BIOLOGICAL FLUID MONOAMINE LEVELS TO EXPLORE THE NEUROCHEMICAL CONTINUUM BETWEEN FRONTOTEMPORAL DEMENTIA AND AMYOTROPHIC LATERAL SCLEROSIS

Abstract

Behavioral variant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are early-onset debilitating diseases with genetic and clinicopathological commonalities, and are hypothesized to be part of a disease continuum alongside FTD-ALS. Although serotonergic and dopaminergic disturbances were recently identified in brain and spinal cord of ALS patients, information about neurochemical status of these disorders in body fluids remains scarce. Furthermore, few studies have compared neurochemical parameters directly between FTD and ALS. No FDA-approved disease-modifying drug therapies are available for FTD, nor ALS, with the sole exception of riluzole. An unmet medical need thus exists for both conditions, necessitating the identification of new pharmacological targets or the establishment of biomarkers for early disease detection. We retrospectively analyzed paired cerebrospinal fluid (CSF) – serum samples from 40 FTD, 26 ALS, 4 FTD-ALS and 40 age-matched control subjects using reversed-phase ultra-high-performance liquid chromatography with electrochemical detection. Levels of serotonergic, dopaminergic and (nor) adrenergic compounds were measured for all samples. Statistically significant differences in monoamine concentrations were predominantly present between FTD and age-matched control subjects, with significantly increased CSF (P<0.001) and serum (P<0.001) dopamine (DA) concentrations in FTD subjects. In contrast, levels of 3,4-dihydroxyphenylacetic acid (DOPAC) (P=0.008 for CSF; P=0.003 for serum) and DOPAC/DA ratios (P<0.001 for CSF; P<0.001 for serum), indicative for dopaminergic turnover, were lowered in latter patients. A similar pattern was observed between the ALS and age-matched control group, despite insignificant differences for DOPAC/DA ratios and DOPAC levels in CSF and serum, respectively. Concerning the (nor)adrenergic system, a significant increase in CSF MHPG concentrations was identified in FTD compared to age-matched control subjects (P=0.006). No dissimilarities could be detected in any of the monoaminergic compounds between FTD and ALS patients. Given the dopaminergic differences in CSF and serum samples in the age-matched control group compared to FTD and ALS groups, we hypothesize that both may be characterized by a dopaminergic disturbance. Furthermore, since no monoaminergic differences could be identified between patients, such neurodegenerative disorders do not only seem to belong to a genetic and clinicopathological continuum, but are likely to share a similar neurochemical pathophysiology as well.