Cholinergic system changes of falls and freezing of gait in Parkinson's disease

Nicolaas I. Bohnen, Prabesh Kanel, Zhi Zhou, Robert A. Koeppe, Kirk A. Frey, William T. Dauer, Roger L. Albin, Martijn L.T.M. Müller

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Objective: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. Methods: Ninety-four PD subjects underwent clinical assessment and VAChT ([ 18 F]FEOBV) PET. Results: Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. Interpretation: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538–549.

Original languageEnglish (US)
Pages (from-to)538-549
Number of pages12
JournalAnnals of Neurology
Volume85
Issue number4
DOIs
StatePublished - Apr 2019
Externally publishedYes

Fingerprint

Vesicular Acetylcholine Transport Proteins
Gait
Cholinergic Agents
Freezing
Parkinson Disease
Positron-Emission Tomography
Geniculate Bodies
Corpus Striatum
Thalamus
History
Caudate Nucleus
Interneurons
Acetylcholinesterase
Synapses
Ligands
Brain

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Bohnen, N. I., Kanel, P., Zhou, Z., Koeppe, R. A., Frey, K. A., Dauer, W. T., ... Müller, M. L. T. M. (2019). Cholinergic system changes of falls and freezing of gait in Parkinson's disease. Annals of Neurology, 85(4), 538-549. https://doi.org/10.1002/ana.25430

Cholinergic system changes of falls and freezing of gait in Parkinson's disease. / Bohnen, Nicolaas I.; Kanel, Prabesh; Zhou, Zhi; Koeppe, Robert A.; Frey, Kirk A.; Dauer, William T.; Albin, Roger L.; Müller, Martijn L.T.M.

In: Annals of Neurology, Vol. 85, No. 4, 04.2019, p. 538-549.

Research output: Contribution to journalArticle

Bohnen, NI, Kanel, P, Zhou, Z, Koeppe, RA, Frey, KA, Dauer, WT, Albin, RL & Müller, MLTM 2019, 'Cholinergic system changes of falls and freezing of gait in Parkinson's disease', Annals of Neurology, vol. 85, no. 4, pp. 538-549. https://doi.org/10.1002/ana.25430
Bohnen, Nicolaas I. ; Kanel, Prabesh ; Zhou, Zhi ; Koeppe, Robert A. ; Frey, Kirk A. ; Dauer, William T. ; Albin, Roger L. ; Müller, Martijn L.T.M. / Cholinergic system changes of falls and freezing of gait in Parkinson's disease. In: Annals of Neurology. 2019 ; Vol. 85, No. 4. pp. 538-549.
@article{67cd2a1d50014334b70f863d7e9cee93,
title = "Cholinergic system changes of falls and freezing of gait in Parkinson's disease",
abstract = "Objective: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. Methods: Ninety-four PD subjects underwent clinical assessment and VAChT ([ 18 F]FEOBV) PET. Results: Thirty-five subjects (37.2{\%}) reported a history of falls, and 15 (16{\%}) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. Interpretation: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538–549.",
author = "Bohnen, {Nicolaas I.} and Prabesh Kanel and Zhi Zhou and Koeppe, {Robert A.} and Frey, {Kirk A.} and Dauer, {William T.} and Albin, {Roger L.} and M{\"u}ller, {Martijn L.T.M.}",
year = "2019",
month = "4",
doi = "10.1002/ana.25430",
language = "English (US)",
volume = "85",
pages = "538--549",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

TY - JOUR

T1 - Cholinergic system changes of falls and freezing of gait in Parkinson's disease

AU - Bohnen, Nicolaas I.

AU - Kanel, Prabesh

AU - Zhou, Zhi

AU - Koeppe, Robert A.

AU - Frey, Kirk A.

AU - Dauer, William T.

AU - Albin, Roger L.

AU - Müller, Martijn L.T.M.

PY - 2019/4

Y1 - 2019/4

N2 - Objective: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. Methods: Ninety-four PD subjects underwent clinical assessment and VAChT ([ 18 F]FEOBV) PET. Results: Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. Interpretation: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538–549.

AB - Objective: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. Methods: Ninety-four PD subjects underwent clinical assessment and VAChT ([ 18 F]FEOBV) PET. Results: Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. Interpretation: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538–549.

UR - http://www.scopus.com/inward/record.url?scp=85062964469&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062964469&partnerID=8YFLogxK

U2 - 10.1002/ana.25430

DO - 10.1002/ana.25430

M3 - Article

C2 - 30720884

AN - SCOPUS:85062964469

VL - 85

SP - 538

EP - 549

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 4

ER -