Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

Abstract

Huntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

Clinical Correlates Identify ProBDNF and Thrombo-Inflammatory Markers as Key Predictors of Circulating p75NTR Extracellular Domain Levels in Older Adults

“…The follow-up of the BEL-AGE cohort in the next years will hopefully help to answer this open question. In addition to the possibility of p75 NTR as an early diagnostic biomarker, its role could be extended to disease progression ( Shepheard et al, 2017 ), and also be of interest as a pharmacodynamic biomarker to assess the effect of treatment, which is lacking in multiple neurological and psychiatric diseases ( Simmons et al, 2021 ). These latter possibilities have been extensively discussed by Shepheard et al (2017) and Simmons et al (2021) and were also discussed in a recent meta-analysis by Shi et al (2021) .…”

“…The present study identified high p75 NTR levels in 15% of the BEL-AGE individuals. The p75 NTR receptor is recently being proposed as a diagnostic biomarker of Alzheimer's disease in serum (Jiao et al, 2015), and was also proposed as a prognostic, disease progression and potential pharmacodynamic biomarker for ALS and Huntington's disease in urine, with increase in p75 NTR ECD happening prior to symptoms appearance in ALS (Shepheard et al, 2014(Shepheard et al, , 2017Shi et al, 2021;Simmons et al, 2021). Whether this predictive pattern is specific to these diseases remains unknown.…”

“…Upon activation, the p75 NTR receptor undergoes shedding, causing its extracellular domain (ECD) to be released into circulation ( Bergmeier et al, 2004 ; Weskamp et al, 2004 ; Duerschmied et al, 2009 ; Skeldal et al, 2011 ). Interestingly, elevated circulating p75 NTR ECD levels are observed in Alzheimer’s disease and major depressive disorders ( Zhou et al, 2013 ; Jiao et al, 2015 ), while high urinary p75 NTR levels are reported in amyotrophic lateral sclerosis (ALS) and Huntington’s disease patients ( Shepheard et al, 2014 , 2017 ; Jia et al, 2017 ; Simmons et al, 2021 ). Conversely, reduced circulating levels are reported in schizophrenia, and bipolar mania ( Zakharyan et al, 2014 ; Chen et al, 2017 ).…”

Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington’s Disease

“…Among them, because of the leakage of CNS molecules through the BBB, blood represents a reliable source of several biomarkers, such as NfL [ 27 ]. Other biofluids have been tested, such as urine , from which Simmons et al, 2021 [ 37 ] could detect higher p75NTR in HD mice compared to controls. Saliva was demonstrated to contain detectable levels of tHTT, correlating with some HD clinical measures [ 38 ] and feces was used to detect bacterial alterations related to clinical features [ 39 ].…”

“…In search of other sources of accessible biofluids, several studies started to explore the presence of possible biomarkers in the urine of R6/2 HD mouse models. Indeed, the levels of p75 NTR were increased in R6/2 mice compared to WT mice urinary levels [ 37 ]. p75 NTR was already shown to play a role in memory dysfunction in HD patients [ 43 ] and to be altered in HD patients’ striatum [ 44 ].…”