Insulin-like growth factor-1 and cognition in normoglycemia, prediabetes, and type 2 diabetes mellitus.

BACKGROUND: The relationship between insulin-like growth factor-1 (IGF-1) and cognition has been studied in healthy individuals, but not extensively with regards to insulin resistance and type 2 diabetes mellitus (T2DM). In this retrospective observational study, we investigated relationships of IGF-1 with memory and executive function across people with normoglycemia, prediabetes, and T2DM. METHODS: Data from the Midlife in the United States (MIDUS) study were used. Episodic memory and executive function were assessed using the Brief Test of Adult Cognition by Telephone approximately 21.42 ± 12.10 months prior to measuring IGF-1 levels from a fasting blood sample. Normoglycemia was identified as individuals without a physician diagnosis of diabetes and glycated hemoglobin (HbA1c) ≤5.6%. Prediabetes was identified as those without a physician diagnosis of diabetes and HbA1c between 5.7%-6.4%. T2DM was identified as anyone with a physician diagnosis of diabetes, or HbA1c ≥6.5%, or anyone using an oral hypoglycemic medication. The associations were assessed using linear regressions controlling for age, sex, education, body mass index, C-reactive protein, HbA1c or homeostatic model of insulin resistance, MIDUS wave, exercise, smoking status, sleep quality, alcohol intake, oral hypoglycemic use, and insulin use. RESULTS: The study included 1400 participants, which consisted of 583 normoglycemic (48.4% female, mean age 51.0 ± 12.2 years), 512 prediabetes (58.4% female, mean age 57.3 ± 11.8 years), and 305 T2DM participants (53.8% female, mean age 57.6 ± 11.5 years). Peripheral IGF-1 concentrations were lower (F2,1397 = 28.29, p < 0.001) in people with prediabetes or T2DM, vs. normoglycemia. Participants with prediabetes or T2DM had lower episodic memory (F2,1397 = 9.21, p < 0.001) and executive function (F2,1397 = 20.29, p < 0.001) composite z-scores than people with normoglycemia. Higher IGF-1 concentrations were associated with better executive performance in individuals with prediabetes (ß = 0.115 [0.028, 0.202], p = 0.010), but not in individuals with normoglycemia or T2DM. An interaction between IGF-1 and sex in predicting executive function was observed in the prediabetes group (ß = -0.344, p = 0.042), where the relationship was weaker in females (ß = 0.106 [-0.012, 0.224], p = 0.077) than males (ß = 0.251 [0.123, 0.380], p < 0.001). No associations were seen between IGF-1 and memory. CONCLUSION: The results suggest that peripheral IGF-1 concentrations may be related to executive function, and that the relationship may be sex-specific and dependent on diabetes status.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Depression interacts with allostatic load to predict cognitive decline in middle age.

BACKGROUND: Allostatic load (AL) indicates the cumulative impact of stress on homeostatic mechanisms. Depression and AL have been associated with cognitive deficits, but it is unclear if they do so independently. METHODS: Using data from middle-aged participants in the observational longitudinal Midlife in the United States (MIDUS) study (n = 704, 57.5 % female, 63.8 ± 10.6 years old in 2014), we assessed whether the effect of prior depression (Composite International Diagnostic Interview Short-Form in 1995) on cognitive decline between 2004 and 2013 (composite Z-scores derived from the Brief Test of Adult Cognition by Telephone and the Stop & Go Switch Task) was moderated by AL Z-scores in 2004 (calculated from biomarkers in blood, urine, and electrocardiography). RESULTS: A significant depression × AL interaction predicted a decline in a composite cognitive score (ß = -0.066, SE=0.029, p = 0.024) and executive function (ß = -0.068, SE=0.025, p = 0.007). Depression predicted a decline in composite cognition among those with AL Z-scores above - 0.055. AL subdomains of inflammation and lipid metabolism showed evidence of moderation. CONCLUSION: Middle-aged adults with depression who had higher allostatic load were at greater risk of cognitive decline. Future studies should evaluate whether the interaction predicts incident dementia, and whether interventions targeting depression or elevated AL in people who have both can attenuate cognitive decline.

Depression in type 2 diabetes: A systematic review and meta-analysis of blood inflammatory markers.

The prevalence of depression is higher among people with type 2 diabetes (T2DM). Individually, both conditions are associated with systemic inflammation. This study aimed to summarize the clinical data comparing peripheral inflammatory markers in blood between people with T2DM, with and without comorbid depression. From 2187 records, we identified 20 original peer-reviewed articles from which blood inflammatory marker concentrations could be combined and compared between people with T2DM and comorbid depression (D) vs. no depression (ND) as standardized mean differences (SMD) in random effects meta-analysis. Concentrations of C-reactive protein (CRP; ND/NND = 1742/15244, SMD = 0.31 95% confidence interval [0.16, 0.45], Z16 = 4.03, p < 0.01; I2 = 84.0%) and interleukin-6 (IL-6; ND/NND = 677/4349, SMD = 0.17 [0.04, 0.30], Z4 = 2.58, p = 0.01; I2 = 48.1%), were higher, and concentrations of brain derived neurotrophic factor (BDNF; ND/NND = 358/1512, SMD = -0.37 95% confidence interval [-0.64,-0.10], Z2 = -2.68, p = 0.01; I2 = 61.2%) were lower, among those with depression. Depression in T2DM was associated with systemic inflammation and lower peripheral blood BDNF concentrations. Inconsistency between studies suggests the need to explore further population heterogeneity and pathophysiological elements. PROSPERO (CRD42020188509).

Parvalbumin interneuron alterations in stress-related mood disorders: A systematic review.

Stress-related psychiatric disorders including depression involve complex cellular and molecular changes in the brain, and GABAergic signaling dysfunction is increasingly implicated in the etiology of mood disorders. Parvalbumin (PV)-expressing neurons are fast-spiking interneurons that, among other roles, coordinate synchronous neuronal firing. Mounting evidence suggests that the PV neuron phenotype is altered by stress and in mood disorders. In this systematic review, we assessed PV interneuron alterations in psychiatric disorders as reported in human postmortem brain studies and animal models of environmental stress. This review aims to 1) comprehensively catalog evidence of PV cell function in mood disorders (humans) and stress models of mood disorders (animals); 2) analyze the strength of evidence of PV interneuron alterations in various brain regions in humans and rodents; 3) determine whether the modulating effect of antidepressant treatment, physical exercise, and environmental enrichment on stress in animals associates with particular effects on PV function; and 4) use this information to guide future research avenues. Its principal findings, derived mainly from rodent studies, are that stress-related changes in PV cells are only reported in a minority of studies, that positive findings are region-, age-, sex-, and stress recency-dependent, and that antidepressants protect from stress-induced apparent PV cell loss. These observations do not currently translate well to humans, although the postmortem literature on the topic remains limited.

Extracellular matrix composition of connective tissues: a systematic review and meta-analysis.

The function of connective tissues depends on the physical and biochemical properties of their extracellular matrix (ECM), which are in turn dictated by ECM protein composition. With the primary objective of obtaining quantitative estimates for absolute and relative amounts of ECM proteins, we performed a systematic review of papers reporting protein composition of human connective tissues. Articles were included in meta-analysis if they contained absolute or relative quantification of proteins found in the ECM of human bone, adipose tissue, tendon, ligament, cartilage and skeletal muscle. We generated absolute quantitative estimates for collagen in articular cartilage, intervertebral disk (IVD), skeletal muscle, tendon, and adipose tissue. In addition, sulfated glycosaminoglycans were quantified in articular cartilage, tendon and skeletal muscle; total proteoglycans in IVD and articular cartilage, fibronectin in tendon, ligament and articular cartilage, and elastin in tendon and IVD cartilage. We identified significant increases in collagen content in the annulus fibrosus of degenerating IVD and osteoarthritic articular cartilage, and in elastin content in degenerating disc. In contrast, collagen content was decreased in the scoliotic IVD. Finally, we built quantitative whole-tissue component breakdowns. Quantitative estimates improve our understanding of composition of human connective tissues, providing insights into their function in physiology and pathology.