Hope Center Member Publications

Functional consequences of neurite orientation dispersion and density in humans across the adult lifespan” (2015) Journal of Neuroscience

Functional consequences of neurite orientation dispersion and density in humans across the adult lifespan
Journal of Neuroscience, Volume 35, Issue 4, Pages 1753 – 176228 January 2015

Nazeri, Arasha, b; Chakravarty, Mallara, b, c, d; Rotenberg, David J.a; Rajji, Tarek K.b, e, f; Rathi, Xyogeshg; Michailovich, Oleg V.h; Voineskos, Aristotle N.a, b, e, f

Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, M5T 1R8, Toronto, ON, Canada
Department of Psychiatry, University of Toronto, M5T 1R8, Toronto, ON, Canada
Cerebral Imaging Centre, Douglas Institute, H4H 1R3, Verdun, QC, Canada
Departments of Psychiatry and Biomedical Engineering, McGill University, H3A 2B4, Montreal, QC, Canada
Institute of Medical Science, University of Toronto, M5S 1A8, Toronto, ON, Canada
Geriatric Mental Health Service, Centre for Addiction and Mental Health, M6J 1H4, Toronto, ON, Canada
Laboratory of Mathematics in Imaging, Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02215, MA, United States
Department of Electrical and Computer Engineering, University of Waterloo, N2L 3G1, Waterloo, ON, Canada

As humans age, a characteristic pattern of widespread neocortical dendritic disruption coupled with compensatory effects in hippocampus and other subcortical structures is shown in postmortem investigations. It is now possible to address age-related effects on gray matter (GM) neuritic organization and density in humans using multishell diffusion-weighted MRI and the neurite-orientation dispersion and density imaging (NODDI) model. In 45 healthy individuals across the adult lifespan (21– 84 years), we used a multishell diffusion imaging and the NODDI model to assess the intraneurite volume fraction and neurite orientation-dispersion index (ODI) in GM tissues. Wealso determined the functional correlates of variations inGMmicrostructure by obtaining resting-state fMRI and behavioral data.We found a significant age-related deficit in neocortical ODI (most prominently in frontoparietal regions), whereas increased ODI was observed in hippocampus and cerebellum with advancing age. Neocortical ODI outperformed cortical thickness and white matter fractional anisotropy for the prediction of chronological age in the same individuals. Higher GM ODI sampled from resting-state networks with known age-related susceptibility (default mode and visual association networks) was associated with increased functional connectivity of these networks, whereas the task-positive networks tended to show no association or even decreased connectivity. Frontal pole ODI mediated the negative relationship of age with executive function, whereas hippocampal ODI mediated the positive relationship of age with executive function. Our in vivo findings align very closely with the postmortem data and provide evidence for vulnerability and compensatory neural mechanisms of aging in GM microstructure that have functional and cognitive impact in vivo. © 2015 J. Neurosci All rights received.

Author keywords
Cognitive aging; Diffusion-weighted MRI; GBSS; Gray matter; Neurite orientation dispersion; Structure–function relationship

Focused Ultrasound–mediated Liquid Biopsy in a Tauopathy Mouse Model” (2023) Radiology

Focused Ultrasound–mediated Liquid Biopsy in a Tauopathy Mouse Model
(2023) Radiology, Volume 307, Issue 2, April 2023 Article number e220869

Pacia, Christopher Phama; Yuan, Jinyuna; Yue, Yimeia; Leuthardt, Eric C.a, b; Benzinger, Tammie L.S.c; Nazeri, Arashc; Chen, Honga, d

Department of Biomedical Engineering, Washington University in St Louis, 4511 Forest Park Ave, St Louis, 63108, MO, United States
Department of Neurosurgery, Washington University in St Louis, 4511 Forest Park Ave, St Louis, 63108, MO, United States
Mallinckrodt Institute of Radiology, Washington University in St Louis, 4511 Forest Park Ave, St Louis, 63108, MO, United States
Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, United States

Background: Neurodegenerative disorders (such as Alzheimer disease) characterized by the deposition of various pathogenic forms of tau protein in the brain are collectively referred to as tauopathies. Identification of the molecular drivers and pathways of neurodegeneration is critical to individualized targeted treatment of these disorders. However, despite important advances in fluid biomarker detection, characterization of these molecular subtypes is limited by the blood-brain barrier. Purpose: To evaluate the feasibility and safety of focused ultrasound–mediated liquid biopsy (sonobiopsy) in the detection of brain-derived protein biomarkers in a transgenic mouse model of tauopathy (PS19 mice). Materials and Methods: Sonobiopsy was performed by sonicating the cerebral hemisphere in 2-month-old PS19 and wild-type mice, followed by measurement of plasma phosphorylated tau (p-tau) species (30 minutes after sonication in the sonobiopsy group). Next, spatially targeted sonobiopsy was performed by sonicating either the cerebral cortex or the hippocampus in 6-month-old PS19 mice. To detect changes in plasma neurofilament light chain (a biomarker of neurodegeneration) levels, blood samples were collected before and after sonication (15 and 45–60 minutes after sonication). Histologic staining was performed to evaluate tissue damage after sonobiopsy. The Shapiro-Wilk test, unpaired and paired t tests, and the Mann-Whitney U test were used. Results: In the 2-month-old mice, sonobiopsy significantly increased the normalized levels of plasma p-tau species compared with the conventional blood-based liquid biopsy (p-tau-181–to–mouse tau [m-tau] ratio: 1.7-fold increase, P = .006; p-tau-231–to–m-tau ratio: 1.4-fold increase, P = .048). In the 6-month-old PS19 mice, spatially targeted sonobiopsy resulted in a 2.3-fold increase in plasma neurofilament light chain after sonication of the hippocampus and cerebral cortex (P < .001). After optimization of the sonobiopsy parameters, no excess microhemorrhage was observed in the treated cerebral hemisphere compared with the contralateral side. Conclusion: This study showed the feasibility of sonobiopsy to release phosphorylated tau species and neurofilament light chain to the blood circulation, potentially facilitating diagnosis of neurodegenerative disorders. © RSNA, 2023.