Neurological Sciences

, Volume 40, Issue 2, pp 283–291 | Cite as

Association of olfaction dysfunction with brain microstructure in prodromal Parkinson disease

  • Hossein Sanjari Moghaddam
  • Mahsa Dolatshahi
  • Elaheh Salardini
  • Mohammad Hadi AarabiEmail author
Original Article



Although olfaction dysfunction is now considered as an established clinical marker of prodromal Parkinson disease (PD), little is known about the neural underpinnings of olfaction dysfunction in the prodromal phase of PD. The aim of this study was to examine the microstructural association of olfaction in prodromal PD compared to early stage drug-naïve PD patients.


Diffusion MRI connectometry was conducted on 18 early PD and 17 prodromal PD patients to investigate the differences in group in terms of altered connectivity, i.e., integrity of white matter tracts, and subsequently to study the correlation of University of Pennsylvania Smell Identification Test (UPSIT) score to white matter integrity in each group using a multiple regression model considering age, sex, RBD, and MoCA, as covariates.


Individuals with prodromal PD had significantly higher quantitative anisotropy (QA) comparing with PD patients in bilateral middle cerebellar peduncles and right arcuate fasciculus. Multiple regression analysis in prodromal PD demonstrated positive association between UPSIT score and connectivity in left and right subgenual cingulum, right inferior fronto-occipital fasciculus, left corticospinal tract, left parietopontine, left corticothalamic tract, and the body and the splenium of corpus callosum.


These results indicate that PD and prodromal PD patients, which were matched for sex, UPSIT, and MoCA scores, have different white matter fiber architecture. Thus, it is postulated that olfaction dysfunction in prodromal and early clinical phases of PD may involve distinct pathogenesis. Increased network connectivity in prodromal and early PD may suggest the neural compensation.


Prodromal PD Olfaction UPSIT Diffusion MRI Parkinson disease 



We thank Christian Beckmann and Simon Eickhoff for their advice on data analysis. Data used in this article were obtained from the Parkinsons Progression Markers Initiative (PPMI) database ( For up-to-date information on the study, visit

Authors’ contributions

H.S.M, M.H.A. contributed to the conception and design of the study; M.H.A. contributed to data collection and analysis; and H.S.M, M.D, and E.S.D contributed to writing and revising the manuscript.

Funding information

This dataset of this work was funded by grants from the Michael J Fox Foundation for Parkinson’s Research, the W Garfield Weston Foundation, and the Alzheimer’s Association, the Canadian Institutes for Health Research, and the Natural Sciences and Engineering Research Council of Canada. PPMI is sponsored and partially funded by the Michael J Fox Foundation for Parkinsons Research and funding partners, including AbbVie, Avid Radiopharmaceuticals, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline (GSK), Eli Lilly and Company, Lundbeck, Merck, Meso Scale Discovery (MSD), Pfizer, Piramal Imaging, Roche, Servier, and UCB (

Compliance with ethical standards

Ethical approval

All procedures performed here, including human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Brooks DJ (1998) The early diagnosis of Parkinson’s disease. Ann Neurol 44(3 Suppl 1):S10–S18PubMedCrossRefGoogle Scholar
  2. 2.
    Ghazi Sherbaf F, Rostam Abadi Y, Mojtahed Zadeh M, Ashraf-Ganjouei A, Sanjari Moghaddam H, Aarabi MH (2018) Microstructural changes in patients with Parkinson’s disease comorbid with REM sleep behaviour disorder and depressive symptoms. Front Neurol 9:441. PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Ansari M, Adib Moradi S, Ghazi Sherbaf F, Hedayatnia A, Aarabi MH (2018) Comparison of structural connectivity in Parkinson’s disease with depressive symptoms versus non-depressed: a diffusion MRI connectometry study. Int Psychogeriatr:1–8.
  4. 4.
    Ashraf-Ganjouei A, Majd A, Javinani A, Aarabi MH (2018) Autonomic dysfunction and white matter microstructural changes in drug-naïve patients with Parkinson’s disease. PeerJ 6:e5539. PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G (2015) MDS research criteria for prodromal Parkinson’s disease. Mov Dis 30(12):1600–1611. CrossRefGoogle Scholar
  6. 6.
    Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, Goetz CG, Halliday GM, Hardy J, Lang AE, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G (2014) Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Dis 29(4):454–462. CrossRefGoogle Scholar
  7. 7.
    Salat D, Noyce AJ, Schrag A, Tolosa E (2016) Challenges of modifying disease progression in prediagnostic Parkinson’s disease. Lancet Neurol 15(6):637–648. PubMedCrossRefGoogle Scholar
  8. 8.
    Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, Ziemssen T (2012) Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord 27(5):617–626PubMedCrossRefGoogle Scholar
  9. 9.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211CrossRefGoogle Scholar
  10. 10.
    Chu S, Downes JJ (2000) Odour-evoked autobiographical memories: psychological investigations of Proustian phenomena. Chem Senses 25(1):111–116PubMedCrossRefGoogle Scholar
  11. 11.
    Doty RL (2012) Olfactory dysfunction in Parkinson disease. Nat Rev Neurol 8(6):329–339. PubMedCrossRefGoogle Scholar
  12. 12.
    Berg D, Marek K, Ross GW, Poewe W (2012) Defining at-risk populations for Parkinson’s disease: lessons from ongoing studies. Mov Disord 27(5):656–665PubMedCrossRefGoogle Scholar
  13. 13.
    Haehner A, Hummel T, Hummel C, Sommer U, Junghanns S, Reichmann H (2007) Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord 22(6):839–842PubMedCrossRefGoogle Scholar
  14. 14.
    Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K, Launer L, White LR (2008) Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann Neurol 63(2):167–173PubMedCrossRefGoogle Scholar
  15. 15.
    Ponsen MM, Stoffers D, Twisk JW, Wolters EC, Berendse HW (2009) Hyposmia and executive dysfunction as predictors of future Parkinson’s disease: a prospective study. Mov Disord 24(7):1060–1065PubMedCrossRefGoogle Scholar
  16. 16.
    Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY (2011) Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder. Ann Neurol 69(5):811–818PubMedCrossRefGoogle Scholar
  17. 17.
    Mahlknecht P, Iranzo A, Högl B, Frauscher B, Müller C, Santamaría J, Tolosa E, Serradell M, Mitterling T, Gschliesser V (2015) Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD. Neurology 84(7):654–658PubMedCrossRefGoogle Scholar
  18. 18.
    Jennings D, Stern M, Siderowf A, Eberly S, Oakes D, Marek K (2015) Longitudinal imaging and phenoconversion in the PARS prodromal cohort. Mov Disord 30:S383Google Scholar
  19. 19.
    Postuma RB, Berg D (2016) Advances in markers of prodromal Parkinson disease. Nat Rev Neurol 12(11):622–634PubMedCrossRefGoogle Scholar
  20. 20.
    Rodríguez-violante M, Ospina-García N, Pérez-Lohman C, Cervantes-Arriaga A (2017) Spotlight on olfactory dysfunction in Parkinson’s disease. J Parkinsonism Restless Legs Syndr 55:33–41.
  21. 21.
    Haehner A, Boesveldt S, Berendse HW, Mackay-Sim A, Fleischmann J, Silburn PA, Johnston AN, Mellick GD, Herting B, Reichmann H, Hummel T (2009) Prevalence of smell loss in Parkinson’s disease--a multicenter study. Parkinsonism Relat Disord 15(7):490–494. PubMedCrossRefGoogle Scholar
  22. 22.
    Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters E, Berendse HW (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56(2):173–181. PubMedCrossRefGoogle Scholar
  23. 23.
    Stern MB, Doty RL, Dotti M, Corcoran P, Crawford D, McKeown DA, Adler C, Gollomp S, Hurtig H (1994) Olfactory function in Parkinson’s disease subtypes. Neurology 44(2):266–268PubMedCrossRefGoogle Scholar
  24. 24.
    Doty RL, Shaman P, Dann M (1984) Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav 32(3):489–502PubMedCrossRefGoogle Scholar
  25. 25.
    Baba T, Kikuchi A, Hirayama K, Nishio Y, Hosokai Y, Kanno S, Hasegawa T, Sugeno N, Konno M, Suzuki K, Takahashi S, Fukuda H, Aoki M, Itoyama Y, Mori E, Takeda A (2012) Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson’s disease: a 3 year longitudinal study. Brain 135(Pt 1):161–169. PubMedCrossRefGoogle Scholar
  26. 26.
    Baba T, Takeda A, Kikuchi A, Nishio Y, Hosokai Y, Hirayama K, Hasegawa T, Sugeno N, Suzuki K, Mori E, Takahashi S, Fukuda H, Itoyama Y (2011) Association of olfactory dysfunction and brain. Metabolism in Parkinson’s disease. Mov Dis 26(4):621–628. CrossRefGoogle Scholar
  27. 27.
    Berendse HW, Booij J, Francot CM, Bergmans PL, Hijman R, Stoof JC, Wolters EC (2001) Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease patients’ relatives with a decreased sense of smell. Ann Neurol 50(1):34–41PubMedCrossRefGoogle Scholar
  28. 28.
    Bohnen NI, Gedela S, Herath P, Constantine GM, Moore RY (2008) Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity. Neurosci Lett 447(1):12–16. PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Bohnen NI, Gedela S, Kuwabara H, Constantine GM, Mathis CA, Studenski SA, Moore RY (2007) Selective hyposmia and nigrostriatal dopaminergic denervation in Parkinson’s disease. J Neurol 254(1):84–90. PubMedCrossRefGoogle Scholar
  30. 30.
    Bohnen NI, Muller ML, Kotagal V, Koeppe RA, Kilbourn MA, Albin RL, Frey KA (2010) Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain 133(Pt 6):1747–1754. PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Siderowf A, Newberg A, Chou KL, Lloyd M, Colcher A, Hurtig HI, Stern MB, Doty RL, Mozley PD, Wintering N, Duda JE, Weintraub D, Moberg PJ (2005) [99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 64(10):1716–1720. PubMedCrossRefGoogle Scholar
  32. 32.
    Su M, Wang S, Fang W, Zhu Y, Li R, Sheng K, Zou D, Han Y, Wang X, Cheng O (2015) Alterations in the limbic/paralimbic cortices of Parkinson’s disease patients with hyposmia under resting-state functional MRI by regional homogeneity and functional connectivity analysis. Parkinsonism Relat Disord 21(7):698–703. PubMedCrossRefGoogle Scholar
  33. 33.
    Yeh F-C, Tang P-F, Tseng W-YI (2013) Diffusion MRI connectometry automatically reveals affected fiber pathways in individuals with chronic stroke. NeuroImage: Clinical 2:912–921. CrossRefGoogle Scholar
  34. 34.
    Leemans A, Jeurissen B, Sijbers J, Jones D (2009) ExploreDTI: a graphical toolbox for processing, analyzing, and visualizing diffusion MR data. In: 17th Annual Meeting of Intl Soc Mag Reson Med. p 3537Google Scholar
  35. 35.
    Ghazi Sherbaf F, Mojtahed Zadeh M, Haghshomar M, Aarabi MH (2018) Posterior limb of the internal capsule predicts poor quality of life in patients with Parkinson’s disease: connectometry approach. Acta Neurol Belg.
  36. 36.
    Ghazi Sherbaf F, Same K, Aarabi MH (2018) High angular resolution diffusion imaging correlates of depression in Parkinson’s disease: a connectometry study. Acta Neurol Belg.
  37. 37.
    Mojtahed Zadeh M, Ashraf-Ganjouei A, Ghazi Sherbaf F, Haghshomar M, Aarabi MH (2018) White matter tract alterations in drug-naive Parkinson’s disease patients with impulse control disorders. Front Neurol 9:163. PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Lee EY, Eslinger PJ, Du G, Kong L, Lewis MM, Huang X (2014) Olfactory-related cortical atrophy is associated with olfactory dysfunction in Parkinson’s disease. Mov Dis 29(9):1205–1208. CrossRefGoogle Scholar
  39. 39.
    van Uem JM, Marinus J, Canning C, van Lummel R, Dodel R, Liepelt-Scarfone I, Berg D, Morris ME, Maetzler W (2016) Health-related quality of life in patients with Parkinson’s disease—a systematic review based on the ICF model. Neurosci Biobehav Rev 61:26–34PubMedCrossRefGoogle Scholar
  40. 40.
    Wattendorf E, Welge-Lussen A, Fiedler K, Bilecen D, Wolfensberger M, Fuhr P, Hummel T, Westermann B (2009) Olfactory impairment predicts brain atrophy in Parkinson’s disease. J Neurosci 29(49):15410–15413. PubMedCrossRefGoogle Scholar
  41. 41.
    Kwon HG, Hong JH, Jang SH (2011) Anatomic location and somatotopic arrangement of the corticospinal tract at the cerebral peduncle in the human brain. AJNR Am J Neuroradiol 32(11):2116–2119. PubMedCrossRefGoogle Scholar
  42. 42.
    Marek K, Jennings D, Lasch S, Siderowf A, Tanner C, Simuni T, Coffey C, Kieburtz K, Flagg E, Chowdhury S (2011) The parkinson progression marker initiative (PPMI). Prog Neurobiol 95(4):629–635CrossRefGoogle Scholar
  43. 43.
    Yeh FC, Tseng WY (2011) NTU-90: a high angular resolution brain atlas constructed by q-space diffeomorphic reconstruction. NeuroImage 58(1):91–99. PubMedCrossRefGoogle Scholar
  44. 44.
    Yeh F-C, Verstynen TD, Wang Y, Fernández-Miranda JC, Tseng W-YI (2013) Deterministic diffusion fiber tracking improved by quantitative anisotropy. PLoS One 8(11):e80713. PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Schmahmann JD, Smith EE, Eichler FS, Filley CM (2008) Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates. Ann N Y Acad Sci 1142:266–309. PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Tessa C, Lucetti C, Giannelli M, Diciotti S, Poletti M, Danti S, Baldacci F, Vignali C, Bonuccelli U, Mascalchi M, Toschi N (2014) Progression of brain atrophy in the early stages of Parkinson’s disease: a longitudinal tensor-based morphometry study in de novo patients without cognitive impairment. Hum Brain Mapp 35(8):3932–3944. PubMedCrossRefGoogle Scholar
  47. 47.
    Ansari M, Rahmani F, Dolatshahi M, Pooyan A, Aarabi MH (2017) Brain pathway differences between Parkinson’s disease patients with and without REM sleep behavior disorder. Sleep Breath 21(1):155–161. PubMedCrossRefGoogle Scholar
  48. 48.
    Hall JM, Ehgoetz Martens KA, Walton CC, O'Callaghan C, Keller PE, Lewis SJ, Moustafa AA (2016) Diffusion alterations associated with Parkinson’s disease symptomatology: a review of the literature. Parkinsonism Relat Disord 33:12–26. PubMedCrossRefGoogle Scholar
  49. 49.
    Sobhani S, Rahmani F, Aarabi MH, Sadr AV (2017) Exploring white matter microstructure and olfaction dysfunction in early parkinson disease: diffusion MRI reveals new insight. Brain Imaging Behav.
  50. 50.
    Wen MC, Heng HSE, Hsu JL, Xu Z, Liew GM, Au WL, Chan LL, Tan LCS, Tan EK (2017) Structural connectome alterations in prodromal and de novo Parkinson’s disease patients. Parkinsonism Relat Disord 45:21–27. PubMedCrossRefGoogle Scholar
  51. 51.
    Nigro S, Riccelli R, Passamonti L, Arabia G, Morelli M, Nistico R, Novellino F, Salsone M, Barbagallo G, Quattrone A (2016) Characterizing structural neural networks in de novo Parkinson disease patients using diffusion tensor imaging. Hum Brain Mapp 37(12):4500–4510. PubMedCrossRefGoogle Scholar
  52. 52.
    Wei L, Zhang J, Long Z, Wu GR, Hu X, Zhang Y, Wang J (2014) Reduced topological efficiency in cortical-basal Ganglia motor network of Parkinson’s disease: a resting state fMRI study. PLoS One 9(10):e108124. PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Scherfler C, Frauscher B, Schocke M, Iranzo A, Gschliesser V, Seppi K, Santamaria J, Tolosa E, Hogl B, Poewe W (2011) White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: a diffusion-tensor imaging and voxel-based morphometry study. Ann Neurol 69(2):400–407. PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Shao Y, Wang L, Ye E, Jin X, Ni W, Yang Y, Wen B, Hu D, Yang Z (2013) Decreased thalamocortical functional connectivity after 36 hours of total sleep deprivation: evidence from resting state FMRI. PLoS One 8(10):e78830. PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Welge-Lussen A, Wattendorf E, Schwerdtfeger U, Fuhr P, Bilecen D, Hummel T, Westermann B (2009) Olfactory-induced brain activity in Parkinson’s disease relates to the expression of event-related potentials: a functional magnetic resonance imaging study. Neuroscience 162(2):537–543. PubMedCrossRefGoogle Scholar
  56. 56.
    Gottfried JA, Zald DH (2005) On the scent of human olfactory orbitofrontal cortex: meta-analysis and comparison to non-human primates. Brain Res Brain Res Rev 50(2):287–304. PubMedCrossRefGoogle Scholar
  57. 57.
    Ibarretxe-Bilbao N, Junque C, Marti MJ, Valldeoriola F, Vendrell P, Bargallo N, Zarei M, Tolosa E (2010) Olfactory impairment in Parkinson’s disease and white matter abnormalities in central olfactory areas: a voxel-based diffusion tensor imaging study. Mov Dis 25(12):1888–1894. CrossRefGoogle Scholar
  58. 58.
    Wen M-C, Xu Z, Lu Z, Chan LL, Tan EK, Tan LCS (2017) Microstructural network alterations of olfactory dysfunction in newly diagnosed Parkinson’s disease. Sci Rep 7(1):12559. PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Sunwoo MK, Cha J, Ham JH, Song SK, Hong JY, Lee JM, Sohn YH, Lee PH (2015) Olfactory performance and resting state functional connectivity in non-demented drug naive patients with Parkinson’s disease. Hum Brain Mapp 36(5):1716–1727. PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of MedicineTehran University of Medical SciencesTehranIran

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