Pub Date : 2025-01-01Epub Date: 2024-12-13DOI: 10.1016/j.nbas.2024.100134
Robyn A. Honea , Heather Wilkins , Suzanne L. Hunt , Paul J. Kueck , Jeffrey M. Burns , Russell H. Swerdlow , Jill K. Morris
A growing amount of data has implicated the TOMM40 gene in the risk for Alzheimer’s disease (AD), neurodegeneration, and accelerated aging. No studies have investigated the relationship of TOMM40 rs2075650 (‘650) on the structural complexity of the brain or plasma markers of neurodegeneration. We used a comprehensive approach to quantify the impact of TOMM40 ‘650 on brain morphology and multiple cortical attributes in cognitively unimpaired (CU) individuals. We also tested whether the presence of the risk allele, G, of TOMM40 ‘650 was associated with plasma markers of amyloid, tau, and neurodegeneration and if there were interactions with age and sex, controlling for the effects of APOE ε4. We found that the TOMM40 ‘650 G-allele was associated with decreased sulcal depth, increased gyrification index, and decreased gray matter volume. NfL, GFAP, and pTau181 had independent and age-associated increases in individuals with a G-allele. Our data suggest that TOMM40 ‘650 is associated with aging-related plasma biomarkers and brain structure variation in temporal-limbic circuits.
{"title":"TOMM40 may mediate GFAP, neurofilament light Protein, pTau181, and brain morphometry in aging","authors":"Robyn A. Honea , Heather Wilkins , Suzanne L. Hunt , Paul J. Kueck , Jeffrey M. Burns , Russell H. Swerdlow , Jill K. Morris","doi":"10.1016/j.nbas.2024.100134","DOIUrl":"10.1016/j.nbas.2024.100134","url":null,"abstract":"<div><div>A growing amount of data has implicated the <em>TOMM40</em> gene in the risk for Alzheimer’s disease (AD), neurodegeneration, and accelerated aging. No studies have investigated the relationship of <em>TOMM40</em> rs2075650 (‘650<em>)</em> on the structural complexity of the brain or plasma markers of neurodegeneration. We used a comprehensive approach to quantify the impact of <em>TOMM40</em> ‘650 on brain morphology and multiple cortical attributes in cognitively unimpaired (CU) individuals. We also tested whether the presence of the risk allele, G, of <em>TOMM40</em> ‘650 was associated with plasma markers of amyloid, tau, and neurodegeneration and if there were interactions with age and sex, controlling for the effects of <em>APOE</em> ε4. We found that the <em>TOMM40</em> ‘650 G-allele was associated with decreased sulcal depth, increased gyrification index, and decreased gray matter volume. NfL, GFAP, and pTau181 had independent and age-associated increases in individuals with a G-allele. Our data suggest that <em>TOMM40</em> ‘650 is associated with aging-related plasma biomarkers and brain structure variation in temporal-limbic circuits.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"7 ","pages":"Article 100134"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-05-17DOI: 10.1016/j.nbas.2025.100139
Nathan A. Gillespie , Michael C. Neale , Matthew S. Panizzon , Ruth E. McKenzie , Xin M. Tu , Hong Xian , Chandra A. Reynolds , Michael J. Lyons , Robert A. Rissman , Jeremy A. Elman , Carol Franz , William S. Kremen
The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.
{"title":"Testing the causal impact of plasma amyloid on total Tau using a genetically informative sample of adult male twins","authors":"Nathan A. Gillespie , Michael C. Neale , Matthew S. Panizzon , Ruth E. McKenzie , Xin M. Tu , Hong Xian , Chandra A. Reynolds , Michael J. Lyons , Robert A. Rissman , Jeremy A. Elman , Carol Franz , William S. Kremen","doi":"10.1016/j.nbas.2025.100139","DOIUrl":"10.1016/j.nbas.2025.100139","url":null,"abstract":"<div><div>The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"7 ","pages":"Article 100139"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-07-31DOI: 10.1016/j.nbas.2025.100146
Cheyenne Chooi , Brandon E. Gavett , David Ames , Paul Maruff , Vincent Doré , Victor L. Villemagne , Pierrick Bourgeat , Ying Xia , Colin L. Masters , Ralph N. Martins , Kevin Taddei , Christopher C. Rowe , Michael Weinborn , Stephanie R. Rainey-Smith
Sex differences in cognitive reserve might contribute to females being disproportionately affected by Alzheimer’s disease (AD). We investigated sex differences in the protective effects of cognitive reserve, and whether brain beta-amyloid accounts for differences. Older adults (n = 997 from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing) diagnosed as Cognitively Normal, Mild Cognitive Impairment, or AD at baseline were assessed every 18 months for up to a maximum of seven visits. Cognitive reserve was calculated from the variance in episodic memory not explained by demographic or brain measures. Executive functioning (EF) intercept and slope were regressed onto the main and interaction effects of cognitive reserve x brain integrity x sex, plus covariates (age, number of APOE ε4 alleles). A three-way interaction was observed between cognitive reserve, brain integrity, and sex on the EF slope. Females benefitted more than males from the protective effects of cognitive reserve at low levels of brain integrity. Sex differences in the protective effect of cognitive reserve were not moderated by brain beta-amyloid burden.
{"title":"Sex differences in the association between episodic memory residual reserve index and change in executive function","authors":"Cheyenne Chooi , Brandon E. Gavett , David Ames , Paul Maruff , Vincent Doré , Victor L. Villemagne , Pierrick Bourgeat , Ying Xia , Colin L. Masters , Ralph N. Martins , Kevin Taddei , Christopher C. Rowe , Michael Weinborn , Stephanie R. Rainey-Smith","doi":"10.1016/j.nbas.2025.100146","DOIUrl":"10.1016/j.nbas.2025.100146","url":null,"abstract":"<div><div>Sex differences in cognitive reserve might contribute to females being disproportionately affected by Alzheimer’s disease (AD). We investigated sex differences in the protective effects of cognitive reserve, and whether brain beta-amyloid accounts for differences. Older adults (n = 997 from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing) diagnosed as Cognitively Normal, Mild Cognitive Impairment, or AD at baseline were assessed every 18 months for up to a maximum of seven visits. Cognitive reserve was calculated from the variance in episodic memory not explained by demographic or brain measures. Executive functioning (EF) intercept and slope were regressed onto the main and interaction effects of cognitive reserve x brain integrity x sex, plus covariates (age, number of <em>APOE</em> ε4 alleles). A three-way interaction was observed between cognitive reserve, brain integrity, and sex on the EF slope. Females benefitted more than males from the protective effects of cognitive reserve at low levels of brain integrity. Sex differences in the protective effect of cognitive reserve were not moderated by brain beta-amyloid burden.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"8 ","pages":"Article 100146"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-09-09DOI: 10.1016/j.nbas.2025.100151
Emily Whisenant, Arne C. Lekven
Reference genes (RGs) are typically used to normalize gene expression from RT-qPCR experiments. However, the expression of commonly used RGs can vary across different physiological conditions, such as aging, and potentially lead to inaccurate interpretations of results. In African turquoise killifish (Nothobranchius furzeri), the stability of reference genes has not been evaluated during aging. Here, we evaluate six candidate reference genes used in other models of aging (actb, cyc1, gapdh, gusb, oaz1a, and tbp) and examine their brain expression stability in adult males and females from young (10 weeks post-hatching) to old (25 weeks post-hatching). To examine RG stability, we used a combination of summary statistics based on analyses of Cq values, normalized fold change of tyrosine hydroxylase (th), and available computational programs. Overall, we found that cyc1, oaz1a, and gusb were the most stable reference genes during aging across both sexes, with specific rankings reflecting sex-dependent differences, while gapdh and actb were the least reliable. Importantly, when th expression was normalized to our selected RGs, we found that only female samples had an age-related decrease in expression, and expression analysis was highly dependent on the choice of reference gene. Taken together, our findings provide the first systematic evaluation of RG stability in the killifish brain and highlight cyc1, oaz1a, and gusb as reliable RGs for studies of aging. We recommend that future studies use at least two of these RGs in combination for accurate normalization and evaluate RGs for selected experimental conditions within the framework established in this study.
{"title":"Evaluation of candidate RT-qPCR reference genes in the aging African turquoise killifish brain","authors":"Emily Whisenant, Arne C. Lekven","doi":"10.1016/j.nbas.2025.100151","DOIUrl":"10.1016/j.nbas.2025.100151","url":null,"abstract":"<div><div>Reference genes (RGs) are typically used to normalize gene expression from RT-qPCR experiments. However, the expression of commonly used RGs can vary across different physiological conditions, such as aging, and potentially lead to inaccurate interpretations of results. In African turquoise killifish (<em>Nothobranchius furzeri</em>), the stability of reference genes has not been evaluated during aging. Here, we evaluate six candidate reference genes used in other models of aging (<em>actb</em>, <em>cyc1</em>, <em>gapdh</em>, <em>gusb</em>, <em>oaz1a</em>, and <em>tbp</em>) and examine their brain expression stability in adult males and females from young (10 weeks post-hatching) to old (25 weeks post-hatching). To examine RG stability, we used a combination of summary statistics based on analyses of Cq values, normalized fold change of tyrosine hydroxylase (<em>th</em>), and available computational programs. Overall, we found that <em>cyc1</em>, <em>oaz1a</em>, and <em>gusb</em> were the most stable reference genes during aging across both sexes, with specific rankings reflecting sex-dependent differences, while <em>gapdh</em> and <em>actb</em> were the least reliable. Importantly, when <em>th</em> expression was normalized to our selected RGs, we found that only female samples had an age-related decrease in expression, and expression analysis was highly dependent on the choice of reference gene. Taken together, our findings provide the first systematic evaluation of RG stability in the killifish brain and highlight <em>cyc1</em>, <em>oaz1a</em>, and <em>gusb</em> as reliable RGs for studies of aging. We recommend that future studies use at least two of these RGs in combination for accurate normalization and evaluate RGs for selected experimental conditions within the framework established in this study.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"8 ","pages":"Article 100151"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-05-09DOI: 10.1016/j.nbas.2025.100140
Jasmin Joshi, Chandlyr M. Denaro, Alan A. Hartley, Catherine L. Reed
Working memory (WM), the temporary maintenance of a limited amount of information in an accessible state, is required for the performance of many tasks. Studies have shown that WM demands are related to the neural processing of tasks requiring attention: Age affects the ERP components associated with WM context updating processes in the visual oddball task (P3) and semantic processing in the word-pair judgment task (N400). This study investigated whether WM capacity measured by complex span tasks mediates the effects of age on these ERPs. Younger adults (YA, n = 44, ages 18–23 yr) and older adults (OA, n = 41, ages 69–89 yr) completed operation, reading, and symmetry complex span tasks and two ERP tasks (P3/visual oddball; N400/word-pair judgment). Results showed age-related differences for all complex span tests. Principal components analysis of these tests showed a single factor for both groups, so a combined WM capacity factor score was created. Regressions of age group and WM factor score on P3 and N400 amplitudes and latencies showed that OAs had relatively lower amplitudes and longer latencies. However complex span was not related to P3 or N400 amplitudes or latencies and that result was the same for younger and older adults; that is, complex span did not mediate the age effects. WM processes indexed by the P3 and N400 components appear to be different from those elicited by complex span tasks. Attentional control processes of WM influence oddball and semantic judgement tasks more than storage components.
工作记忆（WM）是在可访问状态下对有限数量信息的临时维护，是许多任务的执行所必需的。研究表明，WM需求与需要注意的任务的神经加工有关：年龄影响与视觉怪球任务（P3）和词对判断任务（N400）中WM上下文更新过程相关的ERP成分。本研究探讨了由复杂跨度任务测量的脑记忆能力是否介导了年龄对这些erp的影响。年轻人（YA, n = 44，年龄18-23岁）和老年人（OA, n = 41，年龄69-89岁）完成了操作、阅读和对称复杂跨度任务和两个ERP任务(P3/视觉怪球；N400 /一对词组的判断)。结果显示所有复杂跨度测试的年龄相关差异。这些测试的主成分分析显示两组都有一个单一因素，因此创建了一个综合WM能力因素评分。各年龄组和WM因子评分对P3和N400波幅和潜伏期的回归表明，oa的波幅较低，潜伏期较长。而复杂跨幅与P3、N400的振幅和潜伏期无显著相关性，在年轻人和老年人中结果相同；即复合跨度对年龄的影响没有中介作用。P3和N400组件索引的WM过程似乎与复杂跨任务引发的WM过程不同。WM的注意控制过程对古怪判断和语义判断任务的影响大于存储成分。
{"title":"Complex span measures of working memory do not mediate the effects of age on the P3 and N400 ERPs","authors":"Jasmin Joshi, Chandlyr M. Denaro, Alan A. Hartley, Catherine L. Reed","doi":"10.1016/j.nbas.2025.100140","DOIUrl":"10.1016/j.nbas.2025.100140","url":null,"abstract":"<div><div>Working memory (WM), the temporary maintenance of a limited amount of information in an accessible state, is required for the performance of many tasks. Studies have shown that WM demands are related to the neural processing of tasks requiring attention: Age affects the ERP components associated with WM context updating processes in the visual oddball task (P3) and semantic processing in the word-pair judgment task (N400). This study investigated whether WM capacity measured by complex span tasks mediates the effects of age on these ERPs. Younger adults (YA, n = 44, ages 18–23 yr) and older adults (OA, n = 41, ages 69–89 yr) completed operation, reading, and symmetry complex span tasks and two ERP tasks (P3/visual oddball; N400/word-pair judgment). Results showed age-related differences for all complex span tests. Principal components analysis of these tests showed a single factor for both groups, so a combined WM capacity factor score was created. Regressions of age group and WM factor score on P3 and N400 amplitudes and latencies showed that OAs had relatively lower amplitudes and longer latencies. However complex span was not related to P3 or N400 amplitudes or latencies and that result was the same for younger and older adults; that is, complex span did not mediate the age effects. WM processes indexed by the P3 and N400 components appear to be different from those elicited by complex span tasks. Attentional control processes of WM influence oddball and semantic judgement tasks more than storage components.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"7 ","pages":"Article 100140"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-05-04DOI: 10.1016/j.nbas.2025.100137
A. Lamé , E.G. Thomas , S.A.J. van de Schraaf , C. Groot , C.H. Sudre , F. Barkhof , M. Muller , R. Ossenkoppele , H.F.M. Rhodius-Meester
Differences between men and women in cognitive impairment and neurodegeneration are not yet well understood. Although sex differences in brain structure abnormalities, including white matter hyperintensities (WMH) and grey matter (GM) atrophy, have been associated with cognitive decline in the ageing population, the evidence is limited and inconclusive. Therefore, we explored sex differences in brain structure abnormalities and in the association between brain structure abnormalities and cognitive functioning. We analyzed global and regional volumetric measures of WMH and GM of 475 patients visiting an academic geriatric memory clinic in the Netherlands with multiple linear regression analyses. For both global and regional WMH and GM, we found no sex differences in brain structure abnormalities. We also found no interaction of sex on the association between brain structure abnormalities and cognitive functioning. We reflect on using a binary classification of men and women based on sex in this study, which might overlook individual differences and does not elucidate gender-related factors that influence health and risk of pathology. Future studies should focus on exploring the relationship between sex and gender on brain structure and cognitive functioning beyond this binary model, by including more data on social context, more diverse populations and using intersectional approaches.
{"title":"No sex differences in the association between regional brain structure abnormalities and cognitive functioning in a geriatric memory clinic population","authors":"A. Lamé , E.G. Thomas , S.A.J. van de Schraaf , C. Groot , C.H. Sudre , F. Barkhof , M. Muller , R. Ossenkoppele , H.F.M. Rhodius-Meester","doi":"10.1016/j.nbas.2025.100137","DOIUrl":"10.1016/j.nbas.2025.100137","url":null,"abstract":"<div><div>Differences between men and women in cognitive impairment and neurodegeneration are not yet well understood. Although sex differences in brain structure abnormalities, including white matter hyperintensities (WMH) and grey matter (GM) atrophy, have been associated with cognitive decline in the ageing population, the evidence is limited and inconclusive. Therefore, we explored sex differences in brain structure abnormalities and in the association between brain structure abnormalities and cognitive functioning. We analyzed global and regional volumetric measures of WMH and GM of 475 patients visiting an academic geriatric memory clinic in the Netherlands with multiple linear regression analyses. For both global and regional WMH and GM, we found no sex differences in brain structure abnormalities. We also found no interaction of sex on the association between brain structure abnormalities and cognitive functioning. We reflect on using a binary classification of men and women based on sex in this study, which might overlook individual differences and does not elucidate gender-related factors that influence health and risk of pathology. Future studies should focus on exploring the relationship between sex and gender on brain structure and cognitive functioning beyond this binary model, by including more data on social context, more diverse populations and using intersectional approaches.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"7 ","pages":"Article 100137"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-10-28DOI: 10.1016/j.nbas.2025.100153
Alejandro J. Lopez , Terrence J. Glover , Taylor M. Leone , Catherine F. Mason , Camille Guzman , Lena H. Ting , Michael R. Borich , Trisha M. Kesar
The objective of this study was to evaluate the effects of aging on descending modulation of spinal reflexes across different task conditions. In healthy young (YA; age 27 ± 4 years) and older (OA; age 63 ± 10 years) adults, we utilized paired subthreshold transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) to elicit unconditioned (PNS only) and conditioned (TMS paired with PNS) soleus Hoffmann (H-)reflexes at 3 inter-stimulus intervals (ISIs) (−1.5, +10 ms, +40 ms) and during 3 task conditions − sit rest (SR), sit active (SA), and quiet stance (QS). Our results showed that at the + 40 ms ISI, compared to YA, the OA group showed significant differences in modulation (and reversal from facilitation to inhibition) of soleus H-reflexes during both SA and QS tasks (p < 0.0001). Correlation analysis showed a significant negative relationship between age and the magnitude of H-reflex modulation at the + 40 ms ISI, such that older individuals showed a larger magnitude of H-reflex inhibition. In conclusion, altered task-related modulation of spinal reflexes at the + 40 ms ISI may reflect specific aging-related effects on spinal sensorimotor integration, likely mediated via complex interactions between the influence of polysynaptic slower-conducting descending pathways, sensory afferents, and local spinal circuits, on spinal reflex activity during motor task performance.
本研究的目的是评估年龄对不同任务条件下脊髓反射下行调节的影响。在健康青年（年龄27±4岁）和老年人（年龄63±10岁）中，我们采用阈下经颅磁刺激（TMS）和外周神经刺激（PNS）配对，在3个刺激间隔（- 1.5、+10 ms、+40 ms）和3个任务条件下——坐着休息（SR）、坐着活动（SA）和安静姿势（QS）下诱发非条件（仅PNS）和条件（TMS与PNS配对）比目鱼霍夫曼（H-）反射。我们的研究结果显示，在+ 40 ms ISI时，与YA相比，OA组在SA和QS任务中对比目鱼h -反射的调节（以及从促进到抑制的逆转）表现出显著差异（p < 0.0001）。相关分析显示，年龄与+ 40 ms ISI时h -反射调制强度呈显著负相关，即年龄越大的个体h -反射抑制强度越大。综上所述，在ISI + 40 ms时，脊髓反射的任务相关调节的改变可能反映了与年龄相关的脊髓感觉运动整合的特定影响，这可能是通过多突触传导较慢的下行通路、感觉传入和局部脊髓回路对运动任务中脊髓反射活动的影响之间的复杂相互作用介导的。
{"title":"Influence of aging and task-related activation on descending cortical modulation of spinal sensorimotor circuitry","authors":"Alejandro J. Lopez , Terrence J. Glover , Taylor M. Leone , Catherine F. Mason , Camille Guzman , Lena H. Ting , Michael R. Borich , Trisha M. Kesar","doi":"10.1016/j.nbas.2025.100153","DOIUrl":"10.1016/j.nbas.2025.100153","url":null,"abstract":"<div><div>The objective of this study was to evaluate the effects of aging on descending modulation of spinal reflexes across different task conditions. In healthy young (YA; age 27 ± 4 years) and older (OA; age 63 ± 10 years) adults, we utilized paired subthreshold transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) to elicit unconditioned (PNS only) and conditioned (TMS paired with PNS) soleus Hoffmann (H-)reflexes at 3 inter-stimulus intervals (ISIs) (−1.5, +10 ms, +40 ms) and during 3 task conditions − sit rest (SR), sit active (SA), and quiet stance (QS). Our results showed that at the + 40 ms ISI, compared to YA, the OA group showed significant differences in modulation (and reversal from facilitation to inhibition) of soleus H-reflexes during both SA and QS tasks (p < 0.0001). Correlation analysis showed a significant negative relationship between age and the magnitude of H-reflex modulation at the + 40 ms ISI, such that older individuals showed a larger magnitude of H-reflex inhibition. In conclusion, altered task-related modulation of spinal reflexes at the + 40 ms ISI may reflect specific aging-related effects on spinal sensorimotor integration, likely mediated via complex interactions between the influence of polysynaptic slower-conducting descending pathways, sensory afferents, and local spinal circuits, on spinal reflex activity during motor task performance.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"8 ","pages":"Article 100153"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145416164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-07-30DOI: 10.1016/j.nbas.2025.100147
Chenyang Jiang , Sven J. van der Lee , Niccolò Tesi , Wiesje M. van der Flier , Betty M. Tijms , Lianne M. Reus
Alzheimer’s disease and related dementias (ADRD) are complex neurodegenerative disorders of which the genetic basis remains incompletely understood. Hippocampal volume loss is a core hallmark of AD. Hippocampal volume also has a strong heritable component and its genetic underpinnings may help us to understand the complex biological mechanism underlying ADRD. To identify shared genetic risk loci across late-onset ADRD and bilateral hippocampal volumes, we conducted a cross-trait analysis of existing GWAS data on the two traits using the conjunctional false discovery rate (conjFDR) framework. Functional annotation and phenome-wide association studies (PheWAS) were performed on the identified shared loci to characterize their biological relevance. We identified 11 unique lead genetic loci, of which 7 loci showed discordant directional effects (loci associated with increased risk for ADRD and smaller hippocampal volumes). We found that SHARPIN and TNIP1 genes play a role in ADRD by affecting hippocampal volumes. In addition, we observed 9 novel ADRD-hippocampus loci in genes previously implicated in AD (IGIP and ACE) and novel ADRD-genes (KCTD13, HINT1, SH3TC2, FAM53B, TPM1, IL34 and SSH2). PheWAS results show that most shared loci associated with neuroimaging measurements, white blood cell markers, red blood cell markers, and lipids. This study shows a shared genetic basis between ADRD and bilateral hippocampal volumes. By integrating summary statistics for these two traits, we identified both novel and previously reported ADRD-hippocampus loci. Functional analysis highlights the role of immune cells and lipid markers in the shared loci, suggesting a shared neurobiological basis for ADRD and bilateral hippocampal volumes.
{"title":"Identification of novel candidate loci for Alzheimer’s disease and related dementias by leveraging the shared genetic basis with hippocampal volume","authors":"Chenyang Jiang , Sven J. van der Lee , Niccolò Tesi , Wiesje M. van der Flier , Betty M. Tijms , Lianne M. Reus","doi":"10.1016/j.nbas.2025.100147","DOIUrl":"10.1016/j.nbas.2025.100147","url":null,"abstract":"<div><div>Alzheimer’s disease and related dementias (ADRD) are complex neurodegenerative disorders of which the genetic basis remains incompletely understood. Hippocampal volume loss is a core hallmark of AD. Hippocampal volume also has a strong heritable component and its genetic underpinnings may help us to understand the complex biological mechanism underlying ADRD. To identify shared genetic risk loci across late-onset ADRD and bilateral hippocampal volumes, we conducted a cross-trait analysis of existing GWAS data on the two traits using the conjunctional false discovery rate (conjFDR) framework. Functional annotation and phenome-wide association studies (PheWAS) were performed on the identified shared loci to characterize their biological relevance. We identified 11 unique lead genetic loci, of which 7 loci showed discordant directional effects (loci associated with increased risk for ADRD and smaller hippocampal volumes). We found that <em>SHARPIN</em> and <em>TNIP1</em> genes play a role in ADRD by affecting hippocampal volumes. In addition, we observed 9 novel ADRD-hippocampus loci in genes previously implicated in AD (<em>IGIP</em> and <em>ACE</em>) and novel ADRD-genes (<em>KCTD13</em>, <em>HINT1</em>, <em>SH3TC2</em>, <em>FAM53B</em>, <em>TPM1</em>, <em>IL34</em> and <em>SSH2</em>). PheWAS results show that most shared loci associated with neuroimaging measurements, white blood cell markers, red blood cell markers, and lipids. This study shows a shared genetic basis between ADRD and bilateral hippocampal volumes. By integrating summary statistics for these two traits, we identified both novel and previously reported ADRD-hippocampus loci. Functional analysis highlights the role of immune cells and lipid markers in the shared loci, suggesting a shared neurobiological basis for ADRD and bilateral hippocampal volumes.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"8 ","pages":"Article 100147"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-06-12DOI: 10.1016/j.nbas.2025.100141
O. Polzer , E. Kinloch , C.P. Fitzsimons
Cellular senescence influences normal physiology and ageing-related diseases, including neurodegeneration. Senescent cells accumulate with age in the brain, secreting pro-inflammatory factors that promote neuroinflammation, which has been linked to disorders like Alzheimer’s and Parkinson’s. Neurons and other brain cells such as microglia, astrocytes, and neural stem/progenitor cells (NSPCs), exhibit senescence in aged brains. NSPCs, essential for neurogenesis, may enter senescence due to inflammatory signals and other factors and microRNAs may regulate this process. Here we discuss senescence mechanisms, neuroinflammation, and potential therapeutic targets, proposing that modulating senescence by microRNA-mediated pathways could help combat neurodegenerative diseases.
{"title":"Cellular senescence, neuroinflammation, and microRNAs: Possible interactions driving aging and neurodegeneration in the hippocampal neurogenic niche","authors":"O. Polzer , E. Kinloch , C.P. Fitzsimons","doi":"10.1016/j.nbas.2025.100141","DOIUrl":"10.1016/j.nbas.2025.100141","url":null,"abstract":"<div><div>Cellular senescence influences normal physiology and ageing-related diseases, including neurodegeneration. Senescent cells accumulate with age in the brain, secreting pro-inflammatory factors that promote neuroinflammation, which has been linked to disorders like Alzheimer’s and Parkinson’s. Neurons and other brain cells such as microglia, astrocytes, and neural stem/progenitor cells (NSPCs), exhibit senescence in aged brains. NSPCs, essential for neurogenesis, may enter senescence due to inflammatory signals and other factors and microRNAs may regulate this process. Here we discuss senescence mechanisms, neuroinflammation, and potential therapeutic targets, proposing that modulating senescence by microRNA-mediated pathways could help combat neurodegenerative diseases.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"8 ","pages":"Article 100141"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144262539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Selenium has been shown to be a key regulatory element in the health, survival and proliferation of neural stem and progenitor cells, with various studies underlining its anti-aging properties. However, most of this knowledge is derived from rodent models, leaving its effects on human hippocampal progenitor cells unclear. In this study, we utilized a human hippocampal progenitor cell (HPC) line to examine the effects of varying concentrations of sodium selenite, an inorganic form of selenium (0 µM, 0.1 µM, 0.23 µM, 0.5 µM, and 1.0 µM), on the proliferation, apoptosis, and progenitor integrity of these cells. To do this, HPCs were exposed to these concentrations for 48 h, followed by immunocytochemistry to quantify, cell number (DAPI-positive cells), proliferation (KI67-positve cells), apoptosis (CC3-positve cells), and progenitor integrity (SOX2- and Nestin-positive cells). While our results indicated no significant effects of selenium concentrations on proliferation or apoptosis, we demonstrated that absence of selenium (0 μM) in the culture media significantly reduced both cell number and percentage of Nestin-positive cells, but only when compared to the condition with the highest selenium concentration (1.0 μM). Our findings underscore the role of selenium in regulating the survival and integrity of human HPCs. Lastly, we emphasize the need for further research to uncover the mechanisms underlying these observed changes.
{"title":"Selenium deficiency negatively affects survival and integrity of human hippocampal progenitor cells","authors":"Sahand Farmand, Emaan Ahmed, Hadisa Azizi Zawar, Sandrine Thuret","doi":"10.1016/j.nbas.2025.100138","DOIUrl":"10.1016/j.nbas.2025.100138","url":null,"abstract":"<div><div>Selenium has been shown to be a key regulatory element in the health, survival and proliferation of neural stem and progenitor cells, with various studies underlining its anti-aging properties. However, most of this knowledge is derived from rodent models, leaving its effects on human hippocampal progenitor cells unclear. In this study, we utilized a human hippocampal progenitor cell (HPC) line to examine the effects of varying concentrations of sodium selenite, an inorganic form of selenium (0 µM, 0.1 µM, 0.23 µM, 0.5 µM, and 1.0 µM), on the proliferation, apoptosis, and progenitor integrity of these cells. To do this, HPCs were exposed to these concentrations for 48 h, followed by immunocytochemistry to quantify, cell number (DAPI-positive cells), proliferation (KI67-positve cells), apoptosis (CC3-positve cells), and progenitor integrity (SOX2- and Nestin-positive cells). While our results indicated no significant effects of selenium concentrations on proliferation or apoptosis, we demonstrated that absence of selenium (0 μM) in the culture media significantly reduced both cell number and percentage of Nestin-positive cells, but only when compared to the condition with the highest selenium concentration (1.0 μM). Our findings underscore the role of selenium in regulating the survival and integrity of human HPCs. Lastly, we emphasize the need for further research to uncover the mechanisms underlying these observed changes.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"7 ","pages":"Article 100138"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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