Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia
Authors: Hsiao-Nakamoto Jennifer , Chiu Chi-Lu , VandeVrede Lawren , Ravi Ritesh , Vandenberg Brittany , De Groot Jack , Tsogtbaatar Buyankhishig , Fang Meng , Auger Paul , Gould Neal S. , Marchioni Filippo , Powers Casey A. , Davis Sonnet S. , Suh Jung H. , Alkabsh Jamal , Heuer Hilary W. , Lago Argentina Lario , Scearce-Levie Kimberly , Seeley William W. , Boeve Bradley F. , Rosen Howard J. , Berger Amy , Tsai Richard , Di Paolo Gilbert , Boxer Adam L. , Bhalla Akhil , Huang Fen ,   ALLFTD Consortium
Published: February 2024

AbstractBackgroundFrontotemporal dementia (FTD) is the most common cause of early-onset dementia with 10-20% of cases caused by mutations in one of three genes:GRN,C9orf72, orMAPT. To effectively develop therapeutics for FTD, the identification and characterization of biomarkers to understand disease pathogenesis and evaluate the impact of specific therapeutic strategies on the target biology as well as the underlying disease pathology are essential. Moreover, tracking the longitudinal changes of these biomarkers throughout disease progression is crucial to discern their correlation with clinical manifestations for potential prognostic usage.MethodsWe conducted a comprehensive investigation of biomarkers indicative of lysosomal biology, glial cell activation, synaptic and neuronal health in cerebrospinal fluid (CSF) and plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) and symptomatic carriers of mutations inGRN, C9orf72,orMAPT, as well as asymptomaticGRNmutation carriers. We also assessed the longitudinal changes of biomarkers inGRNmutation carriers. Furthermore, we examined biomarker levels in disease impacted brain regions including middle temporal gyrus (MTG) and superior frontal gyrus (SFG) and disease-unaffected inferior occipital gyrus (IOG) from sporadic FTD and symptomaticGRNcarriers.ResultsWe confirmed glucosylsphingosine (GlcSph), a lysosomal biomarker regulated by progranulin, was elevated in the plasma fromGRNmutation carriers, both symptomatic and asymptomatic. GlcSph and other lysosomal biomarkers such as ganglioside GM2 and globoside GB3 were increased in the disease affected SFG and MTG regions from sporadic FTD and symptomaticGRNmutation carriers, but not in the IOG, compared to the same brain regions from controls. The glial biomarkers GFAP in plasma and YKL40 in CSF were elevated in asymptomaticGRNcarriers, and all symptomatic groups, except the symptomaticC9orf72mutation group. YKL40 was also increased in SFG and MTG regions from sporadic FTD and symptomaticGRNmutation carriers. Neuronal injury and degeneration biomarkers NfL in CSF and plasma, and UCHL1 in CSF were elevated in patients with all forms of FTD. Synaptic biomarkers NPTXR, NPTX1/2, and VGF were reduced in CSF from patients with all forms of FTD, with the most pronounced reductions observed in symptomaticMAPTmutation carriers. Furthermore, we demonstrated plasma NfL was significantly positively correlated with disease severity as measured by CDR+NACC FTLD□SB in genetic forms of FTD and CSF NPTXR was significantly negatively correlated with CDR+NACC FTLD□SB in symptomaticGRNandMAPTmutation carriers.ConclusionsIn conclusion, our comprehensive investigation replicated alterations in biofluid biomarkers indicative of lysosomal function, glial activation, synaptic and neuronal health across sporadic and genetic forms of FTD and unveiled novel insights into the dysregulation of these biomarkers within brain tissues from patients withGRNmutations. The observed correlations between biomarkers and disease severity open promising avenues for prognostic applications and for indicators of drug efficacy in clinical trials. Our data also implicated a complicated relationship between biofluid and tissue biomarker changes and future investigations should delve into the mechanistic underpinnings of these biomarkers, which will serve as a foundation for the development of targeted therapeutics for FTD.