Neurobiology of Aging最新文献

{"title":"Processivity and BDNF-dependent modulation of signalling endosome axonal transport are impaired in mice with advanced age","authors":"David Villarroel-Campos ,&nbsp;Elena R. Rhymes ,&nbsp;Andrew P. Tosolini ,&nbsp;Bilal Malik ,&nbsp;Alessio Vagnoni ,&nbsp;Giampietro Schiavo ,&nbsp;James N. Sleigh","doi":"10.1016/j.neurobiolaging.2025.05.002","DOIUrl":"10.1016/j.neurobiolaging.2025.05.002","url":null,"abstract":"<div><div>A healthy nervous system is reliant upon an efficient transport network to deliver essential cargoes throughout the extensive and polarised architecture of neurons. The trafficking of cargoes, such as organelles and proteins, is particularly challenging within the long projections of neurons, which, in the case of axons, can be more than four orders of magnitude longer than cell bodies. It is therefore unsurprising that disruptions in axonal transport have been reported across neurological diseases. A decline in this essential process has also been identified in many aging models, perhaps compounding age-related neurodegeneration. Via intravital imaging, we recently determined that, despite a reduction in overall motility, the run speed and displacement of anterograde mitochondrial transport were unexpectedly enhanced in 19–22 month-old mouse peripheral nerves. Here, to determine how aging impacts a different axonal cargo, we evaluated <em>in vivo</em> trafficking of signalling endosomes in motor axons of mouse sciatic nerves from 3 to 22 months. Contrasting with mitochondria, we did not detect alterations in signalling endosome speed, but found a consistent rise in pausing that manifested after 18 months. We then treated muscles with brain-derived neurotrophic factor (BDNF), which regulates axonal transport of signalling endosomes in motor neurons; however, we observed no change in the processivity defect at 22 months, consistent with downregulation of the BDNF receptor TrkB at the neuromuscular junction. Together, these findings indicate that aging negatively impacts signalling endosome trafficking in motor axons, likely through dampened BDNF signalling at the motor neuron-muscle interface.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"153 ","pages":"Pages 1-9"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178635","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}

{"title":"Editorial Advisory Board","authors":"","doi":"10.1016/S0197-4580(25)00108-3","DOIUrl":"10.1016/S0197-4580(25)00108-3","url":null,"abstract":"","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"153 ","pages":"Page IFC"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518483","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}

{"title":"Lower locus coeruleus integrity is associated with diminished practice effects in clinically unimpaired older individuals","authors":"Lindsay F. Smegal ,&nbsp;Marion Baillet ,&nbsp;Christoph Schneider ,&nbsp;Roos J. Jutten ,&nbsp;Rory Boyle ,&nbsp;Dorene M. Rentz ,&nbsp;Keith A. Johnson ,&nbsp;Reisa A. Sperling ,&nbsp;Kathryn V. Papp ,&nbsp;Heidi I.L. Jacobs","doi":"10.1016/j.neurobiolaging.2025.03.015","DOIUrl":"10.1016/j.neurobiolaging.2025.03.015","url":null,"abstract":"<div><div>The locus coeruleus (LC), one of the earliest structures affected by tau pathology in Alzheimer’s disease (AD), plays an important role in modulating arousal and learning. In asymptomatic early stages of AD, more sensitive measures to identify subtle cognitive changes are needed. Previous studies indicate that practice effects can signal initial AD-related learning deficits. Here, we assessed the association between LC integrity and practice effects. We combined dedicated LC-MRI methods with at-home computerized face-name letter task (FNLT), a Mnemonic Similarity Task (MST), and a one card learning task (OCL) performed monthly over one year in 76 older participants from the Harvard Aging Brain Study. Higher LC integrity was related to lower MST reaction times at baseline, and lower MST and FNLT reaction times over one year. No significant associations were found with the OCL. Participants with low accuracy practice effect trajectories exhibited low baseline PACC-5 scores, whereas those with higher reaction times over time displayed low LC integrity, high entorhinal, and high amygdala tau at baseline. These findings suggest reaction times measured monthly may be a sensitive measure for early AD-related biomarkers such as LC integrity and tau burden in preclinical AD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Pages 13-24"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890987","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}

{"title":"Editorial Advisory Board","authors":"","doi":"10.1016/S0197-4580(25)00090-9","DOIUrl":"10.1016/S0197-4580(25)00090-9","url":null,"abstract":"","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Page IFC"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144195214","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}

{"title":"Modifiable risk factor profiles moderate the effect of β-amyloid pathology on cognition in aging","authors":"Mohini Bhade ,&nbsp;Stefania Pezzoli ,&nbsp;Joseph Giorgio ,&nbsp;Tyler J. Ward ,&nbsp;Joseph R. Winer ,&nbsp;Theresa M. Harrison ,&nbsp;Susan M. Landau ,&nbsp;William J. Jagust","doi":"10.1016/j.neurobiolaging.2025.05.001","DOIUrl":"10.1016/j.neurobiolaging.2025.05.001","url":null,"abstract":"<div><div>Although modifiable risk factors may account for around 40 % of population variability in dementia risk, the effect of risk factor interrelationships on pathology-cognition relationships is poorly understood. Using risk factor data from a cohort of 203 cognitively normal older adults (73 ± 6.4 years, 56 % female), we used k-means clustering to assign participants to one of three risk-related profiles; namely, positive-active (physical/cognitive activity, education), positive-affective (sleep, depression, personality), and negative multi-domain clusters. Linear mixed-effects models showed an attenuated effect of β-amyloid on non-memory cognition decline in positive profiles (positive-active: β=3.7, p = 0.008, positive-affective: β=3.7, p = 0.007) compared to the negative profile. While a significant entorhinal tau x time effect (p &lt; 0.001) was observed in a model predicting episodic memory decline, cluster membership did not modify this relationship. These findings suggest that different risk profiles moderate pathology-cognition relationships, and highlight the role of groups of modifiable resilience factors in mitigating the effects of β-amyloid deposition.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Pages 54-63"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147192","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}

{"title":"Longitudinal relationships among cerebrospinal fluid biomarkers, cerebral blood flow, and grey matter volume in individuals with a familial history of Alzheimer's disease","authors":"Safa Sanami ,&nbsp;Brittany Intzandt ,&nbsp;Julia Huck ,&nbsp;Sylvia Villeneuve ,&nbsp;Yasser Iturria-Medina ,&nbsp;Claudine J. Gauthier ,&nbsp;Prevent-AD research group","doi":"10.1016/j.neurobiolaging.2025.04.011","DOIUrl":"10.1016/j.neurobiolaging.2025.04.011","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a complex disease that involves complex interactions between protein biomarkers such as amyloid beta (Aβ) and tau, neurodegeneration, cerebrovascular health and inflammation. However, how these factors interact, especially in the early phases of disease development remain unclear. To address this, this study analyzed four-year longitudinal data from 110 cognitively unimpaired older adults with a family history of AD in the PreventAD cohort. We investigated relationships between CSF Aβ, 181-phosphorylated tau (p-tau), interleukin-8 (IL-8), cerebral blood flow (CBF), and grey matter volume (GMV) in groups with high and low cardiovascular risk levels. Longitudinally, lower CSF Aβ within participants (a proxy for higher brain amyloid) was linked to a slower decline in regional CBF, particularly in those with higher cardiovascular risk. Similarly, in the high vascular risk group, higher IL-8 at baseline was associated with greater decline in CBF in the right superior temporal gyrus. Further, lower baseline CBF was associated with greater CSF p-tau accumulation over time. Finally, higher baseline CSF p-tau was associated with faster GM atrophy over 4 years, particularly in the hippocampus. Our results highlight the complex interactions between CSF misfolded proteins, inflammatory markers, and brain regional CBF and atrophy, and how these effects are more pronounced in individuals with higher vascular risk factor load. These findings demonstrate the need for comprehensive models of AD pathophysiology that integrate vascular health and inflammation measures alongside traditional biomarkers.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Pages 43-53"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929153","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}

{"title":"Presenilin 1 hemizygosity has no overt deleterious phenotypic outcomes in sheep: Potential implications for therapeutic targets in Alzheimer's disease","authors":"Natasha E. Mckean ,&nbsp;Jun Liu ,&nbsp;Skye R. Rudiger ,&nbsp;Jennifer M. Kelly ,&nbsp;Clive McLaughlan ,&nbsp;Paul J. Verma ,&nbsp;John Hardy ,&nbsp;James F. Gusella ,&nbsp;Henrik Zetterberg ,&nbsp;Suzanne J. Reid ,&nbsp;Renee H. Handley ,&nbsp;Klaus Lehnert ,&nbsp;Greg T. Sutherland ,&nbsp;Amanda Heslegrave ,&nbsp;Elena Veleva ,&nbsp;Rhiannon Laban ,&nbsp;John F. Pearson ,&nbsp;Simon C. Bawden ,&nbsp;Russell G. Snell","doi":"10.1016/j.neurobiolaging.2025.04.006","DOIUrl":"10.1016/j.neurobiolaging.2025.04.006","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a neurodegenerative condition and one of the most significant medical challenges today. Dominant mutations causing early-onset AD have been identified in the presenilin 1 and 2 (<em>PSEN1</em> and <em>PSEN2</em>), and the amyloid precursor protein (<em>APP</em>) genes. Either PSEN1 or PSEN2 is required by γ-secretase, a functional complex that cleaves APP to produce amyloid-beta (Aβ) peptides of varying lengths. These mutations result in relative or absolute increases in the longer Aβ peptides (Aβ_1–40, Aβ _1–42), which accumulate as plaques, characteristic of both early and late-onset AD. To investigate the effects of modulating PSEN1 expression, we have produced <em>PSEN1</em> hemizygous sheep. Sheep <em>PSEN</em> and <em>APP</em> genes are highly conserved relative to humans, including the APP proteolytic cleavage sites, and like humans, sheep naturally develop plaques and TAU tangles with age. At five years of age, the <em>PSEN1</em> hemizygous animals are phenotypically and biochemically normal. Interestingly, the characteristic Aβ peptide levels in their cerebrospinal fluid and plasma remain at wildtype levels, indicating that a 50 % reduction in PSEN1 abundance does not materially affect γ-secretase’s APP cleavage activity. These results suggest that generalized regulation of <em>PSEN1</em> expression is unlikely to be an effective therapeutic approach for AD on its own. However, it does suggest that loss of one <em>PSEN1</em> allele may be tolerated in higher organisms, with no deleterious side-effects. It is therefore possible that knocking-out or knocking-down one copy of <em>PSEN1</em> via genetic modification will be tolerated in humans, especially as functional hemizygous humans are present in the population (gnomad). These kinds of therapies could potentially prevent AD caused by dominant gain-of-function mutations in <em>PSEN1</em>.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Pages 25-33"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896019","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}

{"title":"Influence of sleep and cardiovascular health on cognitive trajectories in older adults","authors":"Hannah R. Maybrier ,&nbsp;Joshua J. Jackson ,&nbsp;Cristina D. Toedebusch ,&nbsp;Brendan P. Lucey ,&nbsp;Denise Head","doi":"10.1016/j.neurobiolaging.2025.04.008","DOIUrl":"10.1016/j.neurobiolaging.2025.04.008","url":null,"abstract":"<div><div>Age-related changes in sleep have been associated with cognitive decline, yet causal pathways have not been identified. Evidence suggests reduced cardiovascular health may be a consequence of poor sleep and a precursor to cognitive decline. This observational cohort study used path analyses to determine whether cardiovascular disease risk mediated or moderated effects of sleep on yearly longitudinal change in cognition, estimated with linear growth models. Total sleep time (TST), sleep efficiency (SE), and relative spectral power of slow wave activity (SWA; 1–4 Hz) and slow oscillations (SO; 0.5–1 Hz), were measured with single-channel home EEG. Cardiovascular disease risk (CVR) was estimated as 10-year Framingham Risk Score 1-year post-sleep. Outcomes were yearly change in executive function (EF), episodic memory (EM), and processing speed (PS) over 2–5 years post-sleep. 342 participants (mean age 73.5 +/- 5.6 years, 51 % female) were included. Shorter TST was linearly associated with increased CVR across all models (βs = -0.18(0.058) – -0.19(0.059), ps&lt; 0.002). TST was indirectly associated with EF and PS decline through CVR, such that associations between short TST and cognitive decline were partially due to higher CVR. All other mediating and moderating effects were nonsignificant after multiple comparisons. Indirect associations between short sleep duration and greater decline in executive function and processing speed were found through higher CVR, suggesting a potential mechanism by which sleep leads to cognitive decline. Findings support the prioritization of adequate sleep duration to preserve both cardiovascular and cognitive health in later life.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Pages 34-42"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896020","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}

{"title":"Theta-gamma transcranial alternating current stimulation enhances ballistic motor performance in healthy young and older adults","authors":"Nishadi N. Gamage ,&nbsp;Wei-Yeh Liao ,&nbsp;Brodie J. Hand ,&nbsp;Philip J. Atherton ,&nbsp;Mathew Piasecki ,&nbsp;George M. Opie ,&nbsp;John G. Semmler","doi":"10.1016/j.neurobiolaging.2025.04.010","DOIUrl":"10.1016/j.neurobiolaging.2025.04.010","url":null,"abstract":"<div><div>Theta-gamma transcranial alternating current stimulation (TG tACS) over primary motor cortex (M1) can improve ballistic motor performance in young adults, but the effect on older adults is unknown. This study investigated the effects of TG tACS on motor performance and M1 excitability in 18 young and 18 older adults. High-definition TG tACS (6 Hz theta, 75 Hz gamma) or sham tACS was applied over right M1 for 20 min during a ballistic left-thumb abduction motor training task performed in two experimental sessions. Motor performance was quantified as changes in movement acceleration during and up to 60 min after training. Transcranial magnetic stimulation (TMS) was used to assess changes in M1 excitability with motor-evoked potentials (MEP) and short-interval intracortical inhibition (SICI) before and after training. We found that TG tACS increased motor performance compared with sham tACS in young and older adults (<em>P</em> &lt; 0.001), with greater effects for young adults (<em>P</em> = 0.01). The improved motor performance with TG tACS lasted at least 60 min after training in both age groups. Motor training was accompanied by greater MEP amplitudes with TG tACS compared to sham tACS in young and older adults (<em>P</em> &lt; 0.001), but SICI did not vary between tACS sessions (<em>P</em> = 0.40). These findings indicate that TG tACS over M1 improves motor performance and alters training-induced changes in M1 excitability in healthy young and older adults. TG tACS may therefore be beneficial to alleviate motor deficits in the ageing population.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Pages 1-12"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882951","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}

{"title":"Gene age gap estimate (GAGE) for major depressive disorder: A penalized biological age model using gene expression","authors":"Yijie (Jamie) Li ,&nbsp;Rayus Kuplicki ,&nbsp;Bart N. Ford ,&nbsp;Elizabeth Kresock ,&nbsp;Leandra Figueroa-Hall ,&nbsp;Jonathan Savitz ,&nbsp;Brett A. McKinney","doi":"10.1016/j.neurobiolaging.2025.01.012","DOIUrl":"10.1016/j.neurobiolaging.2025.01.012","url":null,"abstract":"<div><div>Recent associations between Major Depressive Disorder (MDD) and measures of premature aging suggest accelerated biological aging as a potential biomarker for MDD susceptibility or MDD as a risk factor for age-related diseases. Residuals or “gaps” between the predicted biological age and chronological age have been used for statistical inference, such as testing whether an increased age gap is associated with a given disease state. Recently, a gene expression-based model of biological age showed a higher age gap for individuals with MDD compared to healthy controls (HC). In the current study, we propose an approach that simplifies gene selection using a least absolute shrinkage and selection operator (LASSO) penalty to construct an expression-based Gene Age Gap Estimate (GAGE) model. We train a LASSO gene age model on an RNA-Seq study of 78 unmedicated individuals with MDD and 79 HC, resulting in a model with 21 genes. The L-GAGE shows higher biological aging in MDD participants than HC, but the elevation is not statistically significant. However, when we dichotomize chronological age, the interaction between MDD status and age has a significant association with L-GAGE. This effect remains statistically significant even after adjusting for chronological age and sex. Using the 21 age genes, we find a statistically significant elevated biological age in MDD in an independent microarray gene expression dataset. We find functional enrichment of infectious disease and SARS-COV pathways using a broader feature selection of age related genes.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 13-21"},"PeriodicalIF":3.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767827","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}