Type 2 diabetes mellitus (T2DM) and hypertension are established risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible ...perivascular spaces (PVS). Patients with neurodegenerative diseases were stratified by presence or absence of T2DM, and MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH) and lacunes (LACN), and PVS in the white matter (wmPVS) or basal ganglia (bgPVS). Patients with T2DM had greater wmPVS volume, but not other SVD volumes, with greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found total natural indirect effects of T2DM on all other SVD volumes that were mediated by wmPVS: pWMH, dWMH, pLACN, and dLACN, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal targets to mitigate the impact of T2DM on cerebral small vessels.
•Levels of BDNF were lower in type 2 diabetes (T2DM) with cognitive impairment (CI).•IL-6, CRP, sVCAM-1 and AGE levels were higher in T2DM with CI.•Increased inflammatory-vascular interactions may be ...associated with CI in T2DM.
People with type 2 diabetes mellitus (T2DM) are at increased risk of mild cognitive impairment and dementia. Systemic inflammation has been proposed as a common risk factor. This study aimed to summarize the clinical data pertaining to peripheral blood inflammatory markers. We identified original peer-reviewed articles reporting blood inflammatory marker concentrations in groups of people with a T2DM diagnosis who have cognitive impairment (CI; including mild cognitive impairment, Alzheimer’s disease, vascular cognitive impairment) vs. normal cognition (NC). Between-group standardized mean differences (SMD) were summarized in random effects meta-analyses. From 2108 records, data were combined quantitatively from 40 studies. Concentrations of interleukin-6 (IL-6; NCI/NNC = 934/3154, SMD 0.74 95% confidence interval 0.07, 1.42, Z5 = 2.15, p = 0.03; I2 = 98.08%), C-reactive protein (CRP; NCI/NNC = 1610/4363, SMD 0.80 0.50, 1.11, Z14 = 5.25, p < 0.01; I2 = 94.59%), soluble vascular cell adhesion molecule-1 (sVCAM-1; NCI/NNC = 104/1063, SMD 1.64 95% confidence interval 0.21, 3.07, Z2 = 2.25, p = 0.02; I2 = 95.19%), and advanced glycation end products (AGEs; NCI/NNC = 227/317, SMD 0.84 95% confidence interval 0.41, 1.27, Z2 = 3.82, p < 0.01; I2 = 81.07%) were higher among CI groups compared to NC. Brain derived neurotropic factor (BDNF) concentrations were significantly lower in CI compared to NC (NCI/NNC = 848/2063, SMD −0.67 95% confidence interval -0.99, −0.35, Z3 = -4.09, p < 0.01; I2 = 89.20%). Cognitive impairment among people with T2DM was associated with systemic inflammation and lower BDNF concentrations. These inflammatory characteristics support an increased inflammatory-vascular interaction associated with cognitive impairment in T2DM. PROSPERO (CRD42020188625).
Abstract
Context
Human studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased ...diabetes risk. We previously showed that a single high-dose TCDD exposure (20 µg/kg) decreased plasma insulin levels in male and female mice in vivo, but effects on glucose homeostasis were sex-dependent.
Objective
The current study assessed whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in chow-fed or high-fat diet (HFD)-fed mice.
Methods
Male and female mice were exposed to 20 ng/kg/d TCDD 2×/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females for TempO-Seq transcriptomic analysis.
Results
Low-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in females. TCDD caused a modest increase in islet area in males but reduced the percent beta cell area within islets in females. TempO-Seq analysis suggested abnormal changes to endocrine and metabolic pathways in female TCDDHFD islets.
Conclusion
Our data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice but promotes maladaptive metabolic responses in HFD-fed females.
Mixed evidence supports blood-brain barrier (BBB) dysfunction in Lewy body spectrum diseases.
We compare biofluid markers in people with idiopathic Parkinson's disease (PD) and people with PD ...dementia (PDD) and/or dementia with Lewy bodies (DLB), compared with healthy controls (HC). Seven databases were searched up to May 10, 2021. Outcomes included cerebrospinal fluid to blood albumin ratio (Qalb), and concentrations of 7 blood protein markers that also reflect BBB disruption and/or neurodegenerative co-pathology. We further explore differences between PD patients with and without evidence of dementia. Random-effects models were used to obtain standardized mean differences (SMD) with 95% confidence interval.
Of 13,949 unique records, 51 studies were meta-analyzed. Compared to HC, Qalb was higher in PD (NPD/NHC = 224/563; SMD = 0.960 0.227–1.694, p = 0.010; I2 = 92.2%) and in PDD/DLB (NPDD/DLB/NHC = 265/670; SMD = 1.126 0.358–1.893, p < 0.001; I2 = 78.2%). Blood neurofilament light chain (NfL) was higher in PD (NPD/NHC = 1848/1130; SMD = 0.747 0.442–1.052, p < 0.001; I2 = 91.9%) and PDD/DLB (NPDD/DLB/NHC = 183/469; SMD = 1.051 0.678–1.423, p = 0.004; I2 = 92.7%) than in HC. p-tau 181 (NPD/NHC = 276/164; SMD = 0.698 0.149–1.247, p = 0.013; I2 = 82.7%) was also higher in PD compared to HC. In exploratory analyses, blood NfL was higher in PD without dementia (NPDND/NHC = 1005/740; SMD = 0.252 0.042–0.462, p = 0.018; I2 = 71.8%) and higher in PDD (NPDD/NHC = 100/111; SMD = 0.780 0.347–1.214, p < 0.001; I2 = 46.7%) compared to HC. Qalb (NPDD/NPDND = 63/191; SMD = 0.482 0.189–0.774, p = 0.010; I2<0.001%) and NfL (NPDD/NPDND = 100/223; SMD = 0.595 0.346–0.844, p < 0.001; I2 = 3.4%) were higher in PDD than in PD without dementia.
Biofluid markers suggest BBB disruption and neurodegenerative co-pathology involvement in common Lewy body diseases. Greater evidence of BBB breakdown was seen in Lewy body disease with cognitive impairment.
•Qalb was higher in PD and in PDD/DLB patients compared to HC.•Blood NfL concentrations were higher in PD and PDD/DLB compared to HC.•Concentrations of p-tau 181 were higher in PD patients compared to HC.•Qalb and NfL were higher in PDD than in PD without dementia.•Biofluid markers suggest the involvement of BBB breakdown in common Lewy body diseases.
Abstract INTRODUCTION We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial ...fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS PVS was significantly associated with sEF ( c = ‐0.125 ± 0.054, 95% bootstrap confidence interval CI ‐0.2309, ‐0.0189, p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.
•People who had both type 2 diabetes and hypertension had larger volumes of perivascular spaces (PVS) in their white matter visible on MRI•In people with hypertension, PVS) mediated associations ...between type 2 diabetes and small vessel disease (SVD) markers, and SVD progression over 1 year•PVS may be a target to mitigate the impact of T2DM and hypertension on the small cerebral vessels
Type 2 diabetes mellitus (T2DM) and hypertension are established risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). Patients with neurodegenerative diseases were stratified by presence or absence of T2DM. MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, and PVS in the white matter (wmPVS) or basal ganglia (bgPVS). Patients with T2DM had greater wmPVS volume, but not other SVD volumes, 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 markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, 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.
PDF
