ABCD1 dysfunction alters white matter microvascular perfusion

Lauer, Arne; Xiao, Da; Hansen, Mikkel Bo; Boulouis, Grégoire; Ou, Yangming; Cai, Xiao; Pedrotti, Afonso Liberato Celso; Kalpathy–Cramer, Jayashree; Caruso, Paul; Hayden, Douglas; Rost, Natalia S.; Mouridsen, Kim; Eichler, Florian; Rosen, Bruce R.; Musolino, Patricia L.

doi:10.1093/brain/awx262

Cited by 27 publications

(31 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RTH) are therefore thought to reflect abnormal capillary flow patterns, indicative of severe disturbances of capillary morphology and function across tissue microcirculation. Consistent with this notion, we and others have found RTH changes to correlate with disease severity in human conditions known to be associated with microvascular changes, including Alzheimer’s disease ( Eskildsen et al , 2017 ; Nielsen et al , 2017 ), ischemia ( Ostergaard et al , 2015 ; Engedal et al , 2018 ) and X-linked adrenoleukodystrophy ( Lauer et al , 2017 ). When utilizing perfusion MRI sensitized to capillary-sized vessels, we found RTH to be significantly elevated in both WMHs and in the tracts they intersect when compared with NAWM, although the comparison of tracts to NAWM remained a tendency after adjustment for multiple comparisons.…”

Section: Discussionsupporting

confidence: 86%

“…Cardiovascular risk factors, such as hypertension, diabetes and low-grade inflammation, can therefore critically reduce the oxygen availability by disturbing capillary flow patterns in terms of increasing the ‘shunting’ of oxygenated blood though microcirculation. This phenomenon, ‘capillary dysfunction’ ( Ostergaard et al , 2013 a ), has now been implicated in the pathophysiology of dementia ( Eskildsen et al , 2017 ; Nielsen et al , 2017 ), ischemia ( Ostergaard et al , 2015 ; Engedal et al , 2018 ) and inherited white matter disease ( Lauer et al , 2017 ) by specialized perfusion MRI tecniques ( Mouridsen et al , 2014 ). Given the evidence of capillary changes in SVD ( Ostergaard et al , 2016 ), we speculate, that capillary dysfunction reduces oxygen availability within WMHs, over and beyond the effects of altered perfusion and capillary density.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter†

Dalby

Eskildsen

Videbech

et al. 2019

Brain Communications

Self Cite

View full text Add to dashboard Cite

White matter hyperintensities of presumed vascular origin are frequently observed on MRI in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply-demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion-, and diffusion-weighted MRI in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity – the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared to normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply-demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt.

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter†

Dalby

Eskildsen

Videbech

et al. 2019

Brain Communications

Self Cite

View full text Add to dashboard Cite

show abstract

“…In our fatty acid catabolic metabolism-related signature, the protein encoded by ABCD1 is one of the superfamily of ATP-binding cassette transporters and is involved in the catabolic metabolism of very long chain fatty acid. ABCD1 is associated with altered white matter microvascular perfusion [30] and may contribute to the cell differentiation with parallel to tumorigenesis [31]. In previous study, ABCD1 transcript levels were overexpressed in breast cancer [32].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Profiling Identifies a Fatty Acid Metabolism-Related Gene Risk Signature for Malignancy, Prognosis, and Immune Phenotype of Glioma

Chen

et al. 2019

Disease Markers

View full text Add to dashboard Cite

Cancer cells commonly have metabolic abnormalities. Aside from altered glucose and amino acid metabolism, cancers cells often share the attribute of fatty acid metabolic alterations. However, fatty acid metabolism related-gene set has not been systematically investigated in gliomas. Here, we provide a bioinformatic profiling of the fatty acid catabolic metabolism-related gene risk signature for the malignancy, prognosis and immune phenotype of glioma. In this study, a cohort of 325 patients with whole genome RNA-seq expression data from the Chinese Glioma Genome Atlas (CGGA) dataset was used as training set, while another cohort of 667 patients from The Cancer Genome Atlas (TCGA) dataset was used as validating set. After confirmed that fatty acid catabolic metabolism-related gene set could distinguish clinicopathological features of gliomas, we used LASSO regression analysis to develop a fatty-acid metabolism-related gene risk signature for glioma. This 8-gene risk signature was found to be a good predictor of clinical and molecular features involved in the malignancy of gliomas. We also identified that this 8-gene risk signature had high prognostic values in patients with gliomas. Correlation analysis showed that our risk signature was closely associated with the immune cells involved in the microenvironment of glioma. Furthermore, the fatty acid catabolic metabolism-related gene risk signature was also found to be significantly correlated with immune checkpoint members B7-H3 and Tim-3. In summary, we have identified a fatty acid metabolism-related gene risk signature for malignancy, prognosis, and immune phenotype of glioma; and our study might contribute to better understanding of metabolic pathways and further developing of novel therapeutic approaches for gliomas.

show abstract

“…The study of oligodendrocytes derived from pluripotent stem cells from CALD accumulated more VLCFA than those derived from AMN patients (Jang et al, ). The blood–brain barrier may be leaky secondary to oxidative stress caused by increased levels of saturated VLCFA in myelin and cellular membranes (Lauer et al, ). In vitro studies suggest lack of ABCD1 causes endothelial dysfunction preceding the accumulation of VLCFA (Kemp et al, ; Musolino et al, ).…”

Section: Cell‐ and Tissue‐specific Pathologymentioning

confidence: 99%

“…The demyelination begins usually in the splenium of corpus callosum where the white matter fiber bundles are most tightly packed and spreads outward into the periventricular white matter Schaumburg, Powers, Raine, Suzuki, & Richardson, 1975;Schaumburg, Powers, Suzuki, & Raine, 1974). This is the area where the oligodendrocytes express the highest levels of ABCD1 (Lauer et al, 2017).…”

Section: Oxidized Cholesterol Species May Contribute To Inflammationmentioning

confidence: 99%

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

128

113

View full text Add to dashboard Cite

Adrenoleukodystrophy (ALD) is a rare X‐linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell‐ and tissue‐specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long‐chain fatty acid (VLCFA) chain length‐dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety‐specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.

show abstract

ABCD1 dysfunction alters white matter microvascular perfusion

Cited by 27 publications

References 57 publications

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter†

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter†

Bioinformatic Profiling Identifies a Fatty Acid Metabolism-Related Gene Risk Signature for Malignancy, Prognosis, and Immune Phenotype of Glioma

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Contact Info

Product

Resources

About