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August 15, 2017; 89 (7) Article

Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia

Alberto Benussi, Francesco Di Lorenzo, Valentina Dell'Era, Maura Cosseddu, Antonella Alberici, Salvatore Caratozzolo, Maria Sofia Cotelli, Anna Micheli, Luca Rozzini, Alessandro Depari, Alessandra Flammini, Viviana Ponzo, Alessandro Martorana, Carlo Caltagirone, Alessandro Padovani, Giacomo Koch, Barbara Borroni
First published July 26, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004232
Alberto Benussi
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Francesco Di Lorenzo
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Valentina Dell'Era
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Maura Cosseddu
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Antonella Alberici
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Salvatore Caratozzolo
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Maria Sofia Cotelli
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Anna Micheli
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Luca Rozzini
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Alessandro Depari
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Alessandra Flammini
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Viviana Ponzo
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Alessandro Martorana
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Carlo Caltagirone
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Alessandro Padovani
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Giacomo Koch
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Barbara Borroni
From the Neurology Unit (A.B., V.D., M.C., A.A., S.C., L.R., A.P., B.B.), Department of Clinical and Experimental Sciences, University of Brescia; Non-Invasive Brain Stimulation Unit (F.D.L., V.P., A. Martorana, C.C., G.K.), IRCCS Santa Lucia Foundation; Stroke Unit (G.K.), Policlinico Tor Vergata, Rome; Neurology Unit (M.S.C.), Valle Camonica Hospital, Brescia; Casa di Cura San Francesco (A. Micheli), Bergamo; Dipartimento di ingegneria dell'Informazione (A.D., A.F.), University of Brescia; and Neurology Unit (A. Martorana, C.C.), Department of System Medicine, University of Tor Vergata, Rome, Italy.
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Full PDF
Citation
Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia
Alberto Benussi, Francesco Di Lorenzo, Valentina Dell'Era, Maura Cosseddu, Antonella Alberici, Salvatore Caratozzolo, Maria Sofia Cotelli, Anna Micheli, Luca Rozzini, Alessandro Depari, Alessandra Flammini, Viviana Ponzo, Alessandro Martorana, Carlo Caltagirone, Alessandro Padovani, Giacomo Koch, Barbara Borroni
Neurology Aug 2017, 89 (7) 665-672; DOI: 10.1212/WNL.0000000000004232

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Abstract

Objective: To determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish Alzheimer disease (AD) from frontotemporal dementia (FTD).

Methods: Paired-pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis.

Results: A total of 175 participants met the inclusion criteria. We diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. We found that while patients with AD are characterized by a specific impairment of SAI, FTD shows a remarkable dysfunction of SICI-ICF intracortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8% and specificity of 88.6%, AD from HC with a sensitivity of 84.8% and specificity of 90.6%, and FTD from HC with a sensitivity of 90.2% and specificity of 78.1%. These results were confirmed in patients with mild disease.

Conclusions: TMS is a noninvasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice.

Classification of evidence: This study provides Class III evidence that TMS measures can distinguish patients with AD from those with FTD.

GLOSSARY

Aβ42=
β-amyloid42;
AD=
Alzheimer disease;
ANOVA=
analysis of variance;
AUC=
area under the curve;
CI=
confidence interval;
CS=
conditioning stimulus;
FTD=
frontotemporal dementia;
HC=
healthy controls;
ICF=
intracortical facilitation;
ISI=
interstimulus interval;
LICI=
long-interval intracortical inhibition;
mAD=
mild Alzheimer disease;
MEP=
motor evoked potential;
mFTD=
mild frontotemporal dementia;
rMT=
resting motor threshold;
SAI=
short-latency afferent inhibition;
SICI=
short-interval intracortical inhibition;
TMS=
transcranial magnetic stimulation;
TS=
test stimulus

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received November 30, 2016.
  • Accepted in final form May 19, 2017.
  • © 2017 American Academy of Neurology
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