TY - JOUR
T1 - Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease
AU - Buddhala, Chandana
AU - Loftin, Susan K.
AU - Kuley, Brandon M.
AU - Cairns, Nigel J.
AU - Campbell, Meghan C.
AU - Perlmutter, Joel S.
AU - Kotzbauer, Paul T.
N1 - Funding Information:
Support for this work was provided by a grant from the Michael J. Fox Foundation, National Institutes of Health grants NS075321, NS41509, NS058714, and NS48924 from the National Institute of Neurological Disorders and Stroke; P50AG005681 and P01AG003991 from the National Institute on Aging; UL1 TR000448 from the National Institutes of Health National Center for Advancing Translational Sciences; the American Parkinson Disease Association (APDA) Advanced Research Center for Parkinson Disease at Washington University in St. Louis; the Greater St. Louis Chapter of the APDA; and the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund). We are grateful for the technical support of the Betty Martz Laboratory for Neurodegenerative Research at Washington University in Saint Louis.
Funding Information:
Support for this work was provided by a grant from the Michael J. Fox Foundation, National Institutes of Health grants NS075321, NS41509, NS058714, and NS48924 from the National Institute of Neurological Disorders and Stroke; P50AG005681 and P01AG003991 from the National Institute on Aging; UL1 TR000448 from the National Institutes of Health National Center for Advancing Translational Sciences; the American Parkinson Disease Association (APDA) Advanced Research Center for Parkinson Disease at Washington University in St. Louis; the Greater St Louis Chapter of the APDA; and the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund). We are grateful for the technical support of the Betty Martz Laboratory for Neurodegenerative Research at Washington University in Saint Louis.
Publisher Copyright:
© 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
PY - 2015/10
Y1 - 2015/10
N2 - Objective: People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert. Methods: High-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested. Results: PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups. Interpretation: These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia.
AB - Objective: People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert. Methods: High-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested. Results: PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups. Interpretation: These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia.
UR - http://www.scopus.com/inward/record.url?scp=85015593783&partnerID=8YFLogxK
U2 - 10.1002/acn3.246
DO - 10.1002/acn3.246
M3 - Article
C2 - 26478895
AN - SCOPUS:85015593783
SN - 2328-9503
VL - 2
SP - 949
EP - 959
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 10
ER -