Pub Date : 2025-07-30DOI: 10.1016/j.neurobiolaging.2025.07.017
Jordan D. Palms , Ji Hyun Lee , Emily P. Morris , Ketlyne Sol , Monica E. Walters , Kiana A. Scambray , Clarissa D. Morales , Mohamad J. Alshikho , Patrick J. Lao , Jennifer J. Manly , Adam M. Brickman , Laura B. Zahodne
Black older adults experience worse brain and cognitive aging than White older adults, on average. Racially patterned psychosocial stressors may contribute to these disparities. Maintaining white matter health is important for cognitive aging, particularly among Black older adults, and it is uniquely vulnerable to stress. Examining associations between racial discrimination and white matter may elucidate mechanisms of disparities. A sample of Black older adults in the Washington Heights-Inwood Columbia Aging project were included (N = 217). Everyday and major life discrimination were self-reported on well-validated scales. Diffusion tensor imaging quantified white matter fractional anisotropy (FA). Multivariable regressions revealed more major life discrimination was associated with lower FA in the cingulum cingulate gyrus, forceps major, forceps minor, and inferior fronto-occipital fasciculus but greater FA in the superior longitudinal fasciculus temporal projection. Everyday discrimination was not associated with FA. Findings suggest that institutional racism may have a stronger effect on white matter tracts corresponding to cognitive and emotional/affective processing than interpersonal racism. White matter health may be a mechanism through which racially patterned stressors contribute to disparities in brain and cognitive aging.
{"title":"The relationship between racial discrimination and white matter among Black older adults","authors":"Jordan D. Palms , Ji Hyun Lee , Emily P. Morris , Ketlyne Sol , Monica E. Walters , Kiana A. Scambray , Clarissa D. Morales , Mohamad J. Alshikho , Patrick J. Lao , Jennifer J. Manly , Adam M. Brickman , Laura B. Zahodne","doi":"10.1016/j.neurobiolaging.2025.07.017","DOIUrl":"10.1016/j.neurobiolaging.2025.07.017","url":null,"abstract":"<div><div>Black older adults experience worse brain and cognitive aging than White older adults, on average. Racially patterned psychosocial stressors may contribute to these disparities. Maintaining white matter health is important for cognitive aging, particularly among Black older adults, and it is uniquely vulnerable to stress. Examining associations between racial discrimination and white matter may elucidate mechanisms of disparities. A sample of Black older adults in the Washington Heights-Inwood Columbia Aging project were included (N = 217). Everyday and major life discrimination were self-reported on well-validated scales. Diffusion tensor imaging quantified white matter fractional anisotropy (FA). Multivariable regressions revealed more major life discrimination was associated with lower FA in the cingulum cingulate gyrus, forceps major, forceps minor, and inferior fronto-occipital fasciculus but greater FA in the superior longitudinal fasciculus temporal projection. Everyday discrimination was not associated with FA. Findings suggest that institutional racism may have a stronger effect on white matter tracts corresponding to cognitive and emotional/affective processing than interpersonal racism. White matter health may be a mechanism through which racially patterned stressors contribute to disparities in brain and cognitive aging.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 63-72"},"PeriodicalIF":3.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144878303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-28DOI: 10.1016/j.neurobiolaging.2025.07.015
Kevin S. Heffernan , Derek C. Monroe , Andrew S. London , Jose Gutierrez , Adam M. Brickman , Ajay Kumar Nair , Nagesh Adluru , Stacey M. Schaefer
High pulse wave velocity (PWV), a measure of increased arterial stiffness, is a risk factor for cerebrovascular disease. PWV can be estimated (ePWV) from age and blood pressure (BP). Elevated ePWV is associated with cerebral small-vessel disease, cognitive decline, and dementia risk in middle-aged and older adults. We examined data from the Midlife in the United States (MIDUS) Neuroscience Project to examine the association of ePWV with brain white matter microstructure. BP was measured in 132 middle-aged adults (mean age 53+/- 10 years, n = 77 women, n = 38 Black/African American) between 2004 and 2009 and used to calculate ePWV. Diffusion-weighted imaging (DWI) data were acquired between 2017 and 2022 and used to estimate: global white matter fractional anisotropy; axial, radial, and mean diffusivity and kurtosis; neurite density index; and orientation dispersion index. High ePWV was associated with: lower fractional anisotropy; axial, radial, and mean kurtosis; and neurite density index. High ePWV was also associated with higher axial, radial, and mean diffusivity, and orientation dispersion index. Except for axial diffusivity/kurtosis and orientation dispersion, all associations between high ePWV and white matter microstructure remained after adjusting for exogenous controls (sex and race), education, the constituent components of ePWV (age and blood pressure), and the time lag between BP and DWI measures. In conclusion, high ePWV in middle-aged adults is prospectively associated with compromised brain white matter microstructure more than a decade later. ePWV may be a useful metric of vascular aging that can be applied to the study of brain aging.
{"title":"High estimated pulse-wave velocity is associated with lower brain white matter microstructural integrity twelve years later","authors":"Kevin S. Heffernan , Derek C. Monroe , Andrew S. London , Jose Gutierrez , Adam M. Brickman , Ajay Kumar Nair , Nagesh Adluru , Stacey M. Schaefer","doi":"10.1016/j.neurobiolaging.2025.07.015","DOIUrl":"10.1016/j.neurobiolaging.2025.07.015","url":null,"abstract":"<div><div>High pulse wave velocity (PWV), a measure of increased arterial stiffness, is a risk factor for cerebrovascular disease. PWV can be estimated (ePWV) from age and blood pressure (BP). Elevated ePWV is associated with cerebral small-vessel disease, cognitive decline, and dementia risk in middle-aged and older adults. We examined data from the Midlife in the United States (MIDUS) Neuroscience Project to examine the association of ePWV with brain white matter microstructure. BP was measured in 132 middle-aged adults (mean age 53+/- 10 years, n = 77 women, n = 38 Black/African American) between 2004 and 2009 and used to calculate ePWV. Diffusion-weighted imaging (DWI) data were acquired between 2017 and 2022 and used to estimate: global white matter fractional anisotropy; axial, radial, and mean diffusivity and kurtosis; neurite density index; and orientation dispersion index. High ePWV was associated with: lower fractional anisotropy; axial, radial, and mean kurtosis; and neurite density index. High ePWV was also associated with higher axial, radial, and mean diffusivity, and orientation dispersion index. Except for axial diffusivity/kurtosis and orientation dispersion, all associations between high ePWV and white matter microstructure remained after adjusting for exogenous controls (sex and race), education, the constituent components of ePWV (age and blood pressure), and the time lag between BP and DWI measures. In conclusion, high ePWV in middle-aged adults is prospectively associated with compromised brain white matter microstructure more than a decade later. ePWV may be a useful metric of vascular aging that can be applied to the study of brain aging.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"156 ","pages":"Pages 1-9"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-24DOI: 10.1016/j.neurobiolaging.2025.07.014
Maxime Perron , Hannah Shatzer , Michael Zara , Frank Russo
Cognitive aging is associated with increased prefrontal cortex (PFC) activity, often interpreted as either a compensatory mechanism or a sign of neural inefficiency. In the context of speech-in-noise perception, it remains unclear whether this increase supports or impairs performance, as findings across studies are mixed. This study investigated age-related differences in PFC activity during sentence comprehension in noise using functional near-infrared spectroscopy. Fifty-seven participants (22 younger adults, 35 older adults) listened to sentences ending in either a high- or low-predictability word under two signal-to-noise ratio (SNR) conditions. Older adults showed increased PFC activity as SNR decreased, whereas younger adults showed no significant modulation. Among older adults, lower performers exhibited the greatest right-lateralized PFC activity, suggesting the recruitment of suboptimal neural resources. At the trial level, incorrect responses were associated with greater bilateral PFC activity in both age groups. Mediation analyses revealed that the negative effect of age on performance was partially explained by increased bilateral PFC activity, indicating that overactivation contributes to age-related speech-in-noise difficulties. Hearing loss and cognitive ability did not predict overall PFC activity but moderated the effect of SNR on PFC activity. Specifically, older adults with better hearing or higher cognitive scores showed increased PFC activity in the difficult SNR condition compared to the easier one, whereas those with more hearing loss or lower cognition showed similar activity across conditions. No effects of sentence predictability were observed. These findings support a neural inefficiency framework and highlight the importance of addressing PFC overactivation to improve speech-in-noise communication in older adults.
{"title":"Age-related increased frontal activation in sentence comprehension reflects inefficiency, not compensation","authors":"Maxime Perron , Hannah Shatzer , Michael Zara , Frank Russo","doi":"10.1016/j.neurobiolaging.2025.07.014","DOIUrl":"10.1016/j.neurobiolaging.2025.07.014","url":null,"abstract":"<div><div>Cognitive aging is associated with increased prefrontal cortex (PFC) activity, often interpreted as either a compensatory mechanism or a sign of neural inefficiency. In the context of speech-in-noise perception, it remains unclear whether this increase supports or impairs performance, as findings across studies are mixed. This study investigated age-related differences in PFC activity during sentence comprehension in noise using functional near-infrared spectroscopy. Fifty-seven participants (22 younger adults, 35 older adults) listened to sentences ending in either a high- or low-predictability word under two signal-to-noise ratio (SNR) conditions. Older adults showed increased PFC activity as SNR decreased, whereas younger adults showed no significant modulation. Among older adults, lower performers exhibited the greatest right-lateralized PFC activity, suggesting the recruitment of suboptimal neural resources. At the trial level, incorrect responses were associated with greater bilateral PFC activity in both age groups. Mediation analyses revealed that the negative effect of age on performance was partially explained by increased bilateral PFC activity, indicating that overactivation contributes to age-related speech-in-noise difficulties. Hearing loss and cognitive ability did not predict overall PFC activity but moderated the effect of SNR on PFC activity. Specifically, older adults with better hearing or higher cognitive scores showed increased PFC activity in the difficult SNR condition compared to the easier one, whereas those with more hearing loss or lower cognition showed similar activity across conditions. No effects of sentence predictability were observed. These findings support a neural inefficiency framework and highlight the importance of addressing PFC overactivation to improve speech-in-noise communication in older adults.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 100-112"},"PeriodicalIF":3.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-20DOI: 10.1016/j.neurobiolaging.2025.07.013
Olga R. Dobrushina , Larisa A. Dobrynina , Galina A. Arina , Evgenia S. Novikova , Mariia M. Tsypushtanova , Angelina G. Makarova , Mariia V. Gubanova , Viktoriya V. Trubitsyna , Vlada V. Kolomoitseva , Daria A. Kazantseva , Elena I. Kremneva , Marina V. Krotenkova
Cerebral small vessel disease (CSVD) is a prevalent age-related disorder that leads to progressive white matter damage, resulting in cognitive decline and depression. This study explored the neural network mechanisms of emotional dysregulation in CSVD, focusing on both depression and alexithymia and considering the broader context of studies on emotional cardiovascular risk factors. Study participants (n = 196, age 37–75) were assessed for CSVD, arterial hypertension, depressive symptoms, and alexithymia. Emotional dysregulation, defined by depression and alexithymia, was estimated using a structural equation model accounting for the potential of bidirectional links with CSVD. To investigate the connectivity of networks involved in emotional processing, 167 participants underwent resting-state functional MRI. The study showed that emotional dysregulation was associated with reduced functional connectivity between the salience and language networks and within the language network. Age was associated with reduced functional connectivity within the salience and language networks, suggesting a possibility of synergistic deleterious effects. The revealed alterations in brain connectivity might reflect the dysfunction of the system of allostasis, explaining the observed symptoms of depression and alexithymia, as well as the previous findings on emotional cardiovascular risk factors.
{"title":"Neural network mechanisms of emotional dysregulation in cerebral small vessel disease","authors":"Olga R. Dobrushina , Larisa A. Dobrynina , Galina A. Arina , Evgenia S. Novikova , Mariia M. Tsypushtanova , Angelina G. Makarova , Mariia V. Gubanova , Viktoriya V. Trubitsyna , Vlada V. Kolomoitseva , Daria A. Kazantseva , Elena I. Kremneva , Marina V. Krotenkova","doi":"10.1016/j.neurobiolaging.2025.07.013","DOIUrl":"10.1016/j.neurobiolaging.2025.07.013","url":null,"abstract":"<div><div>Cerebral small vessel disease (CSVD) is a prevalent age-related disorder that leads to progressive white matter damage, resulting in cognitive decline and depression. This study explored the neural network mechanisms of emotional dysregulation in CSVD, focusing on both depression and alexithymia and considering the broader context of studies on emotional cardiovascular risk factors. Study participants (n = 196, age 37–75) were assessed for CSVD, arterial hypertension, depressive symptoms, and alexithymia. Emotional dysregulation, defined by depression and alexithymia, was estimated using a structural equation model accounting for the potential of bidirectional links with CSVD. To investigate the connectivity of networks involved in emotional processing, 167 participants underwent resting-state functional MRI. The study showed that emotional dysregulation was associated with reduced functional connectivity between the salience and language networks and within the language network. Age was associated with reduced functional connectivity within the salience and language networks, suggesting a possibility of synergistic deleterious effects. The revealed alterations in brain connectivity might reflect the dysfunction of the system of allostasis, explaining the observed symptoms of depression and alexithymia, as well as the previous findings on emotional cardiovascular risk factors.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 78-86"},"PeriodicalIF":3.7,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-18DOI: 10.1016/j.neurobiolaging.2025.07.011
Axel AS Laurell , Sita N. Shah , Masoud Rahmati , John T. O’Brien , Benjamin R. Underwood
Symptoms related to sleep, weight, and endocrine dysfunction are common in Alzheimer’s disease (AD) and Lewy body dementia (LBD). The cause of these symptoms is not known, but they may be related to hypothalamic neurodegeneration. We performed a systematic search of MEDLINE and EMBASE for studies using MRI or PET imaging to examine the hypothalamus in AD or LBD. The Newcastle-Ottawa scale was used to assess the risk of bias. A random-effects meta-analysis was conducted using the standardised mean difference (SMD) in hypothalamic volume, and a narrative synthesis was used to examine associations between hypothalamic imaging and sleep, weight, and endocrine function. We screened 8891 articles which identified 22 studies for inclusion in the narrative synthesis of which 6 were suitable for meta-analysis. 86 % had a low to moderate risk of bias. People with mild-moderate AD had a smaller hypothalamus compared to controls (SMD=-0.49[-0.86,-0.13],p = 0.018;I2=67 %[21.5 %-86.1 %];n = 454(AD),715(controls)), and had differences in hypothalamic metabolism and connectivity. Two studies in LBD found lower grey matter and serotonin transporter binding in the hypothalamus compared to controls. Hypothalamic differences in AD were associated with male sex, worse sleep, lower bone mineral density and plasma levels of sex hormones. Body mass index was not associated with hypothalamic volume in AD, although further studies are needed. Lower hypothalamic volume is seen in AD and this may influence sleep and endocrine function. A better understanding of hypothalamic degeneration may help elucidate how pathology relates to symptoms in AD and LBD and reveal new targets for intervention.
{"title":"Hypothalamic imaging in Alzheimer’s disease and Lewy body dementia: A systematic review and meta-analysis","authors":"Axel AS Laurell , Sita N. Shah , Masoud Rahmati , John T. O’Brien , Benjamin R. Underwood","doi":"10.1016/j.neurobiolaging.2025.07.011","DOIUrl":"10.1016/j.neurobiolaging.2025.07.011","url":null,"abstract":"<div><div>Symptoms related to sleep, weight, and endocrine dysfunction are common in Alzheimer’s disease (AD) and Lewy body dementia (LBD). The cause of these symptoms is not known, but they may be related to hypothalamic neurodegeneration. We performed a systematic search of MEDLINE and EMBASE for studies using MRI or PET imaging to examine the hypothalamus in AD or LBD. The Newcastle-Ottawa scale was used to assess the risk of bias. A random-effects meta-analysis was conducted using the standardised mean difference (SMD) in hypothalamic volume, and a narrative synthesis was used to examine associations between hypothalamic imaging and sleep, weight, and endocrine function. We screened 8891 articles which identified 22 studies for inclusion in the narrative synthesis of which 6 were suitable for meta-analysis. 86 % had a low to moderate risk of bias. People with mild-moderate AD had a smaller hypothalamus compared to controls (SMD=-0.49[-0.86,-0.13],p = 0.018;I<sup>2</sup>=67 %[21.5 %-86.1 %];n = 454(AD),715(controls)), and had differences in hypothalamic metabolism and connectivity. Two studies in LBD found lower grey matter and serotonin transporter binding in the hypothalamus compared to controls. Hypothalamic differences in AD were associated with male sex, worse sleep, lower bone mineral density and plasma levels of sex hormones. Body mass index was not associated with hypothalamic volume in AD, although further studies are needed. Lower hypothalamic volume is seen in AD and this may influence sleep and endocrine function. A better understanding of hypothalamic degeneration may help elucidate how pathology relates to symptoms in AD and LBD and reveal new targets for intervention.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 87-99"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-18DOI: 10.1016/j.neurobiolaging.2025.06.010
Elaheh Moradi , Robert Dahnke , Vandad Imani , Christian Gaser , Alina Solomon , Jussi Tohka , Alzheimer’s Disease Neuroimaging Initiative
Plasma biomarkers are associated with cognitive performance and decline in Alzheimer’s disease, making them promising for early detection. This study investigates their predictive value, combined with non-invasive measures, in forecasting cognitive decline in individuals without dementia. We developed a multimodal machine-learning approach incorporating plasma biomarkers (Amyloid42/40 (A42/40), p-tau181, NfL), MRI, demographics, APOE4, and cognitive assessments to predict the rate of cognitive decline. Various models were designed to predict decline rates across cognitive domains (memory, executive function, language, and visuospatial abilities) and assess their relevance in predicting dementia progression. Cross-validated correlations between predicted and actual cognitive decline rates were 0.50 for memory, 0.49 for language, 0.42 for executive function, and 0.44 for visuospatial ability. MRI showed greater predictive importance than plasma biomarkers. Among plasma biomarkers, NfL and p-tau181 outperformed A42/40. Predicting cognitive decline and progression to MCI/dementia was most accurate in the memory domain, where plasma biomarkers (A42/40, p-tau181, NfL) added significant value to predictive models, likely due to their AD-specific nature. Plasma biomarkers contributed less to predictions in other cognitive domains. The results indicate that plasma biomarkers, particularly when combined with MRI, demographics, APOE4, and cognitive measures, have significant potential for predicting memory decline and assessing the risk of dementia progression, even in cognitively unimpaired individuals.
血浆生物标志物与阿尔茨海默病的认知能力和衰退有关，这使得它们有望被早期发现。本研究调查了它们的预测价值，结合非侵入性测量，预测无痴呆个体的认知能力下降。我们开发了一种多模式机器学习方法，结合血浆生物标志物（淀粉样蛋白β42/40 (a β42/40), p-tau181, NfL）， MRI，人口统计学，APOE4和认知评估来预测认知能力下降的速度。设计了各种模型来预测认知领域（记忆、执行功能、语言和视觉空间能力）的衰退率，并评估它们在预测痴呆进展中的相关性。交叉验证的预测和实际认知能力下降率之间的相关性为：记忆0.50，语言0.49，执行功能0.42，视觉空间能力0.44。MRI表现出比血浆生物标志物更大的预测重要性。在血浆生物标志物中，NfL和p-tau181优于Aβ42/40。预测认知能力下降和MCI/痴呆的进展在记忆领域是最准确的，其中血浆生物标志物（Aβ42/40, p-tau181, NfL）为预测模型增加了显著价值，可能是由于它们的ad特异性。血浆生物标志物对其他认知领域的预测贡献较小。结果表明，血浆生物标志物，特别是与MRI、人口统计学、APOE4和认知测量相结合时，即使在认知功能未受损的个体中，也具有预测记忆衰退和评估痴呆进展风险的显著潜力。
{"title":"Integrating plasma, MRI, and cognitive biomarkers for personalized prediction of decline across cognitive domains","authors":"Elaheh Moradi , Robert Dahnke , Vandad Imani , Christian Gaser , Alina Solomon , Jussi Tohka , Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1016/j.neurobiolaging.2025.06.010","DOIUrl":"10.1016/j.neurobiolaging.2025.06.010","url":null,"abstract":"<div><div>Plasma biomarkers are associated with cognitive performance and decline in Alzheimer’s disease, making them promising for early detection. This study investigates their predictive value, combined with non-invasive measures, in forecasting cognitive decline in individuals without dementia. We developed a multimodal machine-learning approach incorporating plasma biomarkers (Amyloid<span><math><mi>β</mi></math></span>42/40 (A<span><math><mi>β</mi></math></span>42/40), p-tau181, NfL), MRI, demographics, APOE4, and cognitive assessments to predict the rate of cognitive decline. Various models were designed to predict decline rates across cognitive domains (memory, executive function, language, and visuospatial abilities) and assess their relevance in predicting dementia progression. Cross-validated correlations between predicted and actual cognitive decline rates were 0.50 for memory, 0.49 for language, 0.42 for executive function, and 0.44 for visuospatial ability. MRI showed greater predictive importance than plasma biomarkers. Among plasma biomarkers, NfL and p-tau181 outperformed A<span><math><mi>β</mi></math></span>42/40. Predicting cognitive decline and progression to MCI/dementia was most accurate in the memory domain, where plasma biomarkers (A<span><math><mi>β</mi></math></span>42/40, p-tau181, NfL) added significant value to predictive models, likely due to their AD-specific nature. Plasma biomarkers contributed less to predictions in other cognitive domains. The results indicate that plasma biomarkers, particularly when combined with MRI, demographics, APOE4, and cognitive measures, have significant potential for predicting memory decline and assessing the risk of dementia progression, even in cognitively unimpaired individuals.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 53-65"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695114","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}
Despite the increasing availability of biomarkers in clinical settings, diagnosing individuals with subtle cognitive/behavioral symptoms and normal structural brain imaging remains challenging. In real-world settings, it is not feasible to subject all such patients to costly and invasive second-level assessments, and there are no clear guidelines for identifying those who should undergo these procedures beyond clinical follow-up and structural imaging. The present study explores the potential of repeated magnetic resonance imaging (MRI) in this context. We investigated whether detecting pathological brain volume (BV) changes exceeding normal aging could aid in deciding whether advanced biomarker testing is reasonable. Individuals with subtle cognitive/behavioral complaints underwent baseline and 18-month follow-up assessments (neuropsychological evaluation, MRI, and biomarker tests). Annualized percentage of BV change (PBVC/y), adjusted for age, sex, and scanner, was calculated with SIENA, and classified whether exceeding the 80th/95th percentiles of normative data. At follow-up, participants were classified (I) Converters/Non-Converters based on clinical information, (II) Non‐converters+/Non‐Converters‐ based on biomarkers status, and (III) Underlying disease based on both clinical follow-up and biomarkers. Logistic regressions assessed PBVC/y, baseline BV, and Mini-Mental State Examination change as predictors of participants’ classification. Among 110 participants, PBVC/y exceeding both the 80th/95th percentiles increased the probability of being classified Converters or Alzheimer’s disease/Frontotemporal dementia. Exceeding the 80th percentile increased the odds of being classified Non‐Converters+. Our results suggest that the application of SIENA normative data to repeated MRIs may help in deciding whether or not performing more invasive and high-cost second-level procedures in individuals with early-stage and subtle cognitive/behavioural changes.
{"title":"Repeated brain MRI utility in identifying neurodegenerative disorders at the pre-dementia stage","authors":"Chiara Carbone , Chiara Gallingani , Erica Balboni , Ludovico Luchetti , Giordano Gentile , Riccardo Maramotti , Daniela Ballotta , Najara Iacovino , Silvia Cossutti , Alessandro Marti , Manuela Tondelli , Annalisa Chiari , Marco Battaglini , Giovanna Zamboni","doi":"10.1016/j.neurobiolaging.2025.07.012","DOIUrl":"10.1016/j.neurobiolaging.2025.07.012","url":null,"abstract":"<div><div>Despite the increasing availability of biomarkers in clinical settings, diagnosing individuals with subtle cognitive/behavioral symptoms and normal structural brain imaging remains challenging. In real-world settings, it is not feasible to subject all such patients to costly and invasive second-level assessments, and there are no clear guidelines for identifying those who should undergo these procedures beyond clinical follow-up and structural imaging. The present study explores the potential of repeated magnetic resonance imaging (MRI) in this context. We investigated whether detecting pathological brain volume (BV) changes exceeding normal aging could aid in deciding whether advanced biomarker testing is reasonable. Individuals with subtle cognitive/behavioral complaints underwent baseline and 18-month follow-up assessments (neuropsychological evaluation, MRI, and biomarker tests). Annualized percentage of BV change (PBVC/y), adjusted for age, sex, and scanner, was calculated with SIENA, and classified whether exceeding the 80th/95th percentiles of normative data. At follow-up, participants were classified (I) Converters/Non-Converters based on clinical information, (II) Non‐converters+/Non‐Converters‐ based on biomarkers status, and (III) Underlying disease based on both clinical follow-up and biomarkers. Logistic regressions assessed PBVC/y, baseline BV, and Mini-Mental State Examination change as predictors of participants’ classification. Among 110 participants, PBVC/y exceeding both the 80th/95th percentiles increased the probability of being classified Converters or Alzheimer’s disease/Frontotemporal dementia. Exceeding the 80th percentile increased the odds of being classified Non‐Converters+. Our results suggest that the application of SIENA normative data to repeated MRIs may help in deciding whether or not performing more invasive and high-cost second-level procedures in individuals with early-stage and subtle cognitive/behavioural changes.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 35-43"},"PeriodicalIF":3.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-16DOI: 10.1016/j.neurobiolaging.2025.07.009
Nicholas O’Neill , Nuzulul Kurniansyah , Congcong Zhu , Oluwatosin A. Olayinka , Richard Mayeux , Jonathan L. Haines , Margaret A. Pericak-Vance , Li-San Wang , Gerard D. Schellenberg , Lindsay A. Farrer , Xiaoling Zhang
Alzheimer disease (AD) polygenic risk scores (ADPRS) built from cell-type (ct) specific genetic variants can be used to infer cell-type contributions to AD. We derived two ct-ADPRSs using variants near single-nuclei RNA-seq (snRNA) derived cell-type specific genes or on single-nuclei ATAC-seq (snATAC) derived cell-type specific accessible chromatin regions. We generated a multi-omic ct-ADPRS for eight neuron subtypes using both single-nuclei datasets. SnATAC-derived ct-ADPRSs demonstrated considerably lower correlations among cell types (average r = 0.071) than snRNA-derived ct-ADPRSs (average r = 0.19), indicating their heightened cell-type specificity. The association of these ct-ADPRSs with AD endophenotypes was evaluated using logistic and linear regression models. Tau tangle burden was associated with astrocyte (AST) ct-ADPRS derived from snATAC (β=0.82, FDR=0.0013) and snRNA (β=0.60, FDR=0.045) as well as microglia (MIC) ct-ADPRS from both (snATAC: β=0.75, FDR=0.0047) (snRNA: β=0.63, FDR=0.028). AST ct-ADPRS was significantly associated with Mini-Mental State Examination score only when derived from snATAC data (β=-0.82, FDR=0.011). SST expressing GABAergic neuron ADPRS was strongly associated ct-ADPRS with neuritic plaque burden (β=0.087, FDR=0.0014) and the only neuron subtype ct-ADPRS significantly associated with AD endophenotypes. We investigated 1954 SNPs contributing to this ct-ADPRS and found the strongest association with variants upstream of the neuropeptide Y gene, NPY, particularly rs3940268 (β=-0.13, P = 8.2x10−5). This association is significant even after adjusting for diffuse plaque (β=-0.12, P = 1.5x10−4) or neurofibrillary tangle burden (β=-0.08, P = 3.9x10−3). NPY was expressed in a small subset of neurons, and these findings suggest its strong impact on the association of SST+ GABAergic neurons with early AD pathology.
{"title":"2988Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores","authors":"Nicholas O’Neill , Nuzulul Kurniansyah , Congcong Zhu , Oluwatosin A. Olayinka , Richard Mayeux , Jonathan L. Haines , Margaret A. Pericak-Vance , Li-San Wang , Gerard D. Schellenberg , Lindsay A. Farrer , Xiaoling Zhang","doi":"10.1016/j.neurobiolaging.2025.07.009","DOIUrl":"10.1016/j.neurobiolaging.2025.07.009","url":null,"abstract":"<div><div>Alzheimer disease (AD) polygenic risk scores (ADPRS) built from cell-type (ct) specific genetic variants can be used to infer cell-type contributions to AD. We derived two ct-ADPRSs using variants near single-nuclei RNA-seq (snRNA) derived cell-type specific genes or on single-nuclei ATAC-seq (snATAC) derived cell-type specific accessible chromatin regions. We generated a multi-omic ct-ADPRS for eight neuron subtypes using both single-nuclei datasets. SnATAC-derived ct-ADPRSs demonstrated considerably lower correlations among cell types (average r = 0.071) than snRNA-derived ct-ADPRSs (average r = 0.19), indicating their heightened cell-type specificity. The association of these ct-ADPRSs with AD endophenotypes was evaluated using logistic and linear regression models. Tau tangle burden was associated with astrocyte (AST) ct-ADPRS derived from snATAC (β=0.82, FDR=0.0013) and snRNA (β=0.60, FDR=0.045) as well as microglia (MIC) ct-ADPRS from both (snATAC: β=0.75, FDR=0.0047) (snRNA: β=0.63, FDR=0.028). AST ct-ADPRS was significantly associated with Mini-Mental State Examination score only when derived from snATAC data (β=-0.82, FDR=0.011). SST expressing GABAergic neuron ADPRS was strongly associated ct-ADPRS with neuritic plaque burden (β=0.087, FDR=0.0014) and the only neuron subtype ct-ADPRS significantly associated with AD endophenotypes. We investigated 1954 SNPs contributing to this ct-ADPRS and found the strongest association with variants upstream of the neuropeptide Y gene, <em>NPY</em>, particularly rs3940268 (β=-0.13, P = 8.2x10<sup>−5</sup>). This association is significant even after adjusting for diffuse plaque (β=-0.12, P = 1.5x10<sup>−4</sup>) or neurofibrillary tangle burden (β=-0.08, P = 3.9x10<sup>−3</sup>). <em>NPY</em> was expressed in a small subset of neurons, and these findings suggest its strong impact on the association of SST+ GABAergic neurons with early AD pathology.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 44-52"},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-15DOI: 10.1016/j.neurobiolaging.2025.07.010
Elizabeth Riley, Nicholas Cicero, Khena Swallow, Adam Anderson, Eve De Rosa
Using multi-echo blood oxygenation level-dependent (BOLD) neuroimaging, we examined lifespan differences in three subcortical nuclei important to the neuromodulation of cognition and target sites for early Alzheimer’s pathogenesis in the isodendritic core: the locus coeruleus (LC) the major source of noradrenaline, the nucleus basalis of Meynert (NBM) the major source of acetylcholine, and the ventral tegmental area (VTA) the major source of dopamine. Seventy-one participants, from 19 to 86 years old (young n = 29, middle-aged, n = 18, and older n = 24), were tasked with memorizing visual images while monitoring auditory tones for a predefined target to assess attentional modulation of subsequent memory for the images. Young adults demonstrated a memory advantage for images paired with a target tone relative to no tone, which was diminished in middle age, and absent in older adults. Elevated NBM and VTA BOLD responses to subsequently remembered target-paired images were present in all groups but were selectively absent in the LC of older adults. Moreover, only LC activity explained individual variation in subsequent memory performance. Even though activity in multiple modulatory nuclei contributed, age-related change in the attentional boosting of memory was specifically tied to altered LC activity.
{"title":"Blood oxygenation level-dependent responses in neuromodulatory nuclei and their associations with attention and memory across age groups","authors":"Elizabeth Riley, Nicholas Cicero, Khena Swallow, Adam Anderson, Eve De Rosa","doi":"10.1016/j.neurobiolaging.2025.07.010","DOIUrl":"10.1016/j.neurobiolaging.2025.07.010","url":null,"abstract":"<div><div>Using multi-echo blood oxygenation level-dependent (BOLD) neuroimaging, we examined lifespan differences in three subcortical nuclei important to the neuromodulation of cognition and target sites for early Alzheimer’s pathogenesis in the isodendritic core: the locus coeruleus (LC) the major source of noradrenaline, the nucleus basalis of Meynert (NBM) the major source of acetylcholine, and the ventral tegmental area (VTA) the major source of dopamine. Seventy-one participants, from 19 to 86 years old (young n = 29, middle-aged, n = 18, and older n = 24), were tasked with memorizing visual images while monitoring auditory tones for a predefined target to assess attentional modulation of subsequent memory for the images. Young adults demonstrated a memory advantage for images paired with a target tone relative to no tone, which was diminished in middle age, and absent in older adults. Elevated NBM and VTA BOLD responses to subsequently remembered target-paired images were present in all groups but were selectively absent in the LC of older adults. Moreover, only LC activity explained individual variation in subsequent memory performance. Even though activity in multiple modulatory nuclei contributed, age-related change in the attentional boosting of memory was specifically tied to altered LC activity.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 24-34"},"PeriodicalIF":3.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-12DOI: 10.1016/j.neurobiolaging.2025.07.008
Ghina Zia , Syed Salman Shahid , Ho-Ching Yang , Sujuan Gao , Shannon L. Risacher , Andrew J. Saykin , Yu-Chien Wu
Human brains undergo considerable morphologic variation with age, a primary risk factor for neurodegenerative disorders. While aging often causes neurocognitive decline, its governing biological mechanisms remain unclear. These age-related brain microstructural changes may be quantified by advanced diffusion MRI (dMRI) with tissue-specific compartment modeling approach. This longitudinal study investigates age-related differences in hippocampal subfields vulnerable to early stages of Alzheimer’s disease (AD). Thirty-seven cognitively normal (CN) older adults (70.6 ± 6.7 years) from the Indiana Alzheimer's Disease Research Center (IADRC) underwent baseline and follow-up MRI scans, within 24 ± 11.7 months. Grey matter-specific multi-compartment diffusion model, cortical-neurite orientation dispersion, and density imaging (cortical-NODDI) was used to derive diffusion microstructural metrics, namely orientation dispersion index (ODI) and neurite density index (NDI) in hippocampal-subfields (CA1–3, CA4DG, and subiculum). We investigated rate of change in diffusion metrics and its associations with age and baseline diffusion metrics in hippocampal subfields using linear regression analysis, after adjusting for confounding factors (i.e., sex, education, Apolipoprotein E (APOE) ε4, and baseline subfield volumes). CA1–3 and subiculum volumes significantly decreased between baseline and follow-up scans. ODI rate of change was significantly higher than zero in CA4DG, while rate of change in NDI was significantly lower than zero in CA1–3 and CA4DG. ODI rate of change in CA1–3 was significantly associated with baseline age of participants and initial microstructural value of ODI in CA1–3. Results showed that Cornu Ammonis is most sensitive to age-related changes with increased microstructural dispersion and decreased neurite density with age- and initial state-dependent changes.
{"title":"Longitudinal non-linear changes in the microstructure of the hippocampal subfields in older adults","authors":"Ghina Zia , Syed Salman Shahid , Ho-Ching Yang , Sujuan Gao , Shannon L. Risacher , Andrew J. Saykin , Yu-Chien Wu","doi":"10.1016/j.neurobiolaging.2025.07.008","DOIUrl":"10.1016/j.neurobiolaging.2025.07.008","url":null,"abstract":"<div><div>Human brains undergo considerable morphologic variation with age, a primary risk factor for neurodegenerative disorders. While aging often causes neurocognitive decline, its governing biological mechanisms remain unclear. These age-related brain microstructural changes may be quantified by advanced diffusion MRI (dMRI) with tissue-specific compartment modeling approach. This longitudinal study investigates age-related differences in hippocampal subfields vulnerable to early stages of Alzheimer’s disease (AD). Thirty-seven cognitively normal (CN) older adults (70.6 ± 6.7 years) from the Indiana Alzheimer's Disease Research Center (IADRC) underwent baseline and follow-up MRI scans, within 24 ± 11.7 months. Grey matter-specific multi-compartment diffusion model, cortical-neurite orientation dispersion, and density imaging (cortical-NODDI) was used to derive diffusion microstructural metrics, namely orientation dispersion index (ODI) and neurite density index (NDI) in hippocampal-subfields (CA1–3, CA4DG, and subiculum). We investigated rate of change in diffusion metrics and its associations with age and baseline diffusion metrics in hippocampal subfields using linear regression analysis, after adjusting for confounding factors (i.e., sex, education, Apolipoprotein E <em>(APOE) ε4</em>, and baseline subfield volumes). CA1–3 and subiculum volumes significantly decreased between baseline and follow-up scans. ODI rate of change was significantly higher than zero in CA4DG, while rate of change in NDI was significantly lower than zero in CA1–3 and CA4DG. ODI rate of change in CA1–3 was significantly associated with baseline age of participants and initial microstructural value of ODI in CA1–3. Results showed that Cornu Ammonis is most sensitive to age-related changes with increased microstructural dispersion and decreased neurite density with age- and initial state-dependent changes.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"155 ","pages":"Pages 113-123"},"PeriodicalIF":3.5,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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