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      Visceral obesity relates to deep white matter hyperintensities via inflammation

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          Abstract

          Objective

          White matter hyperintensities (WMHs) are linked to vascular risk factors and increase the risk of cognitive decline, dementia, and stroke. We here aimed to determine whether obesity contributes to regional WMHs using a whole‐brain approach in a well‐characterized population‐based cohort.

          Methods

          Waist‐to‐hip ratio (WHR), body mass index (BMI), systolic/diastolic blood pressure, hypertension, diabetes and smoking status, blood glucose and inflammatory markers, as well as distribution of WMH were assessed in 1,825 participants of the LIFE‐adult study (age, 20–82 years; BMI, 18.4–55.4 kg/m 2) using high‐resolution 3‐Tesla magnetic resonance imaging. Voxel‐wise analyses tested if obesity predicts regional probability of WMH. Additionally, mediation effects of high‐sensitive C‐reactive protein and interleukin‐6 (IL6) measured in blood were related to obesity and WMH using linear regression and structural equation models.

          Results

          WHR related to higher WMH probability predominantly in the deep white matter, even after adjusting for effects of age, sex, and systolic blood pressure (mean ß = 0.0043 [0.0008 SE], 95% confidence interval, [0.00427, 0.0043]; threshold‐free cluster enhancement, family‐wise error‐corrected p < 0.05). Conversely, higher systolic blood pressure was associated with WMH in periventricular white matter regions. Mediation analyses indicated that both higher WHR and higher BMI contributed to increased deep‐to‐periventricular WMH ratio through elevated IL6.

          Interpretation

          Our results indicate an increased WMH burden selectively in the deep white matter in obese subjects with high visceral fat accumulation, independent of common obesity comorbidities such as hypertension. Mediation analyses proposed that visceral obesity contributes to deep white matter lesions through increases in proinflammatory cytokines, suggesting a pathomechanistic link. Longitudinal studies need to confirm this hypothesis. ANN NEUROL 2019;85:194–203.

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          Most cited references29

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          Update on cerebral small vessel disease: a dynamic whole-brain disease

          Yulu Shi, Joanna M. Wardlaw (2016)
          Cerebral small vessel disease (CSVD) is a very common neurological disease in older people. It causes stroke and dementia, mood disturbance and gait problems. Since it is difficult to visualise CSVD pathologies in vivo, the diagnosis of CSVD has relied on imaging findings including white matter hyperintensities, lacunar ischaemic stroke, lacunes, microbleeds, visible perivascular spaces and many haemorrhagic strokes. However, variations in the use of definition and terms of these features have probably caused confusion and difficulties in interpreting results of previous studies. A standardised use of terms should be encouraged in CSVD research. These CSVD features have long been regarded as different lesions, but emerging evidence has indicated that they might share some common intrinsic microvascular pathologies and therefore, owing to its diffuse nature, CSVD should be regarded as a ‘whole-brain disease’. Single antiplatelet (for acute lacunar ischaemic stroke) and management of traditional risk factors still remain the most important therapeutic and preventive approach, due to limited understanding of pathophysiology in CSVD. Increasing evidence suggests that new studies should consider drugs that target endothelium and blood–brain barrier to prevent and treat CSVD. Epidemiology of CSVD might differ in Asian compared with Western populations (where most results and guidelines about CSVD and stroke originate), but more community-based data and clear stratification of stroke types are required to address this.
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            White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury.

            P. Nicholas Shaw, Raj Kalaria, Lynne G. Forster … (2006)
            "Incidental" MRI white matter (WM) lesions, comprising periventricular lesions (PVLs) and deep subcortical lesions (DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions (WMLs) has been lacking, and their pathogenesis is unresolved. A population-based, postmortem cohort (n=456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury. PVL severity was associated with loss of ventricular ependyma (P=0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM (vessel wall thickness and perivascular enlargement; both P<0.001). Capillary endothelial activation (ratio of intercellular adhesion molecule to basement membrane collagen IV; P<0.001) and microglial activation (CD68 expression; P=0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors (HIFs) HIF1alpha and HIF2alpha was elevated in DSCLs (P=0.003 and P=0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 (PVLs P<0.001; DSCLs P=0.009) and the number of neuroglobin-positive cells (WMLs P=0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1alpha expression in DSCLs (P=0.04). The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.
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              Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden.

              Charles DeCarli, Evan Fletcher, W Jagust … (2004)
              MRI segmentation and mapping techniques were used to assess evidence in support of categorical distinctions between periventricular white matter hyperintensities (PVWMH) and deep WMH (DWMH). Qualitative MRI studies generally identify 2 categories of WMH on the basis of anatomical localization. Separate pathophysiologies and behavioral consequences are often attributed to these 2 classes of WMH. However, evidence to support these empirical distinctions has not been rigorously sought. MRI analysis of 55 subjects included quantification of WMH volume, mapping onto a common anatomical image, and spatial localization of each WMH voxel. WMH locations were then divided into PVWMH and DWMH on the basis of distance from the lateral ventricles and correlations, with total WMH volume determined. Periventricular distance histograms of WMH voxels were also calculated. PVWMH and DWMH were highly correlated with total WMH (R2>0.95) and with each other (R2>0.87). Mapping of all WMH revealed smooth expansion from around central cerebrospinal fluid spaces into more distal cerebral white matter with increasing WMH volume. PVWMH, DWMH, and total WMH are highly correlated with each other. Moreover, spatial analysis failed to identify distinct subpopulations for PVWMH and DWMH. These results suggest that categorical distinctions between PVWMH and DWMH may be arbitrary, and conclusions regarding individual relationships between causal factors or behavior for PVWMH and DWMH may more accurately reflect total WMH volume relationships.
              Article 0 comments Cited 138 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Leonie Lampe: lampe@cbs.mpg.de
                A. Veronica Witte: witte@cbs.mpg.de
                Journal
                Journal ID (nlm-ta): Ann Neurol
                Journal ID (iso-abbrev): Ann. Neurol
                Journal ID (doi): 10.1002/(ISSN)1531-8249
                Journal ID (publisher-id): ANA
                Title: Annals of Neurology
                Publisher: John Wiley & Sons, Inc. (Hoboken, USA )
                ISSN (Print): 0364-5134
                ISSN (Electronic): 1531-8249
                Publication date (Electronic): 29 January 2019
                Publication date (Print): February 2019
                Volume: 85
                Issue: 2 ( doiID: 10.1002/ana.v85.2 )
                Pages: 194-203
                Affiliations
                [ 1 ] Department of Neurology Max‐Planck‐Institute for Human Cognitive and Brain Sciences Leipzig Germany
                [ 2 ] Clinic of Cognitive Neurology University Hospital Leipzig Leipzig Germany
                [ 3 ] Research Center Jülich Institute of Neuroscience and Medicine (INM‐7) Jülich Germany
                [ 4 ] Netherlands Institute for Neuroscience Amsterdam The Netherlands
                [ 5 ] Spinoza Centre for Neuroimaging Amsterdam The Netherlands
                Author notes
                [*] [* ]Address correspondence to Dr A. Veronica Witte, Department of Neurology, Max‐Planck‐Institute of Human Cognitive and Brain Sciences, Stephanstraße 1a, 04103 Leipzig, Germany. Email: witte@ 123456cbs.mpg.de ; or Dr Leonie Lampe, Department of Neurology, Max‐Planck‐Institute of Human Cognitive and Brain Sciences, Stephanstraße 1a, 04103 Leipzig, Germany. Email: lampe@ 123456cbs.mpg.de
                Article
                Publisher ID: ANA25396
                DOI: 10.1002/ana.25396
                PMC ID: 6590485
                PubMed ID: 30556596
                SO-VID: 9559268a-0c1d-4321-890d-51f5a1031aae
                Copyright © © 2018 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 21 August 2018
                Date revision received : 12 December 2018
                Date accepted : 13 December 2018
                Page count
                Figures: 3, Tables: 3, Pages: 203, Words: 7023
                Funding
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: CRC1052‐A1
                Award ID: WI3342/3‐1
                Funded by: European Regional Development Fund
                Award ID: 14505/2470
                Award ID: 14575/2470
                Funded by: FP7 Health
                Award ID: 713‐241202
                Categories
                Subject: Research Article
                Subject: Research Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id ana25396
                cover-date February 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:24.06.2019

                ScienceOpen disciplines: Neurology
                Data availability:
                ScienceOpen disciplines: Neurology

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