Biomarker Profiling for Alzheimer‐like Dementia in Aged Non‐human Primates
Ying Yu, Mingyue Wang, Maoyun Tan, Zhichao Jiang, Gaorui Xu, Jiawen Zhou, Xue Gan, Yanlai Peng, Qian Zhong, Rongchen Wen, Yuqing Fan, Guodong Zhang, Deming Xu- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Alzheimer’s disease (AD) places increasingly burdens on global healthcare. Non‐human primates (NHPs) have been used in preclinical pharmacology for AD drug discovery and they were mainly based on induction by amyloid plaque. However, previous strategies focused on clearance and prevention of amyloid plaques and neurofibrillary inclusions have mostly yielded discouraging results in clinical trials for AD. More fitting NHP models reflective of natural ageing of brain with an AD‐related clinical profile would be most desirable for translational pharmacology. To address this, the pilot study herein profiled a group of aged NHPs for biomarkers characteristic of AD‐like dementia, including cognitive behavior, diagnostic neuroimaging, EEG, and amyloid beta 42 (Aβ42) in cerebrospinal fluid (CSF).
Method
Two groups of male Macaca fascicularis (adult: 9‐11 years, n = 4; aged: 20‐25 years, n = 10) were trained to perform a delayed response task (DRT) to assess their short term memory. Meanwhile, their CSF levels of Aβ42 were determined. EEG signals at rest were captured with Neuroscan EEG System and data processed with customized Matlab code. The volume of hippocampus in eight selected animals were analyzed through a 3‐D reconstruction with MRI imaging.
Result
Six (6) out of 10 aged animals showed lower DRT performance (successful rate < 80%) than the remaining 4 and those in the adult group. The overall DRT performance was positively correlated with the CSF levels of Aβ42 in all animals. Moreover, we observed the slowing of EEG activity (increased δ & θ activity and decreased β activity) in the frontal lobe and smaller average volume of hippocampus in the low DRT performers vis‐à‐vis the rest of the animals.
Conclusion
We identified a group of aged NHPs with spontaneous dementia, with cognitive, electrophysiological and brain structural characteristic of mild cognitive impairment in the humans. Their CSF levels of Aβ42 inversely correlated with the memory function. Most notably, EEG and neuroimaging showed promising potential as non‐invasive approaches for the evaluation of aging‐related dementia of NHP in the longitudinal studies. The translational value of such animals could provide important insight to the disease progress and the therapeutic efficacy of AD treatment in the preclinical stages.