Social Support and Family Criticism: Potential Moderators of the Relationship Between Functional Impairment, Illness Burden, and Depression.

Social support and family criticism variables were examined as potential moderators of the association between illness burden and depression and between functional impairment and depression in a secondary data analysis. Participants (n=735) were older adults aged 65 and older from internal medicine and family medicine primary care offices. It was hypothesized that both illness burden and functional impairment would be associated with increased depressive symptoms and a diagnosis of depression. In addition, it was hypothesized that higher levels of social support and lower levels of family criticism would moderate this relationship. Both linear and logistic multivariate hierarchical regression analyses were used to examine these variables as potential moderators. Hypotheses concerning perceived social support and social interaction as moderators were supported. Hypotheses involving family criticism and instrumental social support were not supported. Enhancement of perceived social support and encouragement of social interactions may be important intervention targets for treatment of depressive symptoms in older adults with illness or impairment who are seen in primary care settings

Impulsivity, Venturesomeness, and Pride: Potential Moderators of the Relationship Between Childhood Trauma, Substance Use, and Physical Aggression

Impulsivity, venturesomeness, and pride variables were examined as potential moderators of the associations between childhood trauma and physical aggression, alcohol use and physical aggression, and drug use and physical aggression. Participants (n = 457) were college students recruited from a university in the Southeast. It was hypothesized that childhood trauma, alcohol use, and drug use would be associated with increased scores of physical aggression. In addition, it was hypothesized that impulsivity, venturesomeness, authentic pride, and hubristic pride would moderate these relationships. Linear, multivariate hierarchical regression analyses were used to examine these variables as potential moderators. Hypotheses concerning hubristic pride as a moderator of the relationship between alcohol use and physical aggression as well as the relationship between drug use and physical aggression were supported. In addition, the hypothesis concerning authentic pride as a moderator of the relationship between alcohol use and physical aggression was supported albeit in the opposite direction than predicted. Hypotheses concerning the moderating roles of impulsivity and venturesomeness were not supported. Findings support the idea that the deleterious psychological effects of substance use can be compounded by personality factors such as authentic and hubristic pride. The discussion encompasses why interventions should target attributions and cognitions and why simply encouraging someone to have a more “healthy pride” is likely to be ineffective at reducing physical aggression in the context of drug use and alcohol use

Functional Impairment, Illness Burden, and Depressive Symptoms in Older Adults: Does Type of Social Relationship Matter?

Objective: The nature of interpersonal relationships, whether supportive or critical, may affect the association between health status and mental health outcomes. We examined the potential moderating effects of social support, as a buffer, and family criticism, as an exacerbating factor, on the association between illness burden, functional impairment and depressive symptoms. Methods: Our sample of 735 older adults, 65 years and older, was recruited from internal and family medicine primary care offices. Trained interviewers administered the Hamilton Rating Scale for Depression, Duke Social Support Inventory, and Family Emotional Involvement and Criticism Scale. Physician-rated assessments of health, including the Karnofsky Performance Status Scale and Cumulative Illness Rating Scale, were also completed. Results: Linear multivariable hierarchical regression results indicate that social interaction was a significant buffer, weakening the association between illness burden and depressive symptoms, whereas perceived social support buffered the relationship between functional impairment and depressive symptoms. Family criticism and instrumental social support were not significant moderators. Conclusions: Type of medical dysfunction, whether illness or impairment, may require different therapeutic and supportive approaches. Enhancement of perceived social support, for those who are impaired, and encouragement of social interactions, for those who are ill, may be important intervention targets for treatment of depressive symptoms in older adult primary care patients

Robust neuroinflammation and perivascular pathology in rTg-DI rats, a novel model of microvascular cerebral amyloid angiopathy

Background Cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease of the aged and a prominent comorbidity of Alzheimer’s disease (AD). CAA can promote a variety of vascular-related pathologies including neuroinflammation, cerebral infarction, and hemorrhages, which can all contribute to vascular cognitive impairment and dementia (VCID). Our understanding of the pathogenesis of CAA remains limited and further investigation of this condition requires better preclinical animal models that more accurately reflect the human disease. Recently, we generated a novel transgenic rat model for CAA (rTg-DI) that develops robust and progressive microvascular CAA, consistent microhemorrhages and behavioral deficits. Methods In the current study, we investigated perivascular pathological processes that accompany the onset and progressive accumulation of microvascular CAA in this model. Cohorts of rTg-DI rats were aged to 3 months with the onset of CAA and to 12 months with advanced stage disease and then quantitatively analyzed for progression of CAA, perivascular glial activation, inflammatory markers, and perivascular stress. Results The rTg-DI rats developed early-onset and robust accumulation of microvascular amyloid. As the disease progressed, rTg-DI rats exhibited increased numbers of astrocytes and activated microglia which were accompanied by expression of a distinct subset of inflammatory markers, perivascular pericyte degeneration, astrocytic caspase 3 activation, and disruption of neuronal axonal integrity. Conclusions Taken together, these results demonstrate that rTg-DI rats faithfully mimic numerous aspects of human microvascular CAA and provide new experimental insight into the pathogenesis of neuroinflammation and perivascular stress associated with the onset and progression of this condition, suggesting new potential therapeutic targets for this condition. The rTg-DI rats provide an improved preclinical platform for developing new biomarkers and testing therapeutic strategies for microvascular CAA

Copper Accumulation and the Effect of Chelation Treatment on Cerebral Amyloid Angiopathy Compared to Parenchymal Amyloid Plaques

Accumulation of fibrillar amyloid β-protein (Aβ) in parenchymal plaques and in blood vessels of the brain, the latter condition known as cerebral amyloid angiopathy (CAA), are hallmark pathologies of Alzheimer\u27s disease (AD) and related disorders. Cerebral amyloid deposits have been reported to accumulate various metals, most notably copper and zinc. Here we show that, in human AD, copper is preferentially accumulated in amyloid-containing brain blood vessels compared to parenchymal amyloid plaques. In light of this observation, we evaluated the effects of reducing copper levels in Tg2576 mice, a transgenic model of AD amyloid pathologies. The copper chelator, tetrathiomolybdate (TTM), was administered to twelve month old Tg2576 mice for a period of five months. Copper chelation treatment significantly reduced both CAA and parenchymal plaque load in Tg2576 mice. Further, copper chelation reduced parenchymal plaque copper content but had no effect on CAA copper levels in this model. These findings indicate that copper is associated with both CAA deposits and parenchymal amyloid plaques in humans, but less in Tg2576 mice. TTM only reduces copper levels in plaques in Tg2576 mice. Reducing copper levels in the brain may beneficially lower amyloid pathologies associated with AD

Environmental Enrichment: Disentangling the Influence of Novelty, Social, and Physical Activity on Cerebral Amyloid Angiopathy in a Transgenic Mouse Model

Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer’s disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly understood. These factors, delivered in the form of the environmental enrichment (EE) paradigm in rodents, have been shown to have beneficial effects on the brain and behavior in healthy aging and AD models. However, the relative importance of these subcomponents on CAA pathology has not been investigated. Therefore, we assessed the effects of EE, social enrichment (SOC), and cognitive enrichment (COG) compared to a control group that was single housed without enrichment (SIN) from 4 to 8 months of age in wild-type mice (WT) and Tg-SwDI mice, a transgenic mouse model of CAA that exhibits cognitive/behavioral deficits. The results show that individual facets of enrichment can affect an animal model of CAA, though the SOC and combined EE conditions are generally the most effective at producing physiological, cognitive/behavioral, and neuropathological changes, adding to a growing literature supporting the benefits of lifestyle interventions

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

Accumulation of fibrillar amyloid β protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid β protein in brain and faithfully recapitulates many of the pathologic aspects of human small-vessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions

Neutral Effect of Exenatide on Serum Testosterone in Men with Type 2 Diabetes Mellitus: A Prospective Cohort

BACKGROUND: Endogenous testosterone increases with weight loss from diet, exercise, and bariatric surgery. However, little is known about testosterone levels after weight loss from medication. OBJECTIVES: Uncover the effects of Glucagon-Like Peptide-1 receptor agonist (GLP-1 RA) therapy on serum testosterone. MATERIAL AND METHODS: Prospective cohort study of men starting GLP-1 RA therapy for type 2 diabetes mellitus. RESULTS: 51 men lost 2.27 kg (p = 0.00162) and their HbA1c values improved by 0.7% (p = 0.000503) after 6 months of GLP-1 RA therapy. There was no significant change in testosterone for the group as a whole. However, in subgroup analyses, there was a significant difference in total testosterone change between men starting with baseline total testosterone/dL (238.5 ± 56.5 ng/dL to 272.2 ± 82.3 ng/dL) compared to higher values (438 ± 98.2 ng/dL to 412 ± 141.2 ng/dL) (p = 0.0172);free testosterone increased if the baseline total testosterone was/dL (55.2 ± 12.8 pg/mL to 57.2 ± 17.6 pg/mL) and decreased if \u3e320 ng/dL (74.7 ± 16.3 pg/mL to 64.2 ± 17.7 pg/mL) (p = 0.00807). Additionally, there were significant differences in testosterone change between men with HbA1c improvements ≥1% (351.6 ± 123.9 ng/dL to 394.4 ± 136.5 ng/dL) compared to men with HbA1c changes CONCLUSION: GLP-1 RA therapy improves weight and HbA1c without adverse effects on testosterone. Those starting with lower testosterone values or attaining greater improvement in HbA1c may see additional benefits

Analysis of a threshold model of social contagion on degree-correlated networks

We analytically determine when a range of abstract social contagion models permit global spreading from a single seed on degree-correlated random networks. We deduce the expected size of the largest vulnerable component, a network's tinderbox-like critical mass, as well as the probability that infecting a randomly chosen individual seed will trigger global spreading. In the appropriate limits, our results naturally reduce to standard ones for models of disease spreading and to the condition for the existence of a giant component. Recent advances in the distributed, infinite seed case allow us to further determine the final size of global spreading events, when they occur. To provide support for our results, we derive exact expressions for key spreading quantities for a simple yet rich family of random networks with bimodal degree distributions.Comment: 7 Pages, 1 figure, submitted to Phys. Rev.

Long-term voluntary wheel running does not alter vascular amyloid burden but reduces neuroinflammation in the Tg-SwDI mouse model of cerebral amyloid angiopathy

Background: Cardiovascular exercise (CVE) has been shown to be protective against cognitive decline in aging and the risk for dementias, including Alzheimer’s Disease (AD). CVE has also been shown to have several beneficial effects on brain pathology and behavioral impairments in mouse models of AD; however, no studies have specifically examined the effects of CVE on cerebral amyloid angiopathy (CAA), which is the accumulation of amyloid-beta (Aβ) in the cerebral vasculature. CAA may be uniquely susceptible to beneficial effects of CVE interventions due to the location and nature of the pathology. Alternatively, CVE may exacerbate CAA pathology, due to added stress on already compromised cerebral vasculature. Methods: In the current study, we examined the effects of CVE over many months in mice, thereby modeling a lifelong commitment to CVE in humans. We assessed this voluntary CVE in Tg-SwDI mice, a transgenic mouse model of CAA that exhibits behavioral deficits, fibrillar vascular Aβ pathology, and significant perivascular neuroinflammation. Various “doses” of exercise intervention (0 h (“Sedentary”), 1 h, 3 h, 12 h access to running wheel) were assessed from ~ 4 to 12 months of age for effects on physiology, behavior/cognitive performance, and pathology. Results: The 12 h group performed the greatest volume of exercise, whereas the 1 h and 3 h groups showed high levels of exercise intensity, as defined by more frequent and longer duration running bouts. Tg-SwDI mice exhibited significant cerebral vascular Aβ pathology and increased expression of pro-inflammatory cytokines as compared to WT controls. Tg-SwDI mice did not show motor dysfunction or altered levels of anxiety or sociability compared to WT controls, though Tg-SwDI animals did appear to exhibit a reduced tendency to explore novel environments. At all running levels, CAA pathology in Tg-SwDI mice was not significantly altered, but 12-h high-volume exercise showed increased insoluble Aβ burden. However, CVE attenuated the expression of pro-inflammatory cytokines TNF-α and IL-6 and was generally effective at enhancing motor function and reducing anxiety-like behavior in Tg-SwDI mice, though alterations in learning and memory tasks were varied. Conclusions: Taken together, these results suggest that CAA can still develop regardless of a lifespan of substantial CVE, although downstream effects on neuroinflammation may be reduced and functional outcomes improved