High density lipoprotein cholesterol and apolipoprotein A-I are associated with greater cerebral perfusion in multiple sclerosis
Introduction
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system and important contributor to neurological disability among young adults. MS susceptibility and disease progression have been associated with multiple environmental, and lifestyle-based factors [1]. Neurodegeneration, as measured by global and central brain atrophy on MRI, is key driver of MS disability [2]. Several lines of evidence have demonstrated that cardiovascular and cerebrovascular health, presence of cardiovascular comorbidities and abnormal lipid profile contribute to worsening of the inflammatory and neurodegenerative changes in MS patients [3].
In a 5-year longitudinal study of MS patients, we found that increases in high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I), the characteristic HDL-associated apolipoprotein were associated with lower rates of gray matter (GM) and cortical volume loss and also with risk of progression to secondary progressive MS (SPMS) [4,5]. Multiple studies have investigated the effects of lipid-lowering medications on MS disease progression [6]. A placebo-controlled, randomized 80 mg simvastatin in SPMS reported decreased frontal brain atrophy and improving cognitive functioning [7]. Therefore, understanding the pathophysiological disease mechanisms via which lipids mediate neurodegenerative MS processes is warranted.
Reduced cerebral perfusion has been previously associated as an independent contributor to greater physical disability, cognitive performance, and brain atrophy in MS patients [8]. Furthermore in Alzheimer's disease, low HDL-C is associated with reduced cerebral perfusion in regions associated with memory and learning [9]. Similar HDL-C associated blood flow effects are also seen in atherosclerosis-induced strokes [10]. Interactions between cerebral perfusion and plasma lipids could therefore represent a pathophysiological mechanism that could be mediating the association of HDL on MS neurodegeneration. However, the associations, if any, between plasma lipid and brain perfusion in MS have not been investigated. In this research, we assessed the working hypothesis that greater HDL-C levels are associated with greater perfusion in MS. We also investigated associations of other lipid and apolipoprotein measures with global and cortical perfusion measures.
Section snippets
Study sample
The MS patients included in this study were from a study of cardiovascular, environmental and genetic factors in MS (CEG-MS) [11]. The inclusion criteria included: 1) age 18–75 years old, 2) MS diagnosis according to 2010-revised McDonald criteria [12], 3) availability of 3 T MRI exam and perfusion-weighted imaging (PWI) dynamic susceptibility contrast (DSC) sequence, 4) availability of blood samples acquired at the time of the MRI scan, 5) no steroid use or clinical relapse within 30 days of
Demographic and clinical characteristics
Table 1 summarizes the demographic, clinical, and lipid characteristics of the MS patients. Of the 77 MS patients, 50 (64.9%) were classified as RRMS and 27 (35.1%) were PMS. As expected, PMS patients were on average older (62.1 vs. 50.0 years old, t-test p < 0.001), had longer disease duration (27.1 vs. 17.2 years, t-test p < 0.001), were more disabled (median EDSS 6.3 vs. 2.0, Mann-Whitney U test p < 0.001) and had lower mean 5-year relapse rate (0.025 vs. 0.27, t-test p = 0.001). There were
Discussion
In this cross-sectional PWI-DSC MS study, we demonstrated associations between higher levels of HDL and HDL-associated lipoproteins ApoA-I and ApoA-II with shorter MTT, which is indicative of greater perfusion and with shorter TTP, which is indicative of the brain blood delivery. These findings were present in all investigated brain regions including the NABT, NAWM, GM, cortex, DGM and thalamus. Higher ApoC-II and ApoE levels were associated with lower GM perfusion as demonstrated by lower nCBV.
Availability of data and material
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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The role of cholesterol metabolism in multiple sclerosis: From molecular pathophysiology to radiological and clinical disease activity
2022, Autoimmunity ReviewsCitation Excerpt :This is confirmed over long-term follow-up when a relative increase in HDL-C and ApoA1 levels over 5-years correlates with lower grey matter and cortical volume loss and with lower conversion rate to secondary progressive MS [32]. Interestingly, higher HDL-C levels correlate with lower mean transit time on perfusion weighted MRI indicating higher blood flow (e.g., higher perfusion of brain vessels) [33]. Conversely, high total cholesterol (TC)/HDL-C ratio is associated with faster disability progression [34,35].