Elsevier

Clinical Neurophysiology

Volume 115, Issue 10, October 2004, Pages 2410-2418
Clinical Neurophysiology

Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia

https://doi.org/10.1016/j.clinph.2004.04.022Get rights and content

Abstract

Objective: To investigate putative changes in cortical excitability of patients affected by early-onset mild dementia by means of transcranial magnetic stimulation (TMS) and to verify whether a peculiar neurophysiological profile may contribute to characterise Alzheimer's disease (AD) vs frontotemporal dementia (FTD).

Methods: Motor threshold and intracortical inhibition (ICI) and facilitation (ICF) after paired-pulse TMS (inter-stimulus intervals from 1 to 20 ms) were studied in two groups of early-onset demented patients with a neuropsychological profile suggestive of AD (n=12) and FTD (n=8). Twelve age-matched healthy subjects were considered as control group. In both patient groups, recordings were performed before and after a single oral dose of 4 mg galantamine.

Results: No significant difference in motor threshold was observed among the three studied groups. On the contrary, early-onset AD showed a significant reduction of ICI compared to control group, no changes were detected in FTD patients. No significant changes in ICF were found between both patient groups and healthy subjects. The acute administration of galantamine reversed the modified ICI in AD group.

Conclusions: The differential pattern of ICI exhibited by early-onset AD vs FTD in the early stage of disease may represent a non-invasive, reproducible electrophysiological tool, which may contribute to early differential diagnosis and, possibly, to monitor therapeutic effectiveness.

Significance: The present results support the possibility that subtle, early modifications in intracortical circuitry features AD, but not FTD patients.

Introduction

Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) have similar prevalence in the presenium (≤65 years) (Ratvanalli et al., 2002). In the early stages, each pathological condition presents peculiar cognitive, behavioural and radiological features. Yet, an unequivocal differential diagnosis is, sometimes, difficult to assess. FTD is indeed one of the neurodegenerative disorders commonly mistaken for AD and/or misdiagnosed as primary psychiatric disorder. Thus, additional non-invasive diagnostic approaches, which do not require hospitalisation or cause patient's discomfort, would be welcomed.

Even the diagnosis of AD, although founded on neuropsychological testing and genetic studies, may imply a long-lasting and costly follow-up. The availability of pharmacological therapies with some favourable impact on mild cognitive decline, including acetylcholinesterase inhibitors (AchEI) (Blennow and Hampel, 2003), renders urgent to define new approaches able to ameliorate diagnostic sensibility and specificity.

Transcranial magnetic stimulation (TMS) is a neurophysiological tool increasingly used in clinical practice to investigate cortical excitability in neurological diseases, mostly involving central motor pathways (Ridding et al., 1995; Hallett, 2000; Kobayashi and Pascual-Leon, 2003). In the past, several TMS studies have demonstrated changes in motor cortex excitability of AD patients long before clinical evidence of motor deficit occurred (Alagona et al., 2001; de Carvalho et al., 1997; Di Lazzaro et al., 2002; Ferreri et al., 2003; Liepert et al., 2001; Pepin et al., 1999; Perretti et al., 1996; Pennisi et al., 2002). In this context, Liepert et al. (2001), using a paired-TMS paradigm, showed that intracortical inhibition (ICI) is decreased in AD patients and is related to cognitive deterioration. Moreover, also resting motor threshold (RMT), a reliable parameter of cortical excitability, resulted modified in AD and strictly correlated with the severity of disease progression (Alagona et al., 2001; Pennisi et al., 2002). TMS evaluations were, however, usually carried out in moderately or severely advanced AD subjects, and changes in motor cortex excitability of FTD patients have not been investigated yet. Therefore, in the present TMS study we aimed to identify putative changes in cortical excitability patterns within two selected populations of early stage EOAD and FTD patients.

Moreover, we tested the fast pharmacokinetics of the tertiary alkaloid galantamine (Jann et al., 2002), an AchEI currently utilised in the therapy of AD, to investigate whether its administration may modify acutely intracortical excitability in the two patient groups.

Section snippets

Subjects

A total of 20 subjects with early onset cognitive impairment were enrolled in the study. Twelve were diagnosed as suffering of possible AD (according to the criteria of NINCDS-ADRDA, Varma et al., 1999) and the other eight as affected by FTD. Diagnosis of FTD was based on the clinical criteria proposed by McKhann et al. (2001). EOAD and FTD populations were matched for age and severity of cognitive impairment as assessed by the clinical dementia rating (CDR). The mean age of EOAD was 65.2

Motor thresholds and single MEP amplitude

The mean threshold intensity was not significantly different among the three studied groups, both in relaxed and tonically active muscle (Table 1). Moreover, the statistical analysis did not find any significant difference in MEP amplitude among AD patients, FTD patients and healthy subjects (Table 1).

Intracortical excitability

The three-way ANOVA analysis showed a significant effect (F=27.32;P<0.0001) of the factor ‘group’ because the mean test MEP amplitude over the ISI sequence was greater in EOAD patients (121.5%)

Discussion

Our findings propose that paired-TMS may be considered as a complementary, but useful tool in the differential diagnosis of cortical dementias in the early stage of disease.

In the present work, restricted to EOAD with mild cognitive decline, a significant ICI reduction was found in the very early stages of disease not characterised by gross cortical atrophy. This finding is largely in agreement with at least two previous papers, focusing on TMS features of AD patients with a cognitive profile

Acknowledgements

This work was supported by Ministero della Sanità Grants (PF 086, 087 and 186A to AS and PS).

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