Community Economic Change and Depression Evidence From the 1980\u27s Farm Crisis

This paper examines the effect of aggregate economic conditions in communities on individual levels of depression. While the effect of economic conditions on mental health has been examined at the aggregate level and at the individual level, models including both individual and aggregate processes are necessary to differentiate contextual from individual processes impacting mental health status. Both cross-sectional and panel data from a sample of respondents representative of a Great Plains state on which data were available in 1981,1986, and1989 were used in the analysis. The cross-sectional analysis in 1989 consisted of2,485 respondents. Panel data from 916 respondents in1981-1986 and from 1,299 respondents in 1986-1989 also analyzed In both the cross-sectional and panel data there was little evidence of an effect of living in economically distressed communities on mental health independent of the relationship to the individuals\u27 economic conditions. The research found that while individuals were able to evaluate the state of the local economy with some degree of accuracy, and their perception of the local economy was related to depression, this effect was not strong enough to produce a significant relationship between aggregate economic measures and depression. Implications of these findings for understanding community climate effects in smaller communities is discussed

Changes in Adiposity and Cerebrospinal Fluid Biomarkers Following a Modified Mediterranean Ketogenic Diet in Older Adults at Risk for Alzheimer's Disease

Background: Ketogenic diets have been used to treat both obesity and neurological disorders, including epilepsy and more recently Alzheimer's disease (AD), likely due to favorable effects on both central and peripheral metabolism. Improvements in body composition have also been reported; however, it is unclear if diet-induced changes in adiposity are related to improvements in AD and related neuropathology. Purpose: We examined the effects of a Modified Mediterranean Ketogenic (MMK) diet vs. an American Heart Association (AHA) diet on body weight, body composition, and body fat distribution and their association with cerebrospinal fluid (CSF) biomarkers in older adults at risk for AD. Methods: Twenty adults (mean age: 64.3 ± 6.3 years, 35% Black, 75% female) were randomly assigned to a crossover trial starting with either the MMK or AHA diet for 6 weeks, followed by a 6-week washout and then the opposite diet for 6 weeks. At baseline and after each diet adiposity was assessed by dual-energy x-ray absorptiometry and CSF biomarkers were measured. Linear mixed effect models were used to examine the effect of diet on adiposity. Spearman correlations were examined to assess associations between adiposity and CSF biomarkers. Results: At baseline there was a high prevalence of overweight/obesity and central adiposity, and higher visceral fat and lower peripheral fat were associated with an adverse CSF biomarker profile. The MMK and AHA diets led to similar improvements in body composition and body fat distribution. Significant correlations were found between changes in adiposity and changes in CSF biomarkers (r's = 0.63-0.92, p's < 0.05), with notable differences by diet. Decreases in body fat on the MMK diet were related to changes in Aβ biomarkers, whereas decreases in body fat on the AHA diet were related to changes in tau biomarkers and cholinesterase activity. Interestingly, increases in CSF Aβ on the MMK diet occurred in those with less fat loss. Conclusion: An MMK diet leads to favorable changes in body composition, body fat distribution, and CSF biomarkers. Our data suggest that modest weight loss that maximizes visceral fat loss and preserves peripheral fat, may have the greatest impact on brain health. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT02984540]

Intranasal Treatment of Central Nervous System Dysfunction in Humans

One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke

Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment

Extracellular vesicles (EV) have emerged as a less-invasive nano-tool for discovering biomarkers of Alzheimer’s disease and related dementia. Here, we analyzed different neuron-enriched EV from plasma to predict response and molecular mechanisms of ketogenic diet’s efficacy in mild cognitive impairment participants. The study was a randomized crossover design in which cognitively normal and mild cognitive impairment participants consumed a modified Mediterranean-ketogenic diet (MMKD) or American Heart Association diet (AHAD) for six weeks, followed by other diet after washout. L1 cell adhesion molecule (L1CAM), synaptophysin, and neural cell adhesion molecule (NCAM) surface markers were used to enrich for neuron-secreted small EV (sEVL1CAM, sEVSYP, and sEVNCAM). For the first time, we have presented multiple evidences, including immunogold labeling/Transmission electron microscopy, CD63 (clusters of differentiation 63)-ELISA based assay, confocal microscopy fluorescent images, and flow cytometry data confirming the presence of L1CAM on the surface of sEVL1CAM, validating purity and relative abundance of sEVL1CAM in the plasma. Cargo analysis of sEVL1CAM showed that MMKD intervention reduces amyloid beta 1-42 (50.3%, p = 0.011), p181-tau (34.9%, p = 0.033) and neurofilament light (54.2%, p = 0.020) in mild cognitive impairment participants. Moreover, sEVL1CAM showed better sensitivity compared to CSF in analyzing increased glutamate (6 folds, p &amp;lt; 0.0001) from mild cognitive impairment participants following MMKD intervention. sEVL1CAM characterization also suggested that MMKD differentially targets the expression of various glutamate receptors - glutamate receptor ionotropic NMDA1 (GRIN1), glutamate receptor ionotropic NMDA2A (GRIN2A), glutamate receptor ionotropic NMDA2B (GRIN2B) and glutamate receptor ionotropic AMPA type subunit 1 (GRIA1). Importantly, these sEVL1CAM measures strongly correlated with corresponding clinical CSF biomarkers (neurogranin, amyloid beta 1-42, neurofilament light, and tau). Furthermore, sEVL1CAM were loaded with less advanced-glycation endproducts and exhibited anti-inflammatory activity following MMKD intervention. Most importantly, the expression of monocarboxylate transporter 2 on the surface of sEVL1CAM predicted the amyloid beta 1-42 response to MMKD intervention (Area under the curve = 0.87, p = 0.0044) and offered a novel screening tool to identify participants responsive to this dietary intervention. Finally, sEVL1CAM, sEVSYP, and sEVNCAM showed significantly high concordance in analyzing amyloid beta 1-42 (Pearson correlation coefficient ≥ 0.63, p &amp;lt; 0.01) and neurofilament light (Pearson correlation coefficient ≥ 0.49, p &amp;lt; 0.05). Together, sEV in plasma offers promise in assessing the efficacy of dietary/therapeutic intervention against mild cognitive impairment/Alzheimer’s disease

Killed but metabolically active Leishmania infantum as a novel whole-cell vaccine for visceral leishmaniasis

There are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here, we describe a novel whole-cell vaccine approach using Leishmania infantum chagasi promastigotes treated with the psoralen compound amotosalen (S-59) and low doses of UV A radiation. This treatment generates permanent, covalent DNA cross-links within parasites and results in Leishmania organisms termed killed but metabolically active (KBMA). In this report, we characterize the in vitro growth characteristics of both KBMA L. major and KBMA L. infantum chagasi. Concentrations of S-59 that generate optimally attenuated parasites were identified. Like live L. infantum chagasi, KBMA L. infantum chagasi parasites were able to initially enter liver cells in vivo after intravenous infection. However, whereas live L. infantum chagasi infection leads to hepatosplenomegaly in mice after 6 months, KBMA L. infantum chagasi parasites were undetectable in the organs of mice at this time point. In vitro, KBMA L. infantum chagasi retained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMA L. infantum chagasi correlated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either live L. infantum chagasi or KBMA L. infantum chagasi displayed similar cytokine patterns in vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoan L. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens

Montreal Cognitive Assessment and Modified Mini Mental State Examination in African Americans

Background. Sparse data limit the interpretation of Montreal Cognitive Assessment (MoCA) scores, particularly in minority populations. Additionally, there are no published data on how MoCA scores compare to the widely used Modified Mini Mental State Examination (3MSE). We provide performance data on the MoCA in a large cohort of African Americans and compare 3MSE and MoCA scores, providing a &quot;crosswalk&quot; for interpreting scores. Methods. Five hundred and thirty African Americans with type 2 diabetes were enrolled in African American-Diabetes Heart Study-MIND, a cross-sectional study of cognition and structural and functional brain imaging. After excluding participants with possible cognitive impairment ( = 115), mean (SD) MoCA and 3MSE scores are presented stratified by age and education. Results. Participant mean age was 58.2 years (range: 35-83); 61% were female; and 64.9% had &gt;12 years of education. Mean (SD) 3MSE and MoCA scores were 86.9 (8.2) and 19.8 (3.8), respectively. 93.5% of the cohort had a &quot;positive&quot; screen on the MoCA, scoring &lt;26 (education-adjusted), compared with 47.5% on the 3MSE (cut-point &lt; 88). A 3MSE score of 88 corresponded to a MoCA score of 20 in this population. Conclusion. The present data suggest the need for caution when applying proposed MoCA cutoffs to African Americans

Exploring the Nexus of Alzheimer’s Disease and Related Dementias with Cancer and Cancer Therapies

Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer’s disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation convened a one day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations and partnerships for future action

The association of circulating amylin with β-amyloid in familial Alzheimer's disease.

Introduction: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD). Methods: Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. Results: Amylin-Aβ cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ42 concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aβ exchange and amylin-Aβ cross-seeding. Discussion: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aβ-related pathology/symptoms

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