Transcriptional Profiles in Olfactory Pathway-Associated Brain Regions of African Green Monkeys: Associations With Age and Alzheimer’s Disease Neuropathology

Introduction: Olfactory impairment in older individuals is associated with an increased risk of Alzheimer\u27s disease (AD). Characterization of age versus neuropathology-associated changes in the brain olfactory pathway may elucidate processes underlying early AD pathogenesis. Here, we report age versus AD neuropathology-associated differential transcription in four brain regions in the olfactory pathway of 10 female African green monkeys (vervet, Chlorocebus aethiops sabaeus), a well-described model of early AD-like neuropathology. Methods: Transcriptional profiles were determined by microarray in the olfactory bulb (OB), piriform cortex (PC), temporal lobe white matter (WM), and inferior temporal cortex (ITC). Amyloid beta (Aβ) plaque load in parietal and temporal cortex was determined by immunohistochemistry, and concentrations of Aβ42, Aβ40, and norepinephrine in ITC were determined by enzyme-linked immuosorbent assay (ELISA). Transcriptional profiles were compared between middle-aged and old animals, and associations with AD-relevant neuropathological measures were determined. Results: Transcriptional profiles varied by brain region and age group. Expression levels of TRO and RNU4-1 were significantly lower in all four regions in the older group. An additional 29 genes were differentially expressed by age in three of four regions. Analyses of a combined expression data set of all four regions identified 77 differentially expressed genes (DEGs) by age group. Among these DEGs, older subjects had elevated levels of CTSB , EBAG9, LAMTOR3, and MRPL17, and lower levels of COMMD10 and TYW1B. A subset of these DEGs was associated with neuropathology biomarkers. Notably, CTSB was positively correlated with Aβ plaque counts, Aβ42:Aβ40 ratios, and norepinephrine levels in all brain regions. Discussion: These data demonstrate age differences in gene expression in olfaction-associated brain regions. Biological processes exhibiting age-related enrichment included the regulation of cell death, vascular function, mitochondrial function, and proteostasis. A subset of DEGs was specifically associated with AD phenotypes. These may represent promising targets for future mechanistic investigations and perhaps therapeutic intervention

Blood-Based Bioenergetic Profiling Reflects Differences in Brain Bioenergetics and Metabolism

Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial health shown to be related to key features of aging. Previous studies show that blood cells recapitulate mitochondrial alterations in the central nervous system under pathological conditions, including the development of Alzheimer’s disease. In this study of nonhuman primates, we focus on mitochondrial function and bioenergetic capacity assessed by the respirometric profiling of monocytes, platelets, and frontal cortex mitochondria. Our data indicate that differences in the maximal respiratory capacity of brain mitochondria are reflected by CD14+ monocyte maximal respiratory capacity and platelet and monocyte bioenergetic health index. A subset of nonhuman primates also underwent [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to assess brain glucose metabolism. Our results indicate that platelet respiratory capacity positively correlates to measures of glucose metabolism in multiple brain regions. Altogether, the results of this study provide early evidence that blood-based bioenergetic profiling is related to brain mitochondrial metabolism. While these measures cannot substitute for direct measures of brain metabolism, provided by measures such as FDG-PET, they may have utility as a metabolic biomarker and screening tool to identify individuals exhibiting systemic bioenergetic decline who may therefore be at risk for the development of neurodegenerative diseases

Comparative Microbiome Signatures and Short-Chain Fatty Acids in Mouse, Rat, Non-human Primate, and Human Feces

Gut microbiome plays a fundamental role in several aspects of host health and diseases. There has been an exponential surge in the use of animal models that can mimic different phenotypes of the human intestinal ecosystem. However, data on host species-specific signatures of gut microbiome and its metabolites like short-chain fatty acids (SCFAs; i.e., acetate, propionate, and butyrate) and lactate in these models and their similarities/differences from humans remain limited, due to high variability in protocols and analyses. Here, we analyze the fecal microbiota composition and the fecal levels of SCFAs and lactate in three of the most-widely used animal models, i.e., mice, rats, and non-human primates (NHPs) and compare them with human subjects, using data generated on a single platform with same protocols. The data show several species-specific similarities and differences in the gut microbiota and fecal organic acids between these species groups. Based on β-diversity, the gut microbiota in humans seems to be closer to NHPs than to mice and rats; however, among rodents, mice microbiota appears to be closer to humans than rats. The phylum-level analyses demonstrate higher Firmicutes–Bacteroidetes ratio in humans and NHPs vs. mice and rats. Human microbiota is dominated by Bacteroides followed by Ruminococcaceae and Clostridiales. Mouse gut is predominated by members of the family S24-7 followed by those from the order Clostridiales, whereas rats and NHPs have higher abundance of Prevotella compared with mice and humans. Also, fecal levels of lactate are higher in mice and rats vs. NHPs and humans, while acetate is highest in human feces. These data of host species-specific gut microbiota signatures in some of the most widely used animal models in context to the human microbiota might reflect disparities in host factors, e.g., diets, genetic origin, gender and age, and hence call for prospective studies investigating the features of gut microbiome in such animal models by controlling for these host elements

Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher’s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Social inequalities in health in nonhuman primates

Overall health has been linked to socioeconomic status, with the gap between social strata increasing each year. Studying the impact of social position on health and biological functioning in nonhuman primates has allowed researchers to model the human condition while avoiding ethical complexities or other difficulties characteristic of human studies. Using female cynomolgus macaques (Macaca fascicularis), our lab has examined the link between social status and stress for 30 years. Female nonhuman primates are especially sensitive to social stressors which can deleteriously affect reproductive health, leading to harmful consequences to their overall health. Subordinates have lower progesterone concentrations during the luteal phase of menstrual cycle, which is indicative of absence or impairment of ovulation. Subordinate animals receive more aggression, less affiliative attention, and are more likely to exhibit depressive behaviors. They also express higher stress-related biomarkers such as increased heart rates and lower mean cortisol. While no differences in body weight between dominant and subordinate animals are observed, subordinates have lower bone density and more visceral fat than their dominant counterparts. The latter increases risk for developing inflammatory diseases. Differences are also observed in neurological and autonomic function. A growing body of data suggests that diet composition may amplify or diminish physiological stress responses which have deleterious effects on health. More experimental investigation of the health effects of diet pattern is needed to further elucidate these differences in an ongoing search to find realistic and long-term solutions to the declining health of individuals living across the ever widening socioeconomic spectrum

Stress, depression, and coronary artery disease: Modeling comorbidity in female primates

Depression and coronary heart disease (CHD) are leading contributors to disease burden in women. CHD and depression are comorbid; whether they have common etiology or depression causes CHD is unclear. The underlying pathology of CHD, coronary artery atherosclerosis (CAA), is present decades before CHD, and the temporal relationship between depression and CAA is unclear. The evidence of involvement of depression in early CAA in cynomolgus monkeys, an established model of CAA and depression, is summarized. Like people, monkeys may respond to the stress of low social status with depressive behavior accompanied by perturbations in hypothalamic–pituitary–adrenal (HPA), autonomic nervous system, lipid metabolism, ovarian, and neural serotonergic system function, all of which are associated with exacerbated CAA. The primate data are consistent with the hypothesis that depression may cause CAA, and also with the hypothesis that CAA and depression may be the result of social stress. More study is needed to discriminate between these two possibilities. The primate data paint a compelling picture of depression as a whole-body disease

Behavioral depression is associated with increased vagally mediated heart rate variability in adult female cynomolgus monkeys (Macaca fascicularis)

INTRODUCTION: Depressive symptoms (DS) in humans are associated with decreased resting state vagal activity, but sex seems to moderate this association. Recently, in human females DS have been associated with greater or similar cardiac vagal activity compared to men in both, clinical and non-clinical samples. A previously validated animal model of behavioral depression was used in the present study to investigate the association of DS and cardiac vagal activity in non-human primates. METHODS: The root mean square of successive differences between adjacent heart beats (RMSSD) was used as an indicator of vagally-mediated heart rate variability in 24h heart rate recordings collected via telemetry in 42 adult female cynomolgus monkeys (Macaca fascicularis). Hierarchical regression models were used to estimate differences in RMSSD comparing monkeys with and without DS. To capture circadian variation patterns of RMSSD, additional quadratic, cubic and quartic terms of hour were added. RESULTS: Monkeys showing behavioral DS had higher overall 24-h RMSSD. The interaction term of daytime with DS and polynomials of hour contributed significantly to the variance across models. CONCLUSIONS: This is the first study investigating the association of DS and 24h cardiac vagal control in female non-human primates. Results replicate existing human studies showing higher cardiac vagal control in behavioral depressed vs. non-depressed female monkeys