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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., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Corinne Fischer reports financial support was provided by Canadian Institutes of Health Research. Corinne Fischer reports financial support was provided by Hoffmann-La Roche Limited. Corinne Fischer reports financial support was provided by Vielight Inc. Corinne Fischer reports financial support was provided by Novo Nordisk Inc. Corinne Fischer reports financial support was provided by National Institutes of Health. Corinne Fischer reports financial support was provided by Brain Canada Foundation. Corinne Fischer reports financial support was provided by The Weston Foundation. Corinne Fischer reports financial support was provided by St Michael's Hospital Foundation. David Grimes reports financial support was provided by Canadian Institutes of Health Research. David Grimes reports financial support was provided by Parkinson Society Canada. David Grimes reports financial support was provided by Brain Canada Foundation. David Grimes reports financial support was provided by Parkinson Research Consortium. David Grimes reports financial support was provided by EU Joint Programme Neurodegenerative Disease Research. David Grimes reports financial support was provided by University of Ottawa Brain and Mind Research Institute. David Grimes reports financial support was provided by National Institutes of Health. Sanjeev Kumar reports financial support was provided by Brain and Behavior Research Foundation. Sanjeev Kumar reports financial support was provided by National Institute of Health and Science on Aging. Sanjeev Kumar reports financial support was provided by BrightFocus Foundation. Sanjeev Kumar reports financial support was provided by Brain Canada Foundation. Sanjeev Kumar reports financial support was provided by Canadian Institutes of Health Research. Sanjeev Kumar reports financial support was provided by Canadian Consortium on Neurodegeneration in Aging. Sanjeev Kumar reports financial support was provided by Center for Aging and Brain Health Innovation. Sanjeev Kumar reports financial support was provided by Centre for Addiction and Mental Health. Sanjeev Kumar reports financial support was provided by University of Toronto. Sanjeev Kumar reports equipment, drugs, or supplies was provided by Soterix Medical Inc. Lisa Y. Xiong reports financial support was provided by Canadian Institutes of Health Research. Walter Swardfager reports financial support was provided by Canadian Institutes of Health Research. Walter Swardfager reports financial support was provided by Natural Sciences and Engineering Research Council of Canada. Walter Swardfager reports financial support was provided by Alzheimer's Association. Walter Swardfager reports financial support was provided by Alzheimer's Research UK. Walter Swardfager reports financial support was provided by The Michael J Fox Foundation. Walter Swardfager reports financial support was provided by Canada Research Chairs Program. Walter Swardfager reports financial support was provided by Ontario Ministry of Colleges and Universities. David Grimes reports a relationship with Sunovion Pharmaceuticals Canada Inc that includes consulting or advisory and speaking and lecture fees. David Grimes reports a relationship with Ipsen that includes: speaking and lecture fees. David Grimes reports a relationship with Paladin Labs Inc that includes: consulting or advisory. David Grimes reports a relationship with Allergan Canada that includes:. David Grimes reports a relationship with Cerevel Therapeutics Inc that includes: non-financial support. David Grimes reports a relationship with Genzyme Corporation that includes: non-financial support. David Grimes reports a relationship with Hoffmann-La Roche Limited that includes: non-financial support. David Grimes reports a relationship with UCB Biopharma Ltda that includes: non-financial support. Stephen Arnott reports a relationship with Indoc Research Canada that includes: consulting or advisory., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251, P =0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P <0.001; β=0.362, P <0.001) and white matter MRI-visible perivascular spaces (β=0.302, P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (β=-0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Background: Mixed evidence supports blood-brain barrier (BBB) dysfunction in Lewy body spectrum diseases., Methods: 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 (Q alb ), 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., Results: Of 13,949 unique records, 51 studies were meta-analyzed. Compared to HC, Q alb was higher in PD (N PD /N HC  = 224/563; SMD = 0.960 [0.227-1.694], p = 0.010; I 2  = 92.2%) and in PDD/DLB (N PDD/DLB /N HC  = 265/670; SMD = 1.126 [0.358-1.893], p < 0.001; I 2  = 78.2%). Blood neurofilament light chain (NfL) was higher in PD (N PD /N HC  = 1848/1130; SMD = 0.747 [0.442-1.052], p < 0.001; I 2  = 91.9%) and PDD/DLB (N PDD/DLB /N HC  = 183/469; SMD = 1.051 [0.678-1.423], p = 0.004; I 2  = 92.7%) than in HC. p-tau 181 (N PD /N HC  = 276/164; SMD = 0.698 [0.149-1.247], p = 0.013; I 2  = 82.7%) was also higher in PD compared to HC. In exploratory analyses, blood NfL was higher in PD without dementia (N PDND /N HC  = 1005/740; SMD = 0.252 [0.042-0.462], p = 0.018; I 2  = 71.8%) and higher in PDD (N PDD /N HC  = 100/111; SMD = 0.780 [0.347-1.214], p < 0.001; I 2  = 46.7%) compared to HC. Q alb (N PDD /N PDND  = 63/191; SMD = 0.482 [0.189-0.774], p = 0.010; I 2 <0.001%) and NfL (N PDD /N PDND  = 100/223; SMD = 0.595 [0.346-0.844], p < 0.001; I 2  = 3.4%) were higher in PDD than in PD without dementia., Conclusions: 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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; N CI /N NC  = 934/3154, SMD 0.74 95% confidence interval [0.07, 1.42], Z 5  = 2.15, p = 0.03; I 2  = 98.08%), C-reactive protein (CRP; N CI /N NC  = 1610/4363, SMD 0.80 [0.50, 1.11], Z 14  = 5.25, p < 0.01; I 2  = 94.59%), soluble vascular cell adhesion molecule-1 (sVCAM-1; N CI /N NC  = 104/1063, SMD 1.64 95% confidence interval [0.21, 3.07], Z 2  = 2.25, p = 0.02; I 2  = 95.19%), and advanced glycation end products (AGEs; N CI /N NC  = 227/317, SMD 0.84 95% confidence interval [0.41, 1.27], Z 2  = 3.82, p < 0.01; I 2  = 81.07%) were higher among CI groups compared to NC. Brain derived neurotropic factor (BDNF) concentrations were significantly lower in CI compared to NC (N CI /N NC  = 848/2063, SMD -0.67 95% confidence interval [-0.99, -0.35], Z 3  = -4.09, p < 0.01; I 2  = 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)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)