Journal of Neural Transmission

, Volume 115, Issue 11, pp 1557–1562 | Cite as

Abnormal short latency afferent inhibition in early Alzheimer’s disease: a transcranial magnetic demonstration

  • Raffaele Nardone
  • Jürgen Bergmann
  • Martin Kronbichler
  • Alexander Kunz
  • Stefanie Klein
  • Francesca Caleri
  • Frediano Tezzon
  • Gunther Ladurner
  • Stefan Golaszewski
Alzheimer's Disease and Related Disorders - Original Article

Abstract

The pathogenesis of Alzheimer’s disease (AD) appears to involve several different mechanisms, the most consistent of which is an impairment of cholinergic neurotransmission; however, there is controversy about its relevance at the early stage of disease. A transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with motor cortex TMS (short latency afferent inhibition, SAI) may give direct information about the function of some cholinergic pathways in the human motor cortex. We evaluated SAI in a group of patients with early diagnosis of AD and compared the data with that from a control group. The amount of SAI was significantly smaller in early AD patients than in controls. This study first provides physiological evidence that a central cholinergic dysfunction occurs in the earlier stages of AD. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs.

Keywords

Alzheimer’s disease Cholinergic neurotransmission Transcranial magnetic stimulation Afferent inhibition 

References

  1. Almkvist O, Winblad B (1999) Early diagnosis of Alzheimer dementia based on clinical and biological factors. Eur Arch Psychiatry Clin Neurosci 249:3–9PubMedCrossRefGoogle Scholar
  2. Bartus T (1979) Physostigmine and recent memory: effects in young and aged nonhuman primates. Science 206:1085–1087CrossRefGoogle Scholar
  3. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417PubMedCrossRefGoogle Scholar
  4. Bartus RT, Emerich DF (1999) Cholinergic markers in Alzheimer disease. J Am Med Assoc 282:2208–2209CrossRefGoogle Scholar
  5. Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP, Perl DP, Schmeidler J, Kanof P, Davis KG (1995) Neurochemical correlates of dementia severity in Alzheimer’s disease: relative importance of the cholinergic deficits. J Neurochem 64:749–760PubMedGoogle Scholar
  6. Blokland A (1996) Acetylcholine: a neurotransmitter for learning and memory? Brain Res Rev 21:285–300CrossRefGoogle Scholar
  7. Bohnen NI, Kaufer DI, Hendrickson R, Constantine GM, Mathis CA, Moore RY (2007) Cortical cholinergic denervation is associated with depressive symptoms in Parkinson’s disease and parkinsonian dementia. J Neurol Neurosurg Psychiatry 78:641–643PubMedCrossRefGoogle Scholar
  8. Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2(8000):1403PubMedCrossRefGoogle Scholar
  9. Davis KL, Mohs RC, Marin D, Purohit DP, Perl DP, Lantz M, Austin G, Haroutunian V (1999) Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA 281:1401–1406PubMedCrossRefGoogle Scholar
  10. DeKosky ST, Ikonomovic MD, Styren SD, Beckett L, Wisniewski S, Bennett DA, Cochran EJ, Kordoner JH, Mufson EJ (2002) Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 51:145–155PubMedCrossRefGoogle Scholar
  11. Di Lazzaro V, Oliviero A, Profice P, Pennini MA, Di Giovanni S, Zito G, Tonali P, Rothwell JC (2000) Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex. Exp Brain Res 135:455–461PubMedCrossRefGoogle Scholar
  12. Di Lazzaro V, Oliviero A, Tonali PA, Marra C, Daniele A, Profice P, Saturno E, Pilato F, Masullo C, Rothwll JC (2002) Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology 13:392–397Google Scholar
  13. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Daniele A, Ghirlanda S, Gainotti G, Tonali PA (2004) Motor cortex excitability to transcranial magnetic stimulation in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75:555–559PubMedCrossRefGoogle Scholar
  14. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Daniele A, Ghirlanda S, Gainotti G, Tonali PA (2005a) Neurophysiological predictors of long term response to AchE inhibitors in AD patients. J Neurol Neurosurg Psychiatry 76:1064–1069PubMedCrossRefGoogle Scholar
  15. Di Lazzaro V, Oliviero A, Saturno E, Dileone M, Pilato F, Nardone R, Ranieri F, Musumeci G, Fiorilla T, Tonali P (2005b) Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans. J Physiol 564:661–668PubMedCrossRefGoogle Scholar
  16. Di Lazzaro V, Pilato F, Dileone M, Tonali PA, Ziemann U (2005c) Dissociated effects of diazepam and lorazepam on short-latency afferent inhibition. J Physiol 569:315–323PubMedCrossRefGoogle Scholar
  17. Di Lazzaro V, Pilato F, Dileone M, Saturno E, Oliviero A, Marra C, Daniele A, Ranieri F, Gainotti G, Tonali PA (2006) In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias. Neurology 66:1111–1113PubMedCrossRefGoogle Scholar
  18. Geula C (1998) Abnormalities of neural circuitry in Alzheimer’s disease: hippocampus and cortical cholinergic innervation. Neurology 51:S18–S29PubMedGoogle Scholar
  19. Gilmor ML, Erickson JD, Varoqui H, Hersh LB, Bennett DA, Cochran EJ, Mufson EJ, Levey AI (1999) Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 411:693–704PubMedCrossRefGoogle Scholar
  20. Hallett M (2000) Transcranial magnetic stimulation and the human brain. Nature 406:147–150PubMedCrossRefGoogle Scholar
  21. Herholz K, Bauer B, Wienhard K, Kracht L, Mielke R, Lenz O, Strotmann T, Heiss WD (2000) In-vivo measurements of regional acetylcholine esterase activity in degenerative dementia: comparison with blood flow and glucose metabolism. J Neural Transm 12:1457–1468CrossRefGoogle Scholar
  22. Herholz K, Weisenbach S, Zundorf G, Lenz O, Schroder H, Bauer B, Kalbe E, Heiss WD (2004) In-vivo study of acetylcholine esterase in basel forebrain, amygdala, and cortex in mild to moderate Alzheimer disease. Neuroimage 21:136–143PubMedCrossRefGoogle Scholar
  23. Iyo M, Namba H, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, Sodo Y, Sukuki K, Irie T (1997) Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimers disease. Lancet 349:1805–1809PubMedCrossRefGoogle Scholar
  24. Kasa P, Rakonczay Z, Gulya K (1997) The cholinergic system in Alzheimer’s disease. Prog Neurobiol 52:511–535PubMedCrossRefGoogle Scholar
  25. Kuhl DE, Koeppe RA, Fessler JA, Minoshima S, Ackermann RJ, Carey JE, Gildersleeve DL, Frey KA, Wieland DM (1994) In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM. J Nucl Med 35:405–410PubMedGoogle Scholar
  26. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Cortico-cortical inhibition in human motor cortex. J Physiol 471:501–520PubMedGoogle Scholar
  27. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34:939–944PubMedGoogle Scholar
  28. Mesulam M, Shaw P, Mash D, Weintraub S (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 55(6):815–828PubMedCrossRefGoogle Scholar
  29. Mufson EJ, Ma SY, Cochran EJ, Bennett DA, Beckett LA, Jaffar S, Saragovi HU, Kordower JH (2000) Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 427:9–30CrossRefGoogle Scholar
  30. Nordberg A, Lundqvist H, Hartvig P, Lilja A, Langstrom B (1995) Kinetic analysis of regional (S)(−)11C-nicotine binding in normal and Alzheimer brains—in vivo assessment using positron emission tomography. Alzheimer Dis Assoc Disord 9:21–27PubMedCrossRefGoogle Scholar
  31. O’Brien JT, Colloby SJ, Pakrasi S, Perry EK, Pimlott S, Land DJ, Wyper DJ, McKeith IG, Williams ED (2007) Alpha4beta2 nicotinic receptor status in Alzheimer’s disease using 123I–5IA–85380 single-photon-emission computed tomography. J Neurol Neurosurg Psychiatry 78:356–362PubMedCrossRefGoogle Scholar
  32. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2:1457–1459PubMedCrossRefGoogle Scholar
  33. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild vognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308PubMedCrossRefGoogle Scholar
  34. Reinikainen KJ, Soininen H, Riekkinen PJ (1990) Neurotransmitter changes in Alzheimer’s disease: implications to diagnostics and therapy. J Neurosci Res 27:576–586PubMedCrossRefGoogle Scholar
  35. Rinne JO, Kaasinen V, Jarvenpaa T, Nagren K, Roivainen A, Yu M, Oikonen V, Kurki T (2003) Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74:113–115PubMedCrossRefGoogle Scholar
  36. Rossini PM, Barker T, Berardelli A, Caramia MD, Caruso G, Cracco RQ, Dimitrijevic MR, Hallett M, Katayama Y, Lucking CH, Maertens de Noordhout AL, Marsden CD, Murray NMF, Rothwell JC, Swash M, Tomberg C (1994) Non invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application: report of IFCN committee. Electroencephalogr clin Neurophysiol 91:79–92PubMedCrossRefGoogle Scholar
  37. Rothwell JC (2003) Techniques of transcranial magnetic stimulation. In: Boniface SJ, Ziemann U (eds) Plasticity in human nervous system. Investigations with transcranial magnetic stimulation. University Press, Cambridge, pp 26–61Google Scholar
  38. Sakuma K, Murakami T, Nakashima K (2007) Short latency afferent inhibition is not impaired in mild cognitive impairment. Clin Neurophysiol 118(7):1460–1463PubMedCrossRefGoogle Scholar
  39. Sailer A, Molnar GF, Paradiso G, Gunraj CA, Lang AE, Chen R (2003) Short and long latency afferent inhibition in Parkinson’s disease. Brain 126:1883–1894PubMedCrossRefGoogle Scholar
  40. Saykin AJ, Wishart HA, Rabin LA, Flashman LA, McHugh TL, Mamourian AC (2004) Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain 127:1574–1583PubMedCrossRefGoogle Scholar
  41. Shinotoh H, Namba H, Fukushi K, Nagatsuka S, Tanaka N, Aotsuka A, Ota T, Tanada S, Irie T (2000) Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer’s disease: a positron emission tomography study. Ann Neurol 48:194–200PubMedCrossRefGoogle Scholar
  42. Shinotoh H, Fukushi K, Nagatsuka S, Tanaka N, Aotsuka A, Ota T (2003) The amygdala and Alzheimer’s disease: positron emission tomographic study of the cholinergic system. Ann N Y Acad Sci 985:411–419PubMedCrossRefGoogle Scholar
  43. Smith G (1988) Animal models of Alzheimer’s disease: experimental cholinergic denervation. Brain Res Rev 13:103–118CrossRefGoogle Scholar
  44. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Roman R, Davies P, Masliah E, Williams DsS Goldstein LS (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288PubMedCrossRefGoogle Scholar
  45. Tokimura H, Di Lazzaro V, Tokimura Y, Oliviero A, Profice P, Insola A, Mazzone P, Tonali P, Rothwell JC (2000) Short latency inhibition of human hand motor cortex by somatosensory input from the hand. J Physiol 523:503–513PubMedCrossRefGoogle Scholar
  46. Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL (1994) Basal forebrain lesions in monkeys disrupt attention but not learning and memory. J Neurosci 14:167–186PubMedGoogle Scholar
  47. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126PubMedCrossRefGoogle Scholar
  48. Ziemann U (2002) Assessment of motor cortex and descending motor pathways. In: Brown WF, Bolton CF, Aminoff MJ (eds) Neuromuscular function and disease. Basis, clinical and electrodiagnostic aspects aspects, vol 1. Saunders, Philadelphia, pp 189–221Google Scholar
  49. Ziemann U (2004) TMS and drugs. Clin Neurophysiol 115:1717–1729PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Raffaele Nardone
    • 1
    • 2
  • Jürgen Bergmann
    • 1
  • Martin Kronbichler
    • 1
  • Alexander Kunz
    • 1
  • Stefanie Klein
    • 1
  • Francesca Caleri
    • 2
  • Frediano Tezzon
    • 2
  • Gunther Ladurner
    • 1
  • Stefan Golaszewski
    • 1
  1. 1.Department of Neurology, Christian Doppler ClinicParacelsus Private Medical University SalzburgSalzburgAustria
  2. 2.Department of Neurology“F. Tappeiner” HospitalMerano (BZ)Italy

Personalised recommendations