Human Alzheimer's Disease ATN/ABC Staging Applied to Aging Rhesus Macaque Brains: Association With Cognition and MRI-Based Regional Gray Matter Volume.

The brain changes of Alzheimer's disease (AD) include Abeta (Aß) amyloid plaques ("A"), abnormally phosphorylated tau tangles ("T"), and neurodegeneration ("N"). These have been used to construct in vivo and postmortem diagnostic and staging classifications for evaluating the spectrum of AD in the "ATN" and "ABC" ("B" for Braak tau stage, "C" for Consortium to Establish a Registry for Alzheimer's Disease [CERAD] neuritic plaque density) systems. Another common AD feature involves cerebral amyloid angiopathy (CAA). We report the first experiment to examine relationships among cognition, brain distribution of amyloid plaques, CAA, tau/tangles, and magnetic resonance imaging (MRI)-determined volume changes (as a measure of "N") in the same group of behaviorally characterized nonhuman primates. Both ATN and ABC systems were applied to a group of 32 rhesus macaques aged between 7 and 33 years. When an immunohistochemical method for "T" and "B" was used, some monkeys were "triple positive" on ATN, with a maximum ABC status of A1B2C3. With silver or thioflavin S methods, however, all monkeys were classified as T-negative and B0, indicating the absence of mature neurofibrillary tangles (NFTs) and hence neuropathologically defined AD. Although monkeys at extremes of the ATN and ABC classifications, or with frequent CAA, had significantly lower scores on some cognitive tests, the lack of fully mature NFTs or dementia-consistent cognitive impairment indicates that fully developed AD may not occur in rhesus macaques. There were sex differences noted in the types of histopathology present, and only CAA was significantly related to gray matter volume.

Behavioral Impact of Long-Term Chronic Implantation of Neural Recording Devices in the Rhesus Macaque.

BACKGROUND: Ensemble recording methods are pervasive in basic and clinical neuroscience research. Invasive neural implants are used in patients with drug resistant epilepsy to localize seizure origin, in neuropsychiatric or Parkinson's patients to alleviate symptoms via deep brain stimulation, and with animal models to conduct basic research. Studies addressing the brain's physiological response to chronic electrode implants demonstrate that the mechanical trauma of insertion is followed by an acute inflammatory response as well as a chronic foreign body response. Despite use of invasive recording methods with animal models and humans, little is known of their effect on behavior in healthy populations. OBJECTIVE: To quantify the effect of chronic electrode implantation targeting the hippocampus on recognition memory performance. METHODS: Four healthy female rhesus macaques were tested in a delayed nonmatching-to-sample (DNMS) recognition memory task before and after hippocampal implantation with a tetrode array device. RESULTS: Trials to criterion and recognition memory performance were not significantly different before vs. after chronic electrode implantation. CONCLUSION: Our results suggest that chronic implants did not produce significant impairments on DNMS performance.

Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: Preservation of subfield volumes in aging.

Identification of primate hippocampal subfields in vivo using structural MRI imaging relies on variable anatomical guidelines, signal intensity differences, and heuristics to differentiate between regions (Yushkevich et al., 2015a). Thus, a clear anatomically-driven basis for subfield demarcation is lacking. Recent work, however, has begun to develop methods to use ex vivo histology or ex vivo MRI (Adler et al., 2014; Iglesias et al., 2015) that have the potential to inform subfield demarcations of in vivo images. For optimal results, however, ex vivo and in vivo images should ideally be matched within the same healthy brains, with the goal to develop a neuroanatomically-driven basis for in vivo structural MRI images. Here, we address this issue in young and aging rhesus macaques (young n = 5 and old n = 5) using ex vivo Nissl-stained sections in which we identified the dentate gyrus, CA3, CA2, CA1, subiculum, presubiculum, and parasubiculum guided by morphological cell properties (30 µm thick sections spaced at 240 µm intervals and imaged at 161 nm/pixel). The histologically identified boundaries were merged with in vivo structural MRIs (0.625 × 0.625 × 1 mm) from the same subjects via iterative rigid and diffeomorphic registration resulting in probabilistic atlases of young and old rhesus macaques. Our results indicate stability in hippocampal subfield volumes over an age range of 13 to 32 years, consistent with previous results showing preserved whole hippocampal volume in aged macaques (Shamy et al., 2006). Together, our methods provide a novel approach for identifying hippocampal subfields in non-human primates and a potential 'ground truth' for more accurate identification of hippocampal subfield boundaries on in vivo MRIs. This could, in turn, have applications in humans where accurately identifying hippocampal subfields in vivo is a critical research goal.

The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques.

Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer's disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies.

Network Patterns Associated with Navigation Behaviors Are Altered in Aged Nonhuman Primates.

The ability to navigate through space involves complex interactions between multiple brain systems. Although it is clear that spatial navigation is impaired during aging, the networks responsible for these altered behaviors are not well understood. Here, we used a within-subject design and [18F]FDG-microPET to capture whole-brain activation patterns in four distinct spatial behaviors from young and aged rhesus macaques: constrained space (CAGE), head-restrained passive locomotion (CHAIR), constrained locomotion in space (TREADMILL), and unconstrained locomotion (WALK). The results reveal consistent networks activated by these behavior conditions that were similar across age. For the young animals, however, the coactivity patterns were distinct between conditions, whereas older animals tended to engage the same networks in each condition. The combined observations of less differentiated networks between distinct behaviors and alterations in functional connections between targeted regions in aging suggest changes in network dynamics as one source of age-related deficits in spatial cognition. SIGNIFICANCE STATEMENT: We report how whole-brain networks are involved in spatial navigation behaviors and how normal aging alters these network patterns in nonhuman primates. This is the first study to examine whole-brain network activity in young or old nonhuman primates while they actively or passively traversed an environment. The strength of this study resides in our ability to identify and differentiate whole-brain networks associated with specific navigational behaviors within the same nonhuman primate and to compare how these networks change with age. The use of high-resolution PET (microPET) to capture brain activity of real-world behaviors adds significantly to our understanding of how active circuits critical for navigation are affected by aging.