Monoaminergic Alterations at the Subregional Cervical and Thoracic Spinal Cord Level of Patients Within the FTD-ALS Continuum and Early-Onset AD: Low Thoracic Dopaminergic Activity in ALS

Early-onset neurodegeneration leads to cognitive and behavioral symptoms in frontotemporal dementia (FTD) and motor disturbances in amyotrophic lateral sclerosis (ALS). Despite distinct clinical profiles, more than half of FTD patients experience ALS-related symptoms and vice versa. Spinal cord monoamine neurotransmitter alterations were reported in ALS, but not yet in FTD. Therefore, we compared monoaminergic turnover across the FTD-ALS continuum. Reversed-phase, ultra-high-performance liquid chromatography with electrochemical detection was used to measure levels of the monoamines (nor)adrenaline ((N)A), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in five cervical and thoracic spinal cord regions in 10 FTD, 14 ALS, 6 mixed FTD-ALS, 14 early-onset Alzheimer's disease (EOAD), and 7 control (CONTR) individuals. At the cervical level, NA levels were lower in FTD-ALS versus CONTR, whereas the HVA/5-HIAA ratio was higher in ALS versus EOAD in the lateral funiculus. In the dorsal horn-intermediate gray matter, DA levels were decreased in FTD-ALS compared to FTD. At the thoracic level, DOPAC was lower in ALS than in FTD-ALS patients in the ventral and lateral funiculus, ventral horn, and dorsal horn-intermediate gray matter, as was the DOPAC/DA ratio in the lateral funiculus and dorsal horn-intermediate gray matter. Contrarily, HVA/DA turnover was lower in FTD-ALS than in FTD in the dorsal and ventral funiculus. We observed lower NA levels in FTD-ALS than in FTD in the ventral funiculus, and lower MHPG/NA turnover in the dorsal horn-intermediate gray matter. A levels were lower in ALS versus FTD. This study indicates differences in monoaminergic turnover across the FTD-ALS continuum, at the cervical and thoracic levels, with primarily a decrease in dopaminergic activity in ALS. Characterizing disease-specific neurochemical profiles for FTD, ALS, or FTD-ALS could contribute to the identification of novel interesting pharmacological targets.