Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive function
Abstract Background Alzheimer’s disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles. Recent studies emphasize the role of vascular factors, including the glymphatic system, in AD pathogenesis, particularly in Aβ clearance....
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2025-03-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01707-9 |
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| author | Philine Marie Schirge Robert Perneczky Toshiaki Taoka Adriana L. Ruiz-Rizzo Ersin Ersoezlue Robert Forbrig Selim Guersel Carolin Kurz Matthias Brendel Julian Hellmann-Regen Josef Priller Anja Schneider Frank Jessen Emrah Düzel Katharina Buerger Stefan Teipel Christoph Laske Oliver Peters Eike Spruth Klaus Fliessbach Ayda Rostamzadeh Wenzel Glanz Daniel Janowitz Ingo Kilimann Sebastian Sodenkamp Michael Ewers Boris-Stephan Rauchmann |
| author_facet | Philine Marie Schirge Robert Perneczky Toshiaki Taoka Adriana L. Ruiz-Rizzo Ersin Ersoezlue Robert Forbrig Selim Guersel Carolin Kurz Matthias Brendel Julian Hellmann-Regen Josef Priller Anja Schneider Frank Jessen Emrah Düzel Katharina Buerger Stefan Teipel Christoph Laske Oliver Peters Eike Spruth Klaus Fliessbach Ayda Rostamzadeh Wenzel Glanz Daniel Janowitz Ingo Kilimann Sebastian Sodenkamp Michael Ewers Boris-Stephan Rauchmann |
| author_sort | Philine Marie Schirge |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles. Recent studies emphasize the role of vascular factors, including the glymphatic system, in AD pathogenesis, particularly in Aβ clearance. The diffusion tensor image analysis along the perivascular space (DTI-ALPS; ALPS-Index) has emerged as a novel, non-invasive method to evaluate the glymphatic system in vivo, showing glymphatic insufficiency in AD. This study aimed to investigate alterations in the function of the glymphatic system in individuals with AD versus healthy controls (HC), and to explore its association with Aβ, cerebrovascular disease (CVD), white matter hyperintensities (WMH), and cognitive function. Methods DTI MRI data from three independent study cohorts (ActiGliA: AD n = 16, Controls n = 18; DELCODE: AD n = 54, Controls n = 67; ADNI: AD n = 43, Controls n = 49) were used to evaluate the perivascular space (PVS) integrity; a potential biomarker for glymphatic activity. The DTI-Along the Perivascular Space technique was used to measure water diffusion along PVS providing an index to assess the efficiency of the glymphatic system’s waste clearance function. WMH load was quantified in FLAIR MRI using the lesion segmentation tool. We quantified WMHs volume within our defined region of interest (ROI) and excluded participants with any WMHs to avoid confounding the ALPS-Index. Associations with cerebrospinal fluid (CSF) AD hallmark biomarkers, cognitive performance (MMSE) and clinical severity (CDR) were assessed. Results AD patients had a significantly lower ALPS-Index vs. healthy controls (ActiGliA: AD: mean = 1.22, SD = 0.12; Controls: mean = 1.36, SD = 0.14, p = 0.004; DELCODE: AD: mean = 1.26, SD = 0.18; Controls: mean = 1.34, SD = 0.2, p = 0.035; ADNI: AD: mean = 1.08, SD = 0.24; Controls: mean = 1.19, SD = 0.13, p = 0.008). The ALPS-Index was associated with CSF Aβ concentration, WMH number and MMSE and CDR. WMH, found in the ROIs correlated negatively with the ALPS-Index. Conclusions This study highlights the potential of the DTI-ALPS-Index as a biomarker for glymphatic dysfunction in AD. It underscores the importance of considering vascular factors and the glymphatic system in the pathogenesis and diagnosis of AD as WMHs in the ROI could cause disturbances and inaccurate indices. |
| format | Article |
| id | doaj-art-c56d54f991c54c7eb2b9a9c88be3e00e |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-c56d54f991c54c7eb2b9a9c88be3e00e2025-08-20T03:41:46ZengBMCAlzheimer’s Research & Therapy1758-91932025-03-0117112010.1186/s13195-025-01707-9Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive functionPhiline Marie Schirge0Robert Perneczky1Toshiaki Taoka2Adriana L. Ruiz-Rizzo3Ersin Ersoezlue4Robert Forbrig5Selim Guersel6Carolin Kurz7Matthias Brendel8Julian Hellmann-Regen9Josef Priller10Anja Schneider11Frank Jessen12Emrah Düzel13Katharina Buerger14Stefan Teipel15Christoph Laske16Oliver Peters17Eike Spruth18Klaus Fliessbach19Ayda Rostamzadeh20Wenzel Glanz21Daniel Janowitz22Ingo Kilimann23Sebastian Sodenkamp24Michael Ewers25Boris-Stephan Rauchmann26Department of Psychiatry and Psychotherapy, LMU Hospital, LMU MunichDepartment of Psychiatry and Psychotherapy, LMU Hospital, LMU MunichDepartment of Innovative Biomedical Visualization (iBMV), Graduate School of Medicine, Nagoya UniversityDepartment of Neurology, Jena University HospitalGerman Center for Neurodegenerative Diseases (DZNE)Institute of Neuroradiology, LMU Hospital, LMU MunichDepartment of Psychiatry and Psychotherapy, LMU Hospital, LMU MunichDepartment of Psychiatry and Psychotherapy, LMU Hospital, LMU MunichMunich Cluster for Systems Neurology (SyNergy)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Venusberg-CampusGerman Center for Neurodegenerative Diseases (DZNE)Venusberg-CampusGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Venusberg-CampusDepartment of Psychiatry, University of Cologne, Medical FacultyGerman Center for Neurodegenerative Diseases (DZNE)Institute for Stroke and Dementia Research (ISD), Ludwig Maximilian University Hospital, Ludwig Maximilian UniversityGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE) MunichInstitute of Neuroradiology, LMU Hospital, LMU MunichAbstract Background Alzheimer’s disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles. Recent studies emphasize the role of vascular factors, including the glymphatic system, in AD pathogenesis, particularly in Aβ clearance. The diffusion tensor image analysis along the perivascular space (DTI-ALPS; ALPS-Index) has emerged as a novel, non-invasive method to evaluate the glymphatic system in vivo, showing glymphatic insufficiency in AD. This study aimed to investigate alterations in the function of the glymphatic system in individuals with AD versus healthy controls (HC), and to explore its association with Aβ, cerebrovascular disease (CVD), white matter hyperintensities (WMH), and cognitive function. Methods DTI MRI data from three independent study cohorts (ActiGliA: AD n = 16, Controls n = 18; DELCODE: AD n = 54, Controls n = 67; ADNI: AD n = 43, Controls n = 49) were used to evaluate the perivascular space (PVS) integrity; a potential biomarker for glymphatic activity. The DTI-Along the Perivascular Space technique was used to measure water diffusion along PVS providing an index to assess the efficiency of the glymphatic system’s waste clearance function. WMH load was quantified in FLAIR MRI using the lesion segmentation tool. We quantified WMHs volume within our defined region of interest (ROI) and excluded participants with any WMHs to avoid confounding the ALPS-Index. Associations with cerebrospinal fluid (CSF) AD hallmark biomarkers, cognitive performance (MMSE) and clinical severity (CDR) were assessed. Results AD patients had a significantly lower ALPS-Index vs. healthy controls (ActiGliA: AD: mean = 1.22, SD = 0.12; Controls: mean = 1.36, SD = 0.14, p = 0.004; DELCODE: AD: mean = 1.26, SD = 0.18; Controls: mean = 1.34, SD = 0.2, p = 0.035; ADNI: AD: mean = 1.08, SD = 0.24; Controls: mean = 1.19, SD = 0.13, p = 0.008). The ALPS-Index was associated with CSF Aβ concentration, WMH number and MMSE and CDR. WMH, found in the ROIs correlated negatively with the ALPS-Index. Conclusions This study highlights the potential of the DTI-ALPS-Index as a biomarker for glymphatic dysfunction in AD. It underscores the importance of considering vascular factors and the glymphatic system in the pathogenesis and diagnosis of AD as WMHs in the ROI could cause disturbances and inaccurate indices.https://doi.org/10.1186/s13195-025-01707-9Perivascular spaceDiffusion tensor imagingAmyloid-betaCognitive declineAlzheimer's diseaseDementia |
| spellingShingle | Philine Marie Schirge Robert Perneczky Toshiaki Taoka Adriana L. Ruiz-Rizzo Ersin Ersoezlue Robert Forbrig Selim Guersel Carolin Kurz Matthias Brendel Julian Hellmann-Regen Josef Priller Anja Schneider Frank Jessen Emrah Düzel Katharina Buerger Stefan Teipel Christoph Laske Oliver Peters Eike Spruth Klaus Fliessbach Ayda Rostamzadeh Wenzel Glanz Daniel Janowitz Ingo Kilimann Sebastian Sodenkamp Michael Ewers Boris-Stephan Rauchmann Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive function Alzheimer’s Research & Therapy Perivascular space Diffusion tensor imaging Amyloid-beta Cognitive decline Alzheimer's disease Dementia |
| title | Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive function |
| title_full | Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive function |
| title_fullStr | Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive function |
| title_full_unstemmed | Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive function |
| title_short | Perivascular space and white matter hyperintensities in Alzheimer’s disease: associations with disease progression and cognitive function |
| title_sort | perivascular space and white matter hyperintensities in alzheimer s disease associations with disease progression and cognitive function |
| topic | Perivascular space Diffusion tensor imaging Amyloid-beta Cognitive decline Alzheimer's disease Dementia |
| url | https://doi.org/10.1186/s13195-025-01707-9 |
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