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Papers: W M van der Flier and P Scheltens Use of laboratory and imaging investigations in dementia J Neurol Neurosurg Psychiatry 2005; 76: v45-52v [Full text] [PDF]

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The contribution of neurophysiology in the diagnosis of dementia

Vincenzo Di Lazzaro, Fabio Pilato, Eleonora Saturno, Paolo Profice, Michele Dileone, Federico Ranieri and Pietro A. Tonali   (23 November 2005)

The contribution of neurophysiology in the diagnosis of dementia 23 November 2005
Vincenzo Di Lazzaro, Associate Professor of Neurology Institute of Neurology Università Cattlica S Cuore Rome Italy, Fabio Pilato, Eleonora Saturno, Paolo Profice, Michele Dileone, Federico Ranieri and Pietro A. Tonali Send letter to journal: Re: The contribution of neurophysiology in the diagnosis of dementia vdilazzaro{at}rm.unicatt.it Vincenzo Di Lazzaro, et al.	Dear Editor, Van der Flier and Scheltens[1] provide an interesting overview on the different diagnostic strategies in dementia taking into consideration several diagnostic approaches including neurophysiology. In this specific field, they discuss the contribution of electroencephalography but do not consider different neurophysiological tests. We want to draw attention to a recently introduced technique, based on transcranial magnetic stimulation (TMS) of the brain, that makes it possible to test several intracortical circuits of the human brain including central cholinergic circuits.[2] Using TMS related techniques it is possible to recruit specific neuronal circuits of the human brain and to evaluate in vivo several neurotransmitter systems.[3] Several groups have investigated patients with Alzheimer disease (AD) using TMS documenting an increase in motor cortex excitability.[4-11] It has been proposed that the hyperexcitability of the motor cortex in AD patients could be the hallmark of an impaired glutamatergic transmission representing the consequence of an imbalance between non-NMDA and NMDA neurotransmission in favour of the non-NMDA transmission.[11-12] More recently, a TMS related technique that may give direct information about the function of some cholinergic circuits in the human brain has been described.[13] This technique relies on the phenomenon of short latency afferent inhibition (SAI) of the motor cortex produced by coupling of peripheral nerve stimulation with TMS of the contralateral motor cortex. SAI tests an inhibitory circuit in motor cortex that is controlled by central cholinergic activity.[13] SAI is decreased by the muscarinic receptor antagonist scopolamine in normal subjects,[14] is significantly reduced in Alzheimer’s disease patients[8] and, in these patients, can be increased by acetylcholinesterase inhibitors.[15] Most of the patients with a clinical diagnosis of AD - about seventy percent - have an abnormal SAI.15 The change in SAI appears unrelated to the motor cortex hyperexcitability suggesting that these are two independent abnormalities. In the patients with abnormal SAI, afferent inhibition can be increased within hours of the administration of a single oral dose of rivastigmine.[8,15] However, the change in SAI after the administration of a single oral dose of rivastigmine varies widely between individual patients. Interestingly, the baseline SAI and the increase in SAI after a single dose of rivastigmine seem to be correlated with the response to long term treatment, as evaluated under the Global Deterioration Scale and with an extensive neuropsychological test battery.[15] A normal SAI , or an abnormal SAI that is not greatly increased by a single oral dose of rivastigmine, is invariably associated with a poor response to long-term treatment. While an abnormal SAI in conjunction with a large increase in SAI after a single dose of rivastigmine is associated with a favourable response to long term treatment in most of the patients. The extent of change in SAI after a single dose of rivastigmine is also strongly correlated with changes in cognitive functions assessed by neuropsychological tests after one year of treatment.[15] The study of SAI, together with the evaluation of the effects of a single oral dose of an acetylcholinesterase inhibitor, may contribute to the management of AD patients because it is currently impossible to predict the individual therapeutic response in AD patients. Cumulatively, the studies of SAI in AD patients suggest this test may be useful in the differential diagnosis between the cholinergic forms and the non-cholinergic forms of dementia, and among patients with a central cholinergic dysfunction in an identification of patients who are more likely to respond to the treatment with acetylcholinesterase inhibitors. References 1. W M van der Flier and P Scheltens. Use of laboratory and imaging investigations in dementia. J Neurol Neurosurg Psychiatry 2005;76 v45-v52. 2. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Mazzone P, Insola A, Tonali PA, Rothwell JC. The physiological basis of transcranial motor cortex stimulation in conscious humans. Clinical Neurophysiology 2004;115:255-266. 3. Ziemann, U. TMS and drugs. Clin Neurophysiol 2004;115:1717-1729. 4. de Carvalho M, de Mendonca A, Miranda PC, Garcia C, Luis ML. Magnetic stimulation in Alzheimer's disease. J Neurol 1997; 244:304-307. 5. Pepin JL, Bogacz D, de Pasqua V, Delwaide PJ. Motor cortex inhibition is not impaired in patients with Alzheimer's disease: evidence from paired transcranial magnetic stimulation. J Neurol Sci. 1999;170:119- 23. 6. Liepert J, Bar KJ, Meske U, Weiller C. Motor cortex disinhibition in Alzheimer's disease. Clin Neurophysiol 2001; 112:1436-1441. 7. Alagona G, Bella R, Ferri R, Carnemolla A, Pappalardo A, Costanzo E, Pennisi G. Transcranial magnetic stimulation in Alzheimer disease: motor cortex excitability and cognitive severity. Neurosci Lett 2001; 314:57-60. 8. Di Lazzaro V, Oliviero A, Tonali PA, Marra C, Daniele A, Profice P, Saturno E, Pilato F, Masullo C, Rothwell JC. Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology 2002; 59:392-7. 9. Pennisi G, Alagona G, Ferri R, Greco S, Santonocito D, Pappalardo A, Bella R. Motor cortex excitability in Alzheimer disease: one year follow-up study. Neurosci Lett 2002; 329:293-6. 10. Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, Rossini PM. Motor cortex excitability in Alzheimer's disease: A transcranial magnetic stimulation study. Ann Neurol 2003; 53:102-8. 11. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Daniele A, Ghirlanda S, Gainotti G, Tonali PA. Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004;75:555-9. 12. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Tonali PA. Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease: evidence of impaired glutamatergic neurotransmission? Ann Neurol. 2003;53:824. 13. Tokimura, H., Di Lazzaro, V., Tokimura, Y., Oliviero, A., Profice, P., Insola, A., Mazzone, P., Tonali, P. & Rothwell, J. C.. Short latency inhibition of human hand motor cortex by somatosensory input from the hand. J Physiol 2000;523:503-513. 14. Di Lazzaro, V., Oliviero, A., Profice, P., Pennisi, M. A., Di Giovanni, S., Zito, G., Tonali, P. & Rothwell, J. C. Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in human motor cortex. Exp Brain Res 2000;135:455- 461. 15. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Ghirlanda S, Ranieri F, Gainotti G, Tonali P. Neurophysiological predictors of long term response to AChE inhibitors in AD patients. J Neurol Neurosurg Psychiatry. 2005;76:1064-9.