Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes
Poster No:
224
Submission Type:
Abstract Submission
Authors:
Julie Ottoy1, Min Su Kang1, Eric Yin1, Nesrine Rahmouni2, Jenna Stevenson2, Jean-Paul Soucy3, Andrea Benedet4, Kaj Blennow5, Henrik Zetterberg6,4, Nicolas Ashton4,7, Serge Gauthier2, Sandra Black1, Pedro Rosa-Neto2,8, Maged Goubran1,9
Institutions:
1LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, 2Translational Neuroimaging laboratory, McGill Centre for Studies in Aging, Montreal, Quebec, 3McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, 4Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Mölndal Municipality, 5Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Västergötland, 6UK Dementia Research Institute at University College London, London, United Kingdom, 7Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, King’s College London, London, United Kingdom, 8Montreal Neurological Institute-Hospital BIC, Montreal, Quebec, Canada, 9Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
First Author:
Julie Ottoy, PhD
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
Co-Author(s):
Min Su Kang
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
Eric Yin
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
Nesrine Rahmouni
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging
Montreal, Quebec
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging
Montreal, Quebec
Jenna Stevenson
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging
Montreal, Quebec
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging
Montreal, Quebec
Jean-Paul Soucy
McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University
Montreal, Quebec
McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University
Montreal, Quebec
Andrea Benedet
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg
Mölndal, Mölndal Municipality
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg
Mölndal, Mölndal Municipality
Kaj Blennow
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital
Gothenburg, Västergötland
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital
Gothenburg, Västergötland
Henrik Zetterberg
UK Dementia Research Institute at University College London|Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg
London, United Kingdom|Mölndal, Mölndal Municipality
UK Dementia Research Institute at University College London|Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg
London, United Kingdom|Mölndal, Mölndal Municipality
Nicolas Ashton
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg|Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, King’s College London
Mölndal, Mölndal Municipality|London, United Kingdom
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg|Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, King’s College London
Mölndal, Mölndal Municipality|London, United Kingdom
Serge Gauthier
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging
Montreal, Quebec
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging
Montreal, Quebec
Sandra Black
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto
Toronto, Ontario
Pedro Rosa-Neto
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging|Montreal Neurological Institute-Hospital BIC
Montreal, Quebec|Montreal, Quebec, Canada
Translational Neuroimaging laboratory, McGill Centre for Studies in Aging|Montreal Neurological Institute-Hospital BIC
Montreal, Quebec|Montreal, Quebec, Canada
Maged Goubran
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto|Department of Medical Biophysics, University of Toronto
Toronto, Ontario|Toronto, Ontario, Canada
LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, University of Toronto|Department of Medical Biophysics, University of Toronto
Toronto, Ontario|Toronto, Ontario, Canada
Introduction:
In-vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of patients with Alzheimer's disease (AD) [1]. However, the extent and implication of microglia reactivity in regions of the white matter remains unclear. Here, we explored microglia reactivity in the white matter using PET imaging of the translocator protein (TSPO) [2,3] in relation to core AD biomarkers (amyloid [Aβ], tau, and astrogliosis), microstructural damage (fibre integrity and free water levels), and cognitive decline. We hypothesized that TSPO-PET signal is elevated in posterior white matter regions reflecting ongoing gliosis and tau pathology in AD.
Methods:
Ninety-one participants were recruited from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (45% Aβ-positive, 39% cognitively impaired) with high-affinity binding TSPO genotype. They underwent multi-shell diffusion-weighted MRI, PET imaging of TSPO (11C-PBR28), Aβ (18F-NAV4694), and tau (18F-MK6240), as well as plasma Aβ42/40, ptau181, ptau217, and ptau231. White matter regions were extracted using Freesurfer after masking out the white matter hyperintensities, and were eroded by 2mm3 to account for partial volume effects and lesion borders. For PET, we extracted uptake values using Petsurfer [4] averaged in each of the lobar white matter regions (frontal, temporal, parietal, cingulate, occipital, and insular) and calculated standardized uptake value ratios (SUVR). For diffusion-MRI, we performed two-compartment modeling to differentiate between free water levels and tissue-specific fractional anisotropy (FAt) and mean diffusivity (MDt) [5]. For statistical analysis, we investigated the associations of lobar white matter TSPO-PET with each of the AD biomarkers, diffusion metrics, and cognition, adjusted for age, sex, and global cortical TSPO-PET. Longitudinally, we performed a linear mixed effects model of the interaction between time (up to 2 years) and baseline lobar TSPO-PET on cognitive decline, adjusted for age, sex, education, and cortical Aβ.
Results:
Higher white matter TSPO-PET was observed with older age in all lobes and males showed frontal increases compared to females (p<0.05). In cognitively impaired individuals, TSPO-PET signals were elevated in occipital (p=0.01) and temporal (p=0.02) white matter regions compared to controls. These occipital increases were associated with reactive astrogliosis quantified by plasma GFAP (p=0.011) and with neocortical higher-Braak tau quantified by PET (p=0.003-0.034 for Braak3-4) or plasma ptau181 (p=0.014) (Fig.1A-B), but not with Aβ, ptau231 or ptau217. In addition, higher occipital TSPO-PET was associated with lower fibre integrity (FAt, p=0.025), but not with free water content. Finally, in relation to cognition, higher occipital and parietal TSPO-PET was significantly associated with impaired memory (both delayed and immediate) and language, respectively, independent of Aβ (Fig.1C). Longitudinally, within the same patient, high white matter TSPO-PET uptake at baseline was significantly associated with favorable clinical outcome over time (Fig.1D).
·Figure 1.
Conclusions:
Increased TSPO-PET uptake in posterior white matter may be a later-stage marker associated with astrogliosis, tau pathology, and cognitive dysfunction of the memory and language domains in AD. Importantly, individuals with the highest initial white matter TSPO-PET profile displayed a better clinical prognosis over time, in line with previous findings for TSPO-PET in the cortex [6]. As such, microglia reactivity in the white matter could be a key mechanism of AD pathophysiological progression, serve as an indicator for assessing target engagement in clinical trials of anti-inflammatory drugs, and be employed in patient subtyping to identify individualized treatment approaches.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
PET Modeling and Analysis 2
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
White Matter Anatomy, Fiber Pathways and Connectivity
Keywords:
Aging
Astrocyte
Cognition
Glia
Neurological
Positron Emission Tomography (PET)
White Matter
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
Other - Biomarker
1|2Indicates the priority used for review
Provide references using author date format
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