The impact of transcranial magnetic stimulation on diagnostic confidence in patients with Alzheimer disease

Alberto Benussi,Rosanna Turrone,Valentina Dell’Era,Clarissa Ferrari,Giuliano Binetti,Barbara Paghera,Giacomo Koch,Barbara Borroni,Alessandro Padovani,Maria Sofia Cotelli,Valentina Cantoni,Antonella Alberici

doi:10.1186/s13195-018-0423-6

Abstract

BackgroundCholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0–100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis.MethodsOne hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step.ResultsTMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the “gold standard” diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers).ConclusionsTMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.

Highlights

Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols
According to the “gold-standard” diagnosis, 63 patients were classified as AD and 57 as frontotemporal dementia (FTD)
We have shown that TMS assessment added to the clinical and neuropsychological evaluation may increase diagnostic accuracy up to 98%, comparable to that obtained from the addition of amyloidosis biomarkers, which reached 99% accuracy

Summary

Introduction

Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. We evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0–100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis. Decreased levels of amyloid-β 1–42 (Aβ1–42) in the cerebrospinal fluid (CSF) and/or increased binding of amyloid ligands visualized by positron emission tomography (PET) are the most established and validated amyloid markers [8,9,10,11], being helpful in increasing the diagnostic confidence of Alzheimer disease (DCAD) among clinicians [12, 13]. There is a growing demand to identify inexpensive, easy-to-perform, noninvasive, and safe biomarkers to be used extensively on clinical grounds [14]

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Discussion

Conclusion