Pub Date : 2025-10-09DOI: 10.1016/j.neurobiolaging.2025.10.001
Fatemeh Amjadi-Moheb , Sumangali Gobhidharan , Adith Mohan , Perminder S. Sachdev , Anbupalam Thalamuthu , Karen A. Mather
Circular RNAs (circRNAs) are emerging as crucial regulators of biological processes and have been implicated in age-related diseases. Few studies have explored age-related circRNA expression in the human brain across the adult lifespan. This study aims to identify age-related differentially expressed circRNAs in human post-mortem dorsolateral prefrontal cortex (DLPFC) samples, a region critically involved in cognition that exhibits early signs of age-related changes. Total RNA sequencing was conducted on a discovery cohort of 67 post-mortem DLPFC samples, from individuals with no neurological disease diagnosis at the time of death (35–103 years). CircRNAs were identified using CIRCexplorer2, with 11,907 circRNAs available for analyses. Linear regression was used to analyse the relationships between circRNA expression and age at death. Replication of the results was performed in an independent neurologically healthy dataset from the CommonMind Consortium (n = 321, age at death: 35–91 years). Co-expression network analysis was performed to identify modules of highly co-expressed circRNAs associated with age. Potential microRNA and RNA-binding protein target sites were predicted. In the discovery dataset, 37 circRNAs were age-associated (FDR <0.05). Seven out of the 37 were successfully replicated. The host genes of replicated age-associated circRNAs are implicated in synapse regulation. Co-expression analysis revealed two circRNA modules significantly correlated with age. We identified 484 microRNA and 99 RNA-binding protein target sites on the replicated circRNAs. In conclusion, seven age-associated circRNAs were identified as important candidates for involvement in post-transcriptional regulatory networks in the DLPFC. Future studies should aim to elucidate their functional roles in brain ageing.
{"title":"Identification of circular RNAs associated with ageing of the dorsolateral prefrontal cortex across the adult lifespan","authors":"Fatemeh Amjadi-Moheb , Sumangali Gobhidharan , Adith Mohan , Perminder S. Sachdev , Anbupalam Thalamuthu , Karen A. Mather","doi":"10.1016/j.neurobiolaging.2025.10.001","DOIUrl":"10.1016/j.neurobiolaging.2025.10.001","url":null,"abstract":"<div><div>Circular RNAs (circRNAs) are emerging as crucial regulators of biological processes and have been implicated in age-related diseases. Few studies have explored age-related circRNA expression in the human brain across the adult lifespan. This study aims to identify age-related differentially expressed circRNAs in human post-mortem dorsolateral prefrontal cortex (DLPFC) samples, a region critically involved in cognition that exhibits early signs of age-related changes. Total RNA sequencing was conducted on a discovery cohort of 67 post-mortem DLPFC samples, from individuals with no neurological disease diagnosis at the time of death (35–103 years). CircRNAs were identified using CIRCexplorer2, with 11,907 circRNAs available for analyses. Linear regression was used to analyse the relationships between circRNA expression and age at death. Replication of the results was performed in an independent neurologically healthy dataset from the CommonMind Consortium (n = 321, age at death: 35–91 years). Co-expression network analysis was performed to identify modules of highly co-expressed circRNAs associated with age. Potential microRNA and RNA-binding protein target sites were predicted. In the discovery dataset, 37 circRNAs were age-associated (FDR <0.05). Seven out of the 37 were successfully replicated. The host genes of replicated age-associated circRNAs are implicated in synapse regulation. Co-expression analysis revealed two circRNA modules significantly correlated with age. We identified 484 microRNA and 99 RNA-binding protein target sites on the replicated circRNAs. In conclusion, seven age-associated circRNAs were identified as important candidates for involvement in post-transcriptional regulatory networks in the DLPFC. Future studies should aim to elucidate their functional roles in brain ageing.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"157 ","pages":"Pages 48-59"},"PeriodicalIF":3.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145269708","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 : 2025-10-01DOI: 10.1016/j.neurobiolaging.2025.09.010
Seyed Mostafa Hosseinpour Mashkani , David Bishop , Paul A. Adlard , S. Mojtaba Golzan
Zinc plays a critical role in memory, learning, and neuronal function, with dysregulation increasingly implicated in neurodegenerative diseases such as Alzheimer’s disease (AD). This study aimed to investigate whether changes in the expression of zinc transporter proteins, ZnT3 and ZIP3, in the retina mirror those in the brain, and to explore their potential as non-invasive biomarkers for early AD detection. Immunofluorescence and Western blotting were used to assess ZnT3 and ZIP3 expression in the retina and hippocampus of APP/PS1 and WT mice (9 and 18 months), as well as in human post-mortem tissues (9 AD and 6 control cases). To further investigate the regulatory role of ZnT3 in zinc homeostasis and its influence on tissue zinc concentrations, we quantified zinc levels in retinal and hippocampal tissues from WT and ZnT3 knockout mice using inductively coupled plasma-mass spectrometry (ICP-MS). ZnT3 and ZIP3 levels were significantly higher in the retina and hippocampus of healthy controls compared to AD cases across both mouse and human samples. ICP-MS analysis confirmed significantly lower zinc concentrations in ZnT3 knockout mice compared to WT controls in both the These findings demonstrate that retinal ZnT3 and ZIP3 expression changes mirror those observed in the hippocampus during AD progression. This suggests their potential as retinal biomarkers for Alzheimer's disease. Notably, ZnT3 shows strong promise for early, non-invasive detection of AD. Further validation in larger cohorts is warranted.
{"title":"Zinc transporter proteins in the retina as potential biomarkers for staging early Alzheimer’s disease: Comparative analysis in human and mouse models","authors":"Seyed Mostafa Hosseinpour Mashkani , David Bishop , Paul A. Adlard , S. Mojtaba Golzan","doi":"10.1016/j.neurobiolaging.2025.09.010","DOIUrl":"10.1016/j.neurobiolaging.2025.09.010","url":null,"abstract":"<div><div>Zinc plays a critical role in memory, learning, and neuronal function, with dysregulation increasingly implicated in neurodegenerative diseases such as Alzheimer’s disease (AD). This study aimed to investigate whether changes in the expression of zinc transporter proteins, ZnT3 and ZIP3, in the retina mirror those in the brain, and to explore their potential as non-invasive biomarkers for early AD detection. Immunofluorescence and Western blotting were used to assess ZnT3 and ZIP3 expression in the retina and hippocampus of APP/PS1 and WT mice (9 and 18 months), as well as in human post-mortem tissues (9 AD and 6 control cases). To further investigate the regulatory role of ZnT3 in zinc homeostasis and its influence on tissue zinc concentrations, we quantified zinc levels in retinal and hippocampal tissues from WT and ZnT3 knockout mice using inductively coupled plasma-mass spectrometry (ICP-MS). ZnT3 and ZIP3 levels were significantly higher in the retina and hippocampus of healthy controls compared to AD cases across both mouse and human samples. ICP-MS analysis confirmed significantly lower zinc concentrations in ZnT3 knockout mice compared to WT controls in both the These findings demonstrate that retinal ZnT3 and ZIP3 expression changes mirror those observed in the hippocampus during AD progression. This suggests their potential as retinal biomarkers for Alzheimer's disease. Notably, ZnT3 shows strong promise for early, non-invasive detection of AD. Further validation in larger cohorts is warranted.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"157 ","pages":"Pages 26-35"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145222924","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 : 2025-09-26DOI: 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":"2025-09-26","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 : 2025-09-25DOI: 10.1016/j.neurobiolaging.2025.09.009
Kelsey E. McDermott , Laurel Dieckhaus , Courtney Comrie , Victor Sandrin , Elizabeth B. Hutchinson , Carol A. Barnes
The locus coeruleus (LC) is a brainstem nucleus best known for being the primary site of noradrenaline production for the forebrain and is involved in the modulation and optimization of behavioral performance. The LC has many targets throughout the cortex, and ascending projections from the LC join the central tegmental tract (CTT), a well-defined white matter brainstem tract in the pons that terminates in the thalamus. Evidence indicates that the LC is one of the first brain regions to show pathological burden in Alzheimer’s disease (AD), and AD patients exhibit structural alterations in the LC and its ascending projections. The extent to which changes occur in the LC and its projections in normal aging, however, is less clear. Analysis of LC-forebrain tractography has historically been difficult due to the small size of the LC as well as the abundance of crossing fibers in the brainstem. Ex vivo magnetic resonance imaging (MRI) allows us to overcome some of these setbacks, as longer scan times can be used to generate higher resolution images than is possible in live subjects. Here, we utilize a cohort of bonnet macaques, an excellent model of normative aging, and analyze the microstructure of the LC and its projections that join the CTT with respect to age. We have been able to overcome issues associated with LC tractography and have found a negative association with age and diffusivity.
{"title":"Microstructural changes in locus coeruleus-cortical projections in aged bonnet macaques are independent of myelin loss","authors":"Kelsey E. McDermott , Laurel Dieckhaus , Courtney Comrie , Victor Sandrin , Elizabeth B. Hutchinson , Carol A. Barnes","doi":"10.1016/j.neurobiolaging.2025.09.009","DOIUrl":"10.1016/j.neurobiolaging.2025.09.009","url":null,"abstract":"<div><div>The locus coeruleus (LC) is a brainstem nucleus best known for being the primary site of noradrenaline production for the forebrain and is involved in the modulation and optimization of behavioral performance. The LC has many targets throughout the cortex, and ascending projections from the LC join the central tegmental tract (CTT), a well-defined white matter brainstem tract in the pons that terminates in the thalamus. Evidence indicates that the LC is one of the first brain regions to show pathological burden in Alzheimer’s disease (AD), and AD patients exhibit structural alterations in the LC and its ascending projections. The extent to which changes occur in the LC and its projections in normal aging, however, is less clear. Analysis of LC-forebrain tractography has historically been difficult due to the small size of the LC as well as the abundance of crossing fibers in the brainstem. <em>Ex vivo</em> magnetic resonance imaging (MRI) allows us to overcome some of these setbacks, as longer scan times can be used to generate higher resolution images than is possible in live subjects. Here, we utilize a cohort of bonnet macaques, an excellent model of normative aging, and analyze the microstructure of the LC and its projections that join the CTT with respect to age. We have been able to overcome issues associated with LC tractography and have found a negative association with age and diffusivity.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"157 ","pages":"Pages 17-25"},"PeriodicalIF":3.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207073","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 : 2025-09-20DOI: 10.1016/j.neurobiolaging.2025.09.008
Dakota Z. Smallridge , Kylee Tenney , Gillian L. Barach , Gurveer Singh , Erin N. Beskitt , Justine Busby , Syllissa Duncan , Alexa Wawrzyniak , Brenda Vega , Nick J. Tokar , Andrew P. Ohl , Jesse W. Young , Jeffrey G. Mellott
The inferior colliculus (IC) is a nucleus in the auditory midbrain that plays an important role in sound and speech processing through how it encodes temporal precision. Temporal precision depends on the balance of inhibition and excitation within the IC. This balance degrades during aging. Age-related changes in synapses have been described in the lemniscal IC as a contributing factor for this imbalance. However, it is unknown if aging affects synapses throughout the non-lemniscal IC in a similar manner. We sought to determine this by examining the dorsal cortex of the IC (ICd). The ICd is a non-lemniscal nucleus that is well known for its extensive innervation by the auditory cortex. Electron microscopy techniques were used across age groups of younger age (2–3 months), middle age (19–21 months) and older age (27–29 months) Fischer Brown Norway rats. Our data demonstrates a small loss of GABAergic synaptic density in middle age, with a significant (34 %) loss during older age. Unlike previous reports of the aging ultrastructure of the IC, asymmetric synaptic density in the ICd remained unchanged. We also demonstrate decreases with age in terminal area and mitochondrial ultrastructure across both synaptic types. Lastly, far fewer asymmetric inputs were observed onto larger GABAergic dendrites. Collectively our data suggest a net loss of inhibition in the ICd. Thus, the balance of excitation and inhibition in the ICd is likely altered and may contribute to factors underlying age-related hearing loss.
下丘(IC)是听觉中脑中的一个核,通过编码时间精度在声音和言语处理中起重要作用。时间精度取决于IC内抑制和激发的平衡。这种平衡随着老化而退化。年龄相关的突触变化已被描述为这种不平衡的一个促成因素。然而,尚不清楚衰老是否以类似的方式影响整个非锁骨IC的突触。我们试图通过检查IC (ICd)的背侧皮质来确定这一点。ICd是一种非锁骨核,因其广泛受听觉皮层的神经支配而闻名。采用电镜技术对年龄较小(2-3个月)、中年(19-21个月)和老年(27-29个月)的Fischer Brown Norway大鼠进行观察。我们的数据显示,gaba能突触密度在中年时有少量的损失,在老年时有显著的损失(34% %)。与以往报道的IC老化超微结构不同,ICd中的不对称突触密度保持不变。我们还发现,两种突触类型的终端区和线粒体超微结构随着年龄的增长而减少。最后,在较大的gaba能树突上观察到的不对称输入要少得多。总的来说,我们的数据表明ICd中抑制作用的净损失。因此,ICd中兴奋和抑制的平衡可能被改变,并可能导致与年龄相关的听力损失。
{"title":"Age-related ultrastructural differences in the dorsal cortex of the inferior colliculus in the fischer brown Norway rat","authors":"Dakota Z. Smallridge , Kylee Tenney , Gillian L. Barach , Gurveer Singh , Erin N. Beskitt , Justine Busby , Syllissa Duncan , Alexa Wawrzyniak , Brenda Vega , Nick J. Tokar , Andrew P. Ohl , Jesse W. Young , Jeffrey G. Mellott","doi":"10.1016/j.neurobiolaging.2025.09.008","DOIUrl":"10.1016/j.neurobiolaging.2025.09.008","url":null,"abstract":"<div><div>The inferior colliculus (IC) is a nucleus in the auditory midbrain that plays an important role in sound and speech processing through how it encodes temporal precision. Temporal precision depends on the balance of inhibition and excitation within the IC. This balance degrades during aging. Age-related changes in synapses have been described in the lemniscal IC as a contributing factor for this imbalance. However, it is unknown if aging affects synapses throughout the non-lemniscal IC in a similar manner. We sought to determine this by examining the dorsal cortex of the IC (ICd). The ICd is a non-lemniscal nucleus that is well known for its extensive innervation by the auditory cortex. Electron microscopy techniques were used across age groups of younger age (2–3 months), middle age (19–21 months) and older age (27–29 months) Fischer Brown Norway rats. Our data demonstrates a small loss of GABAergic synaptic density in middle age, with a significant (34 %) loss during older age. Unlike previous reports of the aging ultrastructure of the IC, asymmetric synaptic density in the ICd remained unchanged. We also demonstrate decreases with age in terminal area and mitochondrial ultrastructure across both synaptic types. Lastly, far fewer asymmetric inputs were observed onto larger GABAergic dendrites. Collectively our data suggest a net loss of inhibition in the ICd. Thus, the balance of excitation and inhibition in the ICd is likely altered and may contribute to factors underlying age-related hearing loss.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"157 ","pages":"Pages 1-16"},"PeriodicalIF":3.5,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145128264","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 : 2025-09-18DOI: 10.1016/j.neurobiolaging.2025.09.007
Taylan D. Kuzu , Elena Brinkmann , Anna K. Bonkhoff , Veronika Wunderle , Gérard N. Bischof , Kathrin Giehl , Maximilian H.T. Schmieschek , Oezguer A. Onur , Frank Jessen , Gereon R. Fink , Alexander Drzezga , Peter H. Weiss
Apraxia is a common symptom in Alzheimer’s disease (AD) that reduces autonomy and quality of life. However, the neural basis underlying apraxia in AD, for example, reflected by functional connectivity (FC) alterations, remains unexplored. We investigated static and dynamic FC using resting-state functional imaging in 14 patients with biomarker-confirmed AD pathology and 14 matched healthy participants. FC was estimated as average (static) and short-term (dynamic) connectivity strengths between motor- and praxis-related functional networks. Recurring connectivity patterns were clustered into dynamic states to compute temporal connectivity measures. Connectivity measures were used for correlations with apraxic deficits. In AD patients, static connectivity between visual and inferior parietal networks correlated with apraxic imitation (r = 0.762, PFDR = 0.043) and arm/hand gesture deficits (r = 0.848, PFDR = 0.020), while dynamic connectivity between these networks correlated with apraxic imitation deficits (r = 0.851, PFDR = 0.020). Dynamic FC analysis revealed a segregated and integrated state. AD patients spent more time overall (fraction time, PFDR < 0.001) and remained longer without switching (dwell time, PFDR = 0.004) in the segregated state. Both fraction (ρ = –0.858, PFDR = 0.015) and dwell time (ρ = –0.914, PFDR = 0.003) correlated with apraxic imitation deficits. Connectivity strengths between visual and inferior parietal networks and fraction time in the segregated state predicted apraxic imitation deficits (adjusted R2 = 0.782, P < 0.001). We conclude that apraxia in AD patients is associated with altered FC in praxis-related networks, suggesting FC as a potential clinical indicator for predicting motor-cognitive deficits.
{"title":"Apraxic deficits in Alzheimer’s disease are associated with altered dynamic connectivity in praxis-related networks","authors":"Taylan D. Kuzu , Elena Brinkmann , Anna K. Bonkhoff , Veronika Wunderle , Gérard N. Bischof , Kathrin Giehl , Maximilian H.T. Schmieschek , Oezguer A. Onur , Frank Jessen , Gereon R. Fink , Alexander Drzezga , Peter H. Weiss","doi":"10.1016/j.neurobiolaging.2025.09.007","DOIUrl":"10.1016/j.neurobiolaging.2025.09.007","url":null,"abstract":"<div><div>Apraxia is a common symptom in Alzheimer’s disease (AD) that reduces autonomy and quality of life. However, the neural basis underlying apraxia in AD, for example, reflected by functional connectivity (FC) alterations, remains unexplored. We investigated static and dynamic FC using resting-state functional imaging in 14 patients with biomarker-confirmed AD pathology and 14 matched healthy participants. FC was estimated as average (static) and short-term (dynamic) connectivity strengths between motor- and praxis-related functional networks. Recurring connectivity patterns were clustered into dynamic states to compute temporal connectivity measures. Connectivity measures were used for correlations with apraxic deficits. In AD patients, static connectivity between visual and inferior parietal networks correlated with apraxic imitation (<em>r</em> = 0.762, <em>P</em><sub><em>FDR</em></sub> = 0.043) and arm/hand gesture deficits (<em>r</em> = 0.848, <em>P</em><sub><em>FDR</em></sub> = 0.020), while dynamic connectivity between these networks correlated with apraxic imitation deficits (<em>r</em> = 0.851, <em>P</em><sub><em>FDR</em></sub> = 0.020). Dynamic FC analysis revealed a segregated and integrated state. AD patients spent more time overall (fraction time, <em>P</em><sub><em>FDR</em></sub> < 0.001) and remained longer without switching (dwell time, <em>P</em><sub><em>FDR</em></sub> = 0.004) in the segregated state. Both fraction (<em>ρ</em> = –0.858, <em>P</em><sub><em>FDR</em></sub> = 0.015) and dwell time (<em>ρ</em> = –0.914, <em>P</em><sub><em>FDR</em></sub> = 0.003) correlated with apraxic imitation deficits. Connectivity strengths between visual and inferior parietal networks and fraction time in the segregated state predicted apraxic imitation deficits (adjusted <em>R</em><sup><em>2</em></sup> = 0.782, <em>P</em> < 0.001). We conclude that apraxia in AD patients is associated with altered FC in praxis-related networks, suggesting FC as a potential clinical indicator for predicting motor-cognitive deficits.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"157 ","pages":"Pages 36-47"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252256","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 : 2025-09-17DOI: 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":"2025-09-17","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 : 2025-09-17DOI: 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":"2025-09-17","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}
Pub Date : 2025-09-16DOI: 10.1016/j.neurobiolaging.2025.09.003
Sabina Srokova , Nehal S. Shahanawaz , Michael D. Rugg
Age-related neural dedifferentiation, characterized by lower selectivity of neural responses in high-level sensory cortex, is thought to be a major contributor to age-related cognitive decline. However, the mechanisms that underlie dedifferentiation are poorly understood. Building on prior evidence that exploratory eye movements differ with age, we investigated the role that eye movement might play in age-related declines in neural selectivity. Healthy young and older adults underwent fMRI with simultaneous eye-tracking as they viewed words paired with images of scenes and objects prior to a memory test. Consistent with numerous prior reports, multivoxel pattern similarity analysis (PSA) of the fMRI data revealed age-related neural dedifferentiation in scene-selective, but not object-selective cortex. Eye movements, operationalized as the number of gaze fixations made during stimulus viewing, were elevated in older adults. Analyses examining the relationship between trial-wise estimates of neural selectivity and fixation count revealed an age-invariant positive relationship in the object-selective lateral occipital complex. However, this association was age-dependent in scene-selective cortex, such that there was a robust positive relationship between scene selectivity and fixation count in young adults, but absent or attenuated effects were present in older adults. Lastly, scene-related selectivity in the parahippocampal place area predicted subsequent memory performance independently of age group and fixation counts at encoding. These findings suggest that age-related neural dedifferentiation in scene-selective cortex could be related to declines in the functional specificity of exploratory eye movements during scene viewing.
{"title":"The relationship between category-level neural differentiation and exploratory eye movements in healthy young and older adults","authors":"Sabina Srokova , Nehal S. Shahanawaz , Michael D. Rugg","doi":"10.1016/j.neurobiolaging.2025.09.003","DOIUrl":"10.1016/j.neurobiolaging.2025.09.003","url":null,"abstract":"<div><div>Age-related neural dedifferentiation, characterized by lower selectivity of neural responses in high-level sensory cortex, is thought to be a major contributor to age-related cognitive decline. However, the mechanisms that underlie dedifferentiation are poorly understood. Building on prior evidence that exploratory eye movements differ with age, we investigated the role that eye movement might play in age-related declines in neural selectivity. Healthy young and older adults underwent fMRI with simultaneous eye-tracking as they viewed words paired with images of scenes and objects prior to a memory test. Consistent with numerous prior reports, multivoxel pattern similarity analysis (PSA) of the fMRI data revealed age-related neural dedifferentiation in scene-selective, but not object-selective cortex. Eye movements, operationalized as the number of gaze fixations made during stimulus viewing, were elevated in older adults. Analyses examining the relationship between trial-wise estimates of neural selectivity and fixation count revealed an age-invariant positive relationship in the object-selective lateral occipital complex. However, this association was age-dependent in scene-selective cortex, such that there was a robust positive relationship between scene selectivity and fixation count in young adults, but absent or attenuated effects were present in older adults. Lastly, scene-related selectivity in the parahippocampal place area predicted subsequent memory performance independently of age group and fixation counts at encoding. These findings suggest that age-related neural dedifferentiation in scene-selective cortex could be related to declines in the functional specificity of exploratory eye movements during scene viewing.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 163-177"},"PeriodicalIF":3.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117741","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 : 2025-09-10DOI: 10.1016/j.neurobiolaging.2025.08.007
Lizhi Guo , Yajing Zhou , Hanna Lu , Helene H. Fung
{"title":"Corrigendum to “The moderating effect of cognitive reserve on the association between neuroimaging biomarkers and cognition: A systematic review” [Neurobiology of Aging, Volume 156, December 2025, Pages 10–29]","authors":"Lizhi Guo , Yajing Zhou , Hanna Lu , Helene H. Fung","doi":"10.1016/j.neurobiolaging.2025.08.007","DOIUrl":"10.1016/j.neurobiolaging.2025.08.007","url":null,"abstract":"","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Page 178"},"PeriodicalIF":3.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033895","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}