, Volume 33, Issue 6, pp 749–758 | Cite as

Pink1 −/− Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology

  • Kaylee P. Cullen
  • Laura M. Grant
  • Cynthia A. Kelm-Nelson
  • Alexander F. L. Brauer
  • Luke B. Bickelhaupt
  • John A. Russell
  • Michelle R. Ciucci
Original Article


Parkinson disease (PD) compromises oropharyngeal swallowing, which negatively affects quality of life and contributes to aspiration pneumonia. Dysphagia often begins early in the disease process, and does not improve with standard therapies. As a result, swallowing deficits are undertreated in the PD population. The Pink1 −/− rat is used to model PD, and demonstrates widespread brainstem neuropathology in combination with early-onset sensorimotor dysfunction; however, to date, swallowing behaviors have not been evaluated. To test the hypothesis that Pink1 −/− rats demonstrate early-onset differences in swallowing, we analyzed within-subject oropharyngeal swallowing using videofluoroscopy. Pink1 −/− and wildtype (WT) controls at 4 (Pink1 −/− n = 16, WT = 16) and 8 (Pink1 −/− n = 12, WT = 12) months of age were tested. The average and maximum bolus size was significantly increased in Pink1 −/− rats at both 4 and 8 months. Bolus average velocity was increased at 8 months for all animals; yet, Pink1 −/− animals had significantly increased velocities compared to WT at 8 months. The data show a significant reduction in mastication rate for Pink1 −/− rats at 8 months suggesting the onset of oromotor dysfunction begins at this time point. Relationships among swallowing variables and neuropathological findings, such as increased alpha-synuclein protein in the nucleus ambiguus and reductions in noradrenergic cells in the locus coeruleus in the Pink1 −/− rats, were determined. The presence of early oropharyngeal swallowing deficits and relationships to brainstem pathology in Pink1−/− rat models of PD indicate that this may be a useful model of early swallowing deficits and their mechanisms. These findings suggest clinical implications for early detection and management of dysphagia in PD.


Parkinson disease Dysphagia Deglutition Videofluoroscopy Rat Alpha-synuclein Pink1 



We would like to thank Dr. Glen Leverson, PhD for his assistance with statistical analysis.


This work was funded by the Michael J. Fox foundation (Ciucci) and National Institutes of Health R01 DC014358 (Ciucci), F32 DC014399 (Kelm-Nelson), and R21 DC016135 (Kelm-Nelson).

Compliance with Ethical Standards

Conflict of Interest

The authors have no conflict of interest to report.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


  1. 1.
    Pankratz N, Wojcieszek J, Fouroud T. Parkinson disease overview. Gene Reviews, 2009.Google Scholar
  2. 2.
    de Lau L, Giesbergen P, de Rijk M. Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam Study. Neurology. 2004;63:1240–4.CrossRefGoogle Scholar
  3. 3.
    Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15:14–20.CrossRefGoogle Scholar
  4. 4.
    Hartelius L, Svensson P. Speech and swallowing symptoms associated with Parkinson’s disease and multiple sclerosis: a survey. Folia Phoniatr Logop. 1994;46:9–17.CrossRefGoogle Scholar
  5. 5.
    Ho AK, Iansek R, Marigliani C, Bradshaw JL, Gates S. Speech impairment in a large sample of patients with Parkinson’s disease. Behav Neurol. 1998;11:131.CrossRefGoogle Scholar
  6. 6.
    Ackermann H, Ziegler W. Articulatory deficits in parkinsonian dysarthria: an acoustic analysis. J Neurol Neurosurg Psychiatry. 1991;54:1093–8.CrossRefGoogle Scholar
  7. 7.
    Hammer M, Barlow S. Laryngeal somatosensory deficits in Parkinson’s disease: implications for speech respiratory and phonatory control. Exp Brain Res. 2010;201:401–9.CrossRefGoogle Scholar
  8. 8.
    Logemann JA, Fisher HB, Boshes B, Blonsky ER. Frequency and cooccurrence of vocal tract dysfunctions in the speech of a large sample of Parkinson patients. J Speech Hear Disord. 1978;43:47–57.CrossRefGoogle Scholar
  9. 9.
    Darley FL, Aronson AE, Brown JR. Differential diagnostic patterns of dysarthria. J Speech Hear Res. 1969;12:246–69.CrossRefGoogle Scholar
  10. 10.
    Plowman-Prine EK, Okun MS, Sapienza CM, Shrivastav R, Fernandez HH, Foote KD, Ellis C, Rodriguez AD, Burkhead LM, Rosenbek JC. Perceptual characteristics of Parkinsonian speech: a comparison of the pharmacological effects of levodopa across speech and non-speech motor systems. NeuroRehabilitation. 2009;24:131–44.PubMedGoogle Scholar
  11. 11.
    Leopold NA, Kagel MC. Laryngeal deglutition movement in Parkinson’s disease. Neurology. 1997;48:373–6.CrossRefGoogle Scholar
  12. 12.
    Leopold NA, Kagel MC. Pharyngo-esophageal dysphagia in Parkinson’s disease. Dysphagia. 1997;12:11–8 discussion 19–20.CrossRefGoogle Scholar
  13. 13.
    Wintzen AR, Badrising UA, Roos RA, Vielvoye J, Liauw L. Influence of bolus volume on hyoid movements in normal individuals and patients with Parkinson’s disease. Can J Neurol Sci. 1994;21:57–9.CrossRefGoogle Scholar
  14. 14.
    Nagaya M, Kachi T, Yamada T, Igata A. Videofluorographic study of swallowing in Parkinson’s disease. Dysphagia. 1998;13:95–100.CrossRefGoogle Scholar
  15. 15.
    Miller N, Noble E, Jones D, Burn D. Hard to swallow: dysphagia in Parkinson’s disease. Age Ageing. 2006;35:614–8.CrossRefGoogle Scholar
  16. 16.
    Beyer MK, Herlofson K, Årsland D, Larsen JP. Causes of death in a community-based study of Parkinson’s disease. Acta Neurol Scand. 2001;103:7–11.CrossRefGoogle Scholar
  17. 17.
    Volonté MA, Porta M, Comi G. Clinical assessment of dysphagia in early phases of Parkinson’s disease. Neurol Sci. 2002;23:s121–2.CrossRefGoogle Scholar
  18. 18.
    Muller J, Wenning GK, Verny M, McKee A, Chaudhuri KR, Jellinger K, Poewe W, Litvan I. Progression of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. Arch Neurol. 2001;58:259–64.CrossRefGoogle Scholar
  19. 19.
    Rusz J, Čmejla R, Růžičková H, Klempíř J, Majerová V, Picmausová J, Roth J, Růžička E. Evaluation of speech impairment in early stages of Parkinson’s disease: a prospective study with the role of pharmacotherapy. J Neural Transm. 2013;120:319–29.CrossRefGoogle Scholar
  20. 20.
    Campos FL, Carvalho MM, Cristovao AC, Je G, Baltazar G, Salgado AJ, Kim YS, Sousa N. Rodent models of Parkinson’s disease: beyond the motor symptomatology. Front Behav Neurosci. 2013;7:175.CrossRefGoogle Scholar
  21. 21.
    Cenci MA, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nat Rev Neurosci. 2002;3:574–9.CrossRefGoogle Scholar
  22. 22.
    German RZ, Crompton AW, Gould FD, Thexton AJ. Animal models for dysphagia studies: what have we learnt so far. Dysphagia. 2017;32:73–7.CrossRefGoogle Scholar
  23. 23.
    Guo J-F, Wang L, He D, Yang QHO, Duan Z-X, Zhang X-W, Nie L-L, Yan X-X, Tang B-S. Clinical features and [11C]-CFT PET analysis of PARK2, PARK6, PARK7-linked autosomal recessive early onset Parkinsonism. Neurol Sci. 2011;32:35–40.CrossRefGoogle Scholar
  24. 24.
    Albanese A, Valente EM, Romito LM, Bellacchio E, Elia AE, Dallapiccola B. The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology. 2005;64:1958–60.CrossRefGoogle Scholar
  25. 25.
    Bonifati V, Rohé CF, Breedveld GJ, Fabrizio E, De Mari M, Tassorelli C, Tavella A, Marconi R, Nicholl DJ, Chien HF, Fincati E, Abbruzzese G, Marini P, De Gaetano A, Horstink MW, Maat-Kievit JA, Sampaio C, Antonini A, Stocchi F, Montagna P, Toni V, Guidi M, Libera AD, Tinazzi M, De Pandis F, Fabbrini G, Goldwurm S, de Klein A, Barbosa E, Lopiano L, Martignoni E, Lamberti P, Vanacore N, Meco G, Oostra BA, Network TIPG. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology. 2005;65:87–95.CrossRefGoogle Scholar
  26. 26.
    Bonifati V. Autosomal recessive parkinsonism. Parkinsonism Relat Disord. 2012;18(Supplement 1):S4–6.CrossRefGoogle Scholar
  27. 27.
    Grant LM, Kelm-Nelson CA, Hilby BL, Blue KV, Paul Rajamanickam ES, Pultorak JD, Fleming SM, Ciucci MR. Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 gene knockout rat model of Parkinson’s disease. J Neurosci Res. 2015;93:1713–27.CrossRefGoogle Scholar
  28. 28.
    Dave KD, De Silva S, Sheth NP, Ramboz S, Beck MJ, Quang C, Switzer Iii RC, Ahmad SO, Sunkin SM, Walker D, Cui X, Fisher DA, McCoy AM, Gamber K, Ding X, Goldberg MS, Benkovic SA, Haupt M, Baptista MAS, Fiske BK, Sherer TB, Frasier MA. Phenotypic characterization of recessive gene knockout rat models of Parkinson’s disease. Neurobiol Dis. 2014;70:190–203.CrossRefGoogle Scholar
  29. 29.
    Kelm-Nelson CA, Stevenson SA, Ciucci MR. Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 -/- rat model of Parkinson disease. Neurosci Lett. 2016;621:75–82.CrossRefGoogle Scholar
  30. 30.
    Jones CA, Ciucci MR. Multimodal swallowing evaluation with high-resolution manometry reveals subtle swallowing changes in early and mid-stage Parkinson disease. J Parkinsons Dis. 2016;6:197–208.CrossRefGoogle Scholar
  31. 31.
    Russell JA, Ciucci MR, Hammer MJ, Connor NP. Videofluorographic assessment of deglutitive behaviors in a rat model of aging and Parkinson disease. Dysphagia. 2012;28:95–104.CrossRefGoogle Scholar
  32. 32.
    Ciucci MR, Grant LM, Rajamanickam ESP, Hilby BL, Blue KV, Jones CA, Kelm-Nelson CA. Early identification and treatment of communication and swallowing deficits in Parkinson disease. Semin Speech Lang. 2013;34:185–202.CrossRefGoogle Scholar
  33. 33.
    Sengupta P. The laboratory rat: relating its age with human’s. Int J Prev Med. 2013;4:624–30.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Ibáñez P, Lesage S, Lohmann E, Thobois S, Michele GD, Borg M, Agid Y, Dürr A, Brice A, French Parkinson’s Disease Genetics Study Group. Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain. 2006;129:686–94.CrossRefGoogle Scholar
  35. 35.
    Kumazawa R, Tomiyama H, Li Y, Imamichi Y, Funayama M, Yoshino H, Yokochi F, Fukusako T, Takehisa Y, Kashihara K, Kondo T, Elibol B, Bostantjopoulou S, Toda T, Takahashi H, Yoshii F, Yoshikuni M, Hattori N. Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. Arch Neurol. 2008;65:802–8.CrossRefGoogle Scholar
  36. 36.
    Paxinos G, Watson G. The rat brain in stereotaxic coordinates. 5th ed. Burlington: Elsevier; 2005.Google Scholar
  37. 37.
    Plowman-Prine EK, Sapienza CM, Okun MS, Pollock SL, Jacobson C, Wu SS, Rosenbek JC. The relationship between quality of life and swallowing in Parkinson’s disease. Mov Disord. 2009;24:1352–8.CrossRefGoogle Scholar
  38. 38.
    Arias P, Robles-Garcia V, Espinosa N, Corral Y, Cudeiro J. Validity of the finger tapping test in Parkinson’s disease, elderly and young healthy subjects: is there a role for central fatigue? Clin Neurophysiol. 2012;123:2034–41.CrossRefGoogle Scholar
  39. 39.
    Baltadjieva R, Giladi N, Gruendlinger L, Peretz C, Hausdorff JM. Marked alterations in the gait timing and rhythmicity of patients with de novo Parkinson’s disease. Eur J Neurosci. 2006;24:1815–20.CrossRefGoogle Scholar
  40. 40.
    Skodda S. Aspects of speech rate and regularity in Parkinson’s disease. J Neurol Sci. 2011;310:231–6.CrossRefGoogle Scholar
  41. 41.
    Dromey C, Kumar R, Lang AE, Lozano AM. An investigation of the effects of subthalamic nucleus stimulation on acoustic measures of voice. Mov Disord. 2000;15:1132–8.CrossRefGoogle Scholar
  42. 42.
    Pinto S, Thobois S, Costes N, Le Bars D, Benabid AL, Broussolle E, Pollak P, Gentil M. Subthalamic nucleus stimulation and dysarthria in Parkinson’s disease: a PET study. Brain. 2004;127:602–15.CrossRefGoogle Scholar
  43. 43.
    Schulz GM, Grant MK. Effects of speech therapy and pharmacologic and surgical treatments on voice and speech in Parkinson’s disease: a review of the literature. J Commun Disord. 2000;33:59–88.CrossRefGoogle Scholar
  44. 44.
    Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson’s disease. Parkinsonism Relat Disord. 2010;16:79–84.CrossRefGoogle Scholar
  45. 45.
    Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.CrossRefGoogle Scholar
  46. 46.
    Braak H, Ghebremedhin E, Rüb U, Bratzke H, Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004;318:121–34.CrossRefGoogle Scholar
  47. 47.
    Kessler JP, Jean A. Identification of the medullary swallowing regions in the rat. Exp Brain Res. 1985;57:256–63.CrossRefGoogle Scholar
  48. 48.
    Jean A. Brain stem control of swallowing: neuronal network and cellular mechanisms. Physiol Rev. 2001;81:929–69.CrossRefGoogle Scholar
  49. 49.
    Ciucci MR, Connor NP. Dopaminergic influence on rat tongue function and limb movement initiation. Exp Brain Res. 2009;194:587.CrossRefGoogle Scholar
  50. 50.
    Ciucci MR, Russell JA, Schaser AJ, Doll EJ, Vinney LM, Connor NP. Tongue force and timing deficits in a rat model of Parkinson disease. Behav Brain Res. 2011;222:315–20.CrossRefGoogle Scholar
  51. 51.
    Holman SD, Campbell-Malone R, Ding P, Gierbolini-Norat EM, Griffioen AM, Inokuchi H, Lukasik SL, German RZ. Development, reliability, and validation of an infant mammalian penetration-aspiration scale. Dysphagia. 2013;28:178–87.CrossRefGoogle Scholar
  52. 52.
    Miller AJ. The neurobiology of swallowing and dysphagia. Dev Disabil Res Rev. 2008;14:77–86.CrossRefGoogle Scholar
  53. 53.
    Martin RE. Neuroplasticity and swallowing. Dysphagia. 2009;24:218–29.CrossRefGoogle Scholar
  54. 54.
    Malandraki GA, Sutton BP, Perlman AL, Karampinos DC, Conway C. Neural activation of swallowing and swallowing-related tasks in healthy young adults: an attempt to separate the components of deglutition. Hum Brain Mapp. 2009;30:3209–26.CrossRefGoogle Scholar
  55. 55.
    Humbert IA, Robbins J. Normal swallowing and functional magnetic resonance imaging: a systematic review. Dysphagia. 2007;22:266–75.CrossRefGoogle Scholar
  56. 56.
    Michou E, Hamdy S. Cortical input in control of swallowing. Curr Opin Otolaryngol Head Neck Surg. 2009;17:166–71.CrossRefGoogle Scholar
  57. 57.
    Sung HY, Kim J-S, Lee K-S, Kim Y-I, Song I-U, Chung S-W, Yang D-W, Cho YK, Park JM, Lee IS, Kim SW, Chung I-S, Choi M-G. The prevalence and patterns of pharyngoesophageal dysmotility in patients with early stage Parkinson’s disease. Mov Disord. 2010;25:2361–8.CrossRefGoogle Scholar
  58. 58.
    Rusz J, Čmejla R, Růžičková H, Klempíř J, Majerová V, Picmausová J, Roth J, Růžička E. Acoustic assessment of voice and speech disorders in Parkinson’s disease through quick vocal test. Mov Disord. 2011;26:1951–2.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Communication Sciences and DisordersUniversity of Wisconsin–MadisonMadisonUSA
  2. 2.Division of Otolaryngology, Department of SurgeryUniversity of Wisconsin–MadisonMadisonUSA
  3. 3.Neuroscience Training ProgramUniversity of Wisconsin–MadisonMadisonUSA

Personalised recommendations