Autonomic dysfunction is prevalent in Parkinson’s disease (PD) and can worsen quality of life. We examined: (a) whether specific autonomic symptoms were more strongly associated with anxiety or depression in PD and (b) whether overall autonomic dysfunction predicted mood trajectories over a 5-year period.
Methods
Newly diagnosed individuals with PD (N = 414) from the Parkinson’s Progression Markers Initiative completed self-report measures of depression, anxiety, and autonomic symptoms annually. Cross-sectional linear regressions examined relationships between specific autonomic subdomains (gastrointestinal, cardiovascular, thermoregulatory, etc.) and mood. Multilevel modeling examined longitudinal relationships with total autonomic load.
Results
Gastrointestinal symptoms were associated with both higher anxiety (b = 1.04, 95% CI [.55, 1.53], P < .001) and depression (b = .24, 95% CI [.11, .37], P = .012), as were thermoregulatory symptoms (anxiety: b = 1.06, 95% CI [.46, 1.65], P = .004; depression: b = .25, 95% CI [.09, .42], P = .013), while cardiovascular (b = .36, 95% CI [.10, .62], P = .012) and urinary symptoms (b = .10, 95% CI [.01, .20], P = .037) were associated only with depression. Longitudinally, higher total autonomic load was associated with increases in both depression (b = .01, 95% CI [.00, .02], P = .015) and anxiety (b = .04, 95% CI [.01, .06], P < .001) over time, as well as occasion-to-occasion fluctuations (depression: b = .08, 95% CI [.05, .10], P < .001; anxiety: b = .24, 95% CI [.15, .32], P < .001).
Conclusion
Findings suggest autonomic dysfunction, particularly gastrointestinal and thermoregulatory symptoms, may be an indicator for elevated anxiety/depression and a potential treatment target early on in PD.
MoustafaAAChakravarthySPhillipsJR, et al.Motor symptoms in Parkinson’s disease: a unified framework. Neurosci Biobehav Rev. 2016;68:727-740. doi:10.1016/j.neubiorev.2016.07.010
2.
Bernal-PachecoOLimotaiNGoCLFernandezHH. Nonmotor manifestations in Parkinson disease. Neurol. 2012;18(1):1-16. doi:10.1097/NRL.0b013e31823d7abb
3.
Martinez-MartinPSchapiraAHVStocchiF, et al.Prevalence of nonmotor symptoms in Parkinson’s disease in an international setting; Study using nonmotor symptoms questionnaire in 545 patients. Mov Disord. 2007;22(11):1623-1629. doi:10.1002/mds.21586
4.
LubomskiMDavisRLSueCM. Gastrointestinal dysfunction in Parkinson’s disease. J Neurol. 2020;267(5):1377-1388. doi:10.1007/s00415-020-09723-5
5.
ChenZLiGLiuJ. Autonomic dysfunction in Parkinson’s disease: implications for pathophysiology, diagnosis, and treatment. Neurobiol Dis. 2020;134:104700. doi:10.1016/j.nbd.2019.104700
6.
AbbottRDPetrovitchHWhiteLR, et al.Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology. 2001;57(3):456-462. doi:10.1212/WNL.57.3.456
7.
SavicaRCarlinJMGrossardtBR, et al.Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology. 2009;73(21):1752-1758. doi:10.1212/WNL.0b013e3181c34af5
Adams-CarrKLBestwickJPShribmanSLeesASchragANoyceAJ. Constipation preceding Parkinson’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2016;87(7):710-716. doi:10.1136/jnnp-2015-311680
10.
FricovaDHarsanyiovaJKralova TrancikovaA. Alpha-synuclein in the gastrointestinal tract as a potential biomarker for early detection of Parkinson’s disease. Int J Mol Sci. 2020;21(22):8666. doi:10.3390/ijms21228666
11.
NairATRamachandranVJogheeNMAntonySRamalingamG. Gut microbiota dysfunction as reliable non-invasive early diagnostic biomarkers in the pathophysiology of Parkinson’s disease: a critical review. J Neurogastroenterol Motil. 2018;24(1):30-42. doi:10.5056/jnm17105
12.
BraakHDel TrediciKRübUde VosRAIJansen SteurENHBraakE. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. doi:10.1016/S0197-4580(02)00065-9
CoonEACutsforth-GregoryJKBenarrochEE. Neuropathology of autonomic dysfunction in synucleinopathies. Mov Disord. 2018;33(3):349-358. doi:10.1002/mds.27186
15.
PapapetropoulosSMashDC. Insular pathology in Parkinson’s disease patients with orthostatic hypotension. Parkinsonism Relat Disord. 2007;13(5):308-311. doi:10.1016/j.parkreldis.2006.06.009
16.
SakakibaraRTatenoFKishiMTsuyuzakiYUchiyamaTYamamotoT. Pathophysiology of bladder dysfunction in Parkinson’s disease. Neurobiol Dis. 2012;46(3):565-571. doi:10.1016/j.nbd.2011.10.002
17.
CersosimoMGBenarrochEE. Pathological correlates of gastrointestinal dysfunction in Parkinson’s disease. Neurobiol Dis. 2012;46(3):559-564. doi:10.1016/j.nbd.2011.10.014
18.
MerolaARomagnoloARossoM, et al.Autonomic dysfunction in Parkinson’s disease: a prospective cohort study. Mov Disord. 2018;33(3):391-397. doi:10.1002/mds.27268
LabordeSMosleyEThayerJF. Heart rate variability and cardiac vagal tone in psychophysiological research – recommendations for experiment planning, data analysis, and data reporting. Front Psychol. 2017;8:213. doi:10.3389/fpsyg.2017.00213
21.
MalikMBiggerJTCammAJ. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996;17(3):354-381. doi:10.1093/oxfordjournals.eurheartj.a014868
22.
KochCWilhelmMSalzmannSRiefWEuteneuerF. A meta-analysis of heart rate variability in major depression. Psychol Med. 2019;49(12):1948-1957. doi:10.1017/S0033291719001351
23.
ChalmersJAQuintanaDSAbbottMJAKempAH. Anxiety disorders are associated with reduced heart rate variability: a meta-analysis. Front Psychiatry2014;5:80. doi:10.3389/fpsyt.2014.00080
24.
SgoifoACarnevaliLde los Angeles Pico AlfonsoMAmoreM. Autonomic dysfunction and heart rate variability in depression. Stress2015;18(3):343-352. doi:10.3109/10253890.2015.1045868
25.
ThayerJFHansenALSaus-RoseEJohnsenBH. Heart rate variability, prefrontal neural function, and cognitive performance: the neurovisceral integration perspective on self-regulation, adaptation, and Health. Ann Behav Med. 2009;37(2):141-153. doi:10.1007/s12160-009-9101-z
26.
GibsonJSFlaniganJLPatrieJTDalrympleWAHarrisonMB. Predictors of anxiety in Parkinson’s disease: results from a 3-year longitudinal cohort study. Neurol Sci. 2023;44(2):547-556. doi:10.1007/s10072-022-06427-8
27.
StankovićIPetrovićIPekmezovićT, et al.Longitudinal assessment of autonomic dysfunction in early Parkinson’s disease. Parkinsonism Relat Disord. 2019;66:74-79. doi:10.1016/j.parkreldis.2019.07.008
28.
ParkHEKimJSOhYS, et al.Autonomic nervous system dysfunction in patients with Parkinson disease having depression. J Geriatr Psychiatry Neurol. 2016;29(1):11-17. doi:10.1177/0891988715598234
29.
MatsubaraTSuzukiKFujitaH, et al.Autonomic symptoms correlate with non-autonomic non-motor symptoms and sleep problems in patients with Parkinson’s disease. Eur Neurol. 2018;80(3–4):193-199. doi:10.1159/000495797
30.
SklerovMBrownerNDayanERubinowDFrohlichF. Autonomic and depression symptoms in Parkinson’s disease: clinical evidence for overlapping physiology. J Park Dis. 2022;12(3):1059-1067. doi:10.3233/JPD-213075
31.
SakakibaraROgataTAibaYTatenoFUchiyamaTYamamotoT. Does depression contribute to the bladder and bowel complaint in Parkinson’s disease patients?Mov Disord Clin Pract. 2021;8(2):240-244. doi:10.1002/mdc3.13124
32.
JonesJDDominguezBBunchJUribeCValenzuelaYJacobsJP. A bidirectional relationship between anxiety, depression and gastrointestinal symptoms in Parkinson’s disease. Clin Park Relat Disord. 2021;5:100104. doi:10.1016/j.prdoa.2021.100104
33.
van WamelenDJLetaVPodlewskaAM, et al.Exploring hyperhidrosis and related thermoregulatory symptoms as a possible clinical identifier for the dysautonomic subtype of Parkinson’s disease. J Neurol. 2019;266(7):1736-1742. doi:10.1007/s00415-019-09325-w
34.
Del PinoRMurueta-GoyenaAAceraM, et al.Autonomic dysfunction is associated with neuropsychological impairment in Lewy body disease. J Neurol. 2020;267(7):1941-1951. doi:10.1007/s00415-020-09783-7
35.
SklerovMDayanEBrownerN. Functional neuroimaging of the central autonomic network: recent developments and clinical implications. Clin Auton Res. 2019;29(6):555-566. doi:10.1007/s10286-018-0577-0
36.
RemyPDoderMLeesATurjanskiNBrooksD. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain. 2005;128(6):1314-1322. doi:10.1093/brain/awh445
37.
SharabiYGoldsteinDS. Mechanisms of orthostatic hypotension and supine hypertension in Parkinson disease. J Neurol Sci. 2011;310(1):123-128. doi:10.1016/j.jns.2011.06.047
38.
CellekSJohnAKThangiahR, et al.5-HT4 receptor agonists enhance both cholinergic and nitrergic activities in human isolated colon circular muscle. Neuro Gastroenterol Motil. 2006;18(9):853-861. doi:10.1111/j.1365-2982.2006.00810.x
39.
LiuZSakakibaraROdakaT, et al.Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, ameliorates constipation in parkinsonian patients. Mov Disord. 2005;20(6):680-686. doi:10.1002/mds.20387
40.
JolingMvan den HeuvelOABerendseHWBooijJVriendC. Serotonin transporter binding and anxiety symptoms in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2018;89(1):89-94. doi:10.1136/jnnp-2017-316193
41.
JunakovićASkočić HanžekMAdamecIKrbot SkorićMHabekM. A complex interplay between autonomic symptoms and symptoms of depression, anxiety, and stress. Neurol Sci. 2023;44(9):3169-3179. Published online April 4, 2023. doi:10.1007/s10072-023-06787-9
42.
MartinezJPalmaJANorcliffe-KaufmannLGarakaniAKaufmannH. Impact of depressive symptoms on self-perceived severity of autonomic dysfunction in multiple system atrophy: relevance for patient-reported outcomes in clinical trials. Clin Auton Res. 2020;30(3):215-221. doi:10.1007/s10286-020-00681-6
43.
ZhuKvan HiltenJJMarinusJ. Onset and evolution of anxiety in Parkinson’s disease. Eur J Neurol. 2017;24(2):404-411. doi:10.1111/ene.13217
44.
VasudevAO’BrienJTTanMPParrySWThomasAJ. A study of orthostatic hypotension, heart rate variability and baroreflex sensitivity in late-life depression. J Affect Disord. 2011;131(1):374-378. doi:10.1016/j.jad.2010.11.001
45.
DavydovDMShapiroDCookIAGoldsteinI. Baroreflex mechanisms in major depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(1):164-177. doi:10.1016/j.pnpbp.2006.08.015
46.
BroadleyAJMFrenneauxMPMoskvinaVJonesCJHKorszunA. Baroreflex sensitivity is reduced in depression. Psychosom Med. 2005;67(4):648-651. doi:10.1097/01.psy.0000170829.91643.24
VisserMMarinusJStiggelboutAMVan HiltenJJ. Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord. 2004;19(11):1306-1312. doi:10.1002/mds.20153
49.
Pavy-Le TraonAAmarencoGDuerrS, et al.The Movement Disorders task force review of dysautonomia rating scales in Parkinson’s disease with regard to symptoms of orthostatic hypotension. Mov Disord. 2011;26(11):1985-1992. doi:10.1002/mds.23742
50.
EvattMLChaudhuriKRChouKL, et al.Dysautonomia rating scales in Parkinson’s disease: sialorrhea, dysphagia, and constipation--critique and recommendations by movement disorders task force on rating scales for Parkinson’s disease. Mov Disord. 2009;24(5):635-646. doi:10.1002/mds.22260
51.
YesavageJASheikhJI. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi:10.1300/J018v05n01_09
52.
TorbeyEPachanaNADissanayakaNNW. Depression rating scales in Parkinson’s disease: a critical review updating recent literature. J Affect Disord. 2015;184:216-224. doi:10.1016/j.jad.2015.05.059
53.
SpielbergerCDGorsuchRL. State-Trait Anxiety Inventory for Adults: Manual, Instrument and Scoring Guide. Mind Garden, Inc.; 1983.
54.
KnightRGWaal‐ManningHJSpearsGF. Some norms and reliability data for the state-trait anxiety inventory and the zung self-rating depression scale. Br J Clin Psychol1983;22(4):245-249. doi:10.1111/j.2044-8260.1983.tb00610.x
55.
GoetzCGTilleyBCShaftmanSR, et al.Movement disorder society-sponsored revision of the unified Parkinson’s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129-2170. doi:10.1002/mds.22340
56.
PreacherKJHayesAF. SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behav Res Methods Instrum Comput. 2004;36(4):717-731. doi:10.3758/BF03206553
FianiDCampbellHSolmiMFiedorowiczJGCalargeCA. Impact of antidepressant use on the autonomic nervous system: a meta-analysis and systematic review. Eur Neuropsychopharmacol. 2023;71:75-95. doi:10.1016/j.euroneuro.2023.03.013
59.
TanAHLimSYLangAE. The microbiome–gut–brain axis in Parkinson disease — from basic research to the clinic. Nat Rev Neurol. 2022;18(8):476-495. doi:10.1038/s41582-022-00681-2
60.
LeeYKimYK. Understanding the connection between the gut–brain axis and stress/anxiety disorders. Curr Psychiatry Rep2021;23(5):22. doi:10.1007/s11920-021-01235-x
61.
EvrenselACeylanME. The gut-brain axis: the missing link in depression. Clin Psychopharmacol Neurosci2015;13(3):239-244. doi:10.9758/cpn.2015.13.3.239
62.
PetraAIPanagiotidouSHatziagelakiEStewartJMContiPTheoharidesTC. Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther2015;37(5):984-995. doi:10.1016/j.clinthera.2015.04.002
63.
PeirceJMAlviñaK. The role of inflammation and the gut microbiome in depression and anxiety. J Neurosci Res. 2019;97(10):1223-1241. doi:10.1002/jnr.24476
64.
KoloskiNAJonesMKalantarJWeltmanMZaguirreJTalleyNJ. The brain–gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut. 2012;61(9):1284-1290. doi:10.1136/gutjnl-2011-300474
65.
BenarrochEE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993;68(10):988-1001. doi:10.1016/S0025-6196(12)62272-1
66.
EhlertUGaabJHeinrichsM. Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus–pituitary–adrenal axis. Biol Psychol. 2001;57(1):141-152. doi:10.1016/S0301-0511(01)00092-8
67.
StevensFLHurleyRATaberKHHurleyRAHaymanLATaberKH. Anterior cingulate cortex: unique role in cognition and emotion. J Neuropsychiatry Clin Neurosci. 2011;23(2):121-125. doi:10.1176/jnp.23.2.jnp121
68.
SergerieKChocholCArmonyJL. The role of the amygdala in emotional processing: a quantitative meta-analysis of functional neuroimaging studies. Neurosci Biobehav Rev. 2008;32(4):811-830. doi:10.1016/j.neubiorev.2007.12.002
69.
SteinMBSimmonsANFeinsteinJSPaulusMP. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry. 2007;164(2):318-327. doi:10.1176/ajp.2007.164.2.318
70.
BraakHBraakEYilmazerD, et al.Amygdala pathology in Parkinson’s disease. Acta Neuropathol. 1994;88(6):493-500. doi:10.1007/BF00296485
71.
FereshtehnejadSMZeighamiYDagherAPostumaRB. Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain. 2017;140(7):1959-1976. doi:10.1093/brain/awx118
72.
YooHSLeeSJeongSH, et al.Clinical and dopamine depletion patterns in hyposmia- and dysautonomia-dominant Parkinson’s disease. J Park Dis. 2021;11(4):1703-1713. doi:10.3233/JPD-212747
73.
BerriosGECampbellCPolitynskaBE. Autonomic failure, depression and anxiety in Parkinson’s disease. Br J Psychiatry. 1995;166(6):789-792. doi:10.1192/bjp.166.6.789
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
