Pub Date : 2026-04-01Epub Date: 2026-01-01DOI: 10.1016/j.neurobiolaging.2025.12.010
Elisabeth Hendrickx Van de Craen , Liene Bossaerts , Anne Sieben , Tobi Van den Bossche , Maria Bjerke , Bernard Hanseeuw , Bruno Bergmans , Rik Vandenberghe , Peter P. De Deyn , Patrick Cras , Kristel Sleegers , Sebastiaan Engelborghs , Christine Van Broeckhoven , Julie van der Zee , BELNEU Consortium
Rare mutations in the ATP binding cassette subfamily A member 7 (ABCA7) gene are known risk factors for Alzheimer’s disease (AD). Genetic sequencing in 1372 Belgian patients previously revealed rare ABCA7 mutations in 102 carriers, 58 with a premature termination codon mutation (PTC) and 44 with a missense mutation. Among carriers, 14 received post-mortem examination. Here, we reviewed and report the demographics, clinicopathological phenotypes, and diagnoses of identified ABCA7 mutation carriers. Carriers mostly developed late-onset AD (71 ± 9 years) and had a high familial load (67 % with positive family history). Patients presented with classic amnestic AD based on neuropsychological assessment, imaging and CSF biomarkers. However, vascular involvement was observed in a considerable part of patients, leading to diagnosis of vascular dementia (9 %) and cerebral amyloid angiopathy (CAA) (6 %). In line with this, neuropathology of the 14 examined carriers uncovered extensive levels of CAA and AD hallmarks. Carriers of an ABCA7 missense mutations displayed a less aggressive phenotype, with comparable onset but longer disease duration compared to carriers of a PTC mutation. Furthermore, non-amnestic features including language, dysexecutive and behavioural symptoms, were more frequently seen in PTC patients (18 % vs 9 %), as was the case for concomitant vascular disease (22 % vs 10 %). Taken together, the clinical phenotype of rare ABCA7 mutation carriers spans the AD-CAA spectrum. Patients present with a classical AD phenotype although clinical heterogeneity is observed among carriers. The presence of a cerebrovascular component (CAA) may, in part, explain this heterogeneity.
{"title":"Rare ABCA7 mutations in Alzheimer’s disease and cerebral amyloid angiopathy pathology","authors":"Elisabeth Hendrickx Van de Craen , Liene Bossaerts , Anne Sieben , Tobi Van den Bossche , Maria Bjerke , Bernard Hanseeuw , Bruno Bergmans , Rik Vandenberghe , Peter P. De Deyn , Patrick Cras , Kristel Sleegers , Sebastiaan Engelborghs , Christine Van Broeckhoven , Julie van der Zee , BELNEU Consortium","doi":"10.1016/j.neurobiolaging.2025.12.010","DOIUrl":"10.1016/j.neurobiolaging.2025.12.010","url":null,"abstract":"<div><div>Rare mutations in the ATP binding cassette subfamily A member 7 (<em>ABCA7</em>) gene are known risk factors for Alzheimer’s disease (AD). Genetic sequencing in 1372 Belgian patients previously revealed rare <em>ABCA7</em> mutations in 102 carriers, 58 with a premature termination codon mutation (PTC) and 44 with a missense mutation. Among carriers, 14 received post-mortem examination. Here, we reviewed and report the demographics, clinicopathological phenotypes, and diagnoses of identified <em>ABCA7</em> mutation carriers. Carriers mostly developed late-onset AD (71 ± 9 years) and had a high familial load (67 % with positive family history). Patients presented with classic amnestic AD based on neuropsychological assessment, imaging and CSF biomarkers. However, vascular involvement was observed in a considerable part of patients, leading to diagnosis of vascular dementia (9 %) and cerebral amyloid angiopathy (CAA) (6 %). In line with this, neuropathology of the 14 examined carriers uncovered extensive levels of CAA and AD hallmarks. Carriers of an <em>ABCA7</em> missense mutations displayed a less aggressive phenotype, with comparable onset but longer disease duration compared to carriers of a PTC mutation. Furthermore, non-amnestic features including language, dysexecutive and behavioural symptoms, were more frequently seen in PTC patients (18 % vs 9 %), as was the case for concomitant vascular disease (22 % vs 10 %). Taken together, the clinical phenotype of rare <em>ABCA7</em> mutation carriers spans the AD-CAA spectrum. Patients present with a classical AD phenotype although clinical heterogeneity is observed among carriers. The presence of a cerebrovascular component (CAA) may, in part, explain this heterogeneity.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"160 ","pages":"Pages 33-46"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912390","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 : 2026-04-01Epub Date: 2025-12-24DOI: 10.1016/j.neurobiolaging.2025.12.009
Madeline Nicholson , Rhiannon J. Wood , Simon S. Murray , Jessica L. Fletcher
Lifelong oligodendrogenesis and myelination is critical for healthy brain aging. Using cumulative labelling with thymidine analogue, 5-ethynyl-2’-deoxyuridine (EdU) for 6-weeks commencing at 2-, 12- and 18-months of age in C57BL/6 mice, we found that oligodendrocyte progenitor cell (OPC) proliferation and oligodendroglial densities are relatively stable in the adult mouse optic nerve, corpus callosum and somatosensory cortex. We also found that more proliferative adult OPCs differentiate into oligodendrocytes in the somatosensory cortex than the corpus callosum during aging. To determine the role of neuronal TrkB in adult oligodendrogenesis in the older brain, we generated Thy1-CreERT2-EYFP::TrkBfl/fl mice and administered tamoxifen at 12-months of age, before cumulative EdU labelling. This resulted in TrkB deletion from 10 % of layer V projection neurons in the somatosensory cortex and reduced the level of TrkB in the remaining Thy1-YFP+ neurons by approximately half. Neuronal TrkB reduction had no effect on OPC proliferation in the optic nerve, corpus callosum or somatosensory cortex. However, there was a significant decrease in the proportion of proliferative OPCs that contributed to the post-mitotic oligodendrocyte population in the somatosensory cortex 5-months later. These findings provide insight into regional and age-related changes in oligodendroglial population dynamics and identify that neuronal TrkB supports cortical oligodendrogenesis during healthy brain aging.
{"title":"Neuronal TrkB supports adult cortical oligodendrogenesis in the brains of older adult mice","authors":"Madeline Nicholson , Rhiannon J. Wood , Simon S. Murray , Jessica L. Fletcher","doi":"10.1016/j.neurobiolaging.2025.12.009","DOIUrl":"10.1016/j.neurobiolaging.2025.12.009","url":null,"abstract":"<div><div>Lifelong oligodendrogenesis and myelination is critical for healthy brain aging. Using cumulative labelling with thymidine analogue, 5-ethynyl-2’-deoxyuridine (EdU) for 6-weeks commencing at 2-, 12- and 18-months of age in C57BL/6 mice, we found that oligodendrocyte progenitor cell (OPC) proliferation and oligodendroglial densities are relatively stable in the adult mouse optic nerve, corpus callosum and somatosensory cortex. We also found that more proliferative adult OPCs differentiate into oligodendrocytes in the somatosensory cortex than the corpus callosum during aging. To determine the role of neuronal TrkB in adult oligodendrogenesis in the older brain, we generated <em>Thy1-CreER</em><sup><em>T2</em></sup><em>-EYFP::TrkB</em><sup><em>fl/fl</em></sup> mice and administered tamoxifen at 12-months of age, before cumulative EdU labelling. This resulted in TrkB deletion from 10 % of layer V projection neurons in the somatosensory cortex and reduced the level of TrkB in the remaining Thy1-YFP<sup>+</sup> neurons by approximately half. Neuronal TrkB reduction had no effect on OPC proliferation in the optic nerve, corpus callosum or somatosensory cortex. However, there was a significant decrease in the proportion of proliferative OPCs that contributed to the post-mitotic oligodendrocyte population in the somatosensory cortex 5-months later. These findings provide insight into regional and age-related changes in oligodendroglial population dynamics and identify that neuronal TrkB supports cortical oligodendrogenesis during healthy brain aging.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"160 ","pages":"Pages 64-76"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917843","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 : 2026-04-01Epub Date: 2025-12-16DOI: 10.1016/j.neurobiolaging.2025.12.004
Arthur P. Hamilton , Kaiah N. Sotebeer , John G. Grundy , Katherine Chadwick , Cassandra Morrison , Mahsa Dadar , Ellen Bialystok , John A.E. Anderson , for the Alzheimer’s Disease Metabolomics Consortium
Previous research examining the contribution of white matter hyperintensities (WMHs) to cognitive decline has focused on overall lesion burden. A new approach, afforded by the Lesion Quantification Toolkit (LQT), measures localized connectivity disruption from WMHs to better estimate their impact on cognition. This methodology shifts the focus from lesion volume to the level of network disruption between brain regions. In this novel study, we applied the LQT approach to healthy aging and linked the degree of disconnection of gray matter by WMHs to both cognitive impairment and resilience via cognitive reserve. Using three pre-existing MRI datasets of older adults (total N = 259), we used the LQT to examine localized disruptions to brain connectivity due to WMHs. We then used partial least-squares path modeling to examine the relationships between this disruption, cognitive performance, age, and cognitive reserve. The results support a link between connectivity disruption and reduced cognitive performance. Results from all three individual datasets, one of which included a detailed measure of cognitive reserve, showed a link between cognitive reserve and higher cognitive performance, suggesting cognitive reserve allows for maintained cognitive function in spite of the negative impact of WMHs.
{"title":"Cognitive reserve is associated with less cognitive decline from white matter hyperintensities","authors":"Arthur P. Hamilton , Kaiah N. Sotebeer , John G. Grundy , Katherine Chadwick , Cassandra Morrison , Mahsa Dadar , Ellen Bialystok , John A.E. Anderson , for the Alzheimer’s Disease Metabolomics Consortium","doi":"10.1016/j.neurobiolaging.2025.12.004","DOIUrl":"10.1016/j.neurobiolaging.2025.12.004","url":null,"abstract":"<div><div>Previous research examining the contribution of white matter hyperintensities (WMHs) to cognitive decline has focused on overall lesion burden. A new approach, afforded by the Lesion Quantification Toolkit (LQT), measures localized connectivity disruption from WMHs to better estimate their impact on cognition. This methodology shifts the focus from lesion volume to the level of network disruption between brain regions. In this novel study, we applied the LQT approach to healthy aging and linked the degree of disconnection of gray matter by WMHs to both cognitive impairment and resilience via cognitive reserve. Using three pre-existing MRI datasets of older adults (total N = 259), we used the LQT to examine localized disruptions to brain connectivity due to WMHs. We then used partial least-squares path modeling to examine the relationships between this disruption, cognitive performance, age, and cognitive reserve. The results support a link between connectivity disruption and reduced cognitive performance. Results from all three individual datasets, one of which included a detailed measure of cognitive reserve, showed a link between cognitive reserve and higher cognitive performance, suggesting cognitive reserve allows for maintained cognitive function in spite of the negative impact of WMHs.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"160 ","pages":"Pages 1-9"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145842861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-24DOI: 10.1016/j.neurobiolaging.2025.12.008
Alicia J. Campbell , Toomas Erik Anijärv , Mikael Johansson , Thomas Pace , Jim Lagopoulos , Daniel F. Hermens , Jacob M. Levenstein , Sophie C. Andrews
Memory functions are susceptible to age-related cognitive decline, making it essential to explore the underlying neurophysiological mechanisms that contribute to memory function during healthy ageing. Resting-state EEG (rsEEG) parameters, particularly the aperiodic exponent, a marker of cortical excitation-inhibition balance, and individual alpha peak frequency, a correlate of neural processing efficiency, have demonstrated associations with ageing and cognitive functions. This study investigated associations between these rsEEG markers and performance across multiple memory systems in healthy older adults (n = 99) aged 50–84 years, specifically the direct associations of these markers on memory across episodic, working, and visual short-term memory systems, assessed via computerised tasks, as well as their moderating effects on age-memory relationships. While no direct associations were seen between rsEEG markers and memory performance across tasks beyond the contribution of age, gender and education, results revealed significant moderating effects of the aperiodic exponent on age-related performance in episodic and visual short-term memory. Notably, for individuals with a higher exponent, age was not significantly associated with episodic or visual short-term memory performance, whereas those with average and lower exponent values showed poorer performance with older age. These findings suggest that average and lower aperiodic exponents may reflect a marker of decrement in age-related memory performance and higher exponents may index an underlying protective mechanism against age-related memory decline. This investigation extends the current understanding of cognitive ageing mechanisms by identifying the aperiodic exponent as a potential biomarker explaining individual differences in cognitive ageing trajectories in older adult populations, particularly in episodic and visual short-term memory systems, and establishes a framework for studying neuroprotective mechanisms and developing interventions to preserve cognitive function in older adults.
{"title":"Resting-state EEG aperiodic exponent moderates the association between age and memory performance in older adults","authors":"Alicia J. Campbell , Toomas Erik Anijärv , Mikael Johansson , Thomas Pace , Jim Lagopoulos , Daniel F. Hermens , Jacob M. Levenstein , Sophie C. Andrews","doi":"10.1016/j.neurobiolaging.2025.12.008","DOIUrl":"10.1016/j.neurobiolaging.2025.12.008","url":null,"abstract":"<div><div>Memory functions are susceptible to age-related cognitive decline, making it essential to explore the underlying neurophysiological mechanisms that contribute to memory function during healthy ageing. Resting-state EEG (rsEEG) parameters, particularly the aperiodic exponent, a marker of cortical excitation-inhibition balance, and individual alpha peak frequency, a correlate of neural processing efficiency, have demonstrated associations with ageing and cognitive functions. This study investigated associations between these rsEEG markers and performance across multiple memory systems in healthy older adults (n = 99) aged 50–84 years, specifically the direct associations of these markers on memory across episodic, working, and visual short-term memory systems, assessed via computerised tasks, as well as their moderating effects on age-memory relationships. While no direct associations were seen between rsEEG markers and memory performance across tasks beyond the contribution of age, gender and education, results revealed significant moderating effects of the aperiodic exponent on age-related performance in episodic and visual short-term memory. Notably, for individuals with a higher exponent, age was not significantly associated with episodic or visual short-term memory performance, whereas those with average and lower exponent values showed poorer performance with older age. These findings suggest that average and lower aperiodic exponents may reflect a marker of decrement in age-related memory performance and higher exponents may index an underlying protective mechanism against age-related memory decline. This investigation extends the current understanding of cognitive ageing mechanisms by identifying the aperiodic exponent as a potential biomarker explaining individual differences in cognitive ageing trajectories in older adult populations, particularly in episodic and visual short-term memory systems, and establishes a framework for studying neuroprotective mechanisms and developing interventions to preserve cognitive function in older adults.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"160 ","pages":"Pages 10-21"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864204","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 : 2026-04-01Epub Date: 2026-01-07DOI: 10.1016/j.neurobiolaging.2026.01.002
Talia Salzman , Diana P. Tobón , Vanessa Taler , Sarah Fraser
Older adults with subjective cognitive decline (SCD) may be at a greater risk of cognitive impairment than older adults without SCD (i.e., non-SCD). This study examined dual-task changes in cerebral oxygenation and performance to determine whether these changes may be used as a biomarker in older adults with SCD. Older adults with (n = 24) and without SCD (n = 18) completed neuropsychological assessments and finger tapping and working memory dual-tasks. Cognitive and motor performance were measured, and functional near-infrared spectroscopy (fNIRS) was used to measure changes in prefrontal cortex oxygenation (∆HbO2, ∆HbR). Repeated measures ANOVAs revealed greater ∆HbO2 during the n-back dual-task compared to the single motor (p = .01) and cognitive (p = .04) conditions. Slower responses (p = .002) and less accurate (p = .024) and more variable (p = .001) finger tapping were observed during the dual compared to single tasks. Within the SCD group, ∆HbO2 was greater during the dual compared to single cognitive condition (p = .002) and between the SCD and non-SCD groups (p = .016). Within the SCD group, finger tapping was more accurate during the single compared to dual-task (p = .04). Cognitive accuracy was also higher during the single compared to dual-task condition in the SCD (p < .001) and non-SCD (p = .005) groups. Neural compensation and inefficiency were observed in older adults with SCD: n-back performance was maintained but double number sequence performance declined despite increased ∆HbO2. Longitudinal evidence is needed to determine whether these mechanisms can be used as biomarkers for progressive cognitive impairment in SCD.
{"title":"Investigating dual-task biomarkers of subjective cognitive decline using functional near-infrared spectroscopy","authors":"Talia Salzman , Diana P. Tobón , Vanessa Taler , Sarah Fraser","doi":"10.1016/j.neurobiolaging.2026.01.002","DOIUrl":"10.1016/j.neurobiolaging.2026.01.002","url":null,"abstract":"<div><div>Older adults with subjective cognitive decline (SCD) may be at a greater risk of cognitive impairment than older adults without SCD (i.e., non-SCD). This study examined dual-task changes in cerebral oxygenation and performance to determine whether these changes may be used as a biomarker in older adults with SCD. Older adults with (n = 24) and without SCD (n = 18) completed neuropsychological assessments and finger tapping and working memory dual-tasks. Cognitive and motor performance were measured, and functional near-infrared spectroscopy (fNIRS) was used to measure changes in prefrontal cortex oxygenation (∆HbO2, ∆HbR). Repeated measures ANOVAs revealed greater ∆HbO2 during the n-back dual-task compared to the single motor (<em>p</em> = .01) and cognitive (<em>p</em> = .04) conditions. Slower responses (<em>p</em> = .002) and less accurate (<em>p</em> = .024) and more variable (<em>p</em> = .001) finger tapping were observed during the dual compared to single tasks. Within the SCD group, ∆HbO2 was greater during the dual compared to single cognitive condition (<em>p</em> = .002) and between the SCD and non-SCD groups (<em>p</em> = .016). Within the SCD group, finger tapping was more accurate during the single compared to dual-task (<em>p</em> = .04). Cognitive accuracy was also higher during the single compared to dual-task condition in the SCD (<em>p</em> < .001) and non-SCD (<em>p</em> = .005) groups. Neural compensation and inefficiency were observed in older adults with SCD: n-back performance was maintained but double number sequence performance declined despite increased ∆HbO2. Longitudinal evidence is needed to determine whether these mechanisms can be used as biomarkers for progressive cognitive impairment in SCD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"160 ","pages":"Pages 77-85"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927827","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 : 2026-03-19DOI: 10.1016/j.neurobiolaging.2026.03.005
Debora Mucida Alvim, Maria Del C Valdés Hernández, Mark E Bastin, Una Clancy, Carmen Arteaga-Reyes, Stewart Wiseman, Angela C C Jochems, Daniela Jaime Garcia, Olivia K L Hamilton, Ellen V Backhouse, Yajun Cheng, Michael J Thrippleton, Michael S Stringer, Francesca M Chappell, Fergus N Doubal, Susana Muñoz Maniega, Joanna M Wardlaw
The Diffusion Tensor Imaging along the Perivascular Space (DTI-ALPS) index has been proposed as a non-invasive marker of glymphatic function, but its specific utility in the context of SVD and cognition remains unclear. In 189 patients with mild ischaemic stroke (age 38.8-86.3 years), we computed DTI-ALPS and quantified imaging markers of SVD: enlarged perivascular spaces (PVS), white matter hyperintensities (WMH), and cerebral microbleeds. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA). Linear regression models were used to explore the associations between DTI-ALPS, SVD markers and cognition. We found that lower DTI-ALPS values were associated with higher volume of basal ganglia PVS (β = -0.026, 95% CI [-0.052, -0.001]) and with male sex (-0.058, [-0.105, -0.010]). DTI-ALPS was also negatively associated with fractional anisotropy (FA) (-0.062, [-0.084, -0.040]) and mean diffusivity (MD) (-0.056, [-0.092, -0.021]) and positively associated with both neurite density (NDI) (0.033 [0.001,0.065]) and orientation dispersion (ODI) (0.079 [0.061,0.097]) indices. Higher WMH volume predicted lower DTI-ALPS in patients with non-lacunar stroke (-0.079 [-0.118, -0.041]). No associations were observed between DTI-ALPS values and microbleeds or MoCA scores. These findings suggest that, in post-stroke SVD, the DTI-ALPS index may primarily reflect local tissue fluid changes and microstructure damage, rather than serving as a specific, direct indicator of glymphatic function or cognitive impairment. Future research using region-specific and physiologically dynamic imaging approaches may be better suited to capture the glymphatic contributions to stroke and SVD pathology.
{"title":"Relevance of the diffusion tensor imaging along the perivascular space (DTI-ALPS) index in small vessel disease - A study in patients with mild ischaemic stroke.","authors":"Debora Mucida Alvim, Maria Del C Valdés Hernández, Mark E Bastin, Una Clancy, Carmen Arteaga-Reyes, Stewart Wiseman, Angela C C Jochems, Daniela Jaime Garcia, Olivia K L Hamilton, Ellen V Backhouse, Yajun Cheng, Michael J Thrippleton, Michael S Stringer, Francesca M Chappell, Fergus N Doubal, Susana Muñoz Maniega, Joanna M Wardlaw","doi":"10.1016/j.neurobiolaging.2026.03.005","DOIUrl":"https://doi.org/10.1016/j.neurobiolaging.2026.03.005","url":null,"abstract":"<p><p>The Diffusion Tensor Imaging along the Perivascular Space (DTI-ALPS) index has been proposed as a non-invasive marker of glymphatic function, but its specific utility in the context of SVD and cognition remains unclear. In 189 patients with mild ischaemic stroke (age 38.8-86.3 years), we computed DTI-ALPS and quantified imaging markers of SVD: enlarged perivascular spaces (PVS), white matter hyperintensities (WMH), and cerebral microbleeds. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA). Linear regression models were used to explore the associations between DTI-ALPS, SVD markers and cognition. We found that lower DTI-ALPS values were associated with higher volume of basal ganglia PVS (β = -0.026, 95% CI [-0.052, -0.001]) and with male sex (-0.058, [-0.105, -0.010]). DTI-ALPS was also negatively associated with fractional anisotropy (FA) (-0.062, [-0.084, -0.040]) and mean diffusivity (MD) (-0.056, [-0.092, -0.021]) and positively associated with both neurite density (NDI) (0.033 [0.001,0.065]) and orientation dispersion (ODI) (0.079 [0.061,0.097]) indices. Higher WMH volume predicted lower DTI-ALPS in patients with non-lacunar stroke (-0.079 [-0.118, -0.041]). No associations were observed between DTI-ALPS values and microbleeds or MoCA scores. These findings suggest that, in post-stroke SVD, the DTI-ALPS index may primarily reflect local tissue fluid changes and microstructure damage, rather than serving as a specific, direct indicator of glymphatic function or cognitive impairment. Future research using region-specific and physiologically dynamic imaging approaches may be better suited to capture the glymphatic contributions to stroke and SVD pathology.</p>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"163 ","pages":"35-45"},"PeriodicalIF":3.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147494201","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 : 2026-03-01Epub Date: 2025-12-03DOI: 10.1016/j.neurobiolaging.2025.12.002
Ahmed A. Bahrani , Peter T. Nelson , Erin L. Abner , David K. Powell , Christopher M. Norris , Elif Pinar Coskun , Ann M. Stowe , Larry B. Goldstein , Linda J. Van Eldik , Brian T. Gold , Donna M. Wilcock , Charles S. DeCarli , Steven M. Greenberg , Gregory A. Jicha
White matter hyperintensities (WMH) are an MRI-based biomarker associated with aging, Alzheimer’s disease, and vascular dementia. Although the volume of WMH typically increases over time (growth) for individuals, WMH volume in some cases can also decrease (regress). This suggests the presence of active brain injury recovery mechanisms. Whether WMH regression reflects a true biological phenomenon or results from imaging artifacts or measurement errors, however, remains controversial. Here, we review published reports, following PRISMA search guidelines, describing or referring to WMH regression, the methods used to detect and quantitate regression, and proposed underlying mechanisms. Of 174 reviewed articles, 31 (26 original research studies and five case reports) were identified as directly related to WMH regression. Technical factors such as differences in longitudinal scan parameters, motion artifacts, and the interval between baseline and follow-up scans can affect WMH volume measurements. These factors may lead to inaccurate conclusions if appropriate controls are not employed. Although the use of standardized and systematic measurement protocols is essential, there is strong evidence indicating that WMH regression is a robust and biologically important phenomenon that may be influenced by clinical interventions. Further studies are needed to investigate WMH regression in relation to cerebrovascular risk mitigation and other therapeutic strategies.
{"title":"White matter hyperintensity regression: Fact or artifact?","authors":"Ahmed A. Bahrani , Peter T. Nelson , Erin L. Abner , David K. Powell , Christopher M. Norris , Elif Pinar Coskun , Ann M. Stowe , Larry B. Goldstein , Linda J. Van Eldik , Brian T. Gold , Donna M. Wilcock , Charles S. DeCarli , Steven M. Greenberg , Gregory A. Jicha","doi":"10.1016/j.neurobiolaging.2025.12.002","DOIUrl":"10.1016/j.neurobiolaging.2025.12.002","url":null,"abstract":"<div><div>White matter hyperintensities (WMH) are an MRI-based biomarker associated with aging, Alzheimer’s disease, and vascular dementia. Although the volume of WMH typically increases over time (growth) for individuals, WMH volume in some cases can also decrease (regress). This suggests the presence of active brain injury recovery mechanisms. Whether WMH regression reflects a true biological phenomenon or results from imaging artifacts or measurement errors, however, remains controversial. Here, we review published reports, following PRISMA search guidelines, describing or referring to WMH regression, the methods used to detect and quantitate regression, and proposed underlying mechanisms. Of 174 reviewed articles, 31 (26 original research studies and five case reports) were identified as directly related to WMH regression. Technical factors such as differences in longitudinal scan parameters, motion artifacts, and the interval between baseline and follow-up scans can affect WMH volume measurements. These factors may lead to inaccurate conclusions if appropriate controls are not employed. Although the use of standardized and systematic measurement protocols is essential, there is strong evidence indicating that WMH regression is a robust and biologically important phenomenon that may be influenced by clinical interventions. Further studies are needed to investigate WMH regression in relation to cerebrovascular risk mitigation and other therapeutic strategies.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"159 ","pages":"Pages 33-46"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-29DOI: 10.1016/j.neurobiolaging.2025.11.008
Andy Jeesu Kim , Santiago Morales , Joshua Senior , Mara Mather
Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampering the development of targeted preventative interventions. In this study, we acquired electrophysiological, pupillometric, and behavioral measures in a passive and active auditory oddball paradigm to test the hypothesis that cognitively healthy older adults experience tonic LC hyperactivity. We leveraged the LC-NA system’s role in arousal regulation and manipulated state arousal and noradrenergic activity using the unpredictable threat of electric shock. Based on older adults' hypothesized tonic LC hyperactivity, we predicted that increased arousal would evoke weaker phasic (stimulus-evoked) noradrenergic responses in older adults compared with young adults. Consistent with this hypothesis, arousal differentially modulated behavioral responses and resting-state alpha power across age groups, and older adults showed smaller pupil dilation responses than young adults. Furthermore, linear mixed models revealed that arousal differentially modulated attentional control to salient but task-irrelevant distractors across age groups, with older adults exhibiting less behavioral slowing and longer P300 latency delays under threat of shock than did young adults. Together these findings provide convergent multi-modal evidence that aging is associated with tonic LC-NA system hyperactivity in humans, with consequences for mechanisms supporting attentional control. This research highlights the utility of non-invasive physiological markers to determine when across the adult lifespan the LC-NA system becomes hyperactive and to identify adults who may be at elevated risk for neurodegenerative progression due to emerging changes in LC-NA system function.
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