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Cholinergic nucleus 4 atrophy and gait impairment in Parkinson’s disease

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Abstract

Background

There is evidence that cortical cholinergic denervation contributes to gait and balance impairment in Parkinson’s Disease (PD), especially reduced gait speed.

Objectives

The objective of this study was to determine the relationship between cholinergic basal forebrain gray matter density (GMD) and gait in PD patients.

Methods

We investigated 66 PD patients who underwent a pre-surgical evaluation for a neurosurgical procedure to treat motor symptoms of PD. As part of this evaluation patients had a brain MRI and formal gait assessments. By applying probabilistic maps of the cholinergic basal forebrain to voxel-based morphometry of brain MRI, we calculated gray matter density (GMD) for cholinergic nucleus 4 (Ch4), cholinergic nucleus 1, 2, and 3 (Ch123), and the entire cortex.

Results

Reduced Ch4 GMD was associated with reduced Fast Walking Speed in the “on” medication state (FWSON, p = 0.004). Bilateral cortical GMD was also associated with FWSON (p = 0.009), but Ch123 GMD was not (p = 0.1). Bilateral cortical GMD was not associated with FWSON after adjusting for Ch4 GMD (p = 0.44). While Ch4 GMD was not associated with improvement in Timed Up and Go (TUG) or Cognitive TUG in the “on” medication state, reduced Ch4 GMD was associated with greater percent worsening based on dual tasks (p = 0.021).

Conclusions

Reduced Ch4 GMD is associated with slower gait speed in PD and greater percent worsening in TUG during dual tasks in patients with PD. These findings have implications for planning of future clinical trials investigating cholinergic therapies to improve gait impairment in PD.

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References

  1. Debu B, De Oliveira GC, Lino JC, Moro E (2018) Managing gait, balance, and posture in Parkinson’s disease. Curr Neurol Neurosci Rep 18:23. https://doi.org/10.1007/s11910-018-0828-4

    Article  CAS  PubMed  Google Scholar 

  2. Smulders K, Dale ML, Carlson-Kuhta P et al (2016) Pharmacological treatment in Parkinson’s disease: effects on gait. Parkinsonism Relat Disord 31:3–13. https://doi.org/10.1016/j.parkreldis.2016.07.006

    Article  PubMed  PubMed Central  Google Scholar 

  3. Muslimovic D, Post B, Speelman JD et al (2008) Determinants of disability and quality of life in mild to moderate Parkinson disease. Neurology 70:2241–2247. https://doi.org/10.1212/01.wnl.0000313835.33830.80

    Article  CAS  PubMed  Google Scholar 

  4. Schrag A, Hovris A, Morley D et al (2006) Caregiver-burden in parkinson’s disease is closely associated with psychiatric symptoms, falls, and disability. Parkinsonism Relat Disord 12:35–41. https://doi.org/10.1016/j.parkreldis.2005.06.011

    Article  PubMed  Google Scholar 

  5. Bohnen NI, Jahn K (2013) Imaging: What can it tell us about parkinsonian gait? Mov Disord 28:1492–1500. https://doi.org/10.1002/mds.25534

    Article  PubMed  PubMed Central  Google Scholar 

  6. Morris R, Martini DN, Madhyastha T et al (2019) Overview of the cholinergic contribution to gait, balance and falls in Parkinson’s disease. Parkinsonism Relat Disord 63:20–30. https://doi.org/10.1016/j.parkreldis.2019.02.017

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kucinski A, Paolone G, Bradshaw M et al (2013) Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci 33:16522–16539. https://doi.org/10.1523/JNEUROSCI.2545-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kelly VE, Eusterbrock AJ, Shumway-Cook A (2012) A review of dual-task walking deficits in people with Parkinson’s disease: motor and cognitive contributions, mechanisms, and clinical implications. Parkinsons Dis 2012:918719. https://doi.org/10.1155/2012/918719

    Article  PubMed  Google Scholar 

  9. Bohnen NI, Albin RL (2011) The cholinergic system and Parkinson disease. Behav Brain Res 221:564–573. https://doi.org/10.1016/j.bbr.2009.12.048

    Article  CAS  PubMed  Google Scholar 

  10. Mesulam MM (1996) The systems-level organization of cholinergic innervation in the human cerebral cortex and its alterations in Alzheimer’s disease. Prog Brain Res 109:285–297. https://doi.org/10.1016/s0079-6123(08)62112-3

    Article  CAS  PubMed  Google Scholar 

  11. Karachi C, Grabli D, Bernard FA et al (2010) Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease. J Clin Invest 120:2745–2754. https://doi.org/10.1172/JCI42642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yarnall A, Rochester L, Burn DJ (2011) The interplay of cholinergic function, attention, and falls in Parkinson’s disease. Mov Disord 26:2496–2503. https://doi.org/10.1002/mds.23932

    Article  PubMed  Google Scholar 

  13. Bohnen NI, Muller MLTM, Kotagal V et al (2012) Heterogeneity of cholinergic denervation in Parkinson’s disease without dementia. J Cereb Blood Flow Metab 32:1609–1617. https://doi.org/10.1038/jcbfm.2012.60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bohnen NI, Frey KA, Studenski S et al (2013) Gait speed in Parkinson disease correlates with cholinergic degeneration. Neurology 81:1611–1616. https://doi.org/10.1212/WNL.0b013e3182a9f558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rochester L, Yarnall AJ, Baker MR et al (2012) Cholinergic dysfunction contributes to gait disturbance in early Parkinson’s disease. Brain 135:2779–2788. https://doi.org/10.1093/brain/aws207

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mechelli A, Friston KJ, Frackowiak RS, Price CJ (2005) Structural covariance in the human cortex. J Neurosci 25:8303–8310. https://doi.org/10.1523/JNEUROSCI.0357-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ashburner J, Friston KJ (2000) Voxel-based morphometry–the methods. Neuroimage 11:805–821. https://doi.org/10.1006/nimg.2000.0582

    Article  CAS  PubMed  Google Scholar 

  18. Zaborszky L, Hoemke L, Mohlberg H et al (2008) Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. Neuroimage 42:1127–1141. https://doi.org/10.1016/j.neuroimage.2008.05.055

    Article  PubMed  PubMed Central  Google Scholar 

  19. Morris S, Morris ME, Iansek R (2001) Reliability of measurements obtained with the Timed “Up & Go” test in people with Parkinson disease. Phys Ther 81:810–818. https://doi.org/10.1093/ptj/81.2.810

    Article  CAS  PubMed  Google Scholar 

  20. Barrett MJ, Sperling SA, Blair JC et al (2019) Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease. J Neurol Neurosurg Psychiatry 90:1251–1256. https://doi.org/10.1136/jnnp-2019-320450

    Article  PubMed  Google Scholar 

  21. Bohland JW, Bokil H, Allen CB, Mitra PP (2009) The brain atlas concordance problem: quantitative comparison of anatomical parcellations. PLoS ONE 4:e7200. https://doi.org/10.1371/journal.pone.0007200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Henderson EJ, Lord SR, Brodie MA et al (2016) Rivastigmine for gait stability in patients with Parkinson’s disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15:249–258. https://doi.org/10.1016/S1474-4422(15)00389-0

    Article  CAS  PubMed  Google Scholar 

  23. Bohnen NI, Kaufer DI, Hendrickson R et al (2006) Cognitive correlates of cortical cholinergic denervation in Parkinson’s disease and parkinsonian dementia. J Neurol 253:242–247. https://doi.org/10.1007/s00415-005-0971-0

    Article  CAS  PubMed  Google Scholar 

  24. Bohnen NI, Albin RL, Muller MLTM et al (2015) Frequency of cholinergic and caudate nucleus dopaminergic deficits across the predemented cognitive spectrum of Parkinson disease and evidence of interaction effects. JAMA Neurol 72:194–200. https://doi.org/10.1001/jamaneurol.2014.2757

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bohnen NI, Muller MLTM, Koeppe RA et al (2009) History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 73:1670–1676. https://doi.org/10.1212/WNL.0b013e3181c1ded6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Craig CE, Jenkinson NJ, Brittain J-S et al (2020) Pedunculopontine nucleus microstructure predicts postural and gait symptoms in Parkinson’s disease. Mov Disord. https://doi.org/10.1002/mds.28051

    Article  PubMed  Google Scholar 

  27. Chung KA, Lobb BM, Nutt JG, Horak FB (2010) Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 75:1263–1269. https://doi.org/10.1212/WNL.0b013e3181f6128c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li Z, Yu Z, Zhang J et al (2015) Impact of rivastigmine on cognitive dysfunction and falling in Parkinson’s disease patients. Eur Neurol 74:86–91. https://doi.org/10.1159/000438824

    Article  CAS  PubMed  Google Scholar 

  29. Granger AJ, Mulder N, Saunders A, Sabatini BL (2016) Cotransmission of acetylcholine and GABA. Neuropharmacology 100:40–46. https://doi.org/10.1016/j.neuropharm.2015.07.031

    Article  CAS  PubMed  Google Scholar 

  30. Nickerson Poulin A, Guerci A, El Mestikawy S, Semba K (2006) Vesicular glutamate transporter 3 immunoreactivity is present in cholinergic basal forebrain neurons projecting to the basolateral amygdala in rat. J Comp Neurol 498:690–711. https://doi.org/10.1002/cne.21081

    Article  CAS  PubMed  Google Scholar 

  31. Hampel H, Mesulam M-M, Cuello AC et al (2018) The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141:1917–1933. https://doi.org/10.1093/brain/awy132

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yogev G, Giladi N, Peretz C et al (2005) Dual tasking, gait rhythmicity, and Parkinson’s disease: which aspects of gait are attention demanding? Eur J Neurosci 22:1248–1256. https://doi.org/10.1111/j.1460-9568.2005.04298.x

    Article  PubMed  Google Scholar 

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Funding

This work was supported by Office of the Assistant Secretary of Defense for Health Affairs through the Neurotoxin Exposure Treatment Parkinson's Research Program under Award No. W81XWH- 16-1-0768. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Virginia, 1221 Lee St 4th Floor, Charlottesville, VA, 22908, USA

    W. Alex Dalrymple, Joseph L. Flanigan, Scott A. Sperling, Binit B. Shah, Madaline B. Harrison & Matthew J. Barrett

  2. Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA

    Diane S. Huss

  3. Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA

    Jamie Blair & T. Jason Druzgal

  4. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    James Patrie

  5. Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA

    Matthew J. Barrett

Authors
  1. W. Alex Dalrymple
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  2. Diane S. Huss
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  3. Jamie Blair
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Contributions

Conception and design of the study: MJB. Data collection: DSH, JB, JLF, SAS, BBS, MBH, TJD. Data analysis: WAD, JB, JLF, JP, TJD, MJB. Writing of the first draft: WAD. Manuscript revisions: WAD, DSH, JB, JLF, SAS, BBS, MBH, TJD, MJB.

Corresponding author

Correspondence to W. Alex Dalrymple.

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Conflicts of interest

The authors declare that there are no conflicts of interest relevant to this work.

Consent to participate

Informed consent was not required for this study as it was retrospective in nature and all identifying information was removed.

Consent for publication

The authors certify that this manuscript is an original work, has not been previously published, and is not under consideration for publication in another journal at this time.

Ethical approval

This work was approved by the Institutional Review Board at the University of Virginia. Given the retrospective nature of the work and the fact that all patient information was de-identified, informed patient consent was not necessary for this work. All authors confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

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Dalrymple, W.A., Huss, D.S., Blair, J. et al. Cholinergic nucleus 4 atrophy and gait impairment in Parkinson’s disease. J Neurol 268, 95–101 (2021). https://doi.org/10.1007/s00415-020-10111-2

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  • DOI: https://doi.org/10.1007/s00415-020-10111-2

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