Due to the growing number of Alzheimer’s disease (AD) patients, new drugs are urgently required. A synthetic nonapeptide, JAL-TA9 (YKGSGFRMI), derived from Transducer of ErbB-2.1 (Tob1) protein, cleaves amyloid β (Aβ) 42 with serine protease-like activity. Aβ25–35 was chosen because it is the shortest fragment that forms fibrils and is cytotoxic. Aβ25–35 has been used to create AD model mice, and it appears to be an attractive target for AD therapeutics. Using Thioflavin-T assays, the fluorescence intensity of the reaction of Aβ25–35 and JAL-TA9 was lower than that of Aβ25–35 without JAL-TA9, and the same result was obtained with aggregated Aβ25–35. These data showed that JAL-TA9 inhibits aggregation of Aβ25–35 and dissolves its aggregates. Furthermore, electron microscopy showed that amyloid fibrils of both Aβ25–35 and aggregated Aβ25–35 are reduced in the presence of JAL-TA9. The proteolytic activity of JAL-TA9 against Aβ25–35 was evaluated using HPLC and mass spectrometry. These data showed that JAL-TA9 cleaves both soluble and aggregated forms of Aβ25–35. JAL-TA9 inhibits neuronal cytotoxicity caused by Aβ25–35 aggregation by cleaving Aβ25–35 and its aggregated form. These results suggest that JAL-TA9 is a promising candidate for developing novel drugs against AD.
{"title":"A synthetic nonapeptide, JAL-TA9, inhibits neuronal cytotoxicity caused by Aβ25–35 aggregation with proteolytic activity","authors":"Rina Nakamura , Momoka Okada , Asuka Takahashi , Yoshihiro Hayashi , Motomi Konishi , Fumiaki Ito , Ichiro Murakami , Motoaki Saito , Toshifumi Akizawa","doi":"10.1016/j.neurobiolaging.2025.09.001","DOIUrl":"10.1016/j.neurobiolaging.2025.09.001","url":null,"abstract":"<div><div>Due to the growing number of Alzheimer’s disease (AD) patients, new drugs are urgently required. A synthetic nonapeptide, JAL-TA9 (YKGSGFRMI), derived from Transducer of ErbB-2.1 (Tob1) protein, cleaves amyloid β (Aβ) 42 with serine protease-like activity. Aβ25–35 was chosen because it is the shortest fragment that forms fibrils and is cytotoxic. Aβ25–35 has been used to create AD model mice, and it appears to be an attractive target for AD therapeutics. Using Thioflavin-T assays, the fluorescence intensity of the reaction of Aβ25–35 and JAL-TA9 was lower than that of Aβ25–35 without JAL-TA9, and the same result was obtained with aggregated Aβ25–35. These data showed that JAL-TA9 inhibits aggregation of Aβ25–35 and dissolves its aggregates. Furthermore, electron microscopy showed that amyloid fibrils of both Aβ25–35 and aggregated Aβ25–35 are reduced in the presence of JAL-TA9. The proteolytic activity of JAL-TA9 against Aβ25–35 was evaluated using HPLC and mass spectrometry. These data showed that JAL-TA9 cleaves both soluble and aggregated forms of Aβ25–35. JAL-TA9 inhibits neuronal cytotoxicity caused by Aβ25–35 aggregation by cleaving Aβ25–35 and its aggregated form. These results suggest that JAL-TA9 is a promising candidate for developing novel drugs against AD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 123-132"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019130","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 : 2025-09-03DOI: 10.1016/j.neurobiolaging.2025.08.008
Emilio J. Galván , Ernesto Griego
The physiological decline associated with aging is often accompanied by a progressive deterioration in cognitive processing abilities driven by a series of cellular dysfunctions that remain poorly understood. In the hippocampus, a critical area for learning and memory, aging affects the functional expression of ionotropic and metabotropic receptors, including the metabotropic glutamate receptors (mGluRs). mGluRs play a critical role in multiple cellular functions, including modulation of ion channels and intrinsic excitability, synaptic transmission, and induction of synaptic plasticity, processes considered part of the cellular substrates for learning and memory. This study used patch-clamp recordings and pharmacological tools in acute hippocampal slices to uncover the aging-related disruption in the mGluR-dependent modulation of area CA3 pyramidal neurons. Pharmacological stimulation of group I mGluRs triggers rhythmic firing discharge in CA3 pyramidal neurons of young rats (5 ± 1 weeks of age) and a reduction in the afterhyperpolarization. By contrast, in older adult rats (20–24 months of age), stimulation of group I mGluRs causes a switch from afterhyperpolarization to an afterdepolarization plateau that eases a persistent but non-rhythmic firing discharge. In young animals, postsynaptic activation of group II mGluRs enhances the intrinsic excitability of CA3 pyramidal neurons, and an exacerbated response is observed in older adult rats. By contrast, in older adult animals, the presynaptic inhibition of glutamate release by pharmacological stimulation of group II mGluRs from mossy fibers was significantly reduced. These findings support the notion of older adult-related changes in the functional expression of mGluRs within the hippocampal area CA3 that may contribute to the cognitive alterations commonly associated with aging.
{"title":"Aging-related adaptations of metabotropic glutamate receptors within the CA3 region of the rat hippocampus","authors":"Emilio J. Galván , Ernesto Griego","doi":"10.1016/j.neurobiolaging.2025.08.008","DOIUrl":"10.1016/j.neurobiolaging.2025.08.008","url":null,"abstract":"<div><div>The physiological decline associated with aging is often accompanied by a progressive deterioration in cognitive processing abilities driven by a series of cellular dysfunctions that remain poorly understood. In the hippocampus, a critical area for learning and memory, aging affects the functional expression of ionotropic and metabotropic receptors, including the metabotropic glutamate receptors (mGluRs). mGluRs play a critical role in multiple cellular functions, including modulation of ion channels and intrinsic excitability, synaptic transmission, and induction of synaptic plasticity, processes considered part of the cellular substrates for learning and memory. This study used patch-clamp recordings and pharmacological tools in acute hippocampal slices to uncover the aging-related disruption in the mGluR-dependent modulation of area CA3 pyramidal neurons. Pharmacological stimulation of group I mGluRs triggers rhythmic firing discharge in CA3 pyramidal neurons of young rats (5 ± 1 weeks of age) and a reduction in the afterhyperpolarization. By contrast, in older adult rats (20–24 months of age), stimulation of group I mGluRs causes a switch from afterhyperpolarization to an afterdepolarization plateau that eases a persistent but non-rhythmic firing discharge. In young animals, postsynaptic activation of group II mGluRs enhances the intrinsic excitability of CA3 pyramidal neurons, and an exacerbated response is observed in older adult rats. By contrast, in older adult animals, the presynaptic inhibition of glutamate release by pharmacological stimulation of group II mGluRs from mossy fibers was significantly reduced. These findings support the notion of older adult-related changes in the functional expression of mGluRs within the hippocampal area CA3 that may contribute to the cognitive alterations commonly associated with aging.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 111-122"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996592","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 : 2025-08-26DOI: 10.1016/j.neurobiolaging.2025.08.006
Tuuli Lankinen, Saija Leinonen, Kuu Ikäheimo , Ulla Pirvola
Hallmarks of sensorineural hearing loss are elevated hearing thresholds and defects in temporal auditory processing, the former being often caused by outer hair cell (OHC) damage, and the latter by the loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons. In the well-studied CBA/CaJ mouse strain, these impairments are disconnected, IHC synaptopathy preceding OHC loss. We have investigated the relationship between IHC synaptopathy and OHC loss in the C57BL/6J (B6) and ICR mouse strains that model accelerated age-related hearing loss. Regression analysis revealed a strong correlation between these variables across the high-to-low frequency axis of the cochlea. Using the fluorescent dye FM1–43 as a proxy for mechanotransduction (MET) in the hair-cell stereocilia bundle, we found that MET malfunction coexisted with synaptopathy in IHCs. Thus, our results suggest that a MET defect drives IHC synaptopathy in the B6 and ICR strains known to carry a missense mutation of Cadherin 23, encoding a stereocilia bundle protein. Previous data have suggested that OHC stereocilia abnormalities could trigger OHC death. Therefore, stereocilia defect could be a trigger of intracellular stress that drives both IHC synaptopathy and OHC loss. To determine whether tauroursodeoxycholic acid (TUDCA), known to target several stress signalling pathways, could influence cochlear pathology, we conducted long-term TUDCA delivery to ICR mice. TUDCA provided partial protection against IHC synaptopathy but did not prevent OHC loss. These results in two mouse models of accelerated cochlear pathology provide novel insights into the mechanisms behind age-related hearing loss.
{"title":"Relationship between inner hair cell synaptopathy and outer hair cell loss in two mouse models of accelerated age-related hearing loss","authors":"Tuuli Lankinen, Saija Leinonen, Kuu Ikäheimo , Ulla Pirvola","doi":"10.1016/j.neurobiolaging.2025.08.006","DOIUrl":"10.1016/j.neurobiolaging.2025.08.006","url":null,"abstract":"<div><div>Hallmarks of sensorineural hearing loss are elevated hearing thresholds and defects in temporal auditory processing, the former being often caused by outer hair cell (OHC) damage, and the latter by the loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons. In the well-studied CBA/CaJ mouse strain, these impairments are disconnected, IHC synaptopathy preceding OHC loss. We have investigated the relationship between IHC synaptopathy and OHC loss in the C57BL/6J (B6) and ICR mouse strains that model accelerated age-related hearing loss. Regression analysis revealed a strong correlation between these variables across the high-to-low frequency axis of the cochlea. Using the fluorescent dye FM1–43 as a proxy for mechanotransduction (MET) in the hair-cell stereocilia bundle, we found that MET malfunction coexisted with synaptopathy in IHCs. Thus, our results suggest that a MET defect drives IHC synaptopathy in the B6 and ICR strains known to carry a missense mutation of <em>Cadherin 23,</em> encoding a stereocilia bundle protein. Previous data have suggested that OHC stereocilia abnormalities could trigger OHC death. Therefore, stereocilia defect could be a trigger of intracellular stress that drives both IHC synaptopathy and OHC loss. To determine whether tauroursodeoxycholic acid (TUDCA), known to target several stress signalling pathways, could influence cochlear pathology, we conducted long-term TUDCA delivery to ICR mice. TUDCA provided partial protection against IHC synaptopathy but did not prevent OHC loss. These results in two mouse models of accelerated cochlear pathology provide novel insights into the mechanisms behind age-related hearing loss.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 85-100"},"PeriodicalIF":3.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913045","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 : 2025-08-26DOI: 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":"2025-08-26","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 : 2025-08-14DOI: 10.1016/j.neurobiolaging.2025.08.004
Sonny Bovee , Carolin Jüchter , Georg M. Klump , Christine Köppl , Sonja J. Pyott
Presbycusis, or age-related hearing loss, is a prevalent condition characterized by progressive auditory decline, significantly impacting quality of life in older adults. While sensorineural damage has been widely studied, degeneration of the stria vascularis (SV) remains underexplored despite its essential role in cochlear ion homeostasis. The SV is organized into three cellular layers—marginal, intermediate, and basal cells—each with distinct functions critical for maintaining the endocochlear potential. Using the quiet-aged Mongolian gerbil—a well-established model of metabolic presbycusis—we systematically mapped the structural and cellular degeneration of the SV and linked these changes to cochlear function. We assessed cochlear function using auditory brainstem response (ABR) measurements and quantified age-related atrophy of the strial cell layers using immunofluorescence, confocal microscopy, and 3D reconstruction. We identified a striking, region-specific pattern of degeneration, with the greatest atrophy occurring in ATP1A1-expressing marginal cells, followed by KCNJ10-expressing intermediate cells, and comparatively little atrophy in CLDN11-expressing basal cells. Notably, atrophy was most pronounced in the cochlear apex and base, regions critical for low- and high-frequency hearing. We further established a significant correlation between the decline in cochlear function and the extent of atrophy of the individual strial cell layers, especially in the cochlear base. By moving beyond traditional cross-sectional assessments of age-related degeneration of the SV, this work provides a more nuanced understanding of how strial pathology contributes to age-related decline in cochlear function and may inform therapeutic interventions targeting strial function to mitigate age-related hearing loss even when sensorineural function is compromised.
{"title":"Degeneration of the stria vascularis in quiet-aged gerbils: Linking structural, cellular and molecular changes to cochlear function","authors":"Sonny Bovee , Carolin Jüchter , Georg M. Klump , Christine Köppl , Sonja J. Pyott","doi":"10.1016/j.neurobiolaging.2025.08.004","DOIUrl":"10.1016/j.neurobiolaging.2025.08.004","url":null,"abstract":"<div><div>Presbycusis, or age-related hearing loss, is a prevalent condition characterized by progressive auditory decline, significantly impacting quality of life in older adults. While sensorineural damage has been widely studied, degeneration of the stria vascularis (SV) remains underexplored despite its essential role in cochlear ion homeostasis. The SV is organized into three cellular layers—marginal, intermediate, and basal cells—each with distinct functions critical for maintaining the endocochlear potential. Using the quiet-aged Mongolian gerbil—a well-established model of metabolic presbycusis—we systematically mapped the structural and cellular degeneration of the SV and linked these changes to cochlear function. We assessed cochlear function using auditory brainstem response (ABR) measurements and quantified age-related atrophy of the strial cell layers using immunofluorescence, confocal microscopy, and 3D reconstruction. We identified a striking, region-specific pattern of degeneration, with the greatest atrophy occurring in ATP1A1-expressing marginal cells, followed by KCNJ10-expressing intermediate cells, and comparatively little atrophy in CLDN11-expressing basal cells. Notably, atrophy was most pronounced in the cochlear apex and base, regions critical for low- and high-frequency hearing. We further established a significant correlation between the decline in cochlear function and the extent of atrophy of the individual strial cell layers, especially in the cochlear base. By moving beyond traditional cross-sectional assessments of age-related degeneration of the SV, this work provides a more nuanced understanding of how strial pathology contributes to age-related decline in cochlear function and may inform therapeutic interventions targeting strial function to mitigate age-related hearing loss even when sensorineural function is compromised.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 50-62"},"PeriodicalIF":3.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144864939","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 : 2025-08-13DOI: 10.1016/j.neurobiolaging.2025.08.003
Julia L. Becker , M. Ethan MacDonald , Kirstan A. Vessey , Rebecca J. Williams
The choroid plexus (ChP) is implicated in inflammation and supports the clearance of waste byproducts, particularly those related to the pathogenesis of Alzheimer’s disease. Increases in ChP volume have been associated with older age and cognitive decline in both clinical and healthy cohorts. However, the clearance of waste products in the brain is also related to sleep, and sleep quality may contribute to ChP dysfunction and cognitive decline. In the present work, it was therefore hypothesized that the association between age and cognitive performance is mediated by ChP volume, however this is conditional on sleep quality. A moderated-mediation model was tested on a sample (N = 590) of healthy adults aged 18–87 years from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN). Results showed that the relationship between increasing age and decreased cognitive performance was partially mediated by ChP volume, however, this was not conditional on sleep quality. A moderation analysis indicated that the relationship between ChP volume and cognitive performance was moderated by age, with ChP enlargement associated with worse cognitive performance in participants older than 62 years. In participants younger than 62 years, sleep duration was associated with cognitive performance, but ChP volume was not. These findings provide support for the sensitivity of ChP volume to cognitive performance in older adults.
{"title":"Choroid plexus volume and its association with cognitive performance across the lifespan: Links to sleep quality and healthy brain aging","authors":"Julia L. Becker , M. Ethan MacDonald , Kirstan A. Vessey , Rebecca J. Williams","doi":"10.1016/j.neurobiolaging.2025.08.003","DOIUrl":"10.1016/j.neurobiolaging.2025.08.003","url":null,"abstract":"<div><div>The choroid plexus (ChP) is implicated in inflammation and supports the clearance of waste byproducts, particularly those related to the pathogenesis of Alzheimer’s disease. Increases in ChP volume have been associated with older age and cognitive decline in both clinical and healthy cohorts. However, the clearance of waste products in the brain is also related to sleep, and sleep quality may contribute to ChP dysfunction and cognitive decline. In the present work, it was therefore hypothesized that the association between age and cognitive performance is mediated by ChP volume, however this is conditional on sleep quality. A moderated-mediation model was tested on a sample (<em>N</em> = 590) of healthy adults aged 18–87 years from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN). Results showed that the relationship between increasing age and decreased cognitive performance was partially mediated by ChP volume, however, this was not conditional on sleep quality. A moderation analysis indicated that the relationship between ChP volume and cognitive performance was moderated by age, with ChP enlargement associated with worse cognitive performance in participants older than 62 years. In participants younger than 62 years, sleep duration was associated with cognitive performance, but ChP volume was not. These findings provide support for the sensitivity of ChP volume to cognitive performance in older adults.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 40-49"},"PeriodicalIF":3.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144864926","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 : 2025-08-13DOI: 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":"2025-08-13","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 : 2025-08-06DOI: 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":"2025-08-06","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 : 2025-08-05DOI: 10.1016/j.neurobiolaging.2025.04.004
Eric Bernath , Nancy Kupina , Ming Cheng Liu , Ronald L. Hayes , Colleen Meegan , Kevin K.W. Wang
{"title":"Corrigendum to “Elevation of cytoskeletal protein breakdown in aged Wistar rat brain” [Neurobiol. Aging 27 (2006) 624–632]","authors":"Eric Bernath , Nancy Kupina , Ming Cheng Liu , Ronald L. Hayes , Colleen Meegan , Kevin K.W. Wang","doi":"10.1016/j.neurobiolaging.2025.04.004","DOIUrl":"10.1016/j.neurobiolaging.2025.04.004","url":null,"abstract":"","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"154 ","pages":"Page 103"},"PeriodicalIF":3.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768804","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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