Pub Date : 2025-12-01Epub Date: 2025-09-04DOI: 10.1016/j.neurobiolaging.2025.09.002
Claire L. Anderson , Alden L. Gross , Corinne Pettigrew , Juan P. Vazquez , Abhay Moghekar , Sungtaek Oh , Chan Hyun Na , Marilyn Albert , Paul Worley , Anja Soldan , the BIOCARD Research Team
Prior work suggests higher levels of the synaptic proteins neuronal pentraxin 2 (NPTX2) and neurosecretory protein VGF (VGF) may confer cognitive resilience to Alzheimer’s disease (AD) pathology. Little is known about how these measures relate to long-term cognitive trajectories among individuals initially cognitively unimpaired. This study examined how rates of cognitive decline (mean follow-up=16 years) among 269 initially cognitively unimpaired individuals from the BIOCARD study (M baseline age=57.7 years, 59 % female) are associated with baseline levels of three synaptic proteins measured in cerebrospinal fluid (CSF), using parallel reaction monitoring mass spectrometry: VGF, NPTX2, and the associated AMPA glutamate receptor subunit 4 (GluA4). Baseline CSF biomarker levels of AD pathology (e.g., Aβ1–42/Aβ1–40 and p-tau181) were measured using the Fujirebio Lumipulse G1200 assays. Linear mixed effects models evaluated associations between baseline NPTX2, GluA4, and VGF with level and rate of change in global, executive function, and episodic memory cognitive composite scores. Lower baseline Aβ1–42/Aβ1–40 and higher p-tau181 were associated with greater cognitive decline. When accounting for AD biomarker levels, higher baseline NPTX2 and VGF levels were associated with less decline in the global (both p ≤ 0.002) and episodic memory (both p < 0.03) scores. Higher VGF was associated (p = 0.03) with less executive function decline, with a similar pattern for NPTX2 (p = 0.06). GluA4 was not associated with level or change in cognition (all p > 0.08). These results support the hypothesis that higher levels of NPTX2 and VGF may be associated with cognitive resilience to AD pathology and be potential therapeutic targets for reducing cognitive decline.
{"title":"Cognitive resilience in preclinical Alzheimer’s disease: Higher NPTX2 and VGF levels are associated with reduced cognitive decline","authors":"Claire L. Anderson , Alden L. Gross , Corinne Pettigrew , Juan P. Vazquez , Abhay Moghekar , Sungtaek Oh , Chan Hyun Na , Marilyn Albert , Paul Worley , Anja Soldan , the BIOCARD Research Team","doi":"10.1016/j.neurobiolaging.2025.09.002","DOIUrl":"10.1016/j.neurobiolaging.2025.09.002","url":null,"abstract":"<div><div>Prior work suggests higher levels of the synaptic proteins neuronal pentraxin 2 (NPTX2) and neurosecretory protein VGF (VGF) may confer cognitive resilience to Alzheimer’s disease (AD) pathology. Little is known about how these measures relate to long-term cognitive trajectories among individuals initially cognitively unimpaired. This study examined how rates of cognitive decline (mean follow-up=16 years) among 269 initially cognitively unimpaired individuals from the BIOCARD study (<em>M</em> baseline age=57.7 years, 59 % female) are associated with baseline levels of three synaptic proteins measured in cerebrospinal fluid (CSF), using parallel reaction monitoring mass spectrometry: VGF, NPTX2, and the associated AMPA glutamate receptor subunit 4 (GluA4). Baseline CSF biomarker levels of AD pathology (e.g., Aβ<sub>1–42</sub>/Aβ<sub>1–40</sub> and p-tau<sub>181</sub>) were measured using the Fujirebio Lumipulse G1200 assays. Linear mixed effects models evaluated associations between baseline NPTX2, GluA4, and VGF with level and rate of change in global, executive function, and episodic memory cognitive composite scores. Lower baseline Aβ<sub>1–42</sub>/Aβ<sub>1–40</sub> and higher p-tau<sub>181</sub> were associated with greater cognitive decline. When accounting for AD biomarker levels, higher baseline NPTX2 and VGF levels were associated with less decline in the global (both <em>p</em> ≤ 0.002) and episodic memory (both <em>p</em> < 0.03) scores. Higher VGF was associated (p = 0.03) with less executive function decline, with a similar pattern for NPTX2 (<em>p</em> = 0.06). GluA4 was not associated with level or change in cognition (all p > 0.08). These results support the hypothesis that higher levels of NPTX2 and VGF may be associated with cognitive resilience to AD pathology and be potential therapeutic targets for reducing cognitive decline.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 133-142"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043942","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 : 2025-12-01Epub Date: 2025-09-26DOI: 10.1016/j.neurobiolaging.2025.09.005
N.N. Gamage , Wei-Yeh Liao , B.J. Hand , P.J. Atherton , M. Piasecki , G.M. Opie , J.G. Semmler
{"title":"Corrigendum to “Theta-gamma transcranial alternating current stimulation enhances ballistic motor performance in healthy young and older adults” [Neurobiol. Aging 152 (2025) 1–12]","authors":"N.N. Gamage , Wei-Yeh Liao , B.J. Hand , P.J. Atherton , M. Piasecki , G.M. Opie , J.G. Semmler","doi":"10.1016/j.neurobiolaging.2025.09.005","DOIUrl":"10.1016/j.neurobiolaging.2025.09.005","url":null,"abstract":"","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 179-180"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177068","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 : 2025-12-01Epub Date: 2025-08-26DOI: 10.1016/j.neurobiolaging.2025.08.005
Qingyu Zhao , Natalie M. Zahr
Normative, longitudinal data are necessary for effective modeling of factors underlying disease processes on the brain. Large scale national and international consortium data have characterized human regional brain volume trajectories as complex and prolonged gray and white matter maturation through the third decade of life followed by progressive senescence of cortical and then subcortical gray matter. By middle age (>40 years), white matter volume is also in decline. Although rodents are the mainstay of experimental gerontology, the few studies on brain volume trajectories are based on small samples. Here, 16 longitudinal neuroimaging experiments in Wistar rats were merged to describe regional brain volume growth from peripuberty (32 days, human equivalent ∼12 years) to late middle age (18.8 months, human equivalent ∼60 years). As female relative to male rodents are significantly smaller in weight, brain growth was expected to scale to smaller female size. In a total sample of 1009 male and female wildtype Wistar rats and male, alcohol-preferring P rats derived from the Wistar strain, regional brain volumes peaked at different ages: the cortex, for example, reached a vertex at 6.4 months, and the ventral hippocampus at 13.6 months, but thalamus had yet to plateau at 18.8 months. Age at which regional volumes peaked was differentially modulated by strain and sex. These data provide empirical evidence to recommend that preclinical experiments consider distinct patterns of regional brain volume growth and that studies on senescence, at least in Wistar rats, focus on animals older than 18 months.
{"title":"In vivo growth trajectories of regional brain volumes in the Wistar rat","authors":"Qingyu Zhao , Natalie M. Zahr","doi":"10.1016/j.neurobiolaging.2025.08.005","DOIUrl":"10.1016/j.neurobiolaging.2025.08.005","url":null,"abstract":"<div><div>Normative, longitudinal data are necessary for effective modeling of factors underlying disease processes on the brain. Large scale national and international consortium data have characterized human regional brain volume trajectories as complex and prolonged gray and white matter maturation through the third decade of life followed by progressive senescence of cortical and then subcortical gray matter. By middle age (>40 years), white matter volume is also in decline. Although rodents are the mainstay of experimental gerontology, the few studies on brain volume trajectories are based on small samples. Here, 16 longitudinal neuroimaging experiments in Wistar rats were merged to describe regional brain volume growth from peripuberty (32 days, human equivalent ∼12 years) to late middle age (18.8 months, human equivalent ∼60 years). As female relative to male rodents are significantly smaller in weight, brain growth was expected to scale to smaller female size. In a total sample of 1009 male and female wildtype Wistar rats and male, alcohol-preferring P rats derived from the Wistar strain, regional brain volumes peaked at different ages: the cortex, for example, reached a vertex at 6.4 months, and the ventral hippocampus at 13.6 months, but thalamus had yet to plateau at 18.8 months. Age at which regional volumes peaked was differentially modulated by strain and sex. These data provide empirical evidence to recommend that preclinical experiments consider distinct patterns of regional brain volume growth and that studies on senescence, at least in Wistar rats, focus on animals older than 18 months.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 101-110"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988198","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 : 2025-12-01Epub Date: 2025-09-17DOI: 10.1016/j.neurobiolaging.2025.09.006
Alifiya Kapasi , Maude Wagner , Arnold M. Evia , Debra A. Fleischman , Patricia Boyle , David Marquez , Lisa L. Barnes , David A. Bennett , Sue Leurgans , Julie Schneider , Melissa Lamar , Konstantinos Arfanakis
Brain arteriolosclerosis, a prominent small vessel pathology in the aging brain, is associated with cognitive impairment. Understanding the link between arteriolosclerosis and neurodegeneration may be crucial towards unravelling pathways by which arteriosclerosis contributes to cognitive impairment. Using a novel magnetic resonance imaging (MRI) in-vivo classifier for ARTerioloSclerosis termed ARTS, we examined cross-sectional associations between ARTS, cortical thickness, and cognition. Data came from 1054 older participants who were enrolled in one of five ongoing Rush Alzheimer’s Disease Center cohort studies, underwent an in-vivo 3 T MRI scan, met the data requirements for ARTS and FreeSurfer processing, and completed cognitive evaluation within a year of MRI. Focusing on the last, most recent MRI scan, we assessed cross-sectional associations of ARTS score with cortical thickness (whole brain and regional measures) and cognitive outcomes (global and domain-specific), using separate linear regression models. Further, we examined whether cortical thickness mediates the relationship between ARTS and global cognition. Models were all adjusted for demographics, vascular risk factors, and scanners. At last analytic MRI scan, participants were on average 80 years old (SD=7) and 80 % were women. Higher ARTS score was associated with lower whole brain cortical thickness (estimate per 1-SD increase=-0.029, 95 % CI: −0.036, −0.022), and across each of the lobes (all P < .01), particularly in temporal lobe regions. Higher ARTS scores were associated with worse global cognition (estimate per 1-SD increase=-0.079, 95 % CI: −0.122, −0.035); also, more specifically higher ARTS score was related to poorer performance in the domains of semantic memory, perceptual speed, and visuospatial ability. In mediation analyses, cortical thickness accounted for 32 % of the association between ARTS score and global cognition. More cerebral arteriolosclerosis-related changes, measured by in-vivo ARTS, is associated with lower cortical thickness and cognitive functions. The association between ARTS and cognition is partially mediated by cortical thickness. Findings suggest that cerebral small vessel disease may contribute to cortical thickness, a marker of neurodegeneration, and contribute both directly and indirectly, to cognitive impairment.
脑小动脉硬化是大脑衰老过程中出现的一种突出的小血管病变，与认知障碍有关。了解动脉硬化和神经退行性变之间的联系可能对揭示动脉硬化导致认知障碍的途径至关重要。使用一种新的被称为ARTS的小动脉硬化磁共振成像（MRI）体内分类器，我们研究了ARTS、皮质厚度和认知之间的横断面关联。数据来自1054名老年参与者，他们参加了拉什阿尔茨海默病中心正在进行的五项队列研究之一，接受了体内3 T MRI扫描，满足了ARTS和FreeSurfer处理的数据要求，并在MRI后一年内完成了认知评估。重点关注最近的MRI扫描，我们使用单独的线性回归模型评估了ARTS评分与皮质厚度（全脑和区域测量）和认知结果（全局和特定领域）的横断面关联。此外，我们研究了皮质厚度是否介导了ARTS与整体认知之间的关系。所有模型都根据人口统计学、血管危险因素和扫描仪进行了调整。在最后的分析性MRI扫描中，参与者的平均年龄为80岁（SD=7），其中80% %为女性。较高的ARTS评分与较低的全脑皮质厚度相关（每1-SD增加的估计值=-0.029,95 % CI: -0.036, -0.022），并且在每个脑叶(所有P
{"title":"Association of an in vivo classifier for ARTerioloSclerosis (ARTS) with cortical thickness and cognition in older adults","authors":"Alifiya Kapasi , Maude Wagner , Arnold M. Evia , Debra A. Fleischman , Patricia Boyle , David Marquez , Lisa L. Barnes , David A. Bennett , Sue Leurgans , Julie Schneider , Melissa Lamar , Konstantinos Arfanakis","doi":"10.1016/j.neurobiolaging.2025.09.006","DOIUrl":"10.1016/j.neurobiolaging.2025.09.006","url":null,"abstract":"<div><div>Brain arteriolosclerosis, a prominent small vessel pathology in the aging brain, is associated with cognitive impairment. Understanding the link between arteriolosclerosis and neurodegeneration may be crucial towards unravelling pathways by which arteriosclerosis contributes to cognitive impairment. Using a novel magnetic resonance imaging (MRI) in-vivo classifier for ARTerioloSclerosis termed ARTS, we examined cross-sectional associations between ARTS, cortical thickness, and cognition. Data came from 1054 older participants who were enrolled in one of five ongoing Rush Alzheimer’s Disease Center cohort studies, underwent an in-vivo 3 T MRI scan, met the data requirements for ARTS and FreeSurfer processing, and completed cognitive evaluation within a year of MRI. Focusing on the last, most recent MRI scan, we assessed cross-sectional associations of ARTS score with cortical thickness (whole brain and regional measures) and cognitive outcomes (global and domain-specific), using separate linear regression models. Further, we examined whether cortical thickness mediates the relationship between ARTS and global cognition. Models were all adjusted for demographics, vascular risk factors, and scanners. At last analytic MRI scan, participants were on average 80 years old (SD=7) and 80 % were women. Higher ARTS score was associated with lower whole brain cortical thickness (estimate per 1-SD increase=-0.029, 95 % CI: −0.036, −0.022), and across each of the lobes (all <em>P</em> < .01), particularly in temporal lobe regions. Higher ARTS scores were associated with worse global cognition (estimate per 1-SD increase=-0.079, 95 % CI: −0.122, −0.035); also, more specifically higher ARTS score was related to poorer performance in the domains of semantic memory, perceptual speed, and visuospatial ability. In mediation analyses, cortical thickness accounted for 32 % of the association between ARTS score and global cognition. More cerebral arteriolosclerosis-related changes, measured by in-vivo ARTS, is associated with lower cortical thickness and cognitive functions. The association between ARTS and cognition is partially mediated by cortical thickness. Findings suggest that cerebral small vessel disease may contribute to cortical thickness, a marker of neurodegeneration, and contribute both directly and indirectly, to cognitive impairment.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 143-149"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102944","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 : 2025-12-01Epub Date: 2025-08-13DOI: 10.1016/j.neurobiolaging.2025.08.002
Suril Gohel , Chi C. Chan , Isabelle Baptista , Philip R. Szeszko
The hippocampus has been widely implicated in the neurobiology of neurologic and psychiatric disorders. This structure is heterogeneous, however, and comprised of multiple subregions that have different connectivity patterns and functions. Better understanding how these subregions are affected by age and their relationship with neurocognition could provide information regarding how alterations in normal trajectories play a role in disease and cognitive dysfunction. Using natural splines we modeled the trajectory of 4 hippocampus subregions (i.e., CA composite, DG composite, tail and subiculum) derived from automated segmentation of magnetic resonance images using FreeSurfer in a cohort of 674 (440F/234M) healthy individuals ranging in age from 6 to 85 years. Following adjustment for covariates the best fitting model for all subregions was a spline with 2 degrees of freedom, which included one internal knot and two boundary knots. The peak age at which all subregions achieved maximum volume occurred in the fourth decade of life. Prior to the peak age there was no significant mediating effect of hippocampus subregion volume on the relationship between age and memory. Following the peak age, however, hippocampal subregions partially mediated the relationship between age and memory performance with the proportion mediated ranging from 11 % (subiculum) to 17 % (CA composite), but with no significant effects observed for the tail. These findings provide novel information regarding the trajectory of individual hippocampus subregion volumes across the age span and suggest they mediate the relationship between age and memory performance.
{"title":"Age-associated trajectories of hippocampus subregion volumes from childhood through later adulthood","authors":"Suril Gohel , Chi C. Chan , Isabelle Baptista , Philip R. Szeszko","doi":"10.1016/j.neurobiolaging.2025.08.002","DOIUrl":"10.1016/j.neurobiolaging.2025.08.002","url":null,"abstract":"<div><div>The hippocampus has been widely implicated in the neurobiology of neurologic and psychiatric disorders. This structure is heterogeneous, however, and comprised of multiple subregions that have different connectivity patterns and functions. Better understanding how these subregions are affected by age and their relationship with neurocognition could provide information regarding how alterations in normal trajectories play a role in disease and cognitive dysfunction. Using natural splines we modeled the trajectory of 4 hippocampus subregions (i.e., CA composite, DG composite, tail and subiculum) derived from automated segmentation of magnetic resonance images using FreeSurfer in a cohort of 674 (440F/234M) healthy individuals ranging in age from 6 to 85 years. Following adjustment for covariates the best fitting model for all subregions was a spline with 2 degrees of freedom, which included one internal knot and two boundary knots. The peak age at which all subregions achieved maximum volume occurred in the fourth decade of life. Prior to the peak age there was no significant mediating effect of hippocampus subregion volume on the relationship between age and memory. Following the peak age, however, hippocampal subregions partially mediated the relationship between age and memory performance with the proportion mediated ranging from 11 % (subiculum) to 17 % (CA composite), but with no significant effects observed for the tail. These findings provide novel information regarding the trajectory of individual hippocampus subregion volumes across the age span and suggest they mediate the relationship between age and memory performance.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 73-84"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890743","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 : 2025-12-01Epub Date: 2025-07-28DOI: 10.1016/j.neurobiolaging.2025.07.015
Kevin S. Heffernan , Derek C. Monroe , Andrew S. London , Jose Gutierrez , Adam M. Brickman , Ajay Kumar Nair , Nagesh Adluru , Stacey M. Schaefer
High pulse wave velocity (PWV), a measure of increased arterial stiffness, is a risk factor for cerebrovascular disease. PWV can be estimated (ePWV) from age and blood pressure (BP). Elevated ePWV is associated with cerebral small-vessel disease, cognitive decline, and dementia risk in middle-aged and older adults. We examined data from the Midlife in the United States (MIDUS) Neuroscience Project to examine the association of ePWV with brain white matter microstructure. BP was measured in 132 middle-aged adults (mean age 53+/- 10 years, n = 77 women, n = 38 Black/African American) between 2004 and 2009 and used to calculate ePWV. Diffusion-weighted imaging (DWI) data were acquired between 2017 and 2022 and used to estimate: global white matter fractional anisotropy; axial, radial, and mean diffusivity and kurtosis; neurite density index; and orientation dispersion index. High ePWV was associated with: lower fractional anisotropy; axial, radial, and mean kurtosis; and neurite density index. High ePWV was also associated with higher axial, radial, and mean diffusivity, and orientation dispersion index. Except for axial diffusivity/kurtosis and orientation dispersion, all associations between high ePWV and white matter microstructure remained after adjusting for exogenous controls (sex and race), education, the constituent components of ePWV (age and blood pressure), and the time lag between BP and DWI measures. In conclusion, high ePWV in middle-aged adults is prospectively associated with compromised brain white matter microstructure more than a decade later. ePWV may be a useful metric of vascular aging that can be applied to the study of brain aging.
{"title":"High estimated pulse-wave velocity is associated with lower brain white matter microstructural integrity twelve years later","authors":"Kevin S. Heffernan , Derek C. Monroe , Andrew S. London , Jose Gutierrez , Adam M. Brickman , Ajay Kumar Nair , Nagesh Adluru , Stacey M. Schaefer","doi":"10.1016/j.neurobiolaging.2025.07.015","DOIUrl":"10.1016/j.neurobiolaging.2025.07.015","url":null,"abstract":"<div><div>High pulse wave velocity (PWV), a measure of increased arterial stiffness, is a risk factor for cerebrovascular disease. PWV can be estimated (ePWV) from age and blood pressure (BP). Elevated ePWV is associated with cerebral small-vessel disease, cognitive decline, and dementia risk in middle-aged and older adults. We examined data from the Midlife in the United States (MIDUS) Neuroscience Project to examine the association of ePWV with brain white matter microstructure. BP was measured in 132 middle-aged adults (mean age 53+/- 10 years, n = 77 women, n = 38 Black/African American) between 2004 and 2009 and used to calculate ePWV. Diffusion-weighted imaging (DWI) data were acquired between 2017 and 2022 and used to estimate: global white matter fractional anisotropy; axial, radial, and mean diffusivity and kurtosis; neurite density index; and orientation dispersion index. High ePWV was associated with: lower fractional anisotropy; axial, radial, and mean kurtosis; and neurite density index. High ePWV was also associated with higher axial, radial, and mean diffusivity, and orientation dispersion index. Except for axial diffusivity/kurtosis and orientation dispersion, all associations between high ePWV and white matter microstructure remained after adjusting for exogenous controls (sex and race), education, the constituent components of ePWV (age and blood pressure), and the time lag between BP and DWI measures. In conclusion, high ePWV in middle-aged adults is prospectively associated with compromised brain white matter microstructure more than a decade later. ePWV may be a useful metric of vascular aging that can be applied to the study of brain aging.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 1-9"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757044","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 : 2025-12-01Epub Date: 2025-07-30DOI: 10.1016/j.neurobiolaging.2025.07.016
Lizhi Guo , Yajing Zhou , Hanna Lu , Helene H. Fung
This systematic review aims to investigate the moderating effects of cognitive reserve (CR) on the relationships between cognitive function and multimodal Alzheimer’s disease (AD)-signatured brain changes, measured by positron emission tomography (PET), structural magnetic resonance imaging (sMRI) and functional MRI (fMRI). Through a comprehensive search of PubMed, Scopus, and Web of Science, we identified 55 eligible studies examining the moderating effect of CR on the relationship between neuroimaging biomarkers and cognitive outcomes. CR measurements include sociobehavioral proxies (e.g., education, leisure activities), residual approaches, and functional imaging approaches. Findings were mixed. Of the fifty-five studies, 41 studies reported a protective effect of CR, suggesting its buffering effect against cognitive decline or AD progression during ageing. However, eleven studies reported no interaction between CR and neuroimaging biomarkers. Six studies suggested a detrimental effect of CR in the middle-to-late stages of the disease [e.g., mild cognitive impairment (MCI) and AD] (three studies reported both protective and detrimental effects). The discrepancies may reflect that the influence of CR on the association between neuroimaging biomarkers and cognitive function depends on disease stage. In early stages, it exhibits protective effects, but as pathology accumulates, it may accelerate cognitive decline. This review revealed CR has heterogeneous effects on AD progression. We preliminarily identified a “critical point” for CR within the continuum between cognitively unimpaired (CU) and MCI, although its precise pathological determinants require further clarification. Establishing standardized CR metrics and conducting longitudinal biomarker-integrated studies are critical to pinpoint optimal intervention windows for maximizing CR’s protective effects.
本系统综述旨在通过正电子发射断层扫描（PET）、结构磁共振成像（sMRI）和功能磁共振成像（fMRI）测量认知储备（CR）在认知功能与多模态阿尔茨海默病（AD）特征脑变化之间的关系中的调节作用。通过对PubMed、Scopus和Web of Science的全面搜索，我们确定了55项符合条件的研究，这些研究检验了CR对神经成像生物标志物和认知结果之间关系的调节作用。CR测量包括社会行为代理（如教育、休闲活动）、残差方法和功能成像方法。调查结果喜忧参半。在55项研究中，41项研究报告了CR的保护作用，表明其对衰老过程中认知能力下降或AD进展的缓冲作用。然而，11项研究报告CR与神经成像生物标志物之间没有相互作用。六项研究表明，CR在疾病的中晚期有不利影响[例如，轻度认知障碍（MCI）和AD]（三项研究报告了保护作用和有害作用）。这些差异可能反映了CR对神经成像生物标志物与认知功能相关性的影响取决于疾病分期。在早期阶段，它表现出保护作用，但随着病理积累，它可能会加速认知能力的下降。这篇综述揭示了CR对AD进展的异质性影响。我们初步确定了认知未受损（CU）和MCI之间连续体中CR的“临界点”，尽管其确切的病理决定因素需要进一步澄清。建立标准化的CR指标并进行纵向生物标志物整合研究对于确定最佳干预窗口以最大化CR保护作用至关重要。
{"title":"The moderating effect of cognitive reserve on the association between neuroimaging biomarkers and cognition: A systematic review","authors":"Lizhi Guo , Yajing Zhou , Hanna Lu , Helene H. Fung","doi":"10.1016/j.neurobiolaging.2025.07.016","DOIUrl":"10.1016/j.neurobiolaging.2025.07.016","url":null,"abstract":"<div><div>This systematic review aims to investigate the moderating effects of cognitive reserve (CR) on the relationships between cognitive function and multimodal Alzheimer’s disease (AD)-signatured brain changes, measured by positron emission tomography (PET), structural magnetic resonance imaging (sMRI) and functional MRI (fMRI). Through a comprehensive search of PubMed, Scopus, and Web of Science, we identified 55 eligible studies examining the moderating effect of CR on the relationship between neuroimaging biomarkers and cognitive outcomes. CR measurements include sociobehavioral proxies (e.g., education, leisure activities), residual approaches, and functional imaging approaches. Findings were mixed. Of the fifty-five studies, 41 studies reported a protective effect of CR, suggesting its buffering effect against cognitive decline or AD progression during ageing. However, eleven studies reported no interaction between CR and neuroimaging biomarkers. Six studies suggested a detrimental effect of CR in the middle-to-late stages of the disease [e.g., mild cognitive impairment (MCI) and AD] (three studies reported both protective and detrimental effects). The discrepancies may reflect that the influence of CR on the association between neuroimaging biomarkers and cognitive function depends on disease stage. In early stages, it exhibits protective effects, but as pathology accumulates, it may accelerate cognitive decline. This review revealed CR has heterogeneous effects on AD progression. We preliminarily identified a “critical point” for CR within the continuum between cognitively unimpaired (CU) and MCI, although its precise pathological determinants require further clarification. Establishing standardized CR metrics and conducting longitudinal biomarker-integrated studies are critical to pinpoint optimal intervention windows for maximizing CR’s protective effects.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 10-29"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771750","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 : 2025-12-01Epub Date: 2025-08-06DOI: 10.1016/j.neurobiolaging.2025.08.001
Nina Karalija , Vanessa Crine , Anders Wåhlin , Jarkko Johansson , Goran Papenberg , Micael Andersson , Katrine Riklund , Martin Lövdén , Ulman Lindenberger , Lars Bäckman , Lars Nyberg
Normal aging is associated with decline in dopamine function. Factors associated with individual differences in dopamine decline rates remain unclear but are important to map to spare dopamine-related functions, such as cognition. Here we focused on manifestations of cerebral small-vessel disease from magnetic resonance imaging (white-matter lesions, lacunes, and perivascular space dilation) and vascular risk factors (e.g., hypertension, body mass index (BMI), and hyperlipidemia). We assessed striatal dopamine D2-like receptor (DRD2) reductions across five years in healthy, older adults (n = 129, ages: 64–68 years at baseline) using 11C-raclopride/positron emission tomography. Manifestations of confluent lesions and lacunes at baseline had additive effects on DRD2 decline. Individuals with both manifestations showed fastest DRD2 decline rates (∼ −4 %), followed by those with one manifestation (∼ −2 %), whereas individuals spared of confluent lesions and lacunes showed stable DRD2 levels over time (∼ 0 % change). Furthermore, individuals with confluent lesions or lacunes showed more marked decline in perceptual speed performance, as compared to individuals spared of these manifestations (p < 0.05). Higher systolic blood pressure and lower BMI at baseline were associated with faster 5-year DRD2 decline in the putamen (r = -0.17, p < 0.05) and caudate (r = 0.23, p < 0.05), respectively. Together, confluent lesions and lacunes explained up to 8 % of striatal DRD2 change, and up to 10 % when adding hypertension and BMI to the model. These findings suggest that hallmarks of SVD and certain vascular risk factors predispose faster DRD2 decline in aging and may thus serve as factors to consider in future interventions.
{"title":"Cerebral small-vessel disease severity, hypertension, and body mass index forecast striatal dopamine D2-receptor decline rates in aging","authors":"Nina Karalija , Vanessa Crine , Anders Wåhlin , Jarkko Johansson , Goran Papenberg , Micael Andersson , Katrine Riklund , Martin Lövdén , Ulman Lindenberger , Lars Bäckman , Lars Nyberg","doi":"10.1016/j.neurobiolaging.2025.08.001","DOIUrl":"10.1016/j.neurobiolaging.2025.08.001","url":null,"abstract":"<div><div>Normal aging is associated with decline in dopamine function. Factors associated with individual differences in dopamine decline rates remain unclear but are important to map to spare dopamine-related functions, such as cognition. Here we focused on manifestations of cerebral small-vessel disease from magnetic resonance imaging (white-matter lesions, lacunes, and perivascular space dilation) and vascular risk factors (e.g., hypertension, body mass index (BMI), and hyperlipidemia). We assessed striatal dopamine D2-like receptor (DRD2) reductions across five years in healthy, older adults (n = 129, ages: 64–68 years at baseline) using <sup>11</sup>C-raclopride/positron emission tomography. Manifestations of confluent lesions and lacunes at baseline had additive effects on DRD2 decline. Individuals with both manifestations showed fastest DRD2 decline rates (∼ −4 %), followed by those with one manifestation (∼ −2 %), whereas individuals spared of confluent lesions and lacunes showed stable DRD2 levels over time (∼ 0 % change). Furthermore, individuals with confluent lesions or lacunes showed more marked decline in perceptual speed performance, as compared to individuals spared of these manifestations (<em>p</em> < 0.05). Higher systolic blood pressure and lower BMI at baseline were associated with faster 5-year DRD2 decline in the putamen (<em>r</em> = -0.17, <em>p</em> < 0.05) and caudate (<em>r</em> = 0.23, <em>p</em> < 0.05), respectively. Together, confluent lesions and lacunes explained up to 8 % of striatal DRD2 change, and up to 10 % when adding hypertension and BMI to the model. These findings suggest that hallmarks of SVD and certain vascular risk factors predispose faster DRD2 decline in aging and may thus serve as factors to consider in future interventions.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 30-39"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851791","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 : 2025-12-01Epub Date: 2025-07-30DOI: 10.1016/j.neurobiolaging.2025.07.017
Jordan D. Palms , Ji Hyun Lee , Emily P. Morris , Ketlyne Sol , Monica E. Walters , Kiana A. Scambray , Clarissa D. Morales , Mohamad J. Alshikho , Patrick J. Lao , Jennifer J. Manly , Adam M. Brickman , Laura B. Zahodne
Black older adults experience worse brain and cognitive aging than White older adults, on average. Racially patterned psychosocial stressors may contribute to these disparities. Maintaining white matter health is important for cognitive aging, particularly among Black older adults, and it is uniquely vulnerable to stress. Examining associations between racial discrimination and white matter may elucidate mechanisms of disparities. A sample of Black older adults in the Washington Heights-Inwood Columbia Aging project were included (N = 217). Everyday and major life discrimination were self-reported on well-validated scales. Diffusion tensor imaging quantified white matter fractional anisotropy (FA). Multivariable regressions revealed more major life discrimination was associated with lower FA in the cingulum cingulate gyrus, forceps major, forceps minor, and inferior fronto-occipital fasciculus but greater FA in the superior longitudinal fasciculus temporal projection. Everyday discrimination was not associated with FA. Findings suggest that institutional racism may have a stronger effect on white matter tracts corresponding to cognitive and emotional/affective processing than interpersonal racism. White matter health may be a mechanism through which racially patterned stressors contribute to disparities in brain and cognitive aging.
{"title":"The relationship between racial discrimination and white matter among Black older adults","authors":"Jordan D. Palms , Ji Hyun Lee , Emily P. Morris , Ketlyne Sol , Monica E. Walters , Kiana A. Scambray , Clarissa D. Morales , Mohamad J. Alshikho , Patrick J. Lao , Jennifer J. Manly , Adam M. Brickman , Laura B. Zahodne","doi":"10.1016/j.neurobiolaging.2025.07.017","DOIUrl":"10.1016/j.neurobiolaging.2025.07.017","url":null,"abstract":"<div><div>Black older adults experience worse brain and cognitive aging than White older adults, on average. Racially patterned psychosocial stressors may contribute to these disparities. Maintaining white matter health is important for cognitive aging, particularly among Black older adults, and it is uniquely vulnerable to stress. Examining associations between racial discrimination and white matter may elucidate mechanisms of disparities. A sample of Black older adults in the Washington Heights-Inwood Columbia Aging project were included (N = 217). Everyday and major life discrimination were self-reported on well-validated scales. Diffusion tensor imaging quantified white matter fractional anisotropy (FA). Multivariable regressions revealed more major life discrimination was associated with lower FA in the cingulum cingulate gyrus, forceps major, forceps minor, and inferior fronto-occipital fasciculus but greater FA in the superior longitudinal fasciculus temporal projection. Everyday discrimination was not associated with FA. Findings suggest that institutional racism may have a stronger effect on white matter tracts corresponding to cognitive and emotional/affective processing than interpersonal racism. White matter health may be a mechanism through which racially patterned stressors contribute to disparities in brain and cognitive aging.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 63-72"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144878303","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 : 2025-12-01Epub Date: 2025-09-17DOI: 10.1016/j.neurobiolaging.2025.09.004
Shuer Ye , Arjun Dave , Alireza Salami , Maryam Ziaei
Functional dedifferentiation, a hallmark of brain aging particularly evident within the frontoparietal network (FPN), has been extensively investigated in the context of cognitive decline, yet its implications for late-life mental health remain poorly understood. Leveraging naturalistic paradigm combined with gradient mapping techniques, the present study investigated FPN functional dedifferentiation—quantified by functional dispersion of FPN in the multidimensional gradient space—during real-life emotional experiences and its link to affective outcomes. Here, we estimated functional dispersion during naturalistic movie watching in both younger (N = 72, 34 female, 19–36 yrs) and older (N = 68, 36 female, 65–82 yrs) adult groups with 7 T MRI scanner and assessed their emotion regulation difficulties, anxiety, and depression symptoms as indicators of mental health status. The results demonstrated that greater FPN dispersion (i.e., more dissimilar connectivity) was linked to increased depressive symptoms in older adults and highlighted emotion regulation difficulties as a full mediator of this relationship. Moreover, FPN dispersion distinguished emotionally resilient from vulnerable older individuals. These findings suggest that functional dedifferentiation of the FPN during ecologically valid emotional context constitutes a promising neural signature of affective vulnerability in older adults. By bridging age-related functional dedifferentiation to real-world emotional scenario, this work underscores the translational value of naturalistic paradigms in geriatric psychiatry and identifies potential intervention targets aimed at enhancing FPN specificity to promote mental health in aging population.
功能性去分化是大脑衰老的一个标志，在额顶叶网络（FPN）中尤为明显，已经在认知能力下降的背景下进行了广泛的研究，但其对晚年心理健康的影响仍然知之甚少。本研究利用自然主义范式与梯度映射技术相结合，研究了FPN功能去分化（通过FPN在多维梯度空间中的功能分散来量化）在现实生活中的情感体验及其与情感结果的联系。在这里，我们用7台 T MRI扫描仪估计了年轻（N = 72,34名女性，19-36岁）和老年（N = 68,36名女性，65-82岁）成人组在观看自然主义电影时的功能离散度，并评估了他们的情绪调节困难、焦虑和抑郁症状作为心理健康状况的指标。结果表明，更大的FPN分散（即更多的不同连接）与老年人抑郁症状的增加有关，并强调情绪调节困难是这种关系的完全中介。此外，FPN离散度区分了情绪弹性和脆弱的老年人。这些发现表明，在生态有效的情绪环境中，FPN的功能性去分化构成了老年人情感脆弱性的一个有希望的神经特征。通过将年龄相关的功能去分化与现实世界的情绪情景联系起来，本研究强调了自然主义范式在老年精神病学中的转化价值，并确定了旨在增强FPN特异性以促进老年人心理健康的潜在干预目标。
{"title":"Frontoparietal functional dedifferentiation during naturalistic movie watching among older adults at risk of emotional vulnerability","authors":"Shuer Ye , Arjun Dave , Alireza Salami , Maryam Ziaei","doi":"10.1016/j.neurobiolaging.2025.09.004","DOIUrl":"10.1016/j.neurobiolaging.2025.09.004","url":null,"abstract":"<div><div>Functional dedifferentiation, a hallmark of brain aging particularly evident within the frontoparietal network (FPN), has been extensively investigated in the context of cognitive decline, yet its implications for late-life mental health remain poorly understood. Leveraging naturalistic paradigm combined with gradient mapping techniques, the present study investigated FPN functional dedifferentiation—quantified by functional dispersion of FPN in the multidimensional gradient space—during real-life emotional experiences and its link to affective outcomes. Here, we estimated functional dispersion during naturalistic movie watching in both younger (N = 72, 34 female, 19–36 yrs) and older (N = 68, 36 female, 65–82 yrs) adult groups with 7 T MRI scanner and assessed their emotion regulation difficulties, anxiety, and depression symptoms as indicators of mental health status. The results demonstrated that greater FPN dispersion (i.e., more dissimilar connectivity) was linked to increased depressive symptoms in older adults and highlighted emotion regulation difficulties as a full mediator of this relationship. Moreover, FPN dispersion distinguished emotionally resilient from vulnerable older individuals. These findings suggest that functional dedifferentiation of the FPN during ecologically valid emotional context constitutes a promising neural signature of affective vulnerability in older adults. By bridging age-related functional dedifferentiation to real-world emotional scenario, this work underscores the translational value of naturalistic paradigms in geriatric psychiatry and identifies potential intervention targets aimed at enhancing FPN specificity to promote mental health in aging population.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 150-162"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117743","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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