Nira Cedres1, Daniel Ferreira2, Milan Nemy1, Alejandra Machado1, Joana B Pereira1, Sara Shams1, Lars-Olof Wahlund1, Anna Zettergren1, Olga Stepankova1, Lenka Vyslouzilova1, Maria Eriksdotter1, Stefan Teipel1, Michel J Grothe1, Kaj Blennow1, Henrik Zetterberg1, Michael Schöll1, Silke Kern1, Ingmar Skoog1, Eric Westman1. 1. From the Division of Clinical Geriatrics (N.C., D.F., A.M., J.B.P., S.S., L.-O.W., M.E., E.W.), Centre for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, and the Division of Insurance Medicine (A.M.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; Department of Psychology (N.C.), Sensory Cognitive Interaction Laboratory (SCI-lab), Stockholm University, Sweden; Department of Radiology (D.F.), Mayo Clinic, Rochester, MN; Department of Cybernetics (M.N.), Faculty of Electrical Engineering and Czech Institute of Informatics (M.N., O.S., L.V.), Robotics, and Cybernetics, Czech Technical University, Prague, Czech Republic; Clinical Memory Research Unit (J.B.P.), Department of Clinical Sciences, Lund University, Malmö; Department of Psychiatry Cognition and Old Age Psychiatry, (A.Z., S.K., I.S.), Clinical Neurochemistry Laboratory (K.B., H.Z.), and Department of Clinical Physiology (M.S.), Sahlgrenska University Hospital, Gothenburg; Neuropsychiatric Epidemiology Unit (A.Z., K.B., H.Z., S.K., I.S.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg; Theme Inflammation and Aging (M.E.), Karolinska University Hospital, Huddinge, Sweden; Clinical Dementia Research Section (S.T.), Department of Psychosomatic Medicine, University Medicine Rostock; German Center for Neurodegenerative Diseases (DZNE) (S.T., M.J.G.), Rostock, Germany; Unidad de Trastornos del Movimiento (M.J.G.), Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, London; Dementia Research Institute at UCL (H.Z.), London, UK; Hong Kong Center for Neurodegenerative Diseases (H.Z.), China; Wallenberg Centre for Molecular and Translational Medicine (M.S.) and Department of Psychiatry and Neurochemistry (M.S.), Institute of Physiology and Neuroscience, University of Gothenburg, Sweden; Dementia Research Centre (M.S.), Institute of Neurology, University College London; and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. 2. From the Division of Clinical Geriatrics (N.C., D.F., A.M., J.B.P., S.S., L.-O.W., M.E., E.W.), Centre for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, and the Division of Insurance Medicine (A.M.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm; Department of Psychology (N.C.), Sensory Cognitive Interaction Laboratory (SCI-lab), Stockholm University, Sweden; Department of Radiology (D.F.), Mayo Clinic, Rochester, MN; Department of Cybernetics (M.N.), Faculty of Electrical Engineering and Czech Institute of Informatics (M.N., O.S., L.V.), Robotics, and Cybernetics, Czech Technical University, Prague, Czech Republic; Clinical Memory Research Unit (J.B.P.), Department of Clinical Sciences, Lund University, Malmö; Department of Psychiatry Cognition and Old Age Psychiatry, (A.Z., S.K., I.S.), Clinical Neurochemistry Laboratory (K.B., H.Z.), and Department of Clinical Physiology (M.S.), Sahlgrenska University Hospital, Gothenburg; Neuropsychiatric Epidemiology Unit (A.Z., K.B., H.Z., S.K., I.S.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg; Theme Inflammation and Aging (M.E.), Karolinska University Hospital, Huddinge, Sweden; Clinical Dementia Research Section (S.T.), Department of Psychosomatic Medicine, University Medicine Rostock; German Center for Neurodegenerative Diseases (DZNE) (S.T., M.J.G.), Rostock, Germany; Unidad de Trastornos del Movimiento (M.J.G.), Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, London; Dementia Research Institute at UCL (H.Z.), London, UK; Hong Kong Center for Neurodegenerative Diseases (H.Z.), China; Wallenberg Centre for Molecular and Translational Medicine (M.S.) and Department of Psychiatry and Neurochemistry (M.S.), Institute of Physiology and Neuroscience, University of Gothenburg, Sweden; Dementia Research Centre (M.S.), Institute of Neurology, University College London; and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. daniel.ferreira.padilla@ki.se.
Abstract
BACKGROUND AND OBJECTIVES: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. METHODS: The contribution of amyloid and tau pathology was assessed through CSF levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest. RESULTS: We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123). DISCUSSION: In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.
BACKGROUND AND OBJECTIVES: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. METHODS: The contribution of amyloid and tau pathology was assessed through CSF levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest. RESULTS: We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123). DISCUSSION: In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.
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