Stefanie A. Tremblay , R. Nathan Spreng , Alfie Wearn , Zaki Alasmar , Amir Pirhadi , Christine L. Tardif , Mallar M. Chakravarty , Sylvia Villeneuve , Ilana R. Leppert , Felix Carbonell , Yasser Iturria Medina , Christopher J. Steele , Claudine J. Gauthier , For the PREVENT-AD Research Group
{"title":"Sex and APOE4-specific links between cardiometabolic risk factors and white matter alterations in individuals with a family history of Alzheimer's disease","authors":"Stefanie A. Tremblay , R. Nathan Spreng , Alfie Wearn , Zaki Alasmar , Amir Pirhadi , Christine L. Tardif , Mallar M. Chakravarty , Sylvia Villeneuve , Ilana R. Leppert , Felix Carbonell , Yasser Iturria Medina , Christopher J. Steele , Claudine J. Gauthier , For the PREVENT-AD Research Group","doi":"10.1016/j.neurobiolaging.2025.03.003","DOIUrl":"10.1016/j.neurobiolaging.2025.03.003","url":null,"abstract":"<div><div>Early detection of pathological changes in Alzheimer's disease (AD) has garnered significant attention in the last few decades as interventions aiming to prevent progression will likely be most effective when initiated early. White matter (WM) alterations are among the earliest changes in AD, yet limited work has comprehensively characterized the effects of AD risk factors on WM. In older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors. Multiple MRI-derived metrics were integrated using a multivariate approach based on the Mahalanobis distance (D2). To uncover the specific biological underpinnings of these WM alterations, we then extracted the contribution of each MRI feature to D2 in significant clusters. Lastly, the links between WM D2 and cognition were explored. WM D2 in several regions was associated with high systolic blood pressure, BMI, and glycated hemoglobin, and low cholesterol, in both males and females. APOE4 + displayed a distinct risk pattern, with LDL-cholesterol having a detrimental effect only in carriers, and this pattern was linked to immediate memory performance. Myelination was the main mechanism underlying WM alterations. Our findings reveal that combined exposure to multiple cardiometabolic risk factors negatively impacts microstructural health, which may subsequently affect cognition. Notably, APOE4 carriers exhibited a different risk pattern, especially in the role of LDL, suggesting distinct underlying mechanisms in this group.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"150 ","pages":"Pages 80-96"},"PeriodicalIF":3.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620472","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}
Neha Singh-Reilly , Nha Trang Thu Pham , Jonathan Graff-Radford , Mary M. Machulda , Anthony J. Spychalla , Matthew L. Senjem , Ronald C. Petersen , Val J. Lowe , Bradley F. Boeve , Clifford R. Jack Jr , Keith A. Josephs , Kejal Kantarci , Jennifer L. Whitwell
{"title":"White matter hyperintensities in dementia with lewy bodies and posterior cortical atrophy","authors":"Neha Singh-Reilly , Nha Trang Thu Pham , Jonathan Graff-Radford , Mary M. Machulda , Anthony J. Spychalla , Matthew L. Senjem , Ronald C. Petersen , Val J. Lowe , Bradley F. Boeve , Clifford R. Jack Jr , Keith A. Josephs , Kejal Kantarci , Jennifer L. Whitwell","doi":"10.1016/j.neurobiolaging.2025.03.002","DOIUrl":"10.1016/j.neurobiolaging.2025.03.002","url":null,"abstract":"<div><div>Dementia with Lewy bodies (DLB) and posterior cortical atrophy (PCA) are neurodegenerative disorders that can overlap clinically and in patterns of regional hypometabolism and show elevated white matter hyperintensity (WMH) burden. Little is known about the regional WMH burden in DLB patients without any interference of AD pathology and how these patterns compare to PCA patients. Twenty-two amyloid-negative DLB patients, 40 amyloid-positive PCA patients, and 49 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN. They underwent a 3 T head MRI, a Pittsburgh Compound B (PiB) PET scan, and a fluid-attenuated inversion recovery scan (FLAIR). The relationship between regional WMH volume and diagnosis was evaluated while adjusting for age and sex. DLB showed greater periventricular WMH burden in the temporal, occipital, and frontal lobes and greater WMH burden in the posterior corpus callosum compared to CU. PCA showed greater subcortical WMH burden in temporal, parietal, and occipital lobes, and greater periventricular WMH burden in the temporal, occipital, and frontal lobes, compared to CU. On comparing both dementia groups, PCA showed greater subcortical WMH burden in the temporal and occipital lobes compared to DLB, while DLB showed greater WMH burden in the posterior corpus callosum compared to PCA. Hence, DLB and PCA are both associated with periventricular WMHs, with deep subcortical WMHs being more characteristic of PCA, and callosal WMHs more characteristic of Aβ-negative DLB patients, suggesting different pathophysiological mechanisms underlying the development of WMHs in these two neurodegenerative diseases.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"150 ","pages":"Pages 44-52"},"PeriodicalIF":3.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563603","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}
Shanti Van Malderen , Melina Hehl , Marten Nuyts , Stefanie Verstraelen , Robin E. Heemels , Robert M. Hardwick , Stephan P. Swinnen , Koen Cuypers
{"title":"Age-related differences in task-related modulation of cerebellar brain inhibition","authors":"Shanti Van Malderen , Melina Hehl , Marten Nuyts , Stefanie Verstraelen , Robin E. Heemels , Robert M. Hardwick , Stephan P. Swinnen , Koen Cuypers","doi":"10.1016/j.neurobiolaging.2025.02.009","DOIUrl":"10.1016/j.neurobiolaging.2025.02.009","url":null,"abstract":"<div><div>Age-related reductions in cerebellar integrity predict motor impairments in older adults (OA), but the contribution of cerebro-cerebellar interactions to these impairments remains unclear. Understanding these interactions could reveal underlying mechanisms associated with age-related deficits in motor control. To explore this, twenty younger adults (YA) and twenty OA, all right-handed, participated in a dual-site transcranial magnetic stimulation protocol. Cerebellar brain inhibition (CBI) was measured at rest and during the anticipatory period of a bimanual tracking task (BTT). The results revealed that YA outperformed OA on the BTT. Both age groups demonstrated reduced CBI during the anticipatory period of the BTT compared to CBI at rest, with no differences in CBI levels between both groups. Notably, motor performance was influenced by CBI modulation, as learning progressed (early vs. slightly later short-term learning), and this influence differed between age groups. In summary, resting-state CBI and the task-related release of CBI were maintained in OA, challenging previous assumptions of reduced inhibitory function in OA. However, the modulation of CBI appears to influence short-term motor learning differently for both groups, suggesting potential functional reorganization of the cerebellar neural system.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"150 ","pages":"Pages 53-68"},"PeriodicalIF":3.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580210","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}
Yandara A. Martins, Camila A.E.F. Cardinali, Andréa S. Torrão
{"title":"Age-related differences in long-term memory performance and astrocyte morphology in rat hippocampus","authors":"Yandara A. Martins, Camila A.E.F. Cardinali, Andréa S. Torrão","doi":"10.1016/j.neurobiolaging.2025.02.006","DOIUrl":"10.1016/j.neurobiolaging.2025.02.006","url":null,"abstract":"<div><div>Astrocytes are neuromodulator cells. Their complex and dynamic morphology regulates neuronal signaling, synaptic plasticity, and neurogenesis. The impact of aging on astrocyte morphology is still under ongoing debate. Therefore, this study aimed to characterize astrocyte morphology in the hippocampus of older rats. 2-, 18-, and 20-month-old male Wistar rats were submitted to the object recognition test to assess their short- and long-term memories. CA1, CA2, CA3, and the dentate gyrus were collected for immunohistochemistry analysis and glial fibrillary acid protein (GFAP) immunostaining. Our results indicate that 20-month-old rats did not recognize or discriminate the novel object in the long-term memory test. Also, GFAP staining was greater in the oldest group for all analyzed areas. Morphometric and fractal analysis indicated shorter branch lengths and smaller sizes for astrocytes of 20-month-old rats. Overall, our results suggest that 20-month-old rats have long-term memory impairment, increased GFAP staining, and astrocyte dystrophy. These age-related alterations in astrocyte morphology are a resource for future studies exploring the role of astrocytes in age-related cognitive decline and age-related diseases.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"150 ","pages":"Pages 19-43"},"PeriodicalIF":3.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CSF α-synuclein aggregation is associated with APOE ε4 and progressive cognitive decline in Alzheimer's disease","authors":"Qiang Qiang , Loren Skudder-Hill , Tomoko Toyota , Zhe Huang , Wenshi Wei , Hiroaki Adachi , Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1016/j.neurobiolaging.2025.02.008","DOIUrl":"10.1016/j.neurobiolaging.2025.02.008","url":null,"abstract":"<div><div>At autopsy, around half of the Alzheimer's disease (AD) brains exhibit Lewy body pathology, and the main component of Lewy body pathology is α-synuclein aggregates. This study investigated the prevalence of cerebrospinal fluid (CSF) α-synuclein aggregation and its association with demographic factors and cognitive decline among 1619 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), with the test for α-synuclein aggregation by seed amplification assay (SAA). This cohort consisted of 595 cognitively normal (CN) individuals, 765 with mild cognitive impairment (MCI), and 259 with AD dementia. The results showed a higher prevalence of positive α-synuclein aggregation status in the AD dementia group (37.07 %) and the MCI group (22.75 %) compared to CN controls (16.13 %). Additionally, APOE ε4 carriers exhibited a higher prevalence of α-synuclein aggregation compared to non-carriers: 20.12 % for APOE ε4-/- (non-carriers), 24.82 % for APOE ε4 + /-, and 30.92 % for APOE ε4 + /+ . Longitudinally, positive CSF α-synuclein aggregation associated with accelerated cognitive decline, especially in the MCI and AD groups. Notably, positive aggregation status did not significantly affect cognitive trajectories in CN individuals. Moreover, APOE ε4 carriers with positive CSF α-synuclein aggregation experienced more pronounced cognitive decline. This study provides evidence that CSF α-synuclein aggregation is associated with cognitive function and the APOE ε4 allele. These findings suggest that CSF α-synuclein SAA, in combination with APOE ε4 status, could serve as biomarkers for predicting cognitive decline in AD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"150 ","pages":"Pages 9-18"},"PeriodicalIF":3.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548207","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}
Oluchi Ekenze , Stephan Seiler , Adlin Pinheiro , Charles DeCarli , Pedram Parva , Mohamad Habes , Andreas Charidimou , Pauline Maillard , Alexa Beiser , Sudha Seshadri , Serkalem Demissie , Jose Rafael Romero
{"title":"Relation of MRI visible perivascular spaces with global and regional brain structural connectivity measures: The Framingham Heart Study (FHS)","authors":"Oluchi Ekenze , Stephan Seiler , Adlin Pinheiro , Charles DeCarli , Pedram Parva , Mohamad Habes , Andreas Charidimou , Pauline Maillard , Alexa Beiser , Sudha Seshadri , Serkalem Demissie , Jose Rafael Romero","doi":"10.1016/j.neurobiolaging.2025.02.007","DOIUrl":"10.1016/j.neurobiolaging.2025.02.007","url":null,"abstract":"<div><div>MRI visible perivascular spaces (PVS) are associated with cognitive impairment and dementia, which are also associated with disrupted network connectivity. PVS may relate to dementia risk through disruption in brain connectivity. We studied the relation between PVS grade and global and regional structural connectivity in Framingham Heart Study participants free of stroke and dementia. PVS were rated on axial T2 sequences in the basal ganglia (BG) and centrum semiovale (CSO). We assessed structural global and regional network architecture using global efficiency, local efficiency and modularity. Analysis of covariance was used to relate PVS grades with structural network measures. Models adjusted for age, sex (model 1), and vascular risk factors (model 2). Effect modification on the associations by age, sex, hypertension and APOE-ɛ4 status was assessed. Among 2525 participants (mean age 54 ± 13 years, 53 % female), significant associations were observed between grade III and IV PVS in the BG and CSO with reduced global efficiency. Grade III (β −0.0030; 95 % confidence interval [CI] −0.0041, −0.0019) and IV (β −0.0033, CI −0.0060, −0.0007) PVS in the BG and grade IV (β −0.0015; CI −0.0024, −0.0007) PVS in the CSO were associated with reduced local efficiency. We observed shared and different strength of association by age, hypertension, sex and APOE-ɛ4 in the relationship between high burden PVS in the BG and CSO with structural network measures. Findings suggest that higher grade PVS are associated with disruption of global and regional structural brain networks.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"150 ","pages":"Pages 1-8"},"PeriodicalIF":3.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548206","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}
Anna Uta Rysop , Kathleen Anne Williams , Lea-Maria Schmitt , Marcus Meinzer , Jonas Obleser , Gesa Hartwigsen
{"title":"Aging modulates large-scale neural network interactions during speech comprehension","authors":"Anna Uta Rysop , Kathleen Anne Williams , Lea-Maria Schmitt , Marcus Meinzer , Jonas Obleser , Gesa Hartwigsen","doi":"10.1016/j.neurobiolaging.2025.02.005","DOIUrl":"10.1016/j.neurobiolaging.2025.02.005","url":null,"abstract":"<div><div>Speech comprehension in noisy environments constitutes a critical challenge in everyday life and affects people of all ages. This challenging listening situation can be alleviated using semantic context to predict upcoming words (i.e., predictability gain)—a process associated with the domain-specific semantic network. When no such context can be used, speech comprehension in challenging listening conditions relies on cognitive control functions, underpinned by domain-general networks. Most previous studies focused on regional activity of pre-selected cortical regions or networks in healthy young listeners. Thus, it remains unclear how domain-specific and domain-general networks interact during speech comprehension in noise and how this may change across the lifespan. Here, we used correlational psychophysiological interaction (cPPI) to investigate functional network interactions during sentence comprehension under noisy conditions with varying predictability in healthy young and older listeners. Relative to young listeners, older adults showed increased task-related activity in several domain-general networks but reduced between-network connectivity. Across groups, higher predictability was associated with increased positive coupling between semantic and attention networks and increased negative coupling between semantic and control networks. These results highlight the complex interplay between the semantic network and several domain-general networks underlying the predictability gain. The observed differences in connectivity profiles with age inform the current debate on whether age-related changes in neural activity and functional connectivity reflect compensation or dedifferentiation.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"150 ","pages":"Pages 109-121"},"PeriodicalIF":3.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620474","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}
Margaret E. Caulfield , Molly J. Vander Werp , Jennifer A. Stancati , Timothy J. Collier , Caryl E. Sortwell , Ivette M. Sandoval , Jeffrey H. Kordower , Fredric P. Manfredsson , Kathy Steece-Collier
{"title":"Advancing age and sex modulate antidyskinetic efficacy of striatal CaV1.3 gene therapy in a rat model of Parkinson’s disease","authors":"Margaret E. Caulfield , Molly J. Vander Werp , Jennifer A. Stancati , Timothy J. Collier , Caryl E. Sortwell , Ivette M. Sandoval , Jeffrey H. Kordower , Fredric P. Manfredsson , Kathy Steece-Collier","doi":"10.1016/j.neurobiolaging.2025.02.003","DOIUrl":"10.1016/j.neurobiolaging.2025.02.003","url":null,"abstract":"<div><div>We previously demonstrated that viral vector-mediated striatal Ca<sub>V</sub>1.3 calcium channel downregulation in young adult (3mo) male parkinsonian rats provides uniform, robust protection against levodopa-induced dyskinesias (LID). Acknowledging the association of PD with aging and incidence in male and female sexes, we have expanded our studies to include rats of advancing age of both sexes. The current study directly contrasts age and sex, determining their impact on efficacy of intrastriatal AAV-Ca<sub>V</sub>1.3-shRNA to prevent LID induction, removing the variable of levodopa-priming. Considering both sexes together, late-middle-aged (‘aged’; 15mo) parkinsonian rats receiving AAV-Ca<sub>V</sub>1.3-shRNA developed significantly less severe LID compared control AAV-scramble(SCR)-shRNA rats, however therapeutic benefit was significantly less robust than observed in young males. When considered separately, females showed significantly less therapeutic benefit than males. Furthermore, aged non-cycling/proestrous-negative female rats were refractory to LID induction, regardless of vector. This study provides novel insight into the impact of age and sex on the variable antidyskinetic responses of Ca<sub>V</sub>1.3-targeted gene therapy, highlighting the importance of including clinically relevant age and sex populations in PD studies.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"149 ","pages":"Pages 54-66"},"PeriodicalIF":3.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487187","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}
{"title":"Aging of gray matter microstructure: A brain-wide characterization of, age group differences using NODDI","authors":"Danielle Greenman, Ilana J. Bennett","doi":"10.1016/j.neurobiolaging.2025.02.004","DOIUrl":"10.1016/j.neurobiolaging.2025.02.004","url":null,"abstract":"<div><div>This study aimed to provide a complete characterization of age group differences in cortical lobar, hippocampal, and subcortical gray matter microstructure using a multi-compartment diffusion-weighted MRI (DWI) approach with parameters optimized for gray matter (Neurite Orientation Dispersion and Density Imaging, NODDI). 76 younger (undergraduate students) and 64 older (surrounding communities) adults underwent diffusion-, T1-, and susceptibility-weighted MRI. Results revealed eight unique patterns across the 12 regions of interest in the relative direction and magnitude of age effects across NODDI metrics, which were grouped into three prominent patterns: cortical gray matter had predominantly higher free diffusion in older than younger adults, the hippocampus and amygdala had predominantly higher dispersion of diffusion and intracellular diffusion in older than younger adults, and the putamen and globus pallidus had lower dispersion of diffusion in older than younger adults. Results remained largely unchanged after controlling for normalized regional volume, suggesting that higher free diffusion in older than younger adults in cortical gray matter was not driven by macrostructural atrophy. Results also remained largely unchanged after controlling for iron content (QSM, R<sub>2</sub>*), even in iron-rich subcortical regions. Taken together, these patterns of age effects across NODDI metrics provide evidence of region-specific neurobiological substrates of aging of gray matter microstructure.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"149 ","pages":"Pages 34-43"},"PeriodicalIF":3.7,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453881","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}