Oxidative stress is related to vascular brain injury in mild cognitive impairment of Alzheimer type

296 

Abstract Submission 

Flavie Detcheverry^1,2,3,4,5, Sneha Senthil^6,7,5, Winnie Motue^6,7, Chris Hosein^7,8, Rozie Arnaoutelis^9,7, David Araujo^6,7, Dumitru Fetco^6,7, Samson Antel^6,7, Douglas Arnold^6,7, Jamie Near¹⁰, Hyman Schipper^7,8, AmanPreet Badhwar^1,2,3,4, Sridar Narayanan^7,7

¹Multiomics Investigation of Neurodegenerative Diseases (MIND) lab, Montreal, Quebec, Canada, ²Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada, ³Institute of Biomedical Engineering, University of Montreal, Montreal, Quebec, Canada, ⁴Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM), Montreal, Quebec, Canada, ⁵Denotes equal contribution, Montreal, Quebec, Canada, ⁶McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec, Canada, ⁷Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada, ⁸Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada, ⁹McConnell Brain Imaging Centre, Montreal Neurological Institute, Montréal, Québec, Canada, ¹⁰Sunnybrook Research Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Flavie Detcheverry  
Multiomics Investigation of Neurodegenerative Diseases (MIND) lab|Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal|Institute of Biomedical Engineering, University of Montreal|Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM)|Denotes equal contribution
Montreal, Quebec, Canada|Montreal, Quebec, Canada|Montreal, Quebec, Canada|Montreal, Quebec, Canada|Montreal, Quebec, Canada

Sneha Senthil  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University|Denotes equal contribution
Montreal, Quebec, Canada|Montreal, Quebec, Canada|Montreal, Quebec, Canada

Winnie Motue  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University
Montreal, Quebec, Canada|Montreal, Quebec, Canada

Chris Hosein  
Department of Neurology and Neurosurgery, McGill University|Lady Davis Institute, Jewish General Hospital
Montreal, Quebec, Canada|Montreal, Quebec, Canada

Rozie Arnaoutelis  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University
Montréal, Québec, Canada|Montreal, Quebec, Canada

David Araujo  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University
Montreal, Quebec, Canada|Montreal, Quebec, Canada

Dumitru Fetco  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University
Montreal, Quebec, Canada|Montreal, Quebec, Canada

Samson Antel  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University
Montreal, Quebec, Canada|Montreal, Quebec, Canada

Douglas Arnold  
McConnell Brain Imaging Centre, Montreal Neurological Institute|Department of Neurology and Neurosurgery, McGill University
Montreal, Quebec, Canada|Montreal, Quebec, Canada

Jamie Near  
Sunnybrook Research Institute, Department of Medical Biophysics, University of Toronto
Toronto, Ontario, Canada

Hyman Schipper  
Department of Neurology and Neurosurgery, McGill University|Lady Davis Institute, Jewish General Hospital
Montreal, Quebec, Canada|Montreal, Quebec, Canada

AmanPreet Badhwar  
Multiomics Investigation of Neurodegenerative Diseases (MIND) lab|Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal|Institute of Biomedical Engineering, University of Montreal|Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM)
Montreal, Quebec, Canada|Montreal, Quebec, Canada|Montreal, Quebec, Canada|Montreal, Quebec, Canada

Sridar Narayanan  
Department of Neurology and Neurosurgery, McGill University|Department of Neurology and Neurosurgery, McGill University
Montreal, Quebec, Canada|Montreal, Quebec, Canada

Oxidative stress (OS), an imbalance between production and neutralization of reactive oxygen species, can damage brain cells and contribute to cognitive decline in Alzheimer disease (AD) continuum (Mandal et al., 2015). Levels of glutathione (GSH), the most prevalent endogenous brain antioxidant (Pocernich and Butterfield, 2012), can be assessed with magnetic resonance spectroscopy (MRS), and serves as a brain-OS index. Our systematic reviews (Detcheverry, et al., 2023a; Detcheverry, et al., 2023b) report that brain GSH levels decrease with age in most brain regions, with greater decreases reported in AD. Since the relationship between GSH and vascular-brain injury is not known in the dementia and the mild cognitive impairment (MCI) stages of AD, we address this gap in MCI.

MRI/MRS data from 31 MCI participants (age range: 55-86 years) were obtained using a 3T Siemens Prisma MRI scanner (Siemens, Erlangen, Germany). The MRI protocol included a whole-brain, 3D T1-weighted MP2RAGE for localization and brain volume measurements, and a 3D T2-weighted fluid attenuated inversion recovery (FLAIR) for detection of white matter hyperintensities (WMHs), a marker of small-vessel disease. Single-voxel MRS was performed using the SPin Echo full Intensity Acquired Localized (SPECIAL) technique, with one voxel positioned over the posterior cingulate cortex (PCC) and the other in frontal white matter (FWM) (Figure 1A, B). WMHs were segmented using an automated technique (Elliott et al., 2010) and manually reviewed. Hippocampi (HCP) were segmented using a locally-developed pipeline as previously described (Tremblay et al., 2018). Normalized brain volume (NBV) was computed using SIENAx (Smith et al., 2002). Vascular brain injury was assessed using WMH volume and Fazekas scores (Fazekas et al., 1987). Global and regional brain tissue preservation was assessed using NBV and HCP (whole, left, right) volumes (HCPv), respectively. Finally, cognition was assessed with the Montreal Cognitive Assessment (MoCA). Raw MRS data was preprocessed using the FID Appliance (FID-A) (Simpson et al., 2017), before spectral fitting, and eddy current correction and spectral analysis were performed in LCModel (Provencher, 2001). Pearson correlations between (a) metabolite levels in both regions, and (b) GSH and other markers, were performed in Python (version 3.9.13).

The mean age of our MCI group was 74.41 years (Figure 2A). In general, metabolite levels were higher in PCC relative to FWM, with significant differences (p<0.001) in levels of tNAA, GSH/total creatine (tCr), and total N-acetylaspartate (tNAA)/tCr (Figure 2A). We found significant associations in FWM between GSH/tCr and tNAA/tCr (r=0.38; p=0.04), and between GSH and (a) WMH volume (r=-0.37; p=0.04), and (b) NBV (r=0.38; p=0.04). Linear regressions for these findings are displayed in Figure 2B. No relationship was found between GSH levels and cognition.

In FWM, lower GSH was associated with (a) higher vascular brain injury, as shown with higher WMH volume, and (b) lower brain volume and axonal integrity as shown both with lower NBV and tNAA levels, respectively. Our results suggest that, in WM, OS (as indicated by elevated GSH) contributes to vascular-brain injury in MCI of the Alzheimer's type.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Aging

Anatomical MRI

MR Spectroscopy ²

Physiology, Metabolism and Neurotransmission Other

Aging

Cognition

Degenerative Disease

Magnetic Resonance Spectroscopy (MRS)

MR SPECTROSCOPY

MRI

STRUCTURAL MRI

White Matter