Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer’s disease

Abstract

ObjectiveTo determine the ability of transcranial magnetic stimulation (TMS) in detecting synaptic impairment in patients with Alzheimer’s disease (AD) and predicting cognitive decline since the early phases of the disease.MethodsWe used TMS-based parameters to evaluate long-term potentiation (LTP)-like cortical plasticity and cholinergic activity as measured by short afferent inhibition (SAI) in 60 newly diagnosed patients with AD and 30 healthy age-matched subjects (HS). Receiver operating characteristic (ROC) curves were used to assess TMS ability in discriminating patients with AD from HS. Regression analyses examined the association between TMS-based parameters and cognitive decline. Multivariable regression model revealed the best parameters able to predict disease progression.ResultsArea under the ROC curve was 0.90 for LTP-like cortical plasticity, indicating an excellent accuracy of this parameter in detecting AD pathology. In contrast, area under the curve was only 0.64 for SAI, indicating a poor diagnostic accuracy. Notably, LTP-like cortical plasticity was a significant predictor of disease progression (p=0.02), while no other neurophysiological, neuropsychological and demographic parameters were associated with cognitive decline. Multivariable analysis then promoted LTP-like cortical plasticity as the best significant predictor of cognitive decline (p=0.01). Finally, LTP-like cortical plasticity was found to be strongly associated with the probability of rapid cognitive decline (delta Mini-Mental State Examination score ≤−4 points at 18 months) (p=0.04); patients with AD with lower LTP-like cortical plasticity values showed faster disease progression.ConclusionsTMS-based assessment of LTP-like cortical plasticity could be a viable biomarker to assess synaptic impairment and predict subsequent cognitive decline progression in patients with ADs.

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias

“…A considerable body of literature has historically shown that AD and DLB are characterized by a deficit in short latency afferent inhibition (SAI), a marker of sensorimotor integration that largely relies on cholinergic circuits, and FTD and DLB show a striking alteration in short interval intracortical inhibition and facilitation (SICI‐ICF), which substantially depend on GABAergic and glutamatergic circuits, respectively. These findings have prompted subsequent studies, which have suggested that a neurophysiological assessment might not be far from being ready to be translated from the experimental to the clinical setting . However, to further confirm TMS utility for the diagnosis of AD and other neurodegenerative dementias and to extend its use broadly, multicenter studies assessing the best combination of TMS measures, thus achieving the highest classification performance, are desirable.…”

“…These findings have prompted subsequent studies, which have suggested that a neurophysiological assessment might not be far from being ready to be translated from the experimental to the clinical setting. [26][27][28][29][30] However, to further confirm TMS utility for the diagnosis of AD and other neurodegenerative dementias and to extend its use broadly, multicenter studies assessing the best combination of TMS measures, thus achieving the highest classification performance, are desirable.…”

Emergence of neurophysiological biomarkers of Alzheimer disease

“…Motta and coworkers ( in their JNNP paper1) used a non-invasive repetitive transcranial magnetic stimulation (TMS) protocol to evaluate brain plasticity in patients with Alzheimer disease (AD). More than 15 years ago, we showed for the first time that a TMS test based on coupling motor cortex stimulation with peripheral nerve stimulation, termed short latency afferent inhibition (SAI), can probe central cholinergic pathways in humans2 and reveal cholinergic dysfunction in patients with AD 3.…”

“…Several studies confirmed these findings in the following years and showed that SAI may contribute to (1) diagnosis of other forms of cholinergic dementia such as dementia with Lewy bodies; (2) differential diagnosis of different forms of dementia that present with normal SAI such as frontotemporal dementia and vascular dementia; (3) identify patients with mild cognitive impairment with an increased risk to convert into dementia; (4) identify patients with AD responsive to acetylcholinesterase inhibitors, predicting long-term response to treatment after a single oral dose of the drug4 (see Cantone et al for a review) 5. Using repetitive TMS, Motta found a strong inverse correlation between the amount of long-term potentiation (LTP) (which can in some cases reverse into long-term depression) and AD progression 1. Interestingly, the effectiveness of LTP also correlates inversely with cerebrospinal fluid (CSF) levels of tau, which are thought to interfere directly with physiological mechanisms of neuronal synaptic plasticity.…”

“…The available data strongly suggest that they might provide novel insights into the human brain physiological correlates of dementia. In particular, they can provide information on the function of specific cortical circuits of the AD brain, involving the cholinergic pathways and also the glutamatergic and GABAergic circuits5 and the level of brain plasticity (Motta et al ) 1. The combination of TMS with EEG can also evaluate cortico-cortical connectivity in AD 7.…”