Abstract
Decreased levels of serum high-density lipoprotein (HDL) cholesterol have previously been linked to systemic inflammation and neurodegenerative diseases, such as Alzheimer’s disease. Here, we aimed to analyze the lipoprotein profile and inflammatory indicators, the high-sensitivity C-reactive peptide (hs-CRP) and glycoprotein acetyls (GlycA), in sporadic and C9orf72 repeat expansion-associated frontotemporal lobar degeneration (FTLD) patients. The C9orf72 hexanucleotide repeat expansion is the most frequent genetic etiology underlying FTLD. The concentrations of different lipid measures in the sera of 67 FTLD patients (15 C9orf72 repeat expansion carriers), including GlycA, were analyzed by nuclear magnetic resonance spectroscopy. To verify the state of systemic inflammation, hs-CRP was also quantified from patient sera. We found that the total serum HDL concentration was decreased in C9orf72 repeat expansion carriers when compared to non-carriers. Moreover, decreased concentrations of HDL particles of different sizes and subclass were consistently observed. No differences were detected in the very low- and low-density lipoprotein subclasses between the C9orf72 repeat expansion carriers and non-carriers. Furthermore, hs-CRP and GlycA levels did not differ between the C9orf72 repeat expansion carriers and non-carriers. In conclusion, the HDL-related changes were linked with C9orf72 repeat expansion associated FTLD but were not seen to associate with systemic inflammation. The underlying reason for the HDL changes remains unclear.
Highlights
Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementing diseases in working-age people and accounts for approximately 10% of all progressive dementias [1]
We found that the concentration of total high-density lipoprotein (HDL) cholesterol in the sera of chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers was lower when compared to non-carriers (p = 0.030) (Fig. 1A)
The concentration of total cholesterols in very large HDLs was lower in the C9orf72 repeat expansion carriers when compared to non-carriers (p = 0.004)
Summary
Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementing diseases in working-age people and accounts for approximately 10% of all progressive dementias [1]. FTLD is clinically divided into two main subcategories, namely behavioral variant frontotemporal dementia (bvFTD) [2] and primary progressive aphasias (PPAs) [3]. The logopenic variant of primary progressive aphasia (lvPPA) is clinically considered a subtype of PPA, but is neuropathologically associated with Alzheimer’s disease (AD) [3]. The most common genetic etiology underlying FTLD is the hexanucleotide repeat expansion (GGGGCC) on the short arm of chromosome 9 open reading frame 72 (C9orf72) [6, 7]. This repeat expansion accounts for approximately 25% of familial FTLD cases in Europe and the USA [8]. Several studies have shown that C9orf repeat expansion carriers display an approximately 50% decrease in the levels of normal C9orf RNA and protein, indicating haploinsufficiency as another potential contributor to disease pathogenesis [9]
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