Abstract
To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxybenzovesamicol ([18F]-FEOBV) PET binding in Parkinson’ disease (PD) patients with and without vestibular sensory conflict deficits (VSCD). To examine associations between VSCD-associated cholinergic brain deficits and postural instability and gait difficulties (PIGD). PD persons (M70/F22; mean age 67.6 ± 7.4 years) completed clinical assessments for imbalance, falls, freezing of gait (FoG), modified Romberg sensory conflict testing, and underwent VAChT PET. Volumes of interest (VOI)-based analyses included detailed thalamic and cerebellar parcellations. VSCD-associated VAChT VOI selection used stepwise logistic regression analysis. Vesicular monoamine transporter type 2 (VMAT2) [11C]dihydrotetrabenazine (DTBZ) PET imaging was available in 54 patients. Analyses of covariance were performed to compare VSCD-associated cholinergic deficits between patients with and without PIGD motor features while accounting for confounders. PET sampling passed acceptance criteria in 73 patients. This data-driven analysis identified cholinergic deficits in five brain VOIs associating with the presence of VSCD: medial geniculate nucleus (MGN) (P < 0.0001), para-hippocampal gyrus (P = 0.0043), inferior nucleus of the pulvinar (P = 0.047), fusiform gyrus (P = 0.035) and the amygdala (P = 0.019). Composite VSCD-associated [18F]FEOBV-binding deficits in these 5 regions were significantly lower in patients with imbalance (− 8.3%, F = 6.5, P = 0.015; total model: F = 5.1, P = 0.0008), falls (− 6.9%, F = 4.9, P = 0.03; total model F = 4.7, P = 0.0015), and FoG (− 14.2%, F = 9.0, P = 0.0043; total model F = 5.8, P = 0.0003), independent of age, duration of disease, gender and nigrostriatal dopaminergic losses. Post hoc analysis using MGN VAChT binding as the single cholinergic VOI demonstrated similar significant associations with imbalance, falls and FoG. VSCD-associated cholinergic network changes localize to distinct structures involved in multi-sensory, in particular vestibular, and multimodal cognitive and motor integration brain regions. Relative clinical effects of VSCD-associated cholinergic network deficits were largest for FoG followed by postural imbalance and falls. The MGN was the most significant region identified.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aghourian M, Legault-Denis C, Soucy JP, Rosa-Neto P, Gauthier S, Kostikov A, Gravel P, Bedard MA (2017) Quantification of brain cholinergic denervation in Alzheimer’s disease using PET imaging with [18F]-FEOBV. Mol Psychiatry 22(11):1531–1538. https://doi.org/10.1038/mp.2017.183
Agrawal Y, Carey JP, Hoffman HJ, Sklare DA, Schubert MC (2011) The modified Romberg balance test: normative data in U.S. adults. Otol Neurotol 32(8):1309–1311. https://doi.org/10.1097/MAO.0b013e31822e5bee
Agrawal Y, Davalos-Bichara M, Zuniga MG, Carey JP (2013) Head impulse test abnormalities and influence on gait speed and falls in older individuals. Otol Neurotol 34(9):1729–1735. https://doi.org/10.1097/MAO.0b013e318295313c
Aguirre GK, Detre JA, Alsop DC, D’Esposito M (1996) The parahippocampus subserves topographical learning in man. Cereb Cortex 6(6):823–829. https://doi.org/10.1093/cercor/6.6.823
Becker-Bense S, Wittmann C, van Wensen E, van Leeuwen RB, Bloem B, Dieterich M (2017) Prevalence of Parkinson symptoms in patients with different peripheral vestibular disorders. J Neurol 264(6):1287–1289. https://doi.org/10.1007/s00415-017-8470-7
Benarroch EE (2015) Pulvinar: associative role in cortical function and clinical correlations. Neurology 84(7):738–747. https://doi.org/10.1212/wnl.0000000000001276
Berman RA, Wurtz RH (2010) Functional identification of a pulvinar path from superior colliculus to cortical area MT. J Neurosci 30(18):6342–6354. https://doi.org/10.1523/jneurosci.6176-09.2010
Best C, Lange E, Buchholz HG, Schreckenberger M, Reuss S, Dieterich M (2014) Left hemispheric dominance of vestibular processing indicates lateralization of cortical functions in rats. Brain Struct Funct 219(6):2141–2158. https://doi.org/10.1007/s00429-013-0628-1
Black RD, Rogers LL, Ade KK, Nicoletto HA, Adkins HD, Laskowitz DT (2016) Non-invasive neuromodulation using time-varying caloric vestibular stimulation. IEEE J Transl Eng Health Med 4:2000310. https://doi.org/10.1109/jtehm.2016.2615899
Bohnen NI, Muller ML, Koeppe RA, Studenski SA, Kilbourn MA, Frey KA, Albin RL (2009) History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 73(20):1670–1676. https://doi.org/10.1212/WNL.0b013e3181c1ded6 (73/20/1670[pii])
Bohnen NI, Muller ML, Kotagal V, Koeppe RA, Kilbourn MR, Gilman S, Albin RL, Frey KA (2012) Heterogeneity of cholinergic denervation in Parkinson’s disease without dementia. J Cereb Blood Flow Metab 32(8):1609–1617. https://doi.org/10.1038/jcbfm.2012.60
Bohnen NI, Frey KA, Studenski S, Kotagal V, Koeppe RA, Constantine GM, Scott PJ, Albin RL, Muller ML (2014) Extra-nigral pathological conditions are common in Parkinson’s disease with freezing of gait: an in vivo positron emission tomography study. Mov Disord 29(9):1118–1124. https://doi.org/10.1002/mds.25929
Bohnen NI, Kanel P, Zhou Z, Koeppe RA, Frey KA, Dauer WT, Albin RL, Muller M (2019) Cholinergic system changes of falls and freezing of gait in Parkinson’s disease. Ann Neurol 85(4):538–549. https://doi.org/10.1002/ana.25430
Bohnen NI, Kanel P, Koeppe RA, Sanchez-Catasus CA, Frey KA, Scott P, Constantine GM, Albin RL, Muller MLTM (2021) Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson’s disease. Brain Commun 3(2):fcab109. https://doi.org/10.1093/braincomms/fcab109
Borra E, Luppino G (2017) Functional anatomy of the macaque temporo-parieto-frontal connectivity. Cortex 97:306–326. https://doi.org/10.1016/j.cortex.2016.12.007
Brown AR, Hu B, Kolb B, Teskey GC (2010) Acoustic tone or medial geniculate stimulation cue training in the rat is associated with neocortical neuroplasticity and reduced akinesia under haloperidol challenge. Behav Brain Res 214(1):85–90. https://doi.org/10.1016/j.bbr.2010.03.048
Cohen HS, Kimball KT (2008) Usefulness of some current balance tests for identifying individuals with disequilibrium due to vestibular impairments. J Vestib Res 18(5–6):295–303
Cohen H, Blatchly CA, Gombash LL (1993) A study of the clinical test of sensory interaction and balance. Phys Ther 73(6):346–351. https://doi.org/10.1093/ptj/73.6.346 (discussion 351-344)
Diedrichsen J (2006) A spatially unbiased atlas template of the human cerebellum. Neuroimage 33(1):127–138. https://doi.org/10.1016/j.neuroimage.2006.05.056
Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, Moore CG, Wenning GK, Yahr MD, Seidl L (2004) Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19(9):1020–1028. https://doi.org/10.1002/mds.20213
Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT, Stern MB, Tilley BC, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, Lewitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, Van Hilten JJ, Lapelle N (2007) Movement Disorder Society-sponsored revision of the Unified Parkinson’s disease Rating Scale (MDS-UPDRS): process, format, and clinimetric testing plan. Mov Disord 22:41–47
Halassa MM, Kastner S (2017) Thalamic functions in distributed cognitive control. Nat Neurosci 20(12):1669–1679. https://doi.org/10.1038/s41593-017-0020-1
Heiss WD, Habedank B, Klein JC, Herholz K, Wienhard K, Lenox M, Nutt R (2004) Metabolic rates in small brain nuclei determined by high-resolution PET. J Nucl Med 45(11):1811–1815
Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184
Iglesias JE, Insausti R, Lerma-Usabiaga G, Bocchetta M, Van Leemput K, Greve DN, van der Kouwe A, Fischl B, Caballero-Gaudes C, Paz-Alonso PM (2018) A probabilistic atlas of the human thalamic nuclei combining ex vivo MRI and histology. Neuroimage 183:314–326. https://doi.org/10.1016/j.neuroimage.2018.08.012
Jones EG (2007) The thalamus. Cambridge University Press, Cambridge
Klein A, Tourville J (2012) 101 labeled brain images and a consistent human cortical labeling protocol. Front Neurosci 6:171. https://doi.org/10.3389/fnins.2012.00171
Koeppe RA, Frey KA, Kume A, Albin R, Kilbourn MR, Kuhl DE (1997) Equilibrium versus compartmental analysis for assessment of the vesicular monoamine transporter using (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) and positron emission tomography. J Cereb Blood Flow Metab 17(9):919–931
Kotchabhakdi N, Rinvik E, Walberg F, Yingchareon K (1980) The vestibulothalamic projections in the cat studied by retrograde axonal transport of horseradish peroxidase. Exp Brain Res 40(4):405–418. https://doi.org/10.1007/bf00236149
LeDoux JE, Ruggiero DA, Reis DJ (1985) Projections to the subcortical forebrain from anatomically defined regions of the medial geniculate body in the rat. J Comp Neurol 242(2):182–213. https://doi.org/10.1002/cne.902420204
LeDoux JE, Farb C, Ruggiero DA (1990) Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J Neurosci 10(4):1043–1054. https://doi.org/10.1523/jneurosci.10-04-01043.1990
Lee JM, Koh SB, Chae SW, Seo WK, Kwon DY, Kim JH, Oh K, Baik JS, Park KW (2012) Postural instability and cognitive dysfunction in early Parkinson’s disease. Can J Neurol Sci 39(4):473–482. https://doi.org/10.1017/s0317167100013986
Logan J, Fowler JS, Volkow ND, Ding YS, Wang GJ, Alexoff DL (2001) A strategy for removing the bias in the graphical analysis method. J Cereb Blood Flow Metab 21:307–320
Lopez IC, Ruiz PJ, Del Pozo SV, Bernardos VS (2010) Motor complications in Parkinson’s disease: ten year follow-up study. Mov Disord 25(16):2735–2739. https://doi.org/10.1002/mds.23219
Lyon DC, Nassi JJ, Callaway EM (2010) A disynaptic relay from superior colliculus to dorsal stream visual cortex in macaque monkey. Neuron 65(2):270–279. https://doi.org/10.1016/j.neuron.2010.01.003
Maguire EA, Frackowiak RS, Frith CD (1996) Learning to find your way: a role for the human hippocampal formation. Proc Biol Sci 263(1377):1745–1750. https://doi.org/10.1098/rspb.1996.0255
Mergner T, Deecke L, Wagner HJ (1981) Vestibulo-thalamic projection to the anterior suprasylvian cortex of the cat. Exp Brain Res 44(4):455–458. https://doi.org/10.1007/bf00238841
Motts SD, Schofield BR (2010) Cholinergic and non-cholinergic projections from the pedunculopontine and laterodorsal tegmental nuclei to the medial geniculate body in Guinea pigs. Front Neuroanat 4:137. https://doi.org/10.3389/fnana.2010.00137
Muller ML, Albin RL, Kotagal V, Koeppe RA, Scott PJ, Frey KA, Bohnen NI (2013) Thalamic cholinergic innervation and postural sensory integration function in Parkinson’s disease. Brain 136(Pt 11):3282–3289. https://doi.org/10.1093/brain/awt247awt247[pii]
Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53(4):695–699. https://doi.org/10.1111/j.1532-5415.2005.53221.x (JGS53221[pii])
Nejad-Davarani S, Koeppe RA, Albin RL, Frey KA, Muller M, Bohnen NI (2018) Quantification of brain cholinergic denervation in dementia with Lewy bodies using PET imaging with [(18)F]-FEOBV. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0130-5
Petrou M, Frey KA, Kilbourn MR, Scott PJ, Raffel DM, Bohnen NI, Muller ML, Albin RL, Koeppe RA (2014) In vivo imaging of human cholinergic nerve terminals with (-)-5-18F-fluoroethoxybenzovesamicol: biodistribution, dosimetry, and tracer kinetic analyses. J Nucl Med 55(3):396–404. https://doi.org/10.2967/jnumed.113.124792
Potegal M, Copack P, de Jong J, Krauthamer G, Gilman S (1971) Vestibular input to the caudate nucleus. Exp Neurol 32(3):448–465. https://doi.org/10.1016/0014-4886(71)90011-2
Shao X, Hoareau R, Hockley BG, Tluczek LJ, Henderson BD, Padgett HC, Scott PJ (2011a) Highlighting the versatility of the tracerlab synthesis modules. Part 1: fully automated production of [18F] labelled radiopharmaceuticals using a tracerlab FXFN. J Labelled Comp Radiopharm 54(6):292–307. https://doi.org/10.1002/jlcr.1865
Shao X, Hoareau R, Runkle AC, Tluczek LJM, Hockley BG, Henderson BD, Scott PJH (2011b) Highlighting the versatility of the tracerlab synthesis modules. Part 2: fully automated production of [11C] labelled radiopharmaceuticals using a tracerlab FXC-Pro. J Labelled Comp Radiopharm 54:819–838. https://doi.org/10.1002/jlcr.1865
Shumway-Cook A, Horak FB (1986) Assessing the influence of sensory interaction of balance. Suggestion from the field. Phys Ther 66(10):1548–1550
Squire LR, Zola-Morgan S (1991) The medial temporal lobe memory system. Science 253(5026):1380–1386. https://doi.org/10.1126/science.1896849
Taguchi S, Tanabe N, Niwa JI, Doyu M (2019) Motor improvement-related regional cerebral blood flow changes in Parkinson’s disease in response to antiparkinsonian drugs. Parkinsons Dis 2019:7503230. https://doi.org/10.1155/2019/7503230
van Wensen E, van Leeuwen RB, van der Zaag-Loonen HJ, Masius-Olthof S, Bloem BR (2013) Benign paroxysmal positional vertigo in Parkinson’s disease. Parkinsonism Relat Disord 19(12):1110–1112. https://doi.org/10.1016/j.parkreldis.2013.07.024
Venhovens J, Meulstee J, Bloem BR, Verhagen WI (2016) Neurovestibular analysis and falls in Parkinson’s disease and atypical Parkinsonism. Eur J Neurosci 43(12):1636–1646. https://doi.org/10.1111/ejn.13253
Vu TC, Nutt JG, Holford NH (2012) Progression of motor and nonmotor features of Parkinson’s disease and their response to treatment. Br J Clin Pharmacol 74(2):267–283. https://doi.org/10.1111/j.1365-2125.2012.04192.x
Wang S, Cai H, Cao Z, Li C, Wu T, Xu F, Qian Y, Chen X, Yu Y (2021) More than just static: dynamic functional connectivity changes of the thalamic nuclei to cortex in Parkinson’s disease with freezing of gait. Front Neurol 12:735999. https://doi.org/10.3389/fneur.2021.735999
Wilkinson D, Podlewska A, Banducci SE, Pellat-Higgins T, Slade M, Bodani M, Sakel M, Smith L, LeWitt P, Ade KK (2019) Caloric vestibular stimulation for the management of motor and non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 65:261–266. https://doi.org/10.1016/j.parkreldis.2019.05.031
Zhang C, Zhou P, Yuan T (2016) The cholinergic system in the cerebellum: from structure to function. Rev Neurosci 27(8):769–776. https://doi.org/10.1515/revneuro-2016-0008
Acknowledgements
The authors thank Christine Minderovic, Cyrus Sarosh, the PET technologists, cyclotron operators, and chemists, for their assistance. We are indebted to the subjects who participated in this study.
Funding
This study was funded by National Institutes of Health (R01 AG073100, P01 NS015655, RO1 NS070856, P50 NS091856, P50 NS123067), Department of Veterans Affairs grant (I01 RX001631), the Michael J. Fox Foundation, and the Parkinson’s Foundation. None of the funding agencies had a role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data, in the preparation, review or approval of the manuscript, nor in the decision to submit the manuscript for publication.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bohnen, N.I., Kanel, P., Roytman, S. et al. Cholinergic brain network deficits associated with vestibular sensory conflict deficits in Parkinson’s disease: correlation with postural and gait deficits. J Neural Transm 129, 1001–1009 (2022). https://doi.org/10.1007/s00702-022-02523-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-022-02523-3