By Claire Henchcliffe, MD

Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is on the speakers bureau and advisory boards for Teva, IMPAX, and ACADIA and receives grant/research support from Biogen and Kaneka.

SYNOPSIS: Postmortem brain tissue from 15 individuals with Parkinson’s disease dementia was analyzed by high-performance liquid chromatography and immunoassays, revealing widespread deficits in dopamine, serotonin, and noradrenaline innervation.

Source: Buddhala C, et al. Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease. Ann Clin Transl Neurol 2015;2:949-959.

Dementia in Parkinson’s disease (PD) remains a major challenge to optimal management in the clinic, and has a profound impact on patient quality of life. Recent advances have highlighted widespread pathology associated with PD with dementia, but remaining gaps in understanding hamper efforts to provide better treatment. In this study, the authors have therefore investigated autopsy specimens obtained from 15 patients with PD and dementia, where the presence of dementia was defined either by clinical diagnosis or by the Clinical Dementia Rating scale. The deceased patients’ median age at death was 79 (range 71-93) years, 12/15 were male, and their median disease duration was 14 (range 8-27) years. Medications reported included agents used to control motor symptoms (levodopa equivalents of 800 mg, range 0-1350 mg, daily), cognitive dysfunction (acetylcholinesterase inhibitors in 8/15), mood (serotonin reuptake inhibitors in 10/15 and other antidepressant agents in 2/15), and psychosis, although corresponding clinical diagnoses were not reported. These late-stage patients had widespread alpha-synuclein pathology defined as Braak stage 6 (the most widespread pathology of stages that range from 1-6). Six healthy control brains were used for comparison, with slightly greater age at death of 84 (range 70-100) years, 2/6 males, and none were taking anti-PD, antidepressant, or acetylcholinesterase inhibitors. Multiple cortical and subcortical brain regions were analyzed by high-performance liquid chromatography or immunoassay to quantitatively measure dopamine, dopamine transporter (DAT), serotonin, serotonin transporter (SERT), norepinephrine, and vesicular acetylcholine transporter.

As expected, dopamine levels in PD were lower than control in the caudate (2.5% of control, P = 0.001), but of interest were also markedly decreased in the amygdala (27% of control, P = 0.001), and DAT levels were lower in PD with dementia vs controls in the caudate, hippocampus, amygdala, inferior parietal lobe, precuneus, and visual association cortex. Serotonin levels were decreased in PD with dementia vs controls in the caudate (31.6% of controls, P = 0.003), and in multiple cortical regions including the middle frontal gyrus (19.7% of controls, P = 0.001), inferior parietal cortex (16.8% of controls, P = 0.001), and visual association cortex (11.8%, P = 0.003). Reductions in SERT were observed in the same areas, once again with the most severe deficit present in the visual association cortex (9.9% of controls, P = 0.001). Norepinephrine levels were markedly reduced in all of these regions, most notably the inferior parietal lobe (4.2% of controls, P = 0.001), in addition to the anterior cingulate gyrus (3.9% of controls, P = 0.002). VAChT levels could only be measured in the caudate and hippocampus using assays in this study, and did not differ between PD and controls. In this small sample, neurochemical measures did not correlate with Mini-Mental Status Examination scores, Unified Parkinson’s Disease Rating Scale motor scores, or Clinical Dementia Rating scale scores. Grouping PD study patients by pathology as alpha-synuclein alone vs alpha-synuclein plus beta-amyloid also did not reveal any correlation with neurotransmitter and transporter levels. Only two subjects had tau pathology, precluding any attempt to correlate this subset with neurotransmitter system disruption in this sample.

COMMENTARY

This study demonstrated at postmortem that, in addition to dopaminergic deficits, the serotonergic and noradrenergic systems are profoundly disrupted in PD with dementia when compared with normal controls. The finding of deficits in these neurotransmitter systems in neocortical and limbic, as well as basal ganglia regions, serves to emphasize that a reliance on treatment strategies that focus on dopamine supplementation alone are simply inadequate in late stages of disease, aligning well with current clinical strategies. Perhaps unexpectedly, although serotonin and SERT reductions were quite comparable across regions, dopamine and DAT differed. Loss of DAT exceeded dopamine loss in the caudate, amygdala, hippocampus, inferior parietal lobule, precuneus, and visual association cortex. The authors suggested this may be due to levodopa administration increasing dopamine levels in neurons that possess dopa decarboxylase (but not DAT), thus masking endogenous loss, and further hypothesize that in cortical areas this could relate to cognitive side effects. Whether antipsychotic and antidepressant medications might have affected findings is not addressed and remains therefore unknown. This study also highlights the role of norepinephrine, reflecting loss of neurons in the locus ceruleus, and supports previous findings of decreased levels in frontal, cingulate, and entorhinal cortex as well as hippocampus. Of course, it would be interesting to examine correlation of such changes with clinical profiles and pathology, but, unfortunately, this was limited by the small number of cases. In the future, it would be extremely helpful for the clinician to have a study that correlates postmortem changes with neuroimaging findings. Nonetheless, this study serves to highlight the highly complex and extensive nature of dopamine, serotonin, and norepinephrine deficits in late-stage PD with dementia, and provides a stimulus for further development of non-dopaminergic treatments.