Norepinephrine and dopamine Imbalance in the medial frontal gyrus from patients with Alzheimer's disease

Objective: To investigate catecholaminergic alterations in the medial frontal gyrus (MFG) in Alzheimer's disease (AD) patients, including a case with TDP-43 pathology, with a focus on norepinephrine (NE) and dopamine (DA) signaling. Methods: Postmortem MFG tissue from five human donors, one with AD, one with AD and TDP-43 co-pathology (AD-TDP43), one preclinical AD, and two controls, was analyzed using high-performance liquid chromatography. Concentrations of NE, DA, and their primary metabolites (MHPG, DOPAC, HVA) were measured to assess neurotransmitter levels and turnover ratios. Results: Elevated MHPG levels were observed only in AD and AD-TDP43 patients, despite unchanged NE concentrations, indicating increased NE turnover. DA levels were also selectively elevated in AD and AD-TDP43 brains only. Possible impaired DA metabolism appeared consistent with reduced DOPAC/DA and HVA/DA ratios and DA turnover. Conclusions: Catecholaminergic dysfunction, marked by increased NE turnover and elevated DA levels, characterizes both AD and AD-TDP43 pathology in the MFG, implicating catecholamine imbalance in disease mechanisms. Significance: By revealing a selective increase in NE turnover and DA levels in the medial frontal lobe, these data may help to clarify the neurochemical imbalance linking cortical to subcortical neurodegeneration, such as that of the locus coeruleus and ventral tegmental area, to catecholamine innervation of the frontal cortex.