Altered High Density Lipoprotein Composition in Behavioral Variant Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is a common cause of early onset dementia with behavioral variant FTD (bvFTD) being the most common form. bvFTD is characterized clinically by behavioral and personality changes, eating abnormalities, and pathologically, by systemic lipid dysregulation that impacts on survival. As lipoprotein metabolism is at the core of lipid dysregulation, here, we analyzed the composition, both proteins and lipids, of the two major lipoprotein classes in blood – high density lipoproteins (HDLs) and low density lipoproteins (LDLs). Fasted plasmas from bvFTD and Alzheimer’s disease (AD) patients and controls were fractionated using fast protein liquid chromatography (FPLC) and samples analyzed by lipid assays, ELISA and western blotting. We found that apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) levels in HDLs were decreased in bvFTD compared to controls, whereas apolipoprotein B (apoB) levels in LDLs were unaltered. We also found that cholesterol and triglyceride levels in FPLC fractions were altered in bvFTD compared to controls. The apoB:apoA-I ratio and the standard lipid ratios were significantly increased in bvFTD compared to AD and controls. Furthermore, we found that plasma apolipoprotein C-I and paraoxonase 1 levels were significantly altered in bvFTD and AD, respectively, compared controls. This study represents the first apolipoprotein analysis of bvFTD, and our results suggest altered HDL function and elevated cardiovascular disease risk in bvFTD.

Predictors of survival in frontotemporal lobar degeneration syndromes

“…Patients with bvFTD have been shown to have significantly reduced concentrations of apolipoprotein A-1 and A-II (apoA-I and II), decreased high-density lipoproteincholesterol (HDL) levels, and increased very-low-density-lipoprotein-triglyceride (VLDL) levels compared to healthy controls, confirming manifestation of hypoalphalipoproteinemia and hypertriglyceridemia in bvFTD. 56,57 The apoB:apoA-I ratio, a robust marker of cardiovascular disease, was found to be significantly increased in bvFTD. Additionally, triglyceride:HDL-cholesterol and total cholesterol:HDL-cholesterol ratios were also found to be increased in bvFTD.…”

The Role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy Genes in the Aetiology of Frontotemporal Dementias: Implications for Novel Approaches to Therapeutics

“…Changes in brain lipid metabolism are also evident in FTD. Lipidomic analysis performed on the plasma of bvFTD and AD patients has revealed a significant increase in triglycerides and decreases in phosphatidylserine and phosphatidylglycerol in bvFTD patients compared to AD patients [ 107 , 108 ]. Further, there were strong correlations between changes in certain lipids associated with mitochondrial energy production, proinflammatory pathways or oxidative damages and the pathophysiological changes associated with FTD, which can potentially be used as FTD biomarkers [ 109 ].…”

Paraoxonase Role in Human Neurodegenerative Diseases

“…Apolipoproteins have been associated with neurodegenerative diseases, Table 1 . The low activity of PON1 has also been associated with several neurodegenerative diseases as well as lipid changes and demyelination process (in an animal model) [ 38 , 40 , 88 , 89 ]. Here we review the studies, in humans, of the association between PON1 and four neurodegenerative diseases: Multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease.…”