Skip to main content

Advertisement

SpringerLink
Log in

Cholinergic dysfunction and amnesia in patients with Wernicke–Korsakoff syndrome: a transcranial magnetic stimulation study

  • Dementias - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

The specific neurochemical substrate underlying the amnesia in patients with Wernicke–Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale—Revised (WAIS-R) and the Corsi’s Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders. APA, Washington

    Google Scholar 

  • Angunawela II, Barker A (2001) Anticholinesterase drugs for alcoholic Korsakoff syndrome. Int J Geriatr Psychiatry 16:338–339

    Article  CAS  PubMed  Google Scholar 

  • Arendt T, Allen Y, Sinden J, Schugens MM, Marchbanks RM, Lantos PL, Gray JA (1988) Cholinergic-rich brain transplants reverse alcohol-induced memory deficits. Nature 332:448–450

    Article  CAS  PubMed  Google Scholar 

  • Arendt T, Bruckner MK, Bigl V, Marcova L (1995) Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer’s disease. III. The basal forebrain compared with other subcortical areas. J Comp Neurol 351:223–246

    Article  CAS  PubMed  Google Scholar 

  • Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529

    Article  CAS  PubMed  Google Scholar 

  • Blokland A (1995) Acetylcholine: a neurotransmitter for learning and memory? Brain Res Brain Res Rev 21:285–300

    Article  CAS  PubMed  Google Scholar 

  • Caine D, Halliday GM, Kril JJ, Harper CG (1997) Operational criteria for the classification of chronic alcoholics: identification of Wernicke’s encephalopathy. J Neurol Neurosurg Psychiatry 62:51–60

    Article  CAS  PubMed  Google Scholar 

  • Cochrane M, Cochrane A, Jauhar P, Ashton E (2005) Acetylcholinesterase inhibitors for the treatment of Wernicke–Korsakoff syndrome—three further cases show response to donepezil. Alcohol Alcohol 40:151–154

    CAS  PubMed  Google Scholar 

  • Cullen KM, Halliday GM, Caine D, Kril JJ (1997) The nucleus basalis (Ch4) in the alcoholic Wernicke–Korsakoff syndrome: reduced cell number in both amnesic and non-amnesic patients. J Neurol Neurosurg Psychiatry 63:315–320

    Article  CAS  PubMed  Google Scholar 

  • Di Lazzaro V, Oliviero A, Profice P, Pennisi 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 135:455–461

    Article  CAS  PubMed  Google Scholar 

  • Di Lazzaro V, Oliviero A, Tonali PA, Marra C, Daniele A, Profice P, Saturno E, Pilato F, Masullo C, Rothwell JC (2002) Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology 59:392–397

    PubMed  Google Scholar 

  • 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 75:555–559

    Article  CAS  PubMed  Google Scholar 

  • Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Ghirlanda S, Ranieri F, Gainotti G, Tonali P (2005a) Neurophysiological predictors of long term response to AChE inhibitors in AD patients. J Neurol Neurosurg Psychiatry 76:1064–1069

    Article  CAS  PubMed  Google Scholar 

  • 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 564:661–668

    Article  CAS  PubMed  Google Scholar 

  • 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 569:315–323

    Article  CAS  PubMed  Google Scholar 

  • 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 66:1111–1113

    Google Scholar 

  • Dunnett SB, Robbins TW (1992) The functional role of mesotelencephalic dopamine systems. Biol Rev Camb Philos Soc 67:491–518

    Article  CAS  PubMed  Google Scholar 

  • Fujiki M, Hikawa T, Abe T, Ishii K, Kobayashi H (2006) Reduced short latency afferent inhibition in diffuse axonal injury patients with memory impairment. Neurosci Lett 405:226–230

    Article  CAS  PubMed  Google Scholar 

  • Gibson GE, Jope R, Blass JP (1975) Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces. Biochem J 148:17–23

    CAS  PubMed  Google Scholar 

  • Halliday G, Ellis J, Harper C (1992) The locus coeruleus and memory: a study of chronic alcoholics with and without the memory impairment of Korsakoff’s psychosis. Brain Res 598:33–37

    Article  CAS  PubMed  Google Scholar 

  • Halliday G, Ellis J, Heard R, Caine D, Harper C (1993) Brainstem serotonergic neurons in chronic alcoholics with and without the memory impairment of Korsakoff’s psychosis. J Neuropathol Exp Neurol 52:567–579

    Article  CAS  PubMed  Google Scholar 

  • Harding AJ, Halliday GM, Ng JL, Harper CG, Kril JJ (1996) Loss of vasopressin-immunoreactive neurons in alcoholics is dose-related and time-dependent. Neuroscience 72:699–708

    Article  CAS  PubMed  Google Scholar 

  • Harding AJ, Wong A, Svoboda M, Kril JJ, Halliday GM (1997) Chronic alcohol consumption does not cause hippocampal neuron loss in humans. Hippocampus 7:78–87

    Article  CAS  PubMed  Google Scholar 

  • Harding A, Halliday G, Caine D, Kril J (2000) Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 123(Pt 1):141–154

    Article  PubMed  Google Scholar 

  • Harper CG, Kril JJ (1990) Neuropathology of alcoholism. Alcohol Alcohol 25:207–216

    CAS  PubMed  Google Scholar 

  • Hodges H, Allen Y, Sinden J, Mitchell SN, Arendt T, Lantos PL, Gray JA (1991) The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats. Behav Brain Res 43:7–28

    Article  CAS  PubMed  Google Scholar 

  • Kasa P, Rakonczay Z, Gulya K (1997) The cholinergic system in Alzheimer’s disease. Prog Neurobiol 52:511–535

    Article  CAS  PubMed  Google Scholar 

  • Kopelman MD (1995) The Korsakoff syndrome. Br J Psychiatry 166:154–173

    Article  CAS  PubMed  Google Scholar 

  • Kopelman MD, Corn TH (1988) Cholinergic ‘blockade’ as a model for cholinergic depletion. A comparison of the memory deficits with those of Alzheimer-type dementia and the alcoholic Korsakoff syndrome. Brain 111(Pt 5):1079–1110

    Article  PubMed  Google Scholar 

  • Kril JJ, Halliday GM, Svoboda MD, Cartwright H (1997) The cerebral cortex is damaged in chronic alcoholics. Neuroscience 79:983–998

    Article  CAS  PubMed  Google Scholar 

  • Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519

    CAS  PubMed  Google Scholar 

  • Luykx HJ, Dorresteijn LD, Haffmans PM, Bonebakker A, Kerkmeer M, Hendriks VM (2008) Rivastigmine in Wernicke–Korsakoff’s syndrome: five patients with rivastigmine showed no more improvement than five patients without rivastigmine. Alcohol Alcohol 43:70–72

    CAS  PubMed  Google Scholar 

  • Mair RG, McEntee WJ (1986) Cognitive enhancement in Korsakoff’s psychosis by clonidine: a comparison with L-dopa and ephedrine. Psychopharmacology (Berl) 88:374–380

    Article  CAS  Google Scholar 

  • Manganelli F, Ragno M, Cacchio G, Iodice V, Trojano L, Silvaggio F, Scarcella M, Grazioli M, Santoro L, Perretti A (2008) Motor cortex cholinergic dysfunction in CADASIL: a transcranial magnetic demonstration. Clin Neurophysiol 119:351–355

    Article  PubMed  Google Scholar 

  • Martin PR, Adinoff B, Lane E, Stapleton JM, Bone GA, Weingartner H, Linnoila M, Eckardt MJ (1995) Fluvoxamine treatment of alcoholic amnestic disorder. Eur Neuropsychopharmacol 5:27–33

    Article  CAS  PubMed  Google Scholar 

  • Mayes AR, Meudell PR, Mann D, Pickering A (1988) Location of lesions in Korsakoff’s syndrome: neuropsychological and neuropathological data on two patients. Cortex 24:367–388

    CAS  PubMed  Google Scholar 

  • McEntee WJ, Mair RG (1980) Memory enhancement in Korsakoff’s psychosis by clonidine: further evidence for a noradrenergic deficit. Ann Neurol 7:466–470

    Article  CAS  PubMed  Google Scholar 

  • Nardone R, Marth R, Ausserer H, Bratti A, Tezzon F (2006) Reduced short latency afferent inhibition in patients with Down syndrome and Alzheimer-type dementia. Clin Neurophysiol 117:2204–2210

    Article  CAS  PubMed  Google Scholar 

  • Rogers SL, Friedhoff LT (1998) Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses. Br J Clin Pharmacol 46(Suppl 1):1–6

    Google Scholar 

  • 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. Electroenceph Clin Neurophysiol 91:79–92

    Article  CAS  PubMed  Google Scholar 

  • Sahin HA, Gurvit IH, Bilgic B, Hanagasi HA, Emre M (2002) Therapeutic effects of an acetylcholinesterase inhibitor (donepezil) on memory in Wernicke–Korsakoff’s disease. Clin Neuropharmacol 25:16–20

    Article  CAS  PubMed  Google Scholar 

  • 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(Pt 2):503–513

    Article  CAS  PubMed  Google Scholar 

  • Victor M, Adams RD, Collins GH (1989) The Wernicke–Korsakoff syndrome and related neurologic disorders due to alcoholism and malnutrition. FA Davies Company, Philadelphia

    Google Scholar 

  • 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 14:167–186

    CAS  PubMed  Google Scholar 

  • Witt ED (1985) Neuroanatomical consequences of thiamine deficiency: a comparative analysis. Alcohol Alcohol 20:201–221

    CAS  PubMed  Google Scholar 

  • Ziemann U (2004) TMS and drugs. Clin Neurophysiol 115:1717–1729

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Christian Doppler Clinic, Paracelsus Private Medical University, Salzburg, Austria

    Raffaele Nardone, Jürgen Bergmann, Martin Kronbichler, Jörg Kraus, Gunther Ladurner & Stefan Golaszewski

  2. Department of Neurology, Franz Tappeiner Hospital, Via Rossini, 5, 39012, Merano, BZ, Italy

    Raffaele Nardone, Francesca Caleri & Frediano Tezzon

  3. Department of Statistics and Applied Mathematics, Collegio Carlo Alberto, University of Turin, Turin, Italy

    Pierpaolo De Blasi

Authors
  1. Raffaele Nardone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jürgen Bergmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierpaolo De Blasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Kronbichler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jörg Kraus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesca Caleri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Frediano Tezzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gunther Ladurner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefan Golaszewski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raffaele Nardone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nardone, R., Bergmann, J., De Blasi, P. et al. Cholinergic dysfunction and amnesia in patients with Wernicke–Korsakoff syndrome: a transcranial magnetic stimulation study. J Neural Transm 117, 385–391 (2010). https://doi.org/10.1007/s00702-009-0347-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-009-0347-1

Keywords

Search

Navigation