An examination of the relationship among plasma brain derived neurotropic factor, peripheral vascular function, and body composition with cognition in midlife African Americans/Black individuals.

African American/Black individuals have been excluded from several lines of prominent neuroscience research, despite exhibiting disproportionately higher risk factors associated with the onset and magnitude of neurodegeneration. Therefore, the objective of the current investigation was to examine potential relationships among brain derived neurotropic factor (BDNF), peripheral vascular function, and body composition with cognition in a sample of midlife, African American/Black individuals. Midlife adults (men: n = 3, 60 ± 4 years; women: n = 9, 58 ± 5 years) were invited to complete two baseline visits separated by 4 weeks. Peripheral vascular function was determined by venous occlusion plethysmography, a dual-energy X-ray absorptiometry was used to determine body composition, and plasma was collected to quantify BDNF levels. The CNS Vital Signs computer-based test was used to provide scores on numerous cognitive domains. The principal results included that complex attention (r = 0.629) and processing speed (r = 0.734) were significantly (p < 0.05) related to the plasma BDNF values. However, there was no significant (p > 0.05) relationship between any vascular measure and any cognitive domain or BDNF value. Secondary findings included the relationship between lean mass and peak hyperemia (r = 0.758) as well as total hyperemia (r = 0.855). The major conclusion derived from these results was that there is rationale for future clinical trials to use interventions targeting increasing BDNF to potentially improve cognition. Additionally, these results strongly suggest that clinicians aiming to improve cognitive health via improvements in the known risk factor of vascular function should consider interventions capable of promoting the size and function of skeletal muscle, especially in the African American/Black population.

Neurovascular Dysfunction in Diverse Communities With Health Disparities-Contributions to Dementia and Alzheimer's Disease.

Alzheimer's disease and related dementias (ADRD) are an expanding worldwide crisis. In the absence of scientific breakthroughs, the global prevalence of ADRD will continue to increase as more people are living longer. Racial or ethnic minority groups have an increased risk and incidence of ADRD and have often been neglected by the scientific research community. There is mounting evidence that vascular insults in the brain can initiate a series of biological events leading to neurodegeneration, cognitive impairment, and ADRD. We are a group of researchers interested in developing and expanding ADRD research, with an emphasis on vascular contributions to dementia, to serve our local diverse community. Toward this goal, the primary objective of this review was to investigate and better understand health disparities in Alabama and the contributions of the social determinants of health to those disparities, particularly in the context of vascular dysfunction in ADRD. Here, we explain the neurovascular dysfunction associated with Alzheimer's disease (AD) as well as the intrinsic and extrinsic risk factors contributing to dysfunction of the neurovascular unit (NVU). Next, we ascertain ethnoregional health disparities of individuals living in Alabama, as well as relevant vascular risk factors linked to AD. We also discuss current pharmaceutical and non-pharmaceutical treatment options for neurovascular dysfunction, mild cognitive impairment (MCI) and AD, including relevant studies and ongoing clinical trials. Overall, individuals in Alabama are adversely affected by social and structural determinants of health leading to health disparities, driven by rurality, ethnic minority status, and lower socioeconomic status (SES). In general, these communities have limited access to healthcare and healthy food and other amenities resulting in decreased opportunities for early diagnosis of and pharmaceutical treatments for ADRD. Although this review is focused on the current state of health disparities of ADRD patients in Alabama, future studies must include diversity of race, ethnicity, and region to best be able to treat all individuals affected by ADRD.

Level of injury is an independent determining factor of gut dysbiosis in people with chronic spinal cord injury: A cross-sectional study.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: To investigate the correlations between gut microbiota and metabolic parameters in people with different levels of chronic spinal cord injury (SCI). SETTING: An SCI-specialized rehabilitation facility in a university hospital. METHODS: Forty-three participants with chronic SCI were recruited. Blood samples of each participant were collected for analysis of metabolic parameters. Feces were collected after the bowel opening method the patient routinely uses to evaluate fecal bacterial microbiota using quantitative RT-PCR. Body composition was examined using dual-energy x-ray absorptiometry (DEXA). Data were analyzed to evaluate the correlations between gut microbiota and other parameters. RESULTS: Of the 43 participants, 31 people (72.1%) were paraplegic and 12 people (27.9%) tetraplegic. Thirty-two people (74.4%) were diagnosed with obesity using the percentage of body fat (% body fat) criteria. The mean (SD) ratio of Firmicutes:Bacteroides (F/B), which represents the degree of gut dysbiosis, was 18.3 (2.45). Using stepwise multivariable linear regression analysis, both having tetraplegia and being diagnosed with obesity from % body fat evaluated by DEXA were independent positively-correlating factors of F/B (p < 0.001 and p = 0.001, respectively), indicating more severe gut dysbiosis in people with tetraplegia than paraplegia. CONCLUSION: In people with chronic SCI, having tetraplegia and being diagnosed with obesity from % body fat evaluated by DEXA are independent positive-correlating factors of gut dysbiosis. These results indicate a significant association between gut microbiota and the characteristics of SCI as well as metabolic parameters.

Neurotensin receptor 1 agonist provides neuroprotection in pre-diabetic rats.

Exogenous treatment of a neurotensin receptor 1 (NTR1) agonist exerted the neuroprotection in an obese and Alzheimer's model. However, the effects of NTR1 modulation on peripheral/hippocampal impairment and cognitive deficit following sustained HFD consumption are poorly understood. Forty rats received a normal diet (ND) or HFD for 16 weeks. At week 13, the ND group received a vehicle (n = 8). Thirty-two HFD-fed group were randomized into four subgroups (n = 8/subgroup) with a vehicle, 1 mg/kg of NTR1 agonist, 1 mg/kg of NTR antagonist, and combined treatment (NTR1 agonist-NTR antagonist) for 2 weeks, s.c. injection. Then, the cognitive tests and peripheral/hippocampal parameters were determined. Our findings demonstrated that NTR1 activator reversed obesity and attenuated metabolic impairment in pre-diabetic rats. It also alleviated hippocampal pathologies and synaptic dysplasticity, leading to deceleration or prevention of cognitive impairment progression. Therefore, NTR1 activation would be a possible novel therapy to decelerate or prevent progression of neuropathology and cognitive impairment in the pre-diabetes.

A combination of an antioxidant with a prebiotic exerts greater efficacy than either as a monotherapy on cognitive improvement in castrated-obese male rats.

Previous studies by ourselves and others have demonstrated that both obesity and testosterone deprivation have been related to cognitive decline. We have also shown that a prebiotic and n-acetyl cysteine (NAC) improved cognitive dysfunction in obese rats and castrated-male rats. However, the effects of NAC, a prebiotic (inulin), and a combination of the two on cognition in castrated-obese rats has never been investigated. The hypothesis was that NAC and inulin attenuated cognitive decline in castrated-obese rats by improving gut dysbiosis, and decreasing oxidative stress, glial activation and apoptosis. Male Wistar rats (n = 36) were fed with either a normal diet (ND: n = 6) or a high-fat diet (HFD: n = 30) for twenty-eight weeks. The resultant obese rats had a bilateral orchiectomy (ORX) and were randomly divided into five subgroups (n = 6/ subgroup). Each subgroup was treated with one of five therapies: a vehicle; testosterone replacement (2 mg/kg/day); NAC (100 mg/kg); inulin (10%, w/w), or a combination of the NAC and inulin for four weeks. The results demonstrated that castrated-obese rats developed gut dysbiosis, metabolic disturbance, brain pathologies, and cognitive decline. All of the pathological conditions in the brain were ameliorated to an equal extent by testosterone replacement, NAC, and inulin supplementation. Interestingly, a combination of NAC and inulin had the greatest beneficial effect on cognitive function by synergistically reducing hippocampal inflammation and ameliorating glial dysmorphology. These findings suggest that a combination of NAC and inulin may confer the greatest benefits in improving cognitive function in castrated-obese male rats.

Chronic high-fat diet consumption induces an alteration in plasma/brain neurotensin signaling, metabolic disturbance, systemic inflammation/oxidative stress, brain apoptosis, and dendritic spine loss.

Chronic high-fat diet (HFD) consumption caused not only negative effects on obesity and metabolic disturbance, but also instigated several brain pathologies, including dendritic spine loss. In addition, alterations in plasma/brain neurotensin (NT) levels and NT signaling were observed in obesity. However, the mechanistic link between the NT levels in plasma and brain, NT signaling, and peripheral/brain pathologies following prolonged HFD consumption still needs to be elucidated. We hypothesized that an increase in peripheral/brain NT signaling were associated with peripheral/brain pathologies after prolonged HFD consumption. Male Wistar rats (n = 24) were given either a normal diet (ND) or a HFD for 12 and 40 weeks. At the end of each time course, metabolic parameters and plasma NT levels were measured. Rats were then decapitated and the brains were examined the levels of brain NT, hippocampal reactive oxygen species, the number of Iba-1 positive cells, the dendritic spine densities, and the expression of NT-, mitophagy-, autophagy-, and apoptotic-related proteins. The findings showed an increase in the level of plasma NT with dyslipidemia, metabolic disturbances, systemic inflammation/oxidative stress, and hippocampal pathologies in rats fed HFD for 12 and 40 weeks. The expression of brain NT signaling and brain apoptosis were markedly increased after 40 weeks of HFD feeding. These results indicated that the alteration in the level of circulating/brain NT and its downstream signaling were associated with central and peripheral pathologies after long-term HFD intake. Therefore, these alterations in NT level or its signaling could be considered as a therapeutic target in treating obesity.

Gut dysbiosis develops before metabolic disturbance and cognitive decline in high-fat diet-induced obese condition.

OBJECTIVES: High-fat diet (HFD) consumption caused metabolic disturbance, gut dysbiosis, brain pathology, microglia hyperactivity, and cognitive decline. However, the exact timeline of these abnormalities following HFD consumption is still elusive. Therefore, the aim of this study was to test the hypothesis that gut dysbiosis, peripheral inflammation, and peripheral insulin resistance occur before the brain inflammatory response, hippocampal synaptic dysplasticity, oxidative stress, apoptosis, and cognitive impairment in HFD-fed rats. METHODS: Male Wistar rats received either a normal diet or an HFD for 2, 8, 12, 20, or 40 wk. At the end of each time point, cognitive functions and metabolic parameters were determined. Gut microbiota, brain immune cell activity, amyloid-ß level, microglia morphology, hippocampal reactive oxygen species and apoptosis, hippocampal synaptic plasticity, and dendritic spine density were measured. RESULTS: We found that HFD-fed rats developed gut dysbiosis at week 2 and peripheral insulin resistance at week 8. Rats fed an HFD for 12 wk displayed hippocampal synaptic dysplasticity, decreased dendritic spine density, an elevation of ionized calcium-binding adapter molecule 1+ cells, increased hippocampal reactive oxygen species levels and hippocampal apoptosis with cognitive decline. The decreased percentage of resident microglia and increased percentage of infiltrated macrophage were observed at weeks 20 and 40. Surprisingly, brain amyloid-ß levels were increased after 40 wk of an HFD diet. CONCLUSIONS: These findings demonstrated that gut dysbiosis develops in the earliest phase of consumption of an HFD, followed by brain pathology, which leads to cognitive decline in obese insulin-resistant rats. Therefore, an improvement in gut dysbiosis should provide beneficial effects in the prevention of neuropathology and cognitive decline in the obese.

N-acetyl cysteine, inulin and the two as a combined therapy ameliorate cognitive decline in testosterone-deprived rats.

Our previous studies reported that testosterone-deprived rats developed cognitive decline as a result of increased brain oxidative stress, microglia hyperactivity, and hippocampal dysplasticity. In addition, gut dysbiosis occurred in these rats. Previous studies demonstrated that n-acetyl cysteine (NAC) and a prebiotic (inulin) improved cognition in several pathological conditions. However, its effects on cognition in the testosterone-deprived condition have never been investigated. This study hypothesized that the administration of NAC, inulin, and a combined therapy improved cognition in castrated rats. Here we report that metabolic disturbance was not observed in the ORX rats, but gut dysbiosis was found in these rats. ORX rats developed blood-brain-barrier (BBB) breakdown, and increased brain oxidative stress as indicated by increased hippocampal production of reactive oxygen species (ROS) and an increase in brain malondialdehyde level. ORX rats also demonstrated glia hyperactivation, resulting in hippocampal apoptosis, hippocampal dysplasticity, and cognitive decline. All treatments equally ameliorated cognitive decline by improving gut dysbiosis, alleviating BBB dysfunction, decreasing hippocampal ROS production, decreasing hippocampal apoptosis, and reducing microglia and astrocyte activity. These findings suggest that NAC, inulin, and the combined therapy ameliorated the deleterious effects on the brain in castrated male rats similar to those treated with testosterone.

Pretreatment With PCSK9 Inhibitor Protects the Brain Against Cardiac Ischemia/Reperfusion Injury Through a Reduction of Neuronal Inflammation and Amyloid Beta Aggregation.

Background Cardiac ischemic/reperfusion (I/R) injury leads to brain damage. A new antihyperlipidemic drug is aimed at inhibiting PCSK 9 (proprotein convertase subtilisin/kexin type 9), a molecule first identified in a neuronal apoptosis paradigm. Thus, the PCSK 9 inhibitor ( PCSK 9i) may play a role in neuronal recovery following cardiac I/R insults. We hypothesize that PCSK 9i attenuates brain damage caused by cardiac I/R via diminishing microglial/astrocytic hyperactivation, ß-amyloid aggregation, and loss of dendritic spine. Methods and Results Adult male rats were divided into 7 groups: (1) control (n=4); (2) PCSK 9i without cardiac I/R (n=4); (3) sham (n=4); and cardiac I/R (n=40). Cardiac I/R rats were divided into 4 subgroups (n=10/subgroup): (1) vehicle; (2) PCSK 9i (10 µg/kg, IV) before ischemia; (3) PCSK 9i during ischemia; and (4) PCSK 9i at the onset of reperfusion. At the end of cardiac I/R protocol, brains were removed to determine microglial and astrocytic activities, ß-amyloid aggravation, and dendritic spine density. The cardiac I/R led to the activation of the brain's innate immunity resulting in increasing Iba1+ microglia, GFAP + astrocytes, and CD 11b+/ CD 45+high cell numbers. However, CD 11b+/ CD 45+low cell numbers were decreased following cardiac I/R. In addition, cardiac I/R led to reduced dendritic spine density, and increased ß-amyloid aggregation. Only the administration of PCSK 9i before ischemia effectively attenuated these deleterious effects on the brain following cardiac I/R. PCSK 9i administration under the physiologic condition did not affect the aforementioned parameters. Conclusions Cardiac I/R injury activated microglial activity in the brain, leading to brain damage. Only the pretreatment with PCSK 9i prevented dendritic spine loss via reduction of microglial activation and Aß aggregation.

Potential roles of neurotensin on cognition in conditions of obese-insulin resistance.

Neurotensin is an endogenous tridecapeptide that can be found in both central and peripheral nervous systems. Under normal physiological conditions, neurotensin is involved in the regulation of pain, body temperature, physical activity, appetite as well as learning and memory. In addition, it plays an important role in fat metabolism. Previous studies have demonstrated that alterations of neurotensin levels were associated with several neuropathological conditions such as Alzheimer's disease, mood disorders, and obesity associated eating disorders. Obesity has been shown to be associated with low-grade systemic inflammation, brain inflammation, and cognitive decline. Several pieces of evidence suggest that neurotensin might play a role in cognitive decline following obesity. However, the underlying mechanisms of neurotensin on cognition under obese-insulin resistant condition are still unclear. In this review, the current available evidence from in vitro, in vivo and clinical studies regarding the role of neurotensin in the physiological condition and obesity in association with cognition are comprehensively summarized and discussed. The studies which report controversial findings regarding these issues are also presented and discussed.