Neurodegeneration occurs in a variety of human diseases including Frontotemporal Dementia (FTD). Currently, longitudinal neuroimaging represents the only way to assess neurodegeneration in-vivo, typically following symptom onset. Defining biomarkers of the presymptomatic disease will be important for future therapeutic trials. The development of blood tests to detect neurodegeneration would provide an economical screening method that could be applied earlier in the disease course and easily deployed at the population level. Cell-free DNA (cfDNA) derived from brain tissue holds great potential for the detection and monitoring of neurodegeneration through the blood. Within our lab we exploit the unique DNA methylation profiles of brain cells to create molecular diagnostic assays capable of detecting brain-derived cfDNA within peripheral blood plasma. Using longitudinal structural MRI, we have classified cases with Frontal Cortical (FC) and/ or Cerebellum (CRB) neurodegeneration. Using novel Next Generation Sequencing technology and Bioinformatic approaches we have completed the first proof-of-concept experiments for cfDNA analysis in a population of FTD and Healthy Controls. We found evidence of brain-derived cfDNA within 74% of samples analyzed (N=99). We were able to accurately differentiate cfDNA coming from the Cerebellum (CRB) compared to cfDNA derived from the Dorsolateral Prefrontal Cortex, establishing the first evidence of a peripheral biomarker with brain-region specificity. Interestingly, patients with greater CRB loss compared to FC loss by longitudinal imaging (CRB > FC) exhibited higher amounts of CRB-derived cfDNA then FC > CRB patients (longitudinal imaging). These studies provide important insights for future study design using a novel biomarker of neurodegeneration.