Skip to main content
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1998 Aug;65(2):155–163. doi: 10.1136/jnnp.65.2.155

Brain muscarinic receptors in progressive supranuclear palsy and Parkinson's disease: a positron emission tomographic study

M Asahina 1, T Suhara 1, H Shinotoh 1, O Inoue 1, K Suzuki 1, T Hattori 1
PMCID: PMC2170218  PMID: 9703164

Abstract

OBJECTIVES—To assess muscarinic acetylcholine receptors (mAChRs) in the brains of patients with progressive supranuclear palsy and Parkinson's disease, and to correlate the cholinergic system with cognitive function in progressive supranuclear palsy and Parkinson's disease.
METHODS— Positron emission tomography (PET) and [11C]N-methyl-4-piperidyl benzilate ([11C]NMPB) was used to measure mAChRs in the brain of seven patients with progressive supranuclear palsy, 12 patients with Parkinson's disease, and eight healthy controls. All of the patients with progressive supranuclear palsy were demented. The Parkinson's disease group consisted of 11 non-demented patients and one demented patient. The mini mental state examination (MMSE) was used to assess the severity of cognitive dysfunction in all of the subjects. The modified Wisconsin card sorting test (WCST) was used to evaluate frontal cognitive function in the non-demented patients with Parkinson's disease and controls.
RESULTS—The mean K3 value, an index of mAChR binding, was significantly higher for the frontal cortex in the patients with Parkinson's disease than in the controls (p<0.01). By contrast, the patients with progressive supranuclear palsy had no significant changes in the K3 values of any cerebral cortical regions. The mean score of the MMSE in the progressive supranuclear palsy group was significantly lower than that in the control group. Although there was no difference between the Parkinson's disease and control groups in the MMSE, the non-demented patients with Parkinson's disease showed significant frontal lobe dysfunction in the WCST.
CONCLUSIONS—The increased mAChR binding in the frontal cortex of the patients with Parkinson's disease may reflect denervation hypersensitivity caused by loss of the ascending cholinergic input to that region from the basal forebrain and may be related to frontal lobe dysfunction in Parkinson's disease. The cerebral cortical cholinergic system may not have a major role in cognitive dysfunction in progressive supranuclear palsy.



Full Text

The Full Text of this article is available as a PDF (308.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albert M. L., Feldman R. G., Willis A. L. The 'subcortical dementia' of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 1974 Feb;37(2):121–130. doi: 10.1136/jnnp.37.2.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asahina M., Shinotoh H., Hirayama K., Suhara T., Shishido F., Inoue O., Tateno Y. Hypersensitivity of cortical muscarinic receptors in Parkinson's disease demonstrated by PET. Acta Neurol Scand. 1995 Jun;91(6):437–443. doi: 10.1111/j.1600-0404.1995.tb00443.x. [DOI] [PubMed] [Google Scholar]
  3. Brooks D. J., Ibanez V., Sawle G. V., Playford E. D., Quinn N., Mathias C. J., Lees A. J., Marsden C. D., Bannister R., Frackowiak R. S. Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann Neurol. 1992 Feb;31(2):184–192. doi: 10.1002/ana.410310209. [DOI] [PubMed] [Google Scholar]
  4. Brown R. G., Marsden C. D. 'Subcortical dementia': the neuropsychological evidence. Neuroscience. 1988 May;25(2):363–387. doi: 10.1016/0306-4522(88)90246-1. [DOI] [PubMed] [Google Scholar]
  5. Collins S. J., Ahlskog J. E., Parisi J. E., Maraganore D. M. Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg Psychiatry. 1995 Feb;58(2):167–173. doi: 10.1136/jnnp.58.2.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dewey S. L., Volkow N. D., Logan J., MacGregor R. R., Fowler J. S., Schlyer D. J., Bendriem B. Age-related decreases in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography (PET). J Neurosci Res. 1990 Dec;27(4):569–575. doi: 10.1002/jnr.490270418. [DOI] [PubMed] [Google Scholar]
  7. Divac I. Magnocellular nuclei of the basal forebrain project to neocortex, brain stem, and olfactory bulb. Review of some functional correlates. Brain Res. 1975 Aug 15;93(3):385–398. doi: 10.1016/0006-8993(75)90178-x. [DOI] [PubMed] [Google Scholar]
  8. Dubois B., Ruberg M., Javoy-Agid F., Ploska A., Agid Y. A subcortico-cortical cholinergic system is affected in Parkinson's disease. Brain Res. 1983 Dec 12;288(1-2):213–218. doi: 10.1016/0006-8993(83)90096-3. [DOI] [PubMed] [Google Scholar]
  9. Flynn D. D., Mash D. C. Distinct kinetic binding properties of N-[3H]-methylscopolamine afford differential labeling and localization of M1, M2, and M3 muscarinic receptor subtypes in primate brain. Synapse. 1993 Aug;14(4):283–296. doi: 10.1002/syn.890140406. [DOI] [PubMed] [Google Scholar]
  10. Folstein M. F., Folstein S. E., McHugh P. R. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189–198. doi: 10.1016/0022-3956(75)90026-6. [DOI] [PubMed] [Google Scholar]
  11. Jagust W. J., Reed B. R., Martin E. M., Eberling J. L., Nelson-Abbott R. A. Cognitive function and regional cerebral blood flow in Parkinson's disease. Brain. 1992 Apr;115(Pt 2):521–537. doi: 10.1093/brain/115.2.521. [DOI] [PubMed] [Google Scholar]
  12. Javoy-Agid F. Cholinergic and peptidergic systems in PSP. J Neural Transm Suppl. 1994;42:205–218. doi: 10.1007/978-3-7091-6641-3_16. [DOI] [PubMed] [Google Scholar]
  13. Jones E. G., Burton H., Saper C. B., Swanson L. W. Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates. J Comp Neurol. 1976 Jun 15;167(4):385–419. doi: 10.1002/cne.901670402. [DOI] [PubMed] [Google Scholar]
  14. Juncos J. L., Hirsch E. C., Malessa S., Duyckaerts C., Hersh L. B., Agid Y. Mesencephalic cholinergic nuclei in progressive supranuclear palsy. Neurology. 1991 Jan;41(1):25–30. doi: 10.1212/wnl.41.1.25. [DOI] [PubMed] [Google Scholar]
  15. Kievit J., Kuypers H. G. Basal forebrain and hypothalamic connection to frontal and parietal cortex in the Rhesus monkey. Science. 1975 Feb 21;187(4177):660–662. doi: 10.1126/science.1114317. [DOI] [PubMed] [Google Scholar]
  16. Kish S. J., Chang L. J., Mirchandani L., Shannak K., Hornykiewicz O. Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol. 1985 Nov;18(5):530–536. doi: 10.1002/ana.410180504. [DOI] [PubMed] [Google Scholar]
  17. Kloog Y., Egozi Y., Sokolovsky M. Characterization of muscarinic acetylcholine receptors from mouse brain: evidence for regional heterogeneity and isomerization. Mol Pharmacol. 1979 May;15(3):545–558. [PubMed] [Google Scholar]
  18. Landwehrmeyer B., Palacios J. M. Alterations of neurotransmitter receptors and neurotransmitter transporters in progressive supranuclear palsy. J Neural Transm Suppl. 1994;42:229–246. doi: 10.1007/978-3-7091-6641-3_18. [DOI] [PubMed] [Google Scholar]
  19. Lange K. W., Wells F. R., Jenner P., Marsden C. D. Altered muscarinic and nicotinic receptor densities in cortical and subcortical brain regions in Parkinson's disease. J Neurochem. 1993 Jan;60(1):197–203. doi: 10.1111/j.1471-4159.1993.tb05838.x. [DOI] [PubMed] [Google Scholar]
  20. Leenders K. L., Frackowiak R. S., Lees A. J. Steele-Richardson-Olszewski syndrome. Brain energy metabolism, blood flow and fluorodopa uptake measured by positron emission tomography. Brain. 1988 Jun;111(Pt 3):615–630. doi: 10.1093/brain/111.3.615. [DOI] [PubMed] [Google Scholar]
  21. Lin S. C., Olson K. C., Okazaki H., Richelson E. Studies on muscarinic binding sites in human brain identified with [3H]pirenzepine. J Neurochem. 1986 Jan;46(1):274–279. doi: 10.1111/j.1471-4159.1986.tb12958.x. [DOI] [PubMed] [Google Scholar]
  22. Malessa S., Hirsch E. C., Cervera P., Javoy-Agid F., Duyckaerts C., Hauw J. J., Agid Y. Progressive supranuclear palsy: loss of choline-acetyltransferase-like immunoreactive neurons in the pontine reticular formation. Neurology. 1991 Oct;41(10):1593–1597. doi: 10.1212/wnl.41.10.1593. [DOI] [PubMed] [Google Scholar]
  23. Mesulam M. M., Van Hoesen G. W. Acetylcholinesterase-rich projections from the basal forebrain of the rhesus monkey to neocortex. Brain Res. 1976 Jun 4;109(1):152–157. doi: 10.1016/0006-8993(76)90385-1. [DOI] [PubMed] [Google Scholar]
  24. Mulholland G. K., Kilbourn M. R., Sherman P., Carey J. E., Frey K. A., Koeppe R. A., Kuhl D. E. Synthesis, in vivo biodistribution and dosimetry of [11C]N-methylpiperidyl benzilate ([11C]NMPB), a muscarinic acetylcholine receptor antagonist. Nucl Med Biol. 1995 Jan;22(1):13–17. doi: 10.1016/0969-8051(94)00082-u. [DOI] [PubMed] [Google Scholar]
  25. Nakano I., Hirano A. Parkinson's disease: neuron loss in the nucleus basalis without concomitant Alzheimer's disease. Ann Neurol. 1984 May;15(5):415–418. doi: 10.1002/ana.410150503. [DOI] [PubMed] [Google Scholar]
  26. Otto C. A., Mulholland G. K., Perry S. E., Combs R., Sherman P. S., Fisher S. J. In vitro and ex vivo evaluation of cyclic aminoalkyl benzilates as potential emission tomography ligands for the muscarinic receptor. Int J Rad Appl Instrum B. 1989;16(1):51–55. doi: 10.1016/0883-2897(89)90215-8. [DOI] [PubMed] [Google Scholar]
  27. Oyanagi K., Takahashi H., Wakabayashi K., Ikuta F. Selective decrease of large neurons in the neostriatum in progressive supranuclear palsy. Brain Res. 1988 Aug 23;458(2):218–223. doi: 10.1016/0006-8993(88)90464-7. [DOI] [PubMed] [Google Scholar]
  28. Patlak C. S., Blasberg R. G., Fenstermacher J. D. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983 Mar;3(1):1–7. doi: 10.1038/jcbfm.1983.1. [DOI] [PubMed] [Google Scholar]
  29. Patlak C. S., Blasberg R. G. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985 Dec;5(4):584–590. doi: 10.1038/jcbfm.1985.87. [DOI] [PubMed] [Google Scholar]
  30. Perry E. K., Curtis M., Dick D. J., Candy J. M., Atack J. R., Bloxham C. A., Blessed G., Fairbairn A., Tomlinson B. E., Perry R. H. Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1985 May;48(5):413–421. doi: 10.1136/jnnp.48.5.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pillon B., Dubois B., Agid Y. Testing cognition may contribute to the diagnosis of movement disorders. Neurology. 1996 Feb;46(2):329–334. doi: 10.1212/wnl.46.2.329. [DOI] [PubMed] [Google Scholar]
  32. Rehavi M., Yaavetz B., Kloog Y., Maayani S., Sokolovsky M. In vivo and in vitro studies on the antimuscarinic activity of some amino esters of benzilic acid. Biochem Pharmacol. 1978;27(8):1117–1124. doi: 10.1016/0006-2952(78)90438-0. [DOI] [PubMed] [Google Scholar]
  33. Rogers J. D., Brogan D., Mirra S. S. The nucleus basalis of Meynert in neurological disease: a quantitative morphological study. Ann Neurol. 1985 Feb;17(2):163–170. doi: 10.1002/ana.410170210. [DOI] [PubMed] [Google Scholar]
  34. Ruberg M., Javoy-Agid F., Hirsch E., Scatton B., LHeureux R., Hauw J. J., Duyckaerts C., Gray F., Morel-Maroger A., Rascol A. Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann Neurol. 1985 Nov;18(5):523–529. doi: 10.1002/ana.410180503. [DOI] [PubMed] [Google Scholar]
  35. Ruberg M., Ploska A., Javoy-Agid F., Agid Y. Muscarinic binding and choline acetyltransferase activity in Parkinsonian subjects with reference to dementia. Brain Res. 1982 Jan 28;232(1):129–139. doi: 10.1016/0006-8993(82)90615-1. [DOI] [PubMed] [Google Scholar]
  36. STEELE J. C., RICHARDSON J. C., OLSZEWSKI J. PROGRESSIVE SUPRANUCLEAR PALSY. A HETEROGENEOUS DEGENERATION INVOLVING THE BRAIN STEM, BASAL GANGLIA AND CEREBELLUM WITH VERTICAL GAZE AND PSEUDOBULBAR PALSY, NUCHAL DYSTONIA AND DEMENTIA. Arch Neurol. 1964 Apr;10:333–359. doi: 10.1001/archneur.1964.00460160003001. [DOI] [PubMed] [Google Scholar]
  37. Suhara T., Inoue O., Kobayashi K., Suzuki K., Tateno Y. Age-related changes in human muscarinic acetylcholine receptors measured by positron emission tomography. Neurosci Lett. 1993 Jan 12;149(2):225–228. doi: 10.1016/0304-3940(93)90777-i. [DOI] [PubMed] [Google Scholar]
  38. Tagliavini F., Pilleri G., Gemignani F., Lechi A. Neuronal loss in the basal nucleus of Meynert in progressive supranuclear palsy. Acta Neuropathol. 1983;61(2):157–160. doi: 10.1007/BF00697397. [DOI] [PubMed] [Google Scholar]
  39. Taylor A. E., Saint-Cyr J. A., Lang A. E. Frontal lobe dysfunction in Parkinson's disease. The cortical focus of neostriatal outflow. Brain. 1986 Oct;109(Pt 5):845–883. doi: 10.1093/brain/109.5.845. [DOI] [PubMed] [Google Scholar]
  40. Tejani-Butt S. M., Luthin G. R., Wolfe B. B., Brunswick D. J. N-substituted derivatives of 4-piperidinyl benzilate: affinities for brain muscarinic acetylcholine receptors. Life Sci. 1990;47(10):841–848. doi: 10.1016/0024-3205(90)90596-j. [DOI] [PubMed] [Google Scholar]
  41. Whitehouse P. J., Hedreen J. C., White C. L., 3rd, Price D. L. Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol. 1983 Mar;13(3):243–248. doi: 10.1002/ana.410130304. [DOI] [PubMed] [Google Scholar]
  42. Wilcock G. K., Esiri M. M., Bowen D. M., Smith C. C. Alzheimer's disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. J Neurol Sci. 1982 Dec;57(2-3):407–417. doi: 10.1016/0022-510x(82)90045-4. [DOI] [PubMed] [Google Scholar]
  43. Wolfson L. I., Leenders K. L., Brown L. L., Jones T. Alterations of regional cerebral blood flow and oxygen metabolism in Parkinson's disease. Neurology. 1985 Oct;35(10):1399–1405. doi: 10.1212/wnl.35.10.1399. [DOI] [PubMed] [Google Scholar]
  44. Zweig R. M., Whitehouse P. J., Casanova M. F., Walker L. C., Jankel W. R., Price D. L. Loss of pedunculopontine neurons in progressive supranuclear palsy. Ann Neurol. 1987 Jul;22(1):18–25. doi: 10.1002/ana.410220107. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES