Neural Substrates Of Diffusion Imaging In Cognitively Aging Rhesus Monkeys

The ability to identify and follow structural brain changes during brain maturation and aging is both fundamental to our understanding of brain function, and crucial in clinical studies. While post-mortem studies of human brain can provide data on local histological changes, they are only cross sectional, brain samples are not optimal, and sample sizes are small. In contrast, non-invasive in vivo imaging can provide powerful longitudinal data for large populations. Moreover, post-processing techniques make it possible to analyze the entire brain, providing anatomically specific data that allows for investigating relationships between imaging and function. Recent developments in diffusion MRI and fiber tractography have revealed correlations between imaging changes and cognitive aging in both monkeys (Makris et al, 2007), and humans (Voineskos et al., 2012). Unfortunately, the biological underpinnings of such imaging changes are largely speculative (Paus 2010) and hence the specificity of imaging measures for histological features is unknown. The lack of such "validation" is largely due to the inability to conduct well-controlled studies of both brain tissu and imaging in humans. In this application we propose a multidisciplinary study using the rhesus monkey model of normal aging. This is enabled by a collaboration of three PIs, with unique and complementary expertise in MRI imaging, morphometry, neuroanatomy and cognitive aging. We have available a cohort of over 50 normal aging rhesus monkeys of both sexes, ranging in age from 5 (young adults) to over 30 (oldest of the old) years of age. Most important is the availability of cognitive and DTI data that can be used for histopathological validation of archived, cryoprotected, unstained tissue from all of these monkeys.

Carl-Fredrik Westin, PhD

Carl-Fredrik Westin, PhD

Professor of Radiology, Harvard Medical School
Director, Laboratory for Mathematics in Imaging (LMI)
Center Director, Neuroimaging Analysis Center (NAC)

Carl-Fredrik (C-F) Westin, is the founding director of the Laboratory of Mathematics in Imaging (LMI, http://lmi.med.harvard.edu), Distinguished...

Read more about Carl-Fredrik Westin, PhD
Department of Radiology
Brigham and Women's Hospital, Harvard Medical School
1249 Boylston Street, Boston, MA 02215
p: (+1) 617-525-6209
Wang S, Zhang F, Huang P, Hong H, Jiaerken Y, Yu X, Zhang R, Zeng Q, Zhang Y, Kikinis R, et al. Superficial White Matter Microstructure Affects Processing Speed in Cerebral Small Vessel Disease. Hum Brain Mapp. 2022.Abstract
White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD), which contributes to about 50% of dementias worldwide. Microstructural alterations in deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In 141 CSVD patients, processing speed was assessed using Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (volume on T2-FLAIR) and diffusion MRI measures. SWM imaging measures had a large contribution to processing speed, despite a relatively low SWM WMH burden. Across all imaging measures, SWM free water (FW) had the strongest association with processing speed, followed by SWM mean diffusivity (MD). SWM FW was the only marker to significantly increase between two subgroups with the lowest WMH burdens. When comparing two subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Mediation analysis revealed that SWM FW fully mediated the association between WMH volume and processing speed, while no mediation effect of MD or DWM FW was observed. Overall, results suggest that the SWM has an important contribution to processing speed, while SWM FW is a sensitive imaging marker associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes.