","authors":"Alberto Benussi , Marco Michelutti , Tiziana Maria Isabella Lombardo , Barbara Toffoletto , Federica Palacino , Valentina Cenacchi , Luca Pelusi , Francesco Capacchione , Alina Menichelli , Alberto Perego , Francesca Sirianni , Tatiana Cattaruzza , Paolo Manganotti","doi":"10.1016/j.neurobiolaging.2025.12.005","DOIUrl":"10.1016/j.neurobiolaging.2025.12.005","url":null,"abstract":"<div><div>Early and accurate diagnosis of Alzheimer’s disease (AD) typically relies on invasive or expensive methods like cerebrospinal fluid (CSF) biomarkers and amyloid PET imaging. Blood-based biomarkers, particularly plasma phosphorylated tau (pTau<sub>181</sub>, pTau<sub>217</sub>) and amyloid-beta ratios (Aβ<sub>42</sub>/<sub>40</sub>), offer a more accessible diagnostic alternative. This study assessed the diagnostic accuracy of plasma biomarkers and developed a three-zone classification model to reduce reliance on invasive confirmatory tests. We retrospectively evaluated 109 participants referred to a tertiary memory clinic. Participants underwent cognitive assessments, brain MRI, CSF biomarker analyses (pTau<sub>181</sub>, Aβ<sub>42</sub>/<sub>40</sub>), and plasma biomarker measurements (pTau<sub>181</sub>, pTau<sub>217</sub>, Aβ<sub>42</sub>/<sub>40</sub>, pTau<sub>217</sub>/Aβ<sub>42</sub> ratio). Diagnostic performance was evaluated using ROC analyses, and thresholds achieving ≥ 95 % sensitivity and specificity were used to define low, intermediate and high-risk zones. Plasma biomarkers correlated significantly with CSF biomarkers. For identifying AD pathology (A+/T + vs. others), plasma pTau<sub>217</sub> and the pTau<sub>217</sub>/Aβ<sub>42</sub> ratio demonstrated the highest accuracy (both AUC=0.95), outperforming plasma pTau<sub>181</sub> (AUC=0.88) and Aβ<sub>42</sub>/<sub>40</sub> ratio (AUC=0.73). At optimal thresholds, plasma pTau<sub>217</sub> showed 87.5 % sensitivity and 93.4 % specificity, whereas the pTau<sub>217</sub>/Aβ<sub>42</sub> ratio showed higher sensitivity (95.8 %) but lower specificity (85.2 %). Using the three-zone model, plasma pTau<sub>217</sub> enabled definitive classification in 80.7 % of patients, increasing to 84.4 % with the pTau<sub>217</sub>/Aβ<sub>42</sub> ratio. Among patients with mild cognitive impairment, plasma pTau<sub>217</sub> achieved excellent accuracy (AUC=0.98). Plasma pTau<sub>217</sub>, alone or combined with Aβ<sub>42</sub>, provides highly accurate and scalable identification of AD pathology, substantially reducing the need for invasive diagnostic procedures.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 60-68"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145798013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-03DOI: 10.1016/j.neurobiolaging.2025.12.001
Jarrah O.Z.J. Kron , Jeremy A. Metha , Heather J. Daykin , Leigh C. Walker , Yasmin Potts , Giancarlo Allocca , Ryan J. Keenan , Daniel Hoyer , Laura H. Jacobson
Alzheimer’s disease (AD) is a major public health concern in societies with increasingly ageing populations. Accumulating evidence implies a specific link between the development of tauopathy, cognitive impairment, and sleep loss in AD patients. P301S mutant tau-transgenic (PS19) mice, modelling frontotemporal dementia (FTD) and AD tauopathy, demonstrate sleep loss and cognitive impairment. We aimed to assess the progression of sleep loss and cognitive decline longitudinally in both sexes of PS19 mice. WT and PS19 mice underwent polysomnography (PSG), electroencephalography (EEG) power spectral analysis, locomotor activity assessments at 7, 8 and 9-months of age, and Barnes maze testing at 7 and 9-months. PS19s demonstrated profound sleep loss, and locomotor hyperarousal; paralleling observations in AD patients and other studies of mouse tauopathy. This phenotype was more pronounced in PS19 males than females. WT and PS19 mice showed similar learning in repeated Barnes maze testing at 9-months. At 9-months of age, cognitive performance was best predicted by 7-month locomotor hyperarousal, 9-month EEG power outcomes in wakefulness frequency bands associated with cognition, and balanced physiological NREM and REM sleep. Our longitudinal design revealed that researchers should consider early sleep disruption, hyperarousal, and wakeful EEG power in combination as predictors of cognitive symptoms related to tauopathy. Further investigation into mechanisms to promote balanced sleep, which maintain both NREM and REM sleep with ageing, is indicated as a mechanism to potentially preserve cognition in neurodegenerative disorders.
{"title":"PS19 mouse tauopathy is associated with sex-dependent sleep loss and hyperarousal, and predicts cognitive performance","authors":"Jarrah O.Z.J. Kron , Jeremy A. Metha , Heather J. Daykin , Leigh C. Walker , Yasmin Potts , Giancarlo Allocca , Ryan J. Keenan , Daniel Hoyer , Laura H. Jacobson","doi":"10.1016/j.neurobiolaging.2025.12.001","DOIUrl":"10.1016/j.neurobiolaging.2025.12.001","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a major public health concern in societies with increasingly ageing populations. Accumulating evidence implies a specific link between the development of tauopathy, cognitive impairment, and sleep loss in AD patients. P301S mutant tau-transgenic (PS19) mice, modelling frontotemporal dementia (FTD) and AD tauopathy, demonstrate sleep loss and cognitive impairment. We aimed to assess the progression of sleep loss and cognitive decline longitudinally in both sexes of PS19 mice. WT and PS19 mice underwent polysomnography (PSG), electroencephalography (EEG) power spectral analysis, locomotor activity assessments at 7, 8 and 9-months of age, and Barnes maze testing at 7 and 9-months. PS19s demonstrated profound sleep loss, and locomotor hyperarousal; paralleling observations in AD patients and other studies of mouse tauopathy. This phenotype was more pronounced in PS19 males than females. WT and PS19 mice showed similar learning in repeated Barnes maze testing at 9-months. At 9-months of age, cognitive performance was best predicted by 7-month locomotor hyperarousal, 9-month EEG power outcomes in wakefulness frequency bands associated with cognition, and balanced physiological NREM and REM sleep. Our longitudinal design revealed that researchers should consider early sleep disruption, hyperarousal, and wakeful EEG power in combination as predictors of cognitive symptoms related to tauopathy. Further investigation into mechanisms to promote balanced sleep, which maintain both NREM and REM sleep with ageing, is indicated as a mechanism to potentially preserve cognition in neurodegenerative disorders.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 69-87"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-27DOI: 10.1016/j.neurobiolaging.2025.11.007
Louise M. Ince , Brandy N. Routh , Jeffrey S. Darling , Krishi Manem , Akshay Prabhakar , Sophia Martinez , Emily Chan , Ruizhuo Chen , Andrew D. Gaudet , Laura K. Fonken
The aging brain exhibits an increased inflammatory potential which in turn elicits behavioral changes e.g., social withdrawal. Social isolation is a risk factor for additional health complications, and interventions which can mitigate these negative facets of aging can improve longevity and quality of life in old age. The circadian system critically regulates neuroimmune function and behavior, but circadian rhythms also degrade with age, resulting in lower amplitude oscillations in activity and hormone secretion. Time-restricted feeding (TRF), in which food availability is limited to a specific time-of-day, is a simple dietary intervention which provides timing cues to the circadian system - protecting against metabolic disease and reducing systemic inflammation. We thus tested the hypothesis that TRF could serve as an intervention to bolster circadian rhythms in aged mice and have beneficial effects upon age-associated neuroinflammation and behavior. Here, we demonstrate that 6 weeks of TRF in aged (18 months old) mice ameliorates age-associated social withdrawal and drives distinct molecular and cellular changes within the brain. TRF attenuates age-associated increases in inflammatory gene expression in the hippocampus and prefrontal cortex, and re-establishes circadian phase-appropriate expression of autophagy-related genes in the hippocampus. In addition, TRF promotes a diurnal rhythm in microglial branching complexity in the hippocampus, recapitulating the pattern observed in young adults (3 months old). TRF also reduced blood glucose levels in aged males, but not in aged females, suggesting sex-specific effects on metabolic parameters with age. These results highlight the efficacy of TRF as a therapeutic approach to alleviate age-associated neuroinflammation and social withdrawal.
{"title":"Time-restricted feeding rescues sociability deficits and reduces neuroinflammation in aged mice","authors":"Louise M. Ince , Brandy N. Routh , Jeffrey S. Darling , Krishi Manem , Akshay Prabhakar , Sophia Martinez , Emily Chan , Ruizhuo Chen , Andrew D. Gaudet , Laura K. Fonken","doi":"10.1016/j.neurobiolaging.2025.11.007","DOIUrl":"10.1016/j.neurobiolaging.2025.11.007","url":null,"abstract":"<div><div>The aging brain exhibits an increased inflammatory potential which in turn elicits behavioral changes e.g., social withdrawal. Social isolation is a risk factor for additional health complications, and interventions which can mitigate these negative facets of aging can improve longevity and quality of life in old age. The circadian system critically regulates neuroimmune function and behavior, but circadian rhythms also degrade with age, resulting in lower amplitude oscillations in activity and hormone secretion. Time-restricted feeding (TRF), in which food availability is limited to a specific time-of-day, is a simple dietary intervention which provides timing cues to the circadian system - protecting against metabolic disease and reducing systemic inflammation. We thus tested the hypothesis that TRF could serve as an intervention to bolster circadian rhythms in aged mice and have beneficial effects upon age-associated neuroinflammation and behavior. Here, we demonstrate that 6 weeks of TRF in aged (18 months old) mice ameliorates age-associated social withdrawal and drives distinct molecular and cellular changes within the brain. TRF attenuates age-associated increases in inflammatory gene expression in the hippocampus and prefrontal cortex, and re-establishes circadian phase-appropriate expression of autophagy-related genes in the hippocampus. In addition, TRF promotes a diurnal rhythm in microglial branching complexity in the hippocampus, recapitulating the pattern observed in young adults (3 months old). TRF also reduced blood glucose levels in aged males, but not in aged females, suggesting sex-specific effects on metabolic parameters with age. These results highlight the efficacy of TRF as a therapeutic approach to alleviate age-associated neuroinflammation and social withdrawal.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 1-14"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-10DOI: 10.1016/j.neurobiolaging.2025.11.003
Firat Kara , James M. Joers , Scott A. Przybelski , Alicia Algeciras-Schimnich , Jeffrey L. Gunter , Clifford R. Jack Jr , Ronald C. Petersen , Gülin Öz , Kejal Kantarci
The objective of the study was to evaluate the relationship of plasma biomarkers of Alzheimer’s disease (AD) with in vivo proton magnetic resonance spectroscopy (¹H-MRS) markers, and their association with cognitive function across the early stages of the AD continuum. Determining these associations may clarify the AD-related biological pathways and support the development of integrated AD blood and ¹H-MRS biomarkers for early detection of these pathways. Fifty-five older adults (40 cognitively unimpaired; 15 mild cognitive impairment) from the Mayo Clinic Study of Aging underwent single-voxel ¹H-MRS (sLASER) at 3T in the posterior cingulate gyrus (PCG) and left hippocampus (LH), along with plasma assays for Aβ42/40, phosphorylated tau (p-tau181), and the p-tau181/Aβ42 ratio. Associations between plasma biomarkers and ¹H-MRS metabolites (myo-inositol [mIns]/total creatine [tCr], total N-acetylaspartate [tNAA]/tCr, and tNAA/mIns) were examined using partial Spearman correlations (rho, ρ) adjusted for age and sex. Next, associations of the Mini-Mental State Examination with p-tau181/Aβ42 and tNAA/mIns were examined adjusting for the same covariates plus education. In both PCG and LH regions, lower tNAA/mIns was associated with higher p-tau181/Aβ42 (PCG:ρ=−0.59; LH:ρ=−0.54) and p-tau181 (PCG: ρ=−0.38; LH:ρ =−0.39), as well as with lower Aβ42/40 (PCG:ρ=0.40; LH:ρ=0.32). Higher mIns/tCr was associated with higher p-tau181/Aβ42 (PCG: ρ=0.56; LH:ρ=0.46) and p-tau181 (PCG:ρ=0.37; LH:ρ=0.31). Lower PCG and LH tNAA/mIns ratios were associated with lower MMSE (PCG:ρ=0.53; LH:ρ=0.46), while higher p-tau181/Aβ42 was associated with lower MMSE (ρ=−0.49). ¹H-MRS-derived gliosis and neuronal injury biomarkers are associated with early AD pathology, and cognitive performance, supporting their use as noninvasive biomarkers in early AD.
该研究的目的是评估阿尔茨海默病（AD）血浆生物标志物与体内质子磁共振波谱（H-MRS）标志物的关系，以及它们在AD连续体早期阶段与认知功能的关系。确定这些关联可以澄清AD相关的生物学途径，并支持开发整合AD血液和H-MRS生物标志物，用于早期检测这些途径。来自梅奥诊所衰老研究的55名老年人（40名认知未受损，15名轻度认知障碍）在3T时接受了后扣带回（PCG）和左海马（LH）的单体素¹H-MRS (sLASER)，并进行了a - β42/40、磷酸化tau （p-tau181）和p-tau181/ a - β42比值的血浆检测。血浆生物标志物与H-MRS代谢物（肌醇[mIns]/总肌酸[tCr]、总n -乙酰天冬氨酸[tNAA]/tCr和tNAA/mIns）之间的关系采用调整年龄和性别的部分Spearman相关性（ρ, ρ）进行检验。接下来，对p-tau181/ a - β42和tNAA/ min与迷你精神状态检查的关联进行检查，调整相同的协变量加上教育。在PCG和LH区域，较低的tNAA/ min与较高的p-tau181/ a - β42 （PCG:ρ=−0.59;LH:ρ=−0.54）和p-tau181 （PCG:ρ=−0.38;LH:ρ=−0.39）以及较低的a - β42/40 （PCG:ρ=0.40; LH:ρ=0.32）相关。较高的min /tCr与较高的p-tau181/ a - β42 （PCG:ρ= 0.56; LH:ρ=0.46）和p-tau181 （PCG:ρ=0.37; LH:ρ=0.31）相关。较低的PCG和LH tNAA/ min比值与较低的MMSE相关（PCG:ρ=0.53; LH:ρ=0.46），而较高的p-tau181/ a - β42与较低的MMSE相关（ρ= - 0.49）。¹h - mrs衍生的神经胶质瘤和神经元损伤生物标志物与早期阿尔茨海默病病理和认知表现相关，支持它们作为早期阿尔茨海默病的无创生物标志物。
{"title":"1H-MR spectroscopy biomarkers are associated with plasma-derived biomarkers of amyloid-β and tau in the early phase of AD continuum","authors":"Firat Kara , James M. Joers , Scott A. Przybelski , Alicia Algeciras-Schimnich , Jeffrey L. Gunter , Clifford R. Jack Jr , Ronald C. Petersen , Gülin Öz , Kejal Kantarci","doi":"10.1016/j.neurobiolaging.2025.11.003","DOIUrl":"10.1016/j.neurobiolaging.2025.11.003","url":null,"abstract":"<div><div>The objective of the study was to evaluate the relationship of plasma biomarkers of Alzheimer’s disease (AD) with in vivo proton magnetic resonance spectroscopy (¹H-MRS) markers, and their association with cognitive function across the early stages of the AD continuum. Determining these associations may clarify the AD-related biological pathways and support the development of integrated AD blood and ¹H-MRS biomarkers for early detection of these pathways. Fifty-five older adults (40 cognitively unimpaired; 15 mild cognitive impairment) from the Mayo Clinic Study of Aging underwent single-voxel ¹H-MRS (sLASER) at 3T in the posterior cingulate gyrus (PCG) and left hippocampus (LH), along with plasma assays for Aβ42/40, phosphorylated tau (p-tau181), and the p-tau181/Aβ42 ratio. Associations between plasma biomarkers and ¹H-MRS metabolites (myo-inositol [mIns]/total creatine [tCr], total N-acetylaspartate [tNAA]/tCr, and tNAA/mIns) were examined using partial Spearman correlations (rho, ρ) adjusted for age and sex. Next, associations of the Mini-Mental State Examination with p-tau181/Aβ42 and tNAA/mIns were examined adjusting for the same covariates plus education. In both PCG and LH regions, lower tNAA/mIns was associated with higher p-tau181/Aβ42 (PCG:ρ=−0.59; LH:ρ=−0.54) and p-tau181 (PCG: ρ=−0.38; LH:ρ =−0.39), as well as with lower Aβ42/40 (PCG:ρ=0.40; LH:ρ=0.32). Higher mIns/tCr was associated with higher p-tau181/Aβ42 (PCG: ρ=0.56; LH:ρ=0.46) and p-tau181 (PCG:ρ=0.37; LH:ρ=0.31). Lower PCG and LH tNAA/mIns ratios were associated with lower MMSE (PCG:ρ=0.53; LH:ρ=0.46), while higher p-tau181/Aβ42 was associated with lower MMSE (ρ=−0.49). ¹H-MRS-derived gliosis and neuronal injury biomarkers are associated with early AD pathology, and cognitive performance, supporting their use as noninvasive biomarkers in early AD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"158 ","pages":"Pages 18-27"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontotemporal dementia (FTD) is driven by progranulin haploinsufficiency, in which age-dependent microglial activation promotes neurodegeneration through TDP-43 proteinopathy. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator characterized by a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. A pharmacologically active derivative of cPA has been shown to suppress microglial activation. Based on this, we aimed to investigate the potential of cPA derivatives to prevent the onset of FTD. Specifically, we administered metabolically stabilized cPA derivatives, 2-carba-cPA (2ccPA) and its degradation product, 2-carba-LPA (2cLPA), to presymptomatic progranulin-deficient (Grn-/-) mice. The mice received intraperitoneal injections of 0.9 mg/kg/day of either compound for 6 months. Treatment with 2ccPA, but not 2cLPA, significantly attenuated thalamic neuronal loss, cytoplasmic TDP-43 aggregation, and microglial activation, including reduced transition to an ameboid morphology. These findings led us to hypothesize that 2ccPA mitigates disease onset by suppressing microglial activation. To test this, we examined the effects of 2ccPA on primary Grn-/- microglia and found that treatment reduced markers of accelerated senescence, phagocytic activity, lipid accumulation, and CCL8 secretion. Collectively, our findings identify 2ccPA as a promising candidate for the prevention of FTD. This study also represents a conceptual advance by demonstrating that targeting microglial activation is an effective strategy to delay or attenuate neurodegeneration in FTD.
{"title":"Lysophosphatidic acid derivative is a novel candidate of therapeutic agents for a mouse model of frontotemporal dementia with progranulin deficiency","authors":"Nami Yamamoto , Rino Takei , Mari Gotoh , Yasunori Miyamoto , Kei Hashimoto","doi":"10.1016/j.neurobiolaging.2025.11.006","DOIUrl":"10.1016/j.neurobiolaging.2025.11.006","url":null,"abstract":"<div><div>Frontotemporal dementia (FTD) is driven by progranulin haploinsufficiency, in which age-dependent microglial activation promotes neurodegeneration through TDP-43 proteinopathy. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator characterized by a unique cyclic phosphate ring at the <em>sn-2</em> and <em>sn-3</em> positions of its glycerol backbone. A pharmacologically active derivative of cPA has been shown to suppress microglial activation. Based on this, we aimed to investigate the potential of cPA derivatives to prevent the onset of FTD. Specifically, we administered metabolically stabilized cPA derivatives, 2-carba-cPA (2ccPA) and its degradation product, 2-carba-LPA (2cLPA), to presymptomatic progranulin-deficient (<em>Grn</em><sup><em>-/-</em></sup>) mice. The mice received intraperitoneal injections of 0.9 mg/kg/day of either compound for 6 months. Treatment with 2ccPA, but not 2cLPA, significantly attenuated thalamic neuronal loss, cytoplasmic TDP-43 aggregation, and microglial activation, including reduced transition to an ameboid morphology. These findings led us to hypothesize that 2ccPA mitigates disease onset by suppressing microglial activation. To test this, we examined the effects of 2ccPA on primary <em>Grn</em><sup><em>-/-</em></sup> microglia and found that treatment reduced markers of accelerated senescence, phagocytic activity, lipid accumulation, and CCL8 secretion. Collectively, our findings identify 2ccPA as a promising candidate for the prevention of FTD. This study also represents a conceptual advance by demonstrating that targeting microglial activation is an effective strategy to delay or attenuate neurodegeneration in FTD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"158 ","pages":"Pages 39-51"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-13DOI: 10.1016/j.neurobiolaging.2025.11.004
Anna D. Stumps , Nadia Bounoua , Naomi Sadeh
To further understand whether childhood maltreatment (CM) is associated with indicators of accelerated cognitive aging, this study investigated whether CM moderated the relationship of age with gray matter volume (GMV) and executive functions among community adults aged 21–55. Participants (N = 225) underwent MRI scanning, and a composite measure of executive functions was computed across measures of inhibitory control, switching, and working memory. To interpret interactions, we created high (66th percentile) and low (33rd percentile) CM exposure groups and examined age-related variance in GMV and executive functions in each group. Vertex-wise cortical analysis revealed CM by age interactions in two right prefrontal cortex clusters [rostral middle frontal gyrus and superior frontal gyrus], where age negatively correlated with GMV at low CM (ps < 0.001), but this effect weakened at high CM (ps = 0.095–0.436). Further, a multivariate analysis of five subcortical regions revealed a CM-by-age interaction (p = 0.007), whereby age correlated negatively with GMV at high, but not low, CM. Finally, CM moderated the association between age and an executive functioning composite (p = 0.027), with age correlating more negatively with executive functions in individuals reporting high than low CM. Together, these cross-sectional findings suggest CM may influence age-related neurocognitive changes.
{"title":"Childhood maltreatment alters associations between age and neurocognitive health metrics in community-dwelling adults","authors":"Anna D. Stumps , Nadia Bounoua , Naomi Sadeh","doi":"10.1016/j.neurobiolaging.2025.11.004","DOIUrl":"10.1016/j.neurobiolaging.2025.11.004","url":null,"abstract":"<div><div>To further understand whether childhood maltreatment (CM) is associated with indicators of accelerated cognitive aging, this study investigated whether CM moderated the relationship of age with gray matter volume (GMV) and executive functions among community adults aged 21–55. Participants (N = 225) underwent MRI scanning, and a composite measure of executive functions was computed across measures of inhibitory control, switching, and working memory. To interpret interactions, we created high (66th percentile) and low (33rd percentile) CM exposure groups and examined age-related variance in GMV and executive functions in each group. Vertex-wise cortical analysis revealed CM by age interactions in two right prefrontal cortex clusters [rostral middle frontal gyrus and superior frontal gyrus], where age negatively correlated with GMV at low CM (<em>ps</em> < 0.001), but this effect weakened at high CM (<em>ps</em> = 0.095–0.436). Further, a multivariate analysis of five subcortical regions revealed a CM-by-age interaction (<em>p</em> = 0.007), whereby age correlated negatively with GMV at high, but not low, CM. Finally, CM moderated the association between age and an executive functioning composite (<em>p</em> = 0.027), with age correlating more negatively with executive functions in individuals reporting high than low CM. Together, these cross-sectional findings suggest CM may influence age-related neurocognitive changes.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"158 ","pages":"Pages 28-38"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-13DOI: 10.1016/j.neurobiolaging.2025.11.005
Christina S. Dintica , Leigh Johnson , Melissa Petersen , Sid O’Bryant , Kristine Yaffe
Depression is a known risk factor for dementia and MCI, but its associations with AT(N) biomarkers remain inconsistent and may differ by cognitive status. We cross-sectionally studied 2929 dementia-free participants from the Health & Aging Brain Study—Health Disparities (HABS-HD). Mild cognitive impairment (MCI) was identified as having cognitive complaints, Clinical Dementia Rating scores between 0.5 and 2.0, and at least one cognitive test ≤ 1.5 SD below norms. We defined AT (N) with plasma biomarkers amyloid-β 42/40 (Aβ42/40), phosphorylated tau (p-tau181), neurofilament light (NfL), assessed using SIMOA technology and magnetic resonance imaging (MRI) based Alzheimer disease (AD) signature cortical thickness. Depressive symptoms were measured with the Geriatric Depression Scale (GDS), categorized as high (≥10) or low (<10). We used linear regression to determine association between depressive symptoms and biomarkers, adjusting for age, sex, education, kidney function, and body mass index. High depressive symptoms (19 %) were linked to higher NfL (standardized mean differences [SMD] = 0.10, 95 % confidence interval [CI: 0.02–0.18] and p-tau181 (SMD = 0.15, 95 % CI: 0.07–0.22) levels compared to low symptoms but not with Aβ42/40 or AD cortical thickness. Participants with both MCI and high depressive symptoms had higher NfL (SMD = 0.19, 95 % CI: 0.05–0.33) and p-tau181 (SMD = 0.30, 95 % CI: 0.16–0.45), and lower AD signature cortical thickness (SMD = –0.30, 95 % CI: –0.48 to –0.11). No group differences were found for Aβ42/40. Depressive symptoms, particularly among those with MCI, were linked to greater tau and neurodegeneration; longitudinal studies are needed to clarify this clinical significance.
{"title":"Depressive symptoms and plasma AT(N) biomarkers among cognitively healthy and mild cognitively impaired in a diverse cohort","authors":"Christina S. Dintica , Leigh Johnson , Melissa Petersen , Sid O’Bryant , Kristine Yaffe","doi":"10.1016/j.neurobiolaging.2025.11.005","DOIUrl":"10.1016/j.neurobiolaging.2025.11.005","url":null,"abstract":"<div><div>Depression is a known risk factor for dementia and MCI, but its associations with AT(N) biomarkers remain inconsistent and may differ by cognitive status. We cross-sectionally studied 2929 dementia-free participants from the Health & Aging Brain Study—Health Disparities (HABS-HD). Mild cognitive impairment (MCI) was identified as having cognitive complaints, Clinical Dementia Rating scores between 0.5 and 2.0, and at least one cognitive test ≤ 1.5 SD below norms. We defined AT (N) with plasma biomarkers amyloid-β 42/40 (Aβ42/40), phosphorylated tau (p-tau181), neurofilament light (NfL), assessed using SIMOA technology and magnetic resonance imaging (MRI) based Alzheimer disease (AD) signature cortical thickness. Depressive symptoms were measured with the Geriatric Depression Scale (GDS), categorized as high (≥10) or low (<10). We used linear regression to determine association between depressive symptoms and biomarkers, adjusting for age, sex, education, kidney function, and body mass index. High depressive symptoms (19 %) were linked to higher NfL (standardized mean differences [SMD] = 0.10, 95 % confidence interval [CI: 0.02–0.18] and p-tau181 (SMD = 0.15, 95 % CI: 0.07–0.22) levels compared to low symptoms but not with Aβ42/40 or AD cortical thickness. Participants with both MCI and high depressive symptoms had higher NfL (SMD = 0.19, 95 % CI: 0.05–0.33) and p-tau181 (SMD = 0.30, 95 % CI: 0.16–0.45), and lower AD signature cortical thickness (SMD = –0.30, 95 % CI: –0.48 to –0.11). No group differences were found for Aβ42/40. Depressive symptoms, particularly among those with MCI, were linked to greater tau and neurodegeneration; longitudinal studies are needed to clarify this clinical significance.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"158 ","pages":"Pages 11-17"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-06DOI: 10.1016/j.neurobiolaging.2025.11.002
Etienne Aumont , Brandon J. Hall , Tevy Chan , Lydia Trudel , Gleb Bezgin , Seyyed Ali Hosseini , Joseph Therriault , Arthur C. Macedo , Jaime Fernández Arias , Nesrine Rahmouni , Stijn Servaes , Paolo Vitali , Jenna Stevenson , Vladimir Fonov , Maxime Montembeault , Jesse Klostranec , Yasser Iturria-Medina , Serge Gauthier , Pedro Rosa-Neto , for the Alzheimer’s Disease Neuroimaging Initiative
Positron Emission Tomography (PET) early Braak staging might be susceptible to anatomical variability and atrophy in the medial temporal lobe (MTL) structures. These factors should be accounted for in an optimized atlas to improve staging accuracy. This study aimed to compare the accuracy of early tau detection using traditional standard space methods versus using a native space MTL segmentations. Twelve native space MTL structures were used as regions of interest (ROI) for [18F]MK6240 tau-PET images and compared with standard space Braak stage ROIs for 333 participants aged over 55. We used the Rey Auditory Verbal Learning Test (RAVLT) to assess memory function. Native and standard space tau-PET stage ROIs were compared, then combined with anatomical constraints into an optimized standard space MTL atlas. The native space MTL tau-PET staging identified 34 participants with significantly more advanced tau accumulation. Of these, 14 had significant entorhinal and transentorhinal tau despite being classified as Braak stage I when using the original standard space method (here called pre-I stage). In addition, 19 were classified as Braak stage III despite being at Braak stage II using standard space methods (here called pre-III stage). These pre-III participants displayed a significant memory impairment. We found that a standard space spatial smoothing to 6 mm at FWHM best allowed to replicate native space results, resulting in the optimized atlas identifying 29 of these 33 more advanced cases. Therefore, standard space approaches can be improved to better capture early AD tau pathology and be more sensitive to cognitive impairment.
{"title":"Optimized atlas for early tau-PET staging via native space segmentations","authors":"Etienne Aumont , Brandon J. Hall , Tevy Chan , Lydia Trudel , Gleb Bezgin , Seyyed Ali Hosseini , Joseph Therriault , Arthur C. Macedo , Jaime Fernández Arias , Nesrine Rahmouni , Stijn Servaes , Paolo Vitali , Jenna Stevenson , Vladimir Fonov , Maxime Montembeault , Jesse Klostranec , Yasser Iturria-Medina , Serge Gauthier , Pedro Rosa-Neto , for the Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1016/j.neurobiolaging.2025.11.002","DOIUrl":"10.1016/j.neurobiolaging.2025.11.002","url":null,"abstract":"<div><div>Positron Emission Tomography (PET) early Braak staging might be susceptible to anatomical variability and atrophy in the medial temporal lobe (MTL) structures. These factors should be accounted for in an optimized atlas to improve staging accuracy. This study aimed to compare the accuracy of early tau detection using traditional standard space methods versus using a native space MTL segmentations. Twelve native space MTL structures were used as regions of interest (ROI) for [<sup>18</sup>F]MK6240 tau-PET images and compared with standard space Braak stage ROIs for 333 participants aged over 55. We used the Rey Auditory Verbal Learning Test (RAVLT) to assess memory function. Native and standard space tau-PET stage ROIs were compared, then combined with anatomical constraints into an optimized standard space MTL atlas. The native space MTL tau-PET staging identified 34 participants with significantly more advanced tau accumulation. Of these, 14 had significant entorhinal and transentorhinal tau despite being classified as Braak stage I when using the original standard space method (here called pre-I stage). In addition, 19 were classified as Braak stage III despite being at Braak stage II using standard space methods (here called pre-III stage). These pre-III participants displayed a significant memory impairment. We found that a standard space spatial smoothing to 6 mm at FWHM best allowed to replicate native space results, resulting in the optimized atlas identifying 29 of these 33 more advanced cases. Therefore, standard space approaches can be improved to better capture early AD tau pathology and be more sensitive to cognitive impairment.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"158 ","pages":"Pages 1-10"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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