Obesity impairs cognitive function via metabolic syndrome and cerebrovascular disease: an SEM analysis in 15,000 adults from the UK Biobank

AbstractChronic obesity is associated with several complications, including cognitive impairment and dementia. However, we have piecemeal knowledge of the mechanisms linking obesity to central nervous system damage. Adiposity leads to the metabolic syndrome, consisting of inflammation, hypertension, dyslipidemia and insulin resistance. In turn, these metabolic abnormalities cause cerebrovascular dysfunction, which may cause white and grey matter tissue loss and consequent cognitive impairment. While there have been several neuroimaging studies linking adiposity to changes in brain morphometry, a comprehensive investigation of the relationship has so far not been done. Here we use structural equation modelling applied to over 15,000 individuals from the UK Biobank to identify the causal chain that links adiposity to cognitive dysfunction. We found that body mass index and waist-to-hip ratio were positively related to higher plasma C-reactive protein, dyslipidemia, occurrence of hypertension and diabetes, all of which were in turn related to cerebrovascular disease as measured by volume of white matter hyperintensities on magnetic resonance imaging. White mater hyperintensities were associated with lower cortical thickness and volume and higher subcortical volumes, which were associated with cognitive deficits on tests of visuospatial memory, fluid intelligence, and working memory among others. In follow-up analyses we found that inflammation, hypertension and diabetes mediated 20% of the relationship between obesity and cerebrovascular disease and that cerebrovascular disease mediated a significant proportion of the relationship between obesity and cortical thickness and volume. We also showed that volume of white matter hyperintensities was related to decreased fractional anisotropy and increased mean diffusivity in the majority of white matter tracts, pointing to white matter dysconnectivity as a major cause of impaired cognition. Our results have clinical implications, supporting a role for the management of adiposity in the prevention of late-life dementia and cognitive decline.

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An Assessment of the Relationship between Structural and Functional Imaging of Cerebrovascular Disease and Cognition-Related Fibers

Computational and Mathematical Methods in Medicine ◽

10.1155/2020/4347676 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Xiaoping Tang ◽

Xinlan Xiao ◽

Jianhua Yin ◽

Ting Yang ◽

Bingliang Zeng

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Cerebrovascular Disease ◽

Cognitive Dysfunction ◽

Functional Imaging ◽

Small Vessel Disease ◽

White Matter Lesions ◽

Cerebral Small Vessel Disease ◽

Vessel Disease ◽

The Relationship

In order to assess the relationship between structural and functional imaging of cerebrovascular disease and cognition-related fibers, this paper chooses a total of 120 patients who underwent cerebral small vessel disease (CSVD) treatment at a designated hospital by this study from June 2013 to June 2018 and divides them into 3 groups according to the random number table method: vascular dementia (VaD) group, vascular cognitive impairment no dementia (VCIND) group, and noncognition impairment (NCI) group with 40 cases of patients in each group. Cognitive function measurement and imaging examination were performed for these 3 groups of patients, and the observation indicators of cognitive state examination (CSE), mental assessment scale (MAS), clock drawing test (CDT), adult intelligence scale (AIS), frontal assessment battery (FAB), verbal fluency test (VFT), trail making test (TMT), cognitive index (CI), white matter lesions (WML), third ventricle width (TVW), and frontal horn index (FHI) were tested, respectively. The results shows that the average scores of CSE, MAS, AIS, and VFT in the VaD and VCIND group are lower than those of the NCI group and the differences are statistically significant (P<0.05); the average scores of FAB, TMT, and CI in the VaD group are higher than those of the VCIND group and the differences are also statistically significant (P<0.05); the average scores of FHI and TVW in the VaD group are lower than those of the VCIND and NCI group with statistically significant differences (P<0.05); the average scores of WML, CDT, and AIS in the VaD group are higher than those of the VCIND and NCI group with statistically significant differences (P<0.05). Therefore, it is believed that the structural and functional imaging features of cerebrovascular disease are closely related to cognition-related fibers, and the incidence of white matter lesions is closely related to the degree of lesions and cognitive dysfunction of cerebral small vessel disease, in which a major risk factor for cognitive dysfunction in patients with small blood vessels is the severity of white matter lesions; brain imaging and neuropsychiatric function assessment can better understand the relationship between cerebrovascular disease and cognitive impairment. The results of this study provide a reference for the further research studies on the relationship between structural and functional imaging of cerebrovascular disease and cognition-related fibers.

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Modelling the distribution of white matter hyperintensities due to ageing on MRI images using Bayesian inference

10.1101/327205 ◽

2018 ◽

Cited By ~ 1

Author(s):

Vaanathi Sundaresan ◽

Ludovica Griffanti ◽

Petya Kindalova ◽

Fidel Alfaro-Almagro ◽

Giovanna Zamboni ◽

...

Keyword(s):

White Matter ◽

Vascular Disease ◽

White Matter Hyperintensities ◽

Age Groups ◽

Clinical Importance ◽

Population Level ◽

Distribution Model ◽

Ageing Population ◽

Uk Biobank ◽

The Uk

AbstractWhite matter hyperintensities (WMH), also known as white matter lesions, are localised white matter areas that appear hyperintense on MRI scans. WMH commonly occur in the ageing population, and are often associated with several factors such as cognitive disorders, cardiovascular risk factors, cerebrovascular and neurodegenerative diseases. Despite the fact that some links between lesion location and parametric factors such as age have already been established, the relationship between voxel-wise spatial distribution of lesions and these factors is not yet well understood. Hence, it would be of clinical importance to model the distribution of lesions at the population-level and quantitatively analyse the effect of various factors on the lesion distribution model.In this work we compare various methods, including our proposed method, to generate voxel-wise distributions of WMH within a population with respect to various factors. Our proposed Bayesian spline method models the spatio-temporal distribution of WMH with respect to a parametric factor of interest, in this case age, within a population. Our probabilistic model takes as input the lesion segmentation binary maps of subjects belonging to various age groups and provides a population-level parametric lesion probability map as output. We used a spline representation to ensure a degree of smoothness in space and the dimension associated with the parameter, and formulated our model using a Bayesian framework.We tested our algorithm output on simulated data and compared our results with those obtained using various existing methods with different levels of algorithmic and computational complexity. We then compared the better performing methods on a real dataset, consisting of 1000 subjects of the UK Biobank, divided in two groups based on hypertension diagnosis. Finally, we applied our method on a clinical dataset of patients with vascular disease.On simulated dataset, the results from our algorithm showed a mean square error (MSE) value of 7.27 × 10−5, which was lower than the MSE value reported in the literature, with the advantage of being robust and computationally efficient. In the UK Biobank data, we found that the lesion probabilities are higher for the hypertension group compared to the non-hypertension group and further verified this finding using a statistical t-test. Finally, when applying our method on patients with vascular disease, we observed that the overall probability of lesions is significantly higher in later age groups, which is in line with the current literature.

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Linking cortical atrophy to white matter hyperintensities of presumed vascular origin

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20974170 ◽

2020 ◽

pp. 0271678X2097417

Author(s):

Carola Mayer ◽

Benedikt M Frey ◽

Eckhard Schlemm ◽

Marvin Petersen ◽

Kristin Engelke ◽

...

Keyword(s):

White Matter ◽

Cortical Thickness ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Population Based ◽

Vascular Lesions ◽

Cortical Atrophy ◽

Increased Risk ◽

Cortical Regions ◽

The Relationship

We examined the relationship between white matter hyperintensities (WMH) and cortical neurodegeneration in cerebral small vessel disease (CSVD) by investigating whether cortical thickness is a remote effect of WMH through structural fiber tract connectivity in a population at increased risk of CSVD. We measured cortical thickness on T1-weighted images and segmented WMH on FLAIR images in 930 participants of a population-based cohort study at baseline. DWI-derived whole-brain probabilistic tractography was used to define WMH connectivity to cortical regions. Linear mixed-effects models were applied to analyze the relationship between cortical thickness and connectivity to WMH. Factors associated with cortical thickness (age, sex, hemisphere, region, individual differences in cortical thickness) were added as covariates. Median age was 64 [IQR 46–76] years. Visual inspection of surface maps revealed distinct connectivity patterns of cortical regions to WMH. WMH connectivity to the cortex was associated with reduced cortical thickness ( p = 0.009) after controlling for covariates. This association was found for periventricular WMH ( p = 0.001) only. Our results indicate an association between WMH and cortical thickness via connecting fiber tracts. The results imply a mechanism of secondary neurodegeneration in cortical regions distant, yet connected to subcortical vascular lesions, which appears to be driven by periventricular WMH.

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The relationship of white matter hyperintensities to depression and apathy in mild cognitive impairment

Alzheimer s & Dementia ◽

10.1016/j.jalz.2010.05.970 ◽

2010 ◽

Vol 6 (4) ◽

pp. S296

Author(s):

Melissa J. Slavin ◽

Brian Draper ◽

Wei Wen ◽

Henry Brodaty ◽

Nicole A. Kochan ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

White Matter ◽

White Matter Hyperintensities ◽

Relationship Of ◽

The Relationship

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Abstract MP13: Polygenic Susceptibility to Atrial Fibrillation is Associated With Silent Cerebrovascular Disease in Stroke-Free Persons Without Atrial Fibrillation

Stroke ◽

10.1161/str.52.suppl_1.mp13 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Cameron Both ◽

Julian Acosta ◽

Natalia Szejko ◽

Kevin N Vanent ◽

Audrey C Leasure ◽

...

Keyword(s):

Atrial Fibrillation ◽

White Matter ◽

Cerebrovascular Disease ◽

Genetic Risk ◽

Community Dwelling ◽

Uk Biobank ◽

High Genetic Risk ◽

History Of ◽

The Uk ◽

Study Participants

Introduction: Clinically silent cerebrovascular disease is present in 40% of persons over the age of 60. We hypothesize that polygenic susceptibility to atrial fibrillation is associated with the burden of white matter disease in persons without atrial fibrillation or history of ischemic stroke. Methods: We conducted a nested genetic and neuroimaging study within the UK Biobank, a large cohort study that enrolled community dwelling Britons aged 40 to 65 at recruitment. We used data on a subcohort of patients evaluated with brain MRIs. The volume of white matter hyperintensities (WMH) was estimated using the BIANCA lesion segmentation tool. Genomic data was ascertained via genotyping with the Affymetrix UK Biobank Axiom array followed by imputation with 1000 Genomes reference panels. To model the polygenic susceptibility to atrial fibrillation (AFIB), we constructed a polygenic risk score (PRS) using 957 independent genetic risk variants known to significantly associate with atrial fibrillation. We used logistic and linear regression to test for association between the PRS and WMH. Results: A total of 38,914 study participants underwent brain MRI imaging in the UK Biobank. Of these, we excluded 124 (0.3%) with a history of stroke and 926 (2.4%) with AFIB. 37,864 study participants were included in this study, of which 19,059 (50.3%) had WMH. High genetic risk of AFIB was not associated with no-versus-any WMH (p=0.51). When evaluating persons with WMH lesions, high genetic risk of AFIB was associated with higher WMH volume (per 1 SD increase of the PRS, beta 0.019, SE 0.006; p=0.01). Gender was an important effect modifier of this association (interaction p=0.03): while high genetic risk of AFIB was associated with a significant increase in WMH volume in females (per 1 SD increase of the PRS, beta 0.03, SE 0.008; p<0.001), no association was found for males (p=0.99). Conclusions: Polygenic susceptibility to atrial fibrillation is associated with more severe silent cerebrovascular disease in persons without atrial fibrillation. Further research should evaluate whether this genetic information can be used to identify persons for tailored diagnostic or therapeutic interventions.

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Network Efficiency Mediates the Relationship Between Vascular Burden and Cognitive Impairment

Stroke ◽

10.1161/strokeaha.119.028587 ◽

2020 ◽

Vol 51 (6) ◽

pp. 1682-1689 ◽

Cited By ~ 1

Author(s):

Jun Shen ◽

Daniel J. Tozer ◽

Hugh S. Markus ◽

Jonathan Tay

Keyword(s):

Risk Factors ◽

Cognitive Impairment ◽

White Matter ◽

White Matter Hyperintensities ◽

Vascular Risk Factors ◽

Vascular Risk ◽

Network Efficiency ◽

Global Efficiency ◽

Vascular Burden ◽

The Relationship

Background and Purpose— Cerebrovascular disease contributes to age-related cognitive decline, but the mechanisms underlying this phenomenon remain incompletely understood. We hypothesized that vascular risk factors would lead to cognitive impairment through the disruption of brain white matter network efficiency. Methods— Participants were 19 346 neurologically healthy individuals from UK Biobank that underwent diffusion MRI and cognitive testing (mean age=62.6). Global efficiency, a measure of network integration, was calculated from white matter networks constructed using deterministic diffusion tractography. First, we determined whether demographics (age, sex, ethnicity, socioeconomic status, and education), vascular risk factors (hypertension, hypercholesterolemia, diabetes mellitus, smoking, body mass index), and white matter hyperintensities were related to global efficiency using multivariate linear regression. Next, we used structural equation modeling to model a multiple regression. The dependent variable was a latent cognition variable using all cognitive data, while independent variables were a latent factor including all vascular risk factors (vascular burden), demographic variables, white matter hyperintensities, and global efficiency. Finally, we used mediation analysis to determine whether global efficiency explained the relationship between vascular burden and cognition. Results— Hypertension and diabetes mellitus were consistently associated with reduced global efficiency even after controlling for white matter hyperintensities. Structural equation models revealed that vascular burden was associated with cognition ( P =0.023), but not after adding global efficiency to the model ( P =0.09), suggesting a mediation effect. Mediation analysis revealed a significant indirect effect of global efficiency on cognition through vascular burden ( P <0.001), suggesting a partial mediation effect. Conclusions— Vascular burden is associated with reduced global efficiency and cognitive impairment in the general population. Network efficiency partially mediates the relationship between vascular burden and cognition. This suggests that treating specific risk factors may prevent reductions in brain network efficiency and preserve cognitive functioning in the aging population.

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Midlife blood pressure is associated with the severity of white matter hyperintensities: analysis of the UK Biobank cohort study

European Heart Journal ◽

10.1093/eurheartj/ehaa756 ◽

2020 ◽

Cited By ~ 1

Author(s):

Karolina Agnieszka Wartolowska ◽

Alastair John Stewart Webb

Keyword(s):

Blood Pressure ◽

White Matter ◽

White Matter Hyperintensities ◽

Linear Models ◽

Population Attributable Fraction ◽

Relative Role ◽

Uk Biobank ◽

Assessment Centre ◽

The Uk

Abstract Aims White matter hyperintensities (WMH) progress with age and hypertension, but the key period of exposure to elevated blood pressure (BP), and the relative role of systolic BP (SBP) vs. diastolic BP (DBP), remains unclear. This study aims to determine the relationship between WMH and concurrent vs. past BP. Methods and results UK Biobank is a prospective community-based cohort of 40–69-year olds from 22 centres, with magnetic resonance imaging in a subgroup of over 40 000 people at 4–12 years after baseline assessment. Standardized associations between WMH load (WMH volume normalized by total white matter volume and logit-transformed) and concurrent vs. past BP were determined using linear models, adjusted for age, sex, cardiovascular risk factors, BP source, assessment centre, and time since baseline. Associations adjusted for regression dilution bias were determined between median WMH and usual SBP or DBP, stratified by age and baseline BP. In 37 041 eligible participants with WMH data and BP measures, WMH were more strongly associated with concurrent SBP [DBP: β = 0.064, 95% confidence interval (CI) 0.050–0.078; SBP: β = 0.076, 95% CI 0.062–0.090], but the strongest association was for past DBP (DBP: β = 0.087, 95% CI 0.064–0.109; SBP: β = 0.045, 95% CI 0.022–0.069), particularly under the age of 50 (DBP: β = 0.103, 95% CI 0.055–0.152; SBP: β = 0.012, 95% CI −0.044 to 0.069). Due to the higher prevalence of elevated SBP, median WMH increased 1.126 (95% CI 1.107–1.146) per 10 mmHg usual SBP and 1.106 (95% CI 1.090–1.122) per 5 mmHg usual DBP, whilst the population attributable fraction of WMH in the top decile was greater for elevated SBP (19.1% for concurrent SBP; 24.4% for past SBP). Any increase in BP, even below 140 for SBP and below 90 mmHg for DBP, and especially if requiring antihypertensive medication, was associated with increased WMH. Conclusions WMH were strongly associated with concurrent and past elevated BP with the population burden of severe WMH greatest for SBP. However, before the age of 50, DBP was more strongly associated with WMH. Long-term prevention of WMH may require control of even mildly elevated midlife DBP.

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Cortical and Subcortical Grey Matter Abnormalities in White Matter Hyperintensities and Subsequent Cognitive Impairment

Neuroscience Bulletin ◽

10.1007/s12264-021-00657-0 ◽

2021 ◽

Author(s):

Wenhao Zhu ◽

◽

Hao Huang ◽

Shiqi Yang ◽

Xiang Luo ◽

...

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Cognitive Decline ◽

Grey Matter ◽

White Matter Hyperintensities ◽

Grey Matter Volume ◽

Independent Dataset ◽

The Relationship ◽

Robust Evidence ◽

Bilateral Thalamus

AbstractGrey matter (GM) alterations may contribute to cognitive decline in individuals with white matter hyperintensities (WMH) but no consensus has yet emerged. Here, we investigated cortical thickness and grey matter volume in 23 WMH patients with mild cognitive impairment (WMH-MCI), 43 WMH patients without cognitive impairment, and 55 healthy controls. Both WMH groups showed GM atrophy in the bilateral thalamus, fronto-insular cortices, and several parietal-temporal regions, and the WMH-MCI group showed more extensive and severe GM atrophy. The GM atrophy in the thalamus and fronto-insular cortices was associated with cognitive decline in the WMH-MCI patients and may mediate the relationship between WMH and cognition in WMH patients. Furthermore, the main results were well replicated in an independent dataset from the Alzheimer's Disease Neuroimaging Initiative database and in other control analyses. These comprehensive results provide robust evidence of specific GM alterations underlying WMH and subsequent cognitive impairment.

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White matter hyperintensities and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment

10.1101/791657 ◽

2019 ◽

Author(s):

Karen Misquitta ◽

Mahsa Dadar ◽

D. Louis Collins ◽

Maria Carmela Tartaglia ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

White Matter ◽

Cerebrovascular Disease ◽

Grey Matter ◽

White Matter Hyperintensities ◽

Neuropsychiatric Symptoms ◽

Grey Matter Atrophy

AbstractBackground and Purpose: Neuropsychiatric symptoms (NPS) are frequently encountered in patients with Alzheimer’s disease (AD). Focal grey matter atrophy has been linked to NPS development. Cerebrovascular disease can cause focal lesions and is common among AD patients. As cerebrovascular disease can be detected on MRI as white matter hyperintensities (WMH), this study evaluated WMH burden in mild cognitive impairment (MCI), AD and normal controls and determined their relationship with NPS. Methods: NPS were assessed using the Neuropsychiatric Inventory and grouped into subsyndromes. WMH were measured using an automatic segmentation technique and mean deformation-based morphometry was used to measure atrophy of grey matter regions. Results: WMHs and grey matter atrophy both contributed significantly to NPS subsyndromes in MCI and AD subjects, however, WMH burden played a greater role. Conclusions: This study could provide a better understanding of the pathophysiology of NPS in AD.

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Suffering from cerebral small vessel disease with and without metabolic syndrome

Open Medicine ◽

10.1515/med-2019-0051 ◽

2019 ◽

Vol 14 (1) ◽

pp. 479-484

Author(s):

Tatjana Bošković Matić ◽

Gordana Toncev ◽

Aleksandar Gavrilović ◽

Dejan Aleksić

Keyword(s):

Metabolic Syndrome ◽

Cognitive Impairment ◽

White Matter ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Cognitively Impaired ◽

Vessel Disease ◽

Neurology Clinic

AbstractBackgroundCerebral small vessel disease (CSVD) and metabolic syndrome were separately associated with cognitive impairment and depression. However, whether metabolic syndrome adds to cognitive impairment and depression in patients who already have CSVD remained unanswered.ObjectiveThe aim of our study was to investigate the association of metabolic syndrome with cognitive impairment and depression in patients with CSVD who have lacunar lesions or white matter hyperintensities.MethodsThis prospective cohort study was conducted at Neurology Clinic, Clinical Center, Kragujevac, Serbia. Main outcomes of the study were cognitive assessment, and assessment of depression among hospitalized patients with or without CSVD.ResultsThe study included 74 inpatients, 25 of them having lacunary infarctions, 24 with the white matter hyperintensities, and 25 control patients without CSVD. The CSVD was accompanied by impairment of cognition and depression, the patients with lacunary lesions being more cognitively impaired and more depressive than the patients with the white matter hyperintensities. The patients with CSVD who also had metabolic syndrome were more cognitively impaired and depressed than the patients with CSVD alone.ConclusionsIn conclusion, our study showed that metabolic syndrome is associated with further worsening of already impaired cognition and existing depression in patients with CSVD.

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