Pub Date : 2025-12-16DOI: 10.1016/j.neurobiolaging.2025.12.004
Arthur P. Hamilton , Kaiah N. Sotebeer , John G. Grundy , Katherine Chadwick , Cassandra Morrison , Mahsa Dadar , Ellen Bialystok , John A.E. Anderson , for the Alzheimer’s Disease Metabolomics Consortium
Previous research examining the contribution of white matter hyperintensities (WMHs) to cognitive decline has focused on overall lesion burden. A new approach, afforded by the Lesion Quantification Toolkit (LQT), measures localized connectivity disruption from WMHs to better estimate their impact on cognition. This methodology shifts the focus from lesion volume to the level of network disruption between brain regions. In this novel study, we applied the LQT approach to healthy aging and linked the degree of disconnection of gray matter by WMHs to both cognitive impairment and resilience via cognitive reserve. Using three pre-existing MRI datasets of older adults (total N = 259), we used the LQT to examine localized disruptions to brain connectivity due to WMHs. We then used partial least-squares path modeling to examine the relationships between this disruption, cognitive performance, age, and cognitive reserve. The results support a link between connectivity disruption and reduced cognitive performance. Results from all three individual datasets, one of which included a detailed measure of cognitive reserve, showed a link between cognitive reserve and higher cognitive performance, suggesting cognitive reserve allows for maintained cognitive function in spite of the negative impact of WMHs.
{"title":"Cognitive reserve is associated with less cognitive decline from white matter hyperintensities","authors":"Arthur P. Hamilton , Kaiah N. Sotebeer , John G. Grundy , Katherine Chadwick , Cassandra Morrison , Mahsa Dadar , Ellen Bialystok , John A.E. Anderson , for the Alzheimer’s Disease Metabolomics Consortium","doi":"10.1016/j.neurobiolaging.2025.12.004","DOIUrl":"10.1016/j.neurobiolaging.2025.12.004","url":null,"abstract":"<div><div>Previous research examining the contribution of white matter hyperintensities (WMHs) to cognitive decline has focused on overall lesion burden. A new approach, afforded by the Lesion Quantification Toolkit (LQT), measures localized connectivity disruption from WMHs to better estimate their impact on cognition. This methodology shifts the focus from lesion volume to the level of network disruption between brain regions. In this novel study, we applied the LQT approach to healthy aging and linked the degree of disconnection of gray matter by WMHs to both cognitive impairment and resilience via cognitive reserve. Using three pre-existing MRI datasets of older adults (total N = 259), we used the LQT to examine localized disruptions to brain connectivity due to WMHs. We then used partial least-squares path modeling to examine the relationships between this disruption, cognitive performance, age, and cognitive reserve. The results support a link between connectivity disruption and reduced cognitive performance. Results from all three individual datasets, one of which included a detailed measure of cognitive reserve, showed a link between cognitive reserve and higher cognitive performance, suggesting cognitive reserve allows for maintained cognitive function in spite of the negative impact of WMHs.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"160 ","pages":"Pages 1-9"},"PeriodicalIF":3.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145842861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.neurobiolaging.2025.12.003
Soo-Jin Song, Jung-A Shin
Aging is a natural physiological process that may be accompanied by pathological changes, particularly in the brain. Iron is an essential trace element supporting various physiological functions and maintaining cellular homeostasis. However, iron levels tend to increase in certain brain regions of older adults and are associated with the development of neurodegenerative diseases. Despite this association, the causal relationship between aging, iron accumulation, and neurodegenerative diseases remains unknown. This study aimed to elucidate the potential contribution of systemic iron overload (IO) to brain pathology during aging. An IO model was established by intraperitoneal iron dextran (0.5 g/kg), 5 days/week for 4 weeks into C57BL/6 mice. Animals were divided into control and IO groups and further categorized into younger and older mice. No parenchymal iron accumulation was observed in any group; however, ferritin expression increased with IO and showed as plaques in older mice regardless of IO. Amyloid beta (Aβ) aggregation was observed in the entorhinal cortex and hippocampus, with higher burden in the older IO group. Ferritin plaques localized to the same regions as Aβ aggregation, and both showed a marked increase in older IO mice. The hippocampal Aβ 42/40 ratio was also increased in this group. Additionally, excessive iron was associated with reduced exploratory activity and showed trends toward impaired spatial working memory in older mice. These findings suggest that while aging is not pathological, IO may accelerate Aβ pathology during aging, although the presence of such pathology does not necessarily indicate neurodegeneration or cognitive impairment.
{"title":"Excess iron may accelerate amyloid beta accumulation in the brains of older mice","authors":"Soo-Jin Song, Jung-A Shin","doi":"10.1016/j.neurobiolaging.2025.12.003","DOIUrl":"10.1016/j.neurobiolaging.2025.12.003","url":null,"abstract":"<div><div>Aging is a natural physiological process that may be accompanied by pathological changes, particularly in the brain. Iron is an essential trace element supporting various physiological functions and maintaining cellular homeostasis. However, iron levels tend to increase in certain brain regions of older adults and are associated with the development of neurodegenerative diseases. Despite this association, the causal relationship between aging, iron accumulation, and neurodegenerative diseases remains unknown. This study aimed to elucidate the potential contribution of systemic iron overload (IO) to brain pathology during aging. An IO model was established by intraperitoneal iron dextran (0.5 g/kg), 5 days/week for 4 weeks into C57BL/6 mice. Animals were divided into control and IO groups and further categorized into younger and older mice. No parenchymal iron accumulation was observed in any group; however, ferritin expression increased with IO and showed as plaques in older mice regardless of IO. Amyloid beta (Aβ) aggregation was observed in the entorhinal cortex and hippocampus, with higher burden in the older IO group. Ferritin plaques localized to the same regions as Aβ aggregation, and both showed a marked increase in older IO mice. The hippocampal Aβ 42/40 ratio was also increased in this group. Additionally, excessive iron was associated with reduced exploratory activity and showed trends toward impaired spatial working memory in older mice. These findings suggest that while aging is not pathological, IO may accelerate Aβ pathology during aging, although the presence of such pathology does not necessarily indicate neurodegeneration or cognitive impairment.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 47-59"},"PeriodicalIF":3.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1016/j.neurobiolaging.2025.12.002
Ahmed A. Bahrani , Peter T. Nelson , Erin L. Abner , David K. Powell , Christopher M. Norris , Elif Pinar Coskun , Ann M. Stowe , Larry B. Goldstein , Linda J. Van Eldik , Brian T. Gold , Donna M. Wilcock , Charles S. DeCarli , Steven M. Greenberg , Gregory A. Jicha
White matter hyperintensities (WMH) are an MRI-based biomarker associated with aging, Alzheimer’s disease, and vascular dementia. Although the volume of WMH typically increases over time (growth) for individuals, WMH volume in some cases can also decrease (regress). This suggests the presence of active brain injury recovery mechanisms. Whether WMH regression reflects a true biological phenomenon or results from imaging artifacts or measurement errors, however, remains controversial. Here, we review published reports, following PRISMA search guidelines, describing or referring to WMH regression, the methods used to detect and quantitate regression, and proposed underlying mechanisms. Of 174 reviewed articles, 31 (26 original research studies and five case reports) were identified as directly related to WMH regression. Technical factors such as differences in longitudinal scan parameters, motion artifacts, and the interval between baseline and follow-up scans can affect WMH volume measurements. These factors may lead to inaccurate conclusions if appropriate controls are not employed. Although the use of standardized and systematic measurement protocols is essential, there is strong evidence indicating that WMH regression is a robust and biologically important phenomenon that may be influenced by clinical interventions. Further studies are needed to investigate WMH regression in relation to cerebrovascular risk mitigation and other therapeutic strategies.
{"title":"White matter hyperintensity regression: Fact or artifact?","authors":"Ahmed A. Bahrani , Peter T. Nelson , Erin L. Abner , David K. Powell , Christopher M. Norris , Elif Pinar Coskun , Ann M. Stowe , Larry B. Goldstein , Linda J. Van Eldik , Brian T. Gold , Donna M. Wilcock , Charles S. DeCarli , Steven M. Greenberg , Gregory A. Jicha","doi":"10.1016/j.neurobiolaging.2025.12.002","DOIUrl":"10.1016/j.neurobiolaging.2025.12.002","url":null,"abstract":"<div><div>White matter hyperintensities (WMH) are an MRI-based biomarker associated with aging, Alzheimer’s disease, and vascular dementia. Although the volume of WMH typically increases over time (growth) for individuals, WMH volume in some cases can also decrease (regress). This suggests the presence of active brain injury recovery mechanisms. Whether WMH regression reflects a true biological phenomenon or results from imaging artifacts or measurement errors, however, remains controversial. Here, we review published reports, following PRISMA search guidelines, describing or referring to WMH regression, the methods used to detect and quantitate regression, and proposed underlying mechanisms. Of 174 reviewed articles, 31 (26 original research studies and five case reports) were identified as directly related to WMH regression. Technical factors such as differences in longitudinal scan parameters, motion artifacts, and the interval between baseline and follow-up scans can affect WMH volume measurements. These factors may lead to inaccurate conclusions if appropriate controls are not employed. Although the use of standardized and systematic measurement protocols is essential, there is strong evidence indicating that WMH regression is a robust and biologically important phenomenon that may be influenced by clinical interventions. Further studies are needed to investigate WMH regression in relation to cerebrovascular risk mitigation and other therapeutic strategies.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 33-46"},"PeriodicalIF":3.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1016/j.neurobiolaging.2025.12.001
Jarrah O.Z.J. Kron , Jeremy A. Metha , Heather J. Daykin , Leigh C. Walker , Yasmin Potts , Giancarlo Allocca , Ryan J. Keenan , Daniel Hoyer , Laura H. Jacobson
Alzheimer’s disease (AD) is a major public health concern in societies with increasingly ageing populations. Accumulating evidence implies a specific link between the development of tauopathy, cognitive impairment, and sleep loss in AD patients. P301S mutant tau-transgenic (PS19) mice, modelling frontotemporal dementia (FTD) and AD tauopathy, demonstrate sleep loss and cognitive impairment. We aimed to assess the progression of sleep loss and cognitive decline longitudinally in both sexes of PS19 mice. WT and PS19 mice underwent polysomnography (PSG), electroencephalography (EEG) power spectral analysis, locomotor activity assessments at 7, 8 and 9-months of age, and Barnes maze testing at 7 and 9-months. PS19s demonstrated profound sleep loss, and locomotor hyperarousal; paralleling observations in AD patients and other studies of mouse tauopathy. This phenotype was more pronounced in PS19 males than females. WT and PS19 mice showed similar learning in repeated Barnes maze testing at 9-months. At 9-months of age, cognitive performance was best predicted by 7-month locomotor hyperarousal, 9-month EEG power outcomes in wakefulness frequency bands associated with cognition, and balanced physiological NREM and REM sleep. Our longitudinal design revealed that researchers should consider early sleep disruption, hyperarousal, and wakeful EEG power in combination as predictors of cognitive symptoms related to tauopathy. Further investigation into mechanisms to promote balanced sleep, which maintain both NREM and REM sleep with ageing, is indicated as a mechanism to potentially preserve cognition in neurodegenerative disorders.
{"title":"PS19 mouse tauopathy is associated with sex-dependent sleep loss and hyperarousal, and predicts cognitive performance","authors":"Jarrah O.Z.J. Kron , Jeremy A. Metha , Heather J. Daykin , Leigh C. Walker , Yasmin Potts , Giancarlo Allocca , Ryan J. Keenan , Daniel Hoyer , Laura H. Jacobson","doi":"10.1016/j.neurobiolaging.2025.12.001","DOIUrl":"10.1016/j.neurobiolaging.2025.12.001","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a major public health concern in societies with increasingly ageing populations. Accumulating evidence implies a specific link between the development of tauopathy, cognitive impairment, and sleep loss in AD patients. P301S mutant tau-transgenic (PS19) mice, modelling frontotemporal dementia (FTD) and AD tauopathy, demonstrate sleep loss and cognitive impairment. We aimed to assess the progression of sleep loss and cognitive decline longitudinally in both sexes of PS19 mice. WT and PS19 mice underwent polysomnography (PSG), electroencephalography (EEG) power spectral analysis, locomotor activity assessments at 7, 8 and 9-months of age, and Barnes maze testing at 7 and 9-months. PS19s demonstrated profound sleep loss, and locomotor hyperarousal; paralleling observations in AD patients and other studies of mouse tauopathy. This phenotype was more pronounced in PS19 males than females. WT and PS19 mice showed similar learning in repeated Barnes maze testing at 9-months. At 9-months of age, cognitive performance was best predicted by 7-month locomotor hyperarousal, 9-month EEG power outcomes in wakefulness frequency bands associated with cognition, and balanced physiological NREM and REM sleep. Our longitudinal design revealed that researchers should consider early sleep disruption, hyperarousal, and wakeful EEG power in combination as predictors of cognitive symptoms related to tauopathy. Further investigation into mechanisms to promote balanced sleep, which maintain both NREM and REM sleep with ageing, is indicated as a mechanism to potentially preserve cognition in neurodegenerative disorders.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 69-87"},"PeriodicalIF":3.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1016/j.neurobiolaging.2025.11.008
Andy Jeesu Kim , Santiago Morales , Joshua Senior , Mara Mather
Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampering the development of targeted preventative interventions. In this study, we acquired electrophysiological, pupillometric, and behavioral measures in a passive and active auditory oddball paradigm to test the hypothesis that cognitively healthy older adults experience tonic LC hyperactivity. We leveraged the LC-NA system’s role in arousal regulation and manipulated state arousal and noradrenergic activity using the unpredictable threat of electric shock. Based on older adults' hypothesized tonic LC hyperactivity, we predicted that increased arousal would evoke weaker phasic (stimulus-evoked) noradrenergic responses in older adults compared with young adults. Consistent with this hypothesis, arousal differentially modulated behavioral responses and resting-state alpha power across age groups, and older adults showed smaller pupil dilation responses than young adults. Furthermore, linear mixed models revealed that arousal differentially modulated attentional control to salient but task-irrelevant distractors across age groups, with older adults exhibiting less behavioral slowing and longer P300 latency delays under threat of shock than did young adults. Together these findings provide convergent multi-modal evidence that aging is associated with tonic LC-NA system hyperactivity in humans, with consequences for mechanisms supporting attentional control. This research highlights the utility of non-invasive physiological markers to determine when across the adult lifespan the LC-NA system becomes hyperactive and to identify adults who may be at elevated risk for neurodegenerative progression due to emerging changes in LC-NA system function.
{"title":"Electroencephalography, pupillometry, and behavioral evidence for locus coeruleus-noradrenaline system related tonic hyperactivity in older adults","authors":"Andy Jeesu Kim , Santiago Morales , Joshua Senior , Mara Mather","doi":"10.1016/j.neurobiolaging.2025.11.008","DOIUrl":"10.1016/j.neurobiolaging.2025.11.008","url":null,"abstract":"<div><div>Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function <em>in vivo</em>, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampering the development of targeted preventative interventions. In this study, we acquired electrophysiological, pupillometric, and behavioral measures in a passive and active auditory oddball paradigm to test the hypothesis that cognitively healthy older adults experience tonic LC hyperactivity. We leveraged the LC-NA system’s role in arousal regulation and manipulated state arousal and noradrenergic activity using the unpredictable threat of electric shock. Based on older adults' hypothesized tonic LC hyperactivity, we predicted that increased arousal would evoke weaker phasic (stimulus-evoked) noradrenergic responses in older adults compared with young adults. Consistent with this hypothesis, arousal differentially modulated behavioral responses and resting-state alpha power across age groups, and older adults showed smaller pupil dilation responses than young adults. Furthermore, linear mixed models revealed that arousal differentially modulated attentional control to salient but task-irrelevant distractors across age groups, with older adults exhibiting less behavioral slowing and longer P300 latency delays under threat of shock than did young adults. Together these findings provide convergent multi-modal evidence that aging is associated with tonic LC-NA system hyperactivity in humans, with consequences for mechanisms supporting attentional control. This research highlights the utility of non-invasive physiological markers to determine when across the adult lifespan the LC-NA system becomes hyperactive and to identify adults who may be at elevated risk for neurodegenerative progression due to emerging changes in LC-NA system function.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 15-32"},"PeriodicalIF":3.5,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651936","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 : 2025-11-27DOI: 10.1016/j.neurobiolaging.2025.11.007
Louise M. Ince , Brandy N. Routh , Jeffrey S. Darling , Krishi Manem , Akshay Prabhakar , Sophia Martinez , Emily Chan , Ruizhuo Chen , Andrew D. Gaudet , Laura K. Fonken
The aging brain exhibits an increased inflammatory potential which in turn elicits behavioral changes e.g., social withdrawal. Social isolation is a risk factor for additional health complications, and interventions which can mitigate these negative facets of aging can improve longevity and quality of life in old age. The circadian system critically regulates neuroimmune function and behavior, but circadian rhythms also degrade with age, resulting in lower amplitude oscillations in activity and hormone secretion. Time-restricted feeding (TRF), in which food availability is limited to a specific time-of-day, is a simple dietary intervention which provides timing cues to the circadian system - protecting against metabolic disease and reducing systemic inflammation. We thus tested the hypothesis that TRF could serve as an intervention to bolster circadian rhythms in aged mice and have beneficial effects upon age-associated neuroinflammation and behavior. Here, we demonstrate that 6 weeks of TRF in aged (18 months old) mice ameliorates age-associated social withdrawal and drives distinct molecular and cellular changes within the brain. TRF attenuates age-associated increases in inflammatory gene expression in the hippocampus and prefrontal cortex, and re-establishes circadian phase-appropriate expression of autophagy-related genes in the hippocampus. In addition, TRF promotes a diurnal rhythm in microglial branching complexity in the hippocampus, recapitulating the pattern observed in young adults (3 months old). TRF also reduced blood glucose levels in aged males, but not in aged females, suggesting sex-specific effects on metabolic parameters with age. These results highlight the efficacy of TRF as a therapeutic approach to alleviate age-associated neuroinflammation and social withdrawal.
{"title":"Time-restricted feeding rescues sociability deficits and reduces neuroinflammation in aged mice","authors":"Louise M. Ince , Brandy N. Routh , Jeffrey S. Darling , Krishi Manem , Akshay Prabhakar , Sophia Martinez , Emily Chan , Ruizhuo Chen , Andrew D. Gaudet , Laura K. Fonken","doi":"10.1016/j.neurobiolaging.2025.11.007","DOIUrl":"10.1016/j.neurobiolaging.2025.11.007","url":null,"abstract":"<div><div>The aging brain exhibits an increased inflammatory potential which in turn elicits behavioral changes e.g., social withdrawal. Social isolation is a risk factor for additional health complications, and interventions which can mitigate these negative facets of aging can improve longevity and quality of life in old age. The circadian system critically regulates neuroimmune function and behavior, but circadian rhythms also degrade with age, resulting in lower amplitude oscillations in activity and hormone secretion. Time-restricted feeding (TRF), in which food availability is limited to a specific time-of-day, is a simple dietary intervention which provides timing cues to the circadian system - protecting against metabolic disease and reducing systemic inflammation. We thus tested the hypothesis that TRF could serve as an intervention to bolster circadian rhythms in aged mice and have beneficial effects upon age-associated neuroinflammation and behavior. Here, we demonstrate that 6 weeks of TRF in aged (18 months old) mice ameliorates age-associated social withdrawal and drives distinct molecular and cellular changes within the brain. TRF attenuates age-associated increases in inflammatory gene expression in the hippocampus and prefrontal cortex, and re-establishes circadian phase-appropriate expression of autophagy-related genes in the hippocampus. In addition, TRF promotes a diurnal rhythm in microglial branching complexity in the hippocampus, recapitulating the pattern observed in young adults (3 months old). TRF also reduced blood glucose levels in aged males, but not in aged females, suggesting sex-specific effects on metabolic parameters with age. These results highlight the efficacy of TRF as a therapeutic approach to alleviate age-associated neuroinflammation and social withdrawal.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 1-14"},"PeriodicalIF":3.5,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontotemporal dementia (FTD) is driven by progranulin haploinsufficiency, in which age-dependent microglial activation promotes neurodegeneration through TDP-43 proteinopathy. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator characterized by a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. A pharmacologically active derivative of cPA has been shown to suppress microglial activation. Based on this, we aimed to investigate the potential of cPA derivatives to prevent the onset of FTD. Specifically, we administered metabolically stabilized cPA derivatives, 2-carba-cPA (2ccPA) and its degradation product, 2-carba-LPA (2cLPA), to presymptomatic progranulin-deficient (Grn-/-) mice. The mice received intraperitoneal injections of 0.9 mg/kg/day of either compound for 6 months. Treatment with 2ccPA, but not 2cLPA, significantly attenuated thalamic neuronal loss, cytoplasmic TDP-43 aggregation, and microglial activation, including reduced transition to an ameboid morphology. These findings led us to hypothesize that 2ccPA mitigates disease onset by suppressing microglial activation. To test this, we examined the effects of 2ccPA on primary Grn-/- microglia and found that treatment reduced markers of accelerated senescence, phagocytic activity, lipid accumulation, and CCL8 secretion. Collectively, our findings identify 2ccPA as a promising candidate for the prevention of FTD. This study also represents a conceptual advance by demonstrating that targeting microglial activation is an effective strategy to delay or attenuate neurodegeneration in FTD.
{"title":"Lysophosphatidic acid derivative is a novel candidate of therapeutic agents for a mouse model of frontotemporal dementia with progranulin deficiency","authors":"Nami Yamamoto , Rino Takei , Mari Gotoh , Yasunori Miyamoto , Kei Hashimoto","doi":"10.1016/j.neurobiolaging.2025.11.006","DOIUrl":"10.1016/j.neurobiolaging.2025.11.006","url":null,"abstract":"<div><div>Frontotemporal dementia (FTD) is driven by progranulin haploinsufficiency, in which age-dependent microglial activation promotes neurodegeneration through TDP-43 proteinopathy. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator characterized by a unique cyclic phosphate ring at the <em>sn-2</em> and <em>sn-3</em> positions of its glycerol backbone. A pharmacologically active derivative of cPA has been shown to suppress microglial activation. Based on this, we aimed to investigate the potential of cPA derivatives to prevent the onset of FTD. Specifically, we administered metabolically stabilized cPA derivatives, 2-carba-cPA (2ccPA) and its degradation product, 2-carba-LPA (2cLPA), to presymptomatic progranulin-deficient (<em>Grn</em><sup><em>-/-</em></sup>) mice. The mice received intraperitoneal injections of 0.9 mg/kg/day of either compound for 6 months. Treatment with 2ccPA, but not 2cLPA, significantly attenuated thalamic neuronal loss, cytoplasmic TDP-43 aggregation, and microglial activation, including reduced transition to an ameboid morphology. These findings led us to hypothesize that 2ccPA mitigates disease onset by suppressing microglial activation. To test this, we examined the effects of 2ccPA on primary <em>Grn</em><sup><em>-/-</em></sup> microglia and found that treatment reduced markers of accelerated senescence, phagocytic activity, lipid accumulation, and CCL8 secretion. Collectively, our findings identify 2ccPA as a promising candidate for the prevention of FTD. This study also represents a conceptual advance by demonstrating that targeting microglial activation is an effective strategy to delay or attenuate neurodegeneration in FTD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"158 ","pages":"Pages 39-51"},"PeriodicalIF":3.5,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.neurobiolaging.2025.11.004
Anna D. Stumps , Nadia Bounoua , Naomi Sadeh
To further understand whether childhood maltreatment (CM) is associated with indicators of accelerated cognitive aging, this study investigated whether CM moderated the relationship of age with gray matter volume (GMV) and executive functions among community adults aged 21–55. Participants (N = 225) underwent MRI scanning, and a composite measure of executive functions was computed across measures of inhibitory control, switching, and working memory. To interpret interactions, we created high (66th percentile) and low (33rd percentile) CM exposure groups and examined age-related variance in GMV and executive functions in each group. Vertex-wise cortical analysis revealed CM by age interactions in two right prefrontal cortex clusters [rostral middle frontal gyrus and superior frontal gyrus], where age negatively correlated with GMV at low CM (ps < 0.001), but this effect weakened at high CM (ps = 0.095–0.436). Further, a multivariate analysis of five subcortical regions revealed a CM-by-age interaction (p = 0.007), whereby age correlated negatively with GMV at high, but not low, CM. Finally, CM moderated the association between age and an executive functioning composite (p = 0.027), with age correlating more negatively with executive functions in individuals reporting high than low CM. Together, these cross-sectional findings suggest CM may influence age-related neurocognitive changes.
{"title":"Childhood maltreatment alters associations between age and neurocognitive health metrics in community-dwelling adults","authors":"Anna D. Stumps , Nadia Bounoua , Naomi Sadeh","doi":"10.1016/j.neurobiolaging.2025.11.004","DOIUrl":"10.1016/j.neurobiolaging.2025.11.004","url":null,"abstract":"<div><div>To further understand whether childhood maltreatment (CM) is associated with indicators of accelerated cognitive aging, this study investigated whether CM moderated the relationship of age with gray matter volume (GMV) and executive functions among community adults aged 21–55. Participants (N = 225) underwent MRI scanning, and a composite measure of executive functions was computed across measures of inhibitory control, switching, and working memory. To interpret interactions, we created high (66th percentile) and low (33rd percentile) CM exposure groups and examined age-related variance in GMV and executive functions in each group. Vertex-wise cortical analysis revealed CM by age interactions in two right prefrontal cortex clusters [rostral middle frontal gyrus and superior frontal gyrus], where age negatively correlated with GMV at low CM (<em>ps</em> < 0.001), but this effect weakened at high CM (<em>ps</em> = 0.095–0.436). Further, a multivariate analysis of five subcortical regions revealed a CM-by-age interaction (<em>p</em> = 0.007), whereby age correlated negatively with GMV at high, but not low, CM. Finally, CM moderated the association between age and an executive functioning composite (<em>p</em> = 0.027), with age correlating more negatively with executive functions in individuals reporting high than low CM. Together, these cross-sectional findings suggest CM may influence age-related neurocognitive changes.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"158 ","pages":"Pages 28-38"},"PeriodicalIF":3.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号