Pub Date : 2024-11-10DOI: 10.1016/j.neurobiolaging.2024.11.003
Lorena Sordo , Margo F. Ubele , Kathy A. Boaz , Jennifer L. Mefford , Erin Dehnart Jones , Katie L. McCarty , Hollie Y. van Rooyen , Jeffrey Smiley , Stasia A. Bembenek Bailey , Jessica A. Perpich , Beverly Meacham , David K. Powell , Frederick Bresch , Jacob W. Crump , Michael J. Phelan , Jessica A. Noche , Craig E. Stark , László G. Puskás , Christopher M. Norris , Elizabeth Head
Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern of cognitive maintenance and duration of their effect, there was improvement in spatial learning, as well as maintenance of memory, attention, and working memory relative to placebo dogs. CN/NFAT inhibition is a promising target for prevention of cognitive decline that may be rapidly implemented in human clinical trials.
{"title":"Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease","authors":"Lorena Sordo , Margo F. Ubele , Kathy A. Boaz , Jennifer L. Mefford , Erin Dehnart Jones , Katie L. McCarty , Hollie Y. van Rooyen , Jeffrey Smiley , Stasia A. Bembenek Bailey , Jessica A. Perpich , Beverly Meacham , David K. Powell , Frederick Bresch , Jacob W. Crump , Michael J. Phelan , Jessica A. Noche , Craig E. Stark , László G. Puskás , Christopher M. Norris , Elizabeth Head","doi":"10.1016/j.neurobiolaging.2024.11.003","DOIUrl":"10.1016/j.neurobiolaging.2024.11.003","url":null,"abstract":"<div><div>Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern of cognitive maintenance and duration of their effect, there was improvement in spatial learning, as well as maintenance of memory, attention, and working memory relative to placebo dogs. CN/NFAT inhibition is a promising target for prevention of cognitive decline that may be rapidly implemented in human clinical trials.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"146 ","pages":"Pages 1-14"},"PeriodicalIF":3.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639053","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 : 2024-11-07DOI: 10.1016/j.neurobiolaging.2024.11.001
Marcelo Kenzo Naya Takahashi , Regina Silva Paradela , Lea Tenenholz Grinberg , Renata Elaine Paraizo Leite , Daniela Souza Farias-Itao , Vitor Ribeiro Paes , Maria Eduarda Braga , Michel Satya Naslavsky , Mayana Zatz , Wilson Jacob-Filho , Ricardo Nitrini , Carlos Augusto Pasqualucci , Claudia Kimie Suemoto
Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study.
This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School. Sociodemographic and clinical information was gathered from a reliable next-of-kin informant. Neurofibrillary tangles, neuritic plaques, lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy were evaluated. Causal mediation analyses with natural effect models were performed to examine indirect associations of hypertension with cerebrovascular pathologies and ADNC through morphometric measurements of intracranial artery lumen obstruction.
Hypertensive participants (n = 354) presented a higher rate of stenosed arteries (obstruction ≥ 50 %), critically stenosed arteries (obstruction ≥ 70 %), and more severe ICAD, shown by higher maximum and mean obstruction indexes compared to nonhypertensive participants (n = 166). These measurements of atherosclerosis were associated with neurofibrillary tangles and cSVD lesions. Hypertension was indirectly associated with hyaline arteriolosclerosis and lacunar infarcts through the pathway of ICAD. Presenting hypertension indirectly increased the odds of displaying hyaline arteriolosclerosis by 26 % (95 % CI: 1.08, 1.45, p = 0.002) and lacunar infarcts by 17 % (95 % CI: 1.01, 1.35, p = 0.029). Cognitive and APOE ε4 carrier status did not alter the investigated associations. In this community sample, hypertension was indirectly associated with cSVD through ICAD.
{"title":"Hypertension may associate with cerebral small vessel disease and infarcts through the pathway of intracranial atherosclerosis","authors":"Marcelo Kenzo Naya Takahashi , Regina Silva Paradela , Lea Tenenholz Grinberg , Renata Elaine Paraizo Leite , Daniela Souza Farias-Itao , Vitor Ribeiro Paes , Maria Eduarda Braga , Michel Satya Naslavsky , Mayana Zatz , Wilson Jacob-Filho , Ricardo Nitrini , Carlos Augusto Pasqualucci , Claudia Kimie Suemoto","doi":"10.1016/j.neurobiolaging.2024.11.001","DOIUrl":"10.1016/j.neurobiolaging.2024.11.001","url":null,"abstract":"<div><div>Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study.</div><div>This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School. Sociodemographic and clinical information was gathered from a reliable next-of-kin informant. Neurofibrillary tangles, neuritic plaques, lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy were evaluated. Causal mediation analyses with natural effect models were performed to examine indirect associations of hypertension with cerebrovascular pathologies and ADNC through morphometric measurements of intracranial artery lumen obstruction.</div><div>Hypertensive participants (n = 354) presented a higher rate of stenosed arteries (obstruction ≥ 50 %), critically stenosed arteries (obstruction ≥ 70 %), and more severe ICAD, shown by higher maximum and mean obstruction indexes compared to nonhypertensive participants (n = 166). These measurements of atherosclerosis were associated with neurofibrillary tangles and cSVD lesions. Hypertension was indirectly associated with hyaline arteriolosclerosis and lacunar infarcts through the pathway of ICAD. Presenting hypertension indirectly increased the odds of displaying hyaline arteriolosclerosis by 26 % (95 % CI: 1.08, 1.45, p = 0.002) and lacunar infarcts by 17 % (95 % CI: 1.01, 1.35, p = 0.029). Cognitive and APOE ε4 carrier status did not alter the investigated associations. In this community sample, hypertension was indirectly associated with cSVD through ICAD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 84-95"},"PeriodicalIF":3.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624627","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}
Aging is often accompanied by changes in brain structure and executive functions, particularly in tasks involving cognitive flexibility, such as task-switching. However, substantial individual differences in the degree of cognitive impairment indicate that some individuals can cope with brain changes more effectively than others, suggesting higher cognitive reserve (CR). This study identified a neural basis for CR by examining the longitudinal relationship between task-related brain activation, structural brain changes, and changes in cognitive performance during an executive task-switching paradigm including single and dual conditions. Fifty-two older individuals were assessed at baseline and followed up after five years. Structural brain changes related to task-switching performance were analyzed using elastic net regression. Task-related functional brain activation was measured using ordinal trends canonical variate analysis (OrT CVA), capturing patterns of activation increasing from single to dual conditions. A differential task-related expression score (dOrT) was calculated as the difference in pattern expression scores between single and dual conditions at baseline. A linear regression model tested whether dOrT moderated the impact of brain changes on changes in switch cost over five years. Results showed a significant interaction between changes in brain structure and dOrT activation on switch cost change, indicating a moderation effect of task-related activation. Higher dOrT buffered the impact of brain structural decline on switch costs, enabling older adults to better cope with age-related brain structural changes and preserve cognitive flexibility. These findings suggest that these task-related activation patterns represent a neural basis for CR.
衰老往往伴随着大脑结构和执行功能的变化，特别是在涉及认知灵活性的任务中，如任务转换。然而，认知障碍程度的巨大个体差异表明，有些人比其他人能更有效地应对大脑的变化，这表明他们具有较高的认知储备（CR）。本研究通过研究任务相关的大脑激活、大脑结构变化以及在执行任务切换范式（包括单一和双重条件）中认知表现的变化之间的纵向关系，确定了认知储备的神经基础。52名老年人接受了基线评估和五年后的随访。使用弹性网回归分析了与任务切换表现相关的大脑结构变化。与任务相关的大脑功能激活采用顺序趋势典型变异分析（OrT CVA）进行测量，捕捉从单一条件到双重条件的激活增加模式。与任务相关的差异表达得分（dOrT）被计算为基线时单一和双重条件下模式表达得分的差异。线性回归模型测试了 dOrT 是否会调节大脑变化对五年内转换成本变化的影响。结果显示，大脑结构变化和 dOrT 激活对转换成本变化的影响存在明显的交互作用，这表明任务相关激活具有调节作用。较高的dOrT可以缓冲大脑结构衰退对转换成本的影响，使老年人能够更好地应对与年龄相关的大脑结构变化，保持认知灵活性。这些发现表明，这些与任务相关的激活模式代表了 CR 的神经基础。
{"title":"A neural implementation of cognitive reserve: Insights from a longitudinal fMRI study of set-switching in aging","authors":"Fatemeh Hasanzadeh , Christian Habeck , Yunglin Gazes , Yaakov Stern","doi":"10.1016/j.neurobiolaging.2024.10.008","DOIUrl":"10.1016/j.neurobiolaging.2024.10.008","url":null,"abstract":"<div><div>Aging is often accompanied by changes in brain structure and executive functions, particularly in tasks involving cognitive flexibility, such as task-switching. However, substantial individual differences in the degree of cognitive impairment indicate that some individuals can cope with brain changes more effectively than others, suggesting higher cognitive reserve (CR). This study identified a neural basis for CR by examining the longitudinal relationship between task-related brain activation, structural brain changes, and changes in cognitive performance during an executive task-switching paradigm including single and dual conditions. Fifty-two older individuals were assessed at baseline and followed up after five years. Structural brain changes related to task-switching performance were analyzed using elastic net regression. Task-related functional brain activation was measured using ordinal trends canonical variate analysis (OrT CVA), capturing patterns of activation increasing from single to dual conditions. A differential task-related expression score (dOrT) was calculated as the difference in pattern expression scores between single and dual conditions at baseline. A linear regression model tested whether dOrT moderated the impact of brain changes on changes in switch cost over five years. Results showed a significant interaction between changes in brain structure and dOrT activation on switch cost change, indicating a moderation effect of task-related activation. Higher dOrT buffered the impact of brain structural decline on switch costs, enabling older adults to better cope with age-related brain structural changes and preserve cognitive flexibility. These findings suggest that these task-related activation patterns represent a neural basis for CR.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 76-83"},"PeriodicalIF":3.7,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592857","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 : 2024-10-28DOI: 10.1016/j.neurobiolaging.2024.10.007
Kristen H. Jardine , Emily P. Minard , Cassidy E. Wideman , Haley Edwards , Karim H. Abouelnaga , William S. Messer , Boyer D. Winters
Previously consolidated memories can become temporarily labile upon reactivation. Reactivation-based memory updating is chiefly studied in young subjects, so we aimed to assess this process across the lifespan. To do this, we developed a behavioural paradigm wherein a reactivated object memory is updated with contextual information; 3-month-old and 6-month-old male C57BL/6 mice displayed object memory updating, but 12-month-old mice did not. We found that M1 muscarinic acetylcholine receptor signaling during reactivation was necessary for object memory updating in the young mice. Next, we targeted this mechanism in an attempt to facilitate object memory updating in aging mice. Remarkably, systemic pharmacological M1 receptor activation reversed the age-related deficit. Quantification of cholinergic system markers within perirhinal cortex revealed subtle cellular changes that may contribute to differential performance across age groups. These findings suggest that natural cholinergic change across the lifespan contributes to inflexible memory in the aging brain.
{"title":"M1 muscarinic receptor activation reverses age-related memory updating impairment in mice","authors":"Kristen H. Jardine , Emily P. Minard , Cassidy E. Wideman , Haley Edwards , Karim H. Abouelnaga , William S. Messer , Boyer D. Winters","doi":"10.1016/j.neurobiolaging.2024.10.007","DOIUrl":"10.1016/j.neurobiolaging.2024.10.007","url":null,"abstract":"<div><div>Previously consolidated memories can become temporarily labile upon reactivation. Reactivation-based memory updating is chiefly studied in young subjects, so we aimed to assess this process across the lifespan. To do this, we developed a behavioural paradigm wherein a reactivated object memory is updated with contextual information; 3-month-old and 6-month-old male C57BL/6 mice displayed object memory updating, but 12-month-old mice did not. We found that M1 muscarinic acetylcholine receptor signaling during reactivation was necessary for object memory updating in the young mice. Next, we targeted this mechanism in an attempt to facilitate object memory updating in aging mice. Remarkably, systemic pharmacological M1 receptor activation reversed the age-related deficit. Quantification of cholinergic system markers within perirhinal cortex revealed subtle cellular changes that may contribute to differential performance across age groups. These findings suggest that natural cholinergic change across the lifespan contributes to inflexible memory in the aging brain.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 65-75"},"PeriodicalIF":3.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1016/j.neurobiolaging.2024.10.006
Valentinos Zachariou , Colleen Pappas , Christopher E. Bauer , Elayna R. Seago , Brian T. Gold
This study evaluated longitudinal brain iron accumulation in older adults, its association with cognition, and the role of specific nutrients in mitigating iron accumulation. MRI-based, quantitative susceptibility mapping estimates of brain iron concentration were acquired from seventy-two healthy older adults (47 women, ages 60–86) at a baseline timepoint (TP1) and a follow-up timepoint (TP2) 2.5–3.0 years later. Dietary intake was evaluated at baseline using a validated questionnaire. Cognitive performance was assessed at TP2 using the uniform data set (Version 3) neuropsychological tests of episodic memory (MEM) and executive function (EF). Voxel-wise, linear mixed-effects models, adjusted for longitudinal gray matter volume alterations, age, and several non-dietary lifestyle factors revealed brain iron accumulation in multiple subcortical and cortical brain regions, which was negatively associated with both MEM and EF performance at T2. However, consumption of specific dietary nutrients at TP1 was associated with reduced brain iron accumulation. Our study provides a map of brain regions showing iron accumulation in older adults over a short 2.5-year follow-up and indicates that certain dietary nutrients may slow brain iron accumulation.
{"title":"Exploring the links among brain iron accumulation, cognitive performance, and dietary intake in older adults: A longitudinal MRI study","authors":"Valentinos Zachariou , Colleen Pappas , Christopher E. Bauer , Elayna R. Seago , Brian T. Gold","doi":"10.1016/j.neurobiolaging.2024.10.006","DOIUrl":"10.1016/j.neurobiolaging.2024.10.006","url":null,"abstract":"<div><div>This study evaluated longitudinal brain iron accumulation in older adults, its association with cognition, and the role of specific nutrients in mitigating iron accumulation. MRI-based, quantitative susceptibility mapping estimates of brain iron concentration were acquired from seventy-two healthy older adults (47 women, ages 60–86) at a baseline timepoint (TP1) and a follow-up timepoint (TP2) 2.5–3.0 years later. Dietary intake was evaluated at baseline using a validated questionnaire. Cognitive performance was assessed at TP2 using the uniform data set (Version 3) neuropsychological tests of episodic memory (MEM) and executive function (EF). Voxel-wise, linear mixed-effects models, adjusted for longitudinal gray matter volume alterations, age, and several non-dietary lifestyle factors revealed brain iron accumulation in multiple subcortical and cortical brain regions, which was negatively associated with both MEM and EF performance at T2. However, consumption of specific dietary nutrients at TP1 was associated with reduced brain iron accumulation. Our study provides a map of brain regions showing iron accumulation in older adults over a short 2.5-year follow-up and indicates that certain dietary nutrients may slow brain iron accumulation.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 1-12"},"PeriodicalIF":3.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1016/j.neurobiolaging.2024.10.005
Wenyan Lu, Francis Shue, Aishe Kurti, Suren Jeevaratnam, Jesse R. Macyczko, Bhaskar Roy, Taha Izhar, Ni Wang, Guojun Bu , Takahisa Kanekiyo, Yonghe Li
The hAβ-KI and APPSAA-KI are two amyloid models that harbor mutations in the endogenous mouse App gene. Both hAβ-KI and APPSAA-KI mice contain a humanized Aβ sequence, and APPSAA-KI mice carry three additional familial AD mutations. We herein report that the Aβ levels and Aβ42/Aβ40 ratio in APPSAA-KI homozygotes are dramatically higher than those in hAβ-KI homozygotes at 14 months of age. In addition, APPSAA-KI mice display a widespread distribution of amyloid plaques in the brain, whereas the plaques are undetectable in hAβ-KI mice. Moreover, there are no sex differences in amyloid pathology in APPSAA-KI mice. Both APPSAA-KI and hAβ-KI mice exhibit cognitive impairments, wherein no significant differences are found between these two models, although APPSAA KI mice show a trend towards worse cognitive function. Notably, female hAβ-KI and APPSAA-KI mice have a more pronounced cognitive impairments compared to their respective males. Our findings suggest that Aβ humanization contributes to cognitive deficits in APPSAA-KI mice, and that amyloid deposition might not be closely associated with cognitive impairments in APPSAA-KI mice.
{"title":"Amyloid pathology and cognitive impairment in hAβ-KI and APPSAA-KI mouse models of Alzheimer's disease","authors":"Wenyan Lu, Francis Shue, Aishe Kurti, Suren Jeevaratnam, Jesse R. Macyczko, Bhaskar Roy, Taha Izhar, Ni Wang, Guojun Bu , Takahisa Kanekiyo, Yonghe Li","doi":"10.1016/j.neurobiolaging.2024.10.005","DOIUrl":"10.1016/j.neurobiolaging.2024.10.005","url":null,"abstract":"<div><div>The hAβ-KI and APP<sup>SAA</sup>-KI are two amyloid models that harbor mutations in the endogenous mouse <em>App</em> gene. Both hAβ-KI and APP<sup>SAA</sup>-KI mice contain a humanized Aβ sequence, and APP<sup>SAA</sup>-KI mice carry three additional familial AD mutations. We herein report that the Aβ levels and Aβ42/Aβ40 ratio in APP<sup>SAA</sup>-KI homozygotes are dramatically higher than those in hAβ-KI homozygotes at 14 months of age. In addition, APP<sup>SAA</sup>-KI mice display a widespread distribution of amyloid plaques in the brain, whereas the plaques are undetectable in hAβ-KI mice. Moreover, there are no sex differences in amyloid pathology in APP<sup>SAA</sup>-KI mice. Both APP<sup>SAA</sup>-KI and hAβ-KI mice exhibit cognitive impairments, wherein no significant differences are found between these two models, although APP<sup>SAA</sup> KI mice show a trend towards worse cognitive function. Notably, female hAβ-KI and APP<sup>SAA</sup>-KI mice have a more pronounced cognitive impairments compared to their respective males. Our findings suggest that Aβ humanization contributes to cognitive deficits in APP<sup>SAA</sup>-KI mice, and that amyloid deposition might not be closely associated with cognitive impairments in APP<sup>SAA</sup>-KI mice.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 13-23"},"PeriodicalIF":3.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1016/j.neurobiolaging.2024.10.004
Xi Chen , Alexis Juarez , Suzanne Mason , Sarah Kobayashi , Suzanne L. Baker , Theresa M. Harrison , Susan M. Landau , William J. Jagust
The early accumulation of AD pathology such as Aβ and tau in cognitively normal older people is predictive of cognitive decline, but it has been difficult to dissociate the cognitive effects of these two proteins. Early Aβ and tau target distinct brain regions that have different functional roles. Here, we assessed specific longitudinal pathology-cognition associations in seventy-six cognitively normal older adults from the Berkeley Aging Cohort Study who underwent longitudinal PiB PET, FTP PET, and cognitive assessments. Using linear mixed-effects models to estimate longitudinal changes and residual approach to characterizing cognitive domain-specific associations, we found that Aβ accumulation, especially in frontal/parietal regions, was associated with faster decline in executive function, not memory, whereas tau accumulation, especially in left entorhinal/parahippocampal regions, was associated with faster decline in memory, not executive function, supporting an “Aβ-executive function, tau-memory” double-dissociation in cognitively normal older people. These specific relationships between accumulating pathology and domain-specific cognitive decline may be due to the particular vulnerabilities of the frontal-parietal executive network to Aβ and temporal memory network to tau.
{"title":"Longitudinal relationships between Aβ and tau to executive function and memory in cognitively normal older adults","authors":"Xi Chen , Alexis Juarez , Suzanne Mason , Sarah Kobayashi , Suzanne L. Baker , Theresa M. Harrison , Susan M. Landau , William J. Jagust","doi":"10.1016/j.neurobiolaging.2024.10.004","DOIUrl":"10.1016/j.neurobiolaging.2024.10.004","url":null,"abstract":"<div><div>The early accumulation of AD pathology such as Aβ and tau in cognitively normal older people is predictive of cognitive decline, but it has been difficult to dissociate the cognitive effects of these two proteins. Early Aβ and tau target distinct brain regions that have different functional roles. Here, we assessed specific longitudinal pathology-cognition associations in seventy-six cognitively normal older adults from the Berkeley Aging Cohort Study who underwent longitudinal PiB PET, FTP PET, and cognitive assessments. Using linear mixed-effects models to estimate longitudinal changes and residual approach to characterizing cognitive domain-specific associations, we found that Aβ accumulation, especially in frontal/parietal regions, was associated with faster decline in executive function, not memory, whereas tau accumulation, especially in left entorhinal/parahippocampal regions, was associated with faster decline in memory, not executive function, supporting an “Aβ-executive function, tau-memory” double-dissociation in cognitively normal older people. These specific relationships between accumulating pathology and domain-specific cognitive decline may be due to the particular vulnerabilities of the frontal-parietal executive network to Aβ and temporal memory network to tau.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 32-41"},"PeriodicalIF":3.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142528427","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 : 2024-10-18DOI: 10.1016/j.neurobiolaging.2024.10.003
Jordi H.C. Boons , Elisabeth J. Vinke , Gertjan Dingemanse , Bernd Kremer , André Goedegebure , Meike W. Vernooij
Hearing loss is considered a potentially modifiable risk factor for dementia. The sensory deprivation theory postulates that hearing loss adversely affects cognition in older adults through structural brain changes, but longitudinal studies are scarce. To find evidence for a possible detrimental effect of hearing loss on white matter microstructure, we carried out a longitudinal study in the population-based Rotterdam Study. A total of 1877 participants with a median age at baseline of 56.4 years (IQR: [52.2–60.0]) underwent audiometry and had longitudinal diffusion imaging data available with a mean follow-up of 4.0 years. A lower level of hearing acuity was associated with worse white matter microstructure in the left uncinate fasciculus and superior longitudinal fasciculus at baseline. Poorer hearing acuity was also associated with faster microstructural deterioration over time in the left superior longitudinal fasciculus. The strongest effects were observed for low-frequency hearing thresholds, while the high-frequency thresholds showed the weakest associations. These results suggest that hearing loss may contribute to the age-related decline in brain structure, consistent with the sensory deprivation theory.
{"title":"Hearing loss and its relation to longitudinal changes in white matter microstructure in older adults: The Rotterdam Study","authors":"Jordi H.C. Boons , Elisabeth J. Vinke , Gertjan Dingemanse , Bernd Kremer , André Goedegebure , Meike W. Vernooij","doi":"10.1016/j.neurobiolaging.2024.10.003","DOIUrl":"10.1016/j.neurobiolaging.2024.10.003","url":null,"abstract":"<div><div>Hearing loss is considered a potentially modifiable risk factor for dementia. The sensory deprivation theory postulates that hearing loss adversely affects cognition in older adults through structural brain changes, but longitudinal studies are scarce. To find evidence for a possible detrimental effect of hearing loss on white matter microstructure, we carried out a longitudinal study in the population-based Rotterdam Study. A total of 1877 participants with a median age at baseline of 56.4 years (IQR: [52.2–60.0]) underwent audiometry and had longitudinal diffusion imaging data available with a mean follow-up of 4.0 years. A lower level of hearing acuity was associated with worse white matter microstructure in the left uncinate fasciculus and superior longitudinal fasciculus at baseline. Poorer hearing acuity was also associated with faster microstructural deterioration over time in the left superior longitudinal fasciculus. The strongest effects were observed for low-frequency hearing thresholds, while the high-frequency thresholds showed the weakest associations. These results suggest that hearing loss may contribute to the age-related decline in brain structure, consistent with the sensory deprivation theory.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 24-31"},"PeriodicalIF":3.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1016/j.neurobiolaging.2024.09.014
Grace C. Smith , Keith R. Griffith , Avery R. Sicher , Dakota F. Brockway , Elizabeth A. Proctor , Nicole A. Crowley
Both alcohol use disorder (AUD) and cognitive decline include disruption in the balance of excitation and inhibition in the cortex, but the potential role of alcohol use on excitation and inhibition on the aging brain is unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons. A profound increase in excitatory events onto layer 2/3 non-pyramidal neurons following alcohol consumption was seen, along with altered intrinsic excitability of pyramidal neurons, which could have a range of effects on cognitive disorder progression, such as Alzheimer’s Disease, in humans. These results indicate that moderate voluntary alcohol influences the pre-disease environment in aging and highlight the need for further mechanistic investigation into this risk factor.
{"title":"Alcohol consumption confers lasting impacts on prefrontal cortical neuron intrinsic excitability and spontaneous neurotransmitter signaling in the aging brain in mice","authors":"Grace C. Smith , Keith R. Griffith , Avery R. Sicher , Dakota F. Brockway , Elizabeth A. Proctor , Nicole A. Crowley","doi":"10.1016/j.neurobiolaging.2024.09.014","DOIUrl":"10.1016/j.neurobiolaging.2024.09.014","url":null,"abstract":"<div><div>Both alcohol use disorder (AUD) and cognitive decline include disruption in the balance of excitation and inhibition in the cortex, but the potential role of alcohol use on excitation and inhibition on the aging brain is unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons. A profound increase in excitatory events onto layer 2/3 non-pyramidal neurons following alcohol consumption was seen, along with altered intrinsic excitability of pyramidal neurons, which could have a range of effects on cognitive disorder progression, such as Alzheimer’s Disease, in humans. These results indicate that moderate voluntary alcohol influences the pre-disease environment in aging and highlight the need for further mechanistic investigation into this risk factor.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"145 ","pages":"Pages 42-54"},"PeriodicalIF":3.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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