Blood test spots genetic dementia before symptoms appear
Researchers have identified protein markers in blood that can detect two forms of inherited frontotemporal dementia years before patients show symptoms. The discovery could enable pharmaceutical companies to enroll patients earlier in drug trials and help families identify who needs preventive treatment.
Originaltitel: Plasma Proteomic Changes in GRN and C9orf72 Frontotemporal Dementia.
Goteborgsforskarnas studie identifierar blodbaserade biomarkörer för genetisk frontallobsdemens (FTD) — ett fynd som kan accelerera utvecklingen av patientspecifika behandlingsstrategier. Forskargruppen analyserade 124 hjärnrelaterade proteiner i plasma från 109 individer, varav 67 bar mutationer i GRN- eller C9orf72-generna. Neurofilament light (NfL) visade den starkaste förändringen i båda genotyperna, medan glial fibrillary acidic protein (GFAp) och VCAM1 endast förändrades vid GRN-mutation och korrelerade med sjukdomsvårleksgrad. Neuronal pentraxin receptor (NPTXR) reducerades selektivt vid C9orf72-FTD. Om resultaten valideras i oberoende kohorter kan dessa biomarkörer möjliggöra tidigare diagnostik, mer träffsäker patientstratifiering för kliniska prövningar och monitorering av sjukdomsprogression — kritiska faktorer för regionala hälsovårdscentraler som planerar diagnostiska investitioner.
BACKGROUND: Biomarkers reflecting the complex pathophysiology of genetic frontotemporal dementia (FTD) will be increasingly important with the advent of therapeutic trials aiming to slow or prevent the disease. In this study, we aimed to identify blood biomarker candidates using a multiplex panel of CNS-related proteins. METHODS: We cross-sectionally evaluated 67 carriers (21 presymptomatic and 46 symptomatic) of pathogenic FTD-causing mutations in the GRN (n = 30 symptomatic) and C9orf72 (n = 16 symptomatic) genes and 42 matched non-carriers. Clinical severity was estimated using the CDR Dementia Staging Instrument with National Alzheimer Coordinating Centre Frontotemporal Lobar Degeneration component (CDR plus NACC FTLD). A total of 124 CNS-related proteins were measured in plasma using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) CNS panel. Group-level changes were then investigated using linear and non-linear regression models. RESULTS: In GRN- and C9orf72-FTD, neurofilament light (NfL) was the most clearly altered protein compared with non-carriers (GRN: β [95% CI] = 4.0 standard deviations [3.6-4.4], C9orf72: β = 2.8 [2.2-3.4]), followed by neurofilament heavy (NfH; GRN: β = 0.83 [0.39-1.3], C9orf72: β = 1.4 [0.8-2.0]). Proteins exclusively altered in GRN-FTD included glial fibrillary acidic protein (GFAp; β = 0.50 [0.20-0.81]) and vascular cell adhesion protein 1 (VCAM1; Standardized β = -0.90 [-1.4 to -0.38]), changing with increasing disease severity. Neuronal pentraxin receptor (NPTXR; β = -0.94 [-1.5 to -0.4]) was selectively reduced in C9orf72-FTD. Nominally changed proteins in C9orf72-FTD included several inflammatory mediators. CONCLUSIONS: Using this multiplex panel, established markers recapitulated previously established trends, while less-studied biomarker candidates were also identified. If validated in independent cohorts, these candidates could broaden the repertoire of blood biomarkers reflecting genetic FTD pathophysiology.