Early detection and evaluation of HTLV-1-associated neuro-inflammation and damage

A virus known as HTLV-1 infects approximately 10 million persons worldwide causing a progressive paralysis in about 300,000. Due to the relative rarity of this disease, called HTLV-1-associated myelopathy (HAM), formerly known as Tropical Spastic Paraparesis (TSP), in high income countries it has been neglected. The UK uniquely provides a National Centre for the care of patients with HAM which has led to advances in diagnosis and treatment and the potential for early detection of brain inflammation before it becomes obvious. Colleagues in Brazil, where this infection is more common, are demonstrating that disease occurs more frequently than previously thought and are describing mild forms in up to 30% of HTLV-1 infected persons.
This study brings together the expertise of Neurochemists at University College London, Neurologists in Brazil and Virologists of the Department of Infectious Disease, Imperial College London to find ways to detect inflammation and nerve damage in patients infected with HTLV-1 who do not yet show signs of disease. Our aim is to do this through blood tests rather than having to perform a spinal tap to examine the fluid which bathes the brain and spinal cord.
Work leading up to this proposal has identified a number of proteins detected in blood that may be suitable markers. This will now be tested using a larger number of HTLV-1 infected persons in the UK and in Brazil. Identifying these proteins will allow healthcare professionals to detect brain inflammation which is not obvious, to target such patients for more intense investigation to confirm this and to initiate treatment to suppress the inflammation, ideally in clinical trials of treatment. The results of this study of persons known to be infected with a virus that causes brain and spinal cord inflammation may also provide new insights into other neurological diseases where the cause is not known and those at risk cannot be so readily identified and investigated.

The aim of this project is to develop and validate biochemical markers in CSF and blood to support the diagnosis and management of HTLV-1-associated neuro-inflammation. The study will be conducted at HTLV clinical centres in the UK and Brazil. It has long been known that high HTLV-1 proviral load is a pre-requisite for the development of HAM. Work leading up to this application has identified T-cell activation, b2microglobulin, neopterin, CXCL-10 and neurofilament light as potential markers of risk of sub-clinical and clinical inflammation. In the HTLV clinical cohorts, caring for more than 2000 patients we will conduct two studies:
1: Markers of inflammation and neurological damage in people living with HTLV-1
A. To analyse the usefulness of neopterin, CXCL10, Nf-L, GFAP, Tau and UCH-L1 levels in CSF as a marker of HAM in HTLV-1 infected persons and disease severity.
B. To evaluate CXCL10, Neopterin, Apolipoprotein A2, Calgranulin B, Nf-L, Tau, UCH-L1, GFAP, VCAM-1, SPARC, sOX40 and GBP2 concentrations in plasma from HTLV-1 uninfected controls, HTLV-1 asymptomatic carriers and patients with HAM and their role as markers of inflammation and neurological damage in individuals infected with HTLV-1.
C. To perform a retrospective analysis of the dynamic of those markers in patients with HTLV-1, asymptomatic, including those with a "HAM-like" phenotype and patients with HAM
D. To verify the variation of markers of inflammation and neurological damage over time in incident HAM
E. To use these plasma markers to identify early and subclinical neurological damage in patients infected with HTLV-1.
F. To compare these plasma markers with traditional markers of neuroinflammation
2: An assessment of impact of treatment on markers of inflammation and neurological damage in patients with HAM
A. Retrospective (stored samples from patients treated with Standard of Care)