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

Clinical Neurophysiology 115 (2004) 2410–2418 www.elsevier.com/locate/clinph

Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia M. Pierantozzia,b, M. Panellaa, M.G. Palmieria,b, G. Kocha, A. Giordanoc, M.G. Marciania,b, G. Bernardic, P. Stanzionea,c, A. Stefania,c,* a

IRCCS Fondazione Santa Lucia, Via Ardeatina 306, 00173 Rome, Italy Servizio di Neurofisiopatologia, Policlinico Tor Vergata, Viale Montpellier 1, 00133 Rome, Italy c Department of Neuroscience, Clinica Neurologica, Policlinico Tor Vergata, Viale Montpellier 1,00133 Rome, Italy b

Accepted 27 April 2004 Available online 25 June 2004

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 ðn ¼ 12Þ and FTD ðn ¼ 8Þ: 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 noninvasive, 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. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Cortical dementia; Neurophysiology; Cholinergic transmission; Diagnostic protocols

1. 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 * Corresponding author. Address: Department of Neuroscience, Clinica Neurologica, Policlinico Tor Vergata, Viale Montpellier 1, 00133 Rome, Italy. Tel.: þ39-62-0903119; fax: þ39-62-0903118. E-mail address: [email protected] (A. Stefani).

disorders commonly mistaken for AD and/or misdiagnosed as primary psychiatric disorder. Thus, additional noninvasive 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.

1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.04.022

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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.

2. Methods 2.1. 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 (^ 3.5) years; in the FTD group mean age was 63.4 (^ 2.7). In both sub-groups disease duration did not last more than 18 months and CDR was # 1. None of our patients revealed pyramidal and/or extrapyramidal signs at the neurological examination. In addition, none of them was taking AchEI or any other neuroactive drugs before participating in the study. All patients underwent structural imaging (MRI) or 99 HMPAO SPECT and patients with vascular lesions or other pathological conditions underlying dementia were excluded. The physicians involved in TMS (MP, MGP)

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and neuropsychological tests (MP, GK, AG) were not aware of neuro-imaging data. In addition, 12 age-matched healthy individuals (64.5 ^ 3.2) were studied as a control group. All EOAD and FTD patients showed a cognitive profile consistent with mild dementia, as assessed by a neuropsychological evaluation including the MMSE and a standardised neuropsychological battery (Carlesimo et al., 1996). Mood disorder was ruled out through the Beck depression scale. On the MMSE, the subjects with possible AD scored a mean of 21.8 (^ 2.1). FTD group scored 23.5 (^ 2.8) in the beginning of the study. Behavioural disorders were assessed by Neuropsychiatry Inventory (NPI) in both the groups. 2.2. TMS procedure All participants were tested lying comfortable to achieve a complete relaxation. EMG background was monitored by an acoustic feedback before and during all TMS recordings. TMS was performed with a figure-of-eight coil (each loop diameter 70 mm) connected with two Magstim 200 Stimulators through a Bistim module (Magstim Co. Ltd, UK) discharging a maximum output of 2.2 T. Motor evoked potentials (MEPs) to TMS were recorded from the abductor pollicis brevis (APB) via surface electrodes applied in a belly-tendon montage. Impedance was kept below 5 kV; filtering bandwidth was 2– 2000 Hz (sampling rate: 5 kHz on 200 ms sweep duration). The coil was placed at 6 cm lateral to Cz along the interlobe line, over the scalp region corresponding to the primary hand motor area contralateral to the target muscle. It was held horizontal to the skull with the handle pointing backwards and 458 from the midline. In both control subject and patient groups TMS procedures were performed bilaterally. The resting motor threshold (RMT), expressed as a percentage of the magnetic stimulator maximal output (equal 100%), was established in agreement with international standards (Rossini et al., 1994) as the lowest stimulus intensity able to produce MEPs of 100 mV in 50% of six consecutive trials. Active motor threshold (AMT) was the lowest stimulus intensity producing, in four consecutive trials, a MEP of . 100 mV during a tonic activation of about 20% of the maximum voluntary contraction (as measured via a manual force transducer). The time-course of ICI and intracortical facilitation (ICF) were studied at rest via a paired-pulse paradigm, delivered in a conditioning-test design, as outlined in previous papers (Kujirai et al., 1993; Ridding et al., 1995; Ziemann et al., 1996). Briefly, the conditioning stimulus was set at intensity 5% below the AMT, while the test stimulus was set at 105% of RMT, an intensity at which MEPs of 0.5– 1 mV peak-to-peak amplitude were always obtained in the relaxed muscle of all participants. Interstimulus intervals (ISI) from 1 to 10 ms, at step 1 ms, and at 15 and 20 ms were employed in a pseudorandom sequence to investigate preferentially both the ICI (1 – 4 ms)

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and the ICF (6 –20 ms) (Kujirai et al., 1993; Ziemann et al., 1996). Twelve blocks of eight trials each were recorded three times in all participants. Each block consisted of two different conditions: four control MEPs in response to the test pulse alone, and four paired MEPs given in a conditioned-test design at each of the preset ISI. The sequence of paired conditions within each block, and the order of block presentation were given pseudo-randomly by the computer. The time interval between two consecutive trials was 9.9 s. Recordings were acquired with ESAOTE-Sirius equipment and stored for off-line analysis. We measured the peak-to-peak amplitude of MEPs. The conditioned MEP amplitude was expressed as a percentage of the MEP amplitude to the test stimulus alone. 2.3. Pharmacological treatment A preliminary test-response to placebo was performed in 4 AD patients. Placebo did not promote any substantial changes on both RMT and paired-pulse TMS, thus we started the pharmacological tool. The AchEI galantamine was administered orally in a single dose (4 mg) to EOAD and FTD patients. Given the rapid absorption and the fast pharmacokinetics of galantamine, with a time to peak concentration # 2 h (Jann et al., 2002), patients were tested before and 2 h after the drug intake.

Abnormal individual mean-ICI and mean-ICF values were also assessed in both patient groups. Individual meanICI and mean-ICF were considered abnormal if exceeding the mean þ two standard deviation of healthy subjects corresponding value. Considering the lack of any inter-hemispheric difference found in basal condition (see results, below), the statistical analysis of pharmacological data was performed only on the TMS data obtained by stimulating the right hemisphere. The effects of galantamine on RMT and AMT, as well as on the amplitude of unconditioned test MEP, were separately assessed in AD and FTD patients by means of one-way ANOVA analysis for repeated measures (within factor ‘treatment’ with two levels (basal vs galantamine). Moreover, the effect of galantamine on patient cortical excitability was separately analysed in the two groups by means of two-way ANOVA for repeated measures with two main within factors: ‘treatment’, with two levels (basal vs galantamine) and ‘ISI’, with 12 levels corresponding to the entire series of studied ISI. Whenever a significant interaction between factors was found, singular differences between means for each ISI were measured via post-hoc Tukey HSD test.

3. Results

2.4. Statistical analysis

3.1. Motor thresholds and single MEP amplitude

RMT and AMT, as well as the amplitude of unconditioned test MEP, they were separately compared by means of a two-way ANOVA analysis [‘between’ main factor: ‘group’ with three level (EOAD vs FTD patients vs healthy subjects); ‘within’ main factor: ‘hemisphere’, with two levels (right vs left)]. Statistical evaluation of paired TMS data included a design of a three-way ANOVA analysis consisting in a ‘between’ main factor ‘group’, with three levels (EOAD vs FTD patients vs healthy subjects), and two ‘within’ main factors: ‘hemisphere’, with two levels (right vs left) and ‘ISI’, with 12 levels, corresponding to the ISI sequence exploring the time course of ICI and ICF. The GreenhouseGeisser correction for multiple levels was used when more then two levels were present in a main factor. Whenever a significant interaction between the ‘main factors’ was found, the differences were assessed, at each ISI, by means of post-hoc Tukey honest significant difference (HSD) test. Furthermore, a mean-ICI and a mean-ICF value was individually measured by calculating the average of the conditioned MEP amplitude at ISIs of 1 –4 ms (mean-ICI) and 6– 10 ms (mean-ICF), respectively corresponding to the ISI sequence at which maximal MEP inhibition and MEP facilitation are usually found (Kujirai et al., 1993; Ziemann et al., 1996).

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). 3.2. Intracortical excitability The three-way ANOVA analysis showed a significant effect (F ¼ 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%) than in FTD patients (95.6%) and healthy subjects (102.2%). The ‘within’ factor ‘hemisphere’ revealed no significant difference between the left (104.6%) and the right (108.2%) hemisphere. The ‘within’ factor ‘ISI’ was significant (F ¼ 135:4; 1 ¼ 0:47; P , 0:0001), since the mean test MEP amplitude increased from 19.8 to 144.3% as ISI increased from 1 to 20 ms. According to statistics, the interaction ‘group £ hemisphere’ was not significant, illustrating a negligible inter-side difference in all the three groups. On the contrary, the ‘group £ ISI’ interaction was the unique significant (F ¼ 9:30; 1 ¼ 0:47; P , 0:001), showing that the effect of the conditioning stimulus was different in the three studied

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Table 1 Demographic, clinical and electrophysiological data of three studied groups AD patients

Age

MMSE

Right hemisphere RMT

ATM

MEP ampl (mV)

RMT

AMT

MEP ampl (mV)

48 46 36 32 50 47 49 39 48 50 35 32

832 860 920 870 640 590 640 730 780 920 820 600

63 55 44 43 58 63 60 52 60 68 59 54

44 40 34 36 46 38 48 42 44 48 39 34

720 910 890 618 830 650 730 630 820 880 690 650

1 2 3 4 5 6 7 8 9 10 11 12

66 68 64 55 66 64 67 65 67 66 67 68

22.5 20.5 23 23.5 24.0 22.0 24.0 22.5 19.0 23.7 18.0 19.0

65 62 49 39 65 63 67 56 65 66 59 56

FTD patients

Age

MMSE

Right hemisphere

1 2 3 4 5 6 7 8

57 64 63 64 65 66 65 63

Healthy subjects

Age

1 2 3 4 5 6 7 8 9 10 11 12

64 65 56 67 63 64 67 63 66 69 66 65

Mean ^ SD

Age

AD Patients FTD patients Healthy subjects

65.2 ^ 3.5 63.4 ^ 2.7 65.2 ^ 3.5

26,5 20 25,3 23 24 20,5 23,5 25

Left hemisphere

Left hemisphere

RMT

ATM

MEP ampl (mV)

RMT

AMT

MEP ampl (mV)

64 63 48 65 63 53 63 64

47 38 32 48 47 32 46 42

630 745 950 730 900 580 760 780

68 59 43 64 48 53 62 67

48 40 31 46 42 35 49 46

780 850 880 620 830 850 668 810

Right hemisphere

MMSE

21.8 ^ 2.1 23.5 ^ 2.8

Left hemisphere

RMT

ATM

MEP ampl (mV)

RMT

AMT

MEP ampl (mV)

45 64 57 58 62 65 58 44 68 64 63 57

35 48 46 45 48 47 36 32 48 48 47 41

780 660 670 830 690 730 610 860 745 900 745 700

48 64 61 55 67 62 51 46 64 60 586 63

40 46 44 47 43 42 48 34 42 44 45 38

800 640 730 540 660 520 550 650 630 830 890 640

Right hemisphere

Left hemisphere

RMT

ATM

MEP ampl (mV)

RMT

AMT

MEP ampl (mV)

59.3 ^ 8.3 60.4 ^ 6.2 58.7 ^ 7.4

42.6 ^ 7.2 41.5 ^ 6.7 42.6 ^ 5.9

766.8 ^ 122.9 759.4 ^ 123.3 742.9 ^ 86.3

56.6 ^ 7.5 58.0 ^ 9.1 58.9 ^ 7.1

41.1 ^ 5.0 42.1 ^ 6.4 42.8 ^ 4.0

751.5 ^ 108.7 786.0 ^ 93.3 673.3 ^ 117.6

NS at the ANOVA two way (group £ hemisphere).

populations at different ISIs. In fact, the post-hoc analysis, carried out considering both hemispheres, showed a significant loss of MEP inhibition at 2 and 3 ms ISIs in EOAD patients in comparison FTD patients (2 ms:

P , 0:0001; 3 ms: P , 0:0001) and healthy subjects (2 ms: P , 0:001; 3 ms: P , 0:001) (Figs. 1 and 2). On the contrary, the time-course of ICF was the same in the all studied groups (Figs. 1 and 2).

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Fig. 1. The mean time course of intracortical excitability obtained by stimulating the right (panel A) and the left hemisphere (panel B) of patients and healthy subjects studied at muscular rest are shown. The x-axis is the interstimulus interval (ISI) between the conditioning and the test shock. In the y-axis the amplitude of the conditioned MEP is expressed as a percentage of the MEP amplitude produced by the test shock given alone (unconditioned). The dotted line at 100% represents the size of unconditioned MEP response. Each point represents a mean value; error bars indicate standard deviation.

In order to detect possible overlapping in the amount of individual ICI and ICF among the three different populations, the magnitude of mean-ICI and mean-ICF within each group was illustrated in a scatter plot (Fig. 3). As showed, EOAD revealed no overlap in the distribution of individual mean-ICI in comparison to both FTD and healthy subject groups. On the contrary, FTD patients exhibited a mean-ICI completely similar to that of healthy subjects. Finally, a large overlap in the individual values of mean-ICF was found among the three groups (Fig. 3). Abnormal individual mean-ICI and mean-ICF were also calculated in AD and FTD patients. We found that all AD patients exhibited abnormally reduced mean-ICI by stimulating both hemispheres, whereas only two FTD patients had a meanICI value slightly exceeding the normal value by stimulating the right hemisphere. None of the patients exhibited abnormal mean-ICF values.

Fig. 2. Examples of traces demonstrating the time course of the intracortical excitability detected by paired-pulse TMS delivered at different interstimulus intervals in a representative EOAD patient (A), FTD patient (B) and healthy subject (C) are shown. The top traces show the response to the test stimulus alone. Each trace is the average of eight sweeps. TMS artefacts correspond to the vertical bar at constant and variable positions, respectively.

3.3. Pharmacological treatment In both EOAD and FTD patients, the statistical analysis showed that galantamine did not produce any significant change in RMT (59.3 ^ 8.3 vs 61.0 ^ 7.9 and 60.4 ^ 6.2 vs 59.0 ^ 6.9 in EOAD and FTD, respectively) and AMT (42.6 ^ 7.2 vs 43.5 ^ 6.9 and 41.5 ^ 6.7 vs 40.3 ^ 4.7). Moreover, also the mean MEP amplitude was not affected by galantamine. In EOAD patients, MEP averaged 766.8 ^ 122.9 mV and 751 ^ 82.6 mV before and under galantamine, respectively. In FTD patients, the mean MEP amplitude was 759.4 mV ^ 123.3 pre-galantamine and 763.75 mV ^ 77.0 post-galantamine. On the contrary, in EOAD patients the decreased ICI pattern was reverted by the acute administration of

M. Pierantozzi et al. / Clinical Neurophysiology 115 (2004) 2410–2418

Fig. 3. A scatter-plot illustrating the amount of the mean-ICI (1– 4 ms) and mean-ICF (6 – 10 ms) within each group (panel A and panel B, respectively). As showed, EOAD revealed no overlap in the distribution of individual mean-ICI in comparison to both FTD and healthy subject groups. Conversely, in FTD patients the mean-ICI was similar to that of healthy subjects. Finally, a large overlap in the individual values of meanICF was found among the three groups.

galantamine (Figs. 4 and 5). The ANOVA analysis showed that galantamine reduced the mean test MEP amplitude from 121.4 to 111.1% (factor ‘treatment’: F ¼ 26:5; P , 0:001); the factor ‘ISI’ and the ‘treatment £ ISI’ interaction were also significant (F ¼ 28:0; P , 0:001 and F ¼ 19:40; P , 0:001; respectively). The post-hoc analysis demonstrated that galantamine increased MEP inhibition at 2 ðP , 0:001Þ and 3 ms ðP , 0:001Þ (Fig. 4). Finally, the statistical analysis revealed that galantamine did not produce any changes in intracortical excitability of FTD patients (Figs. 4 and 5).

4. 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

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Fig. 4. The effects of galantamine on the mean time course of intracortical excitability of EOAD (panel A) and FTD (panel B) patient groups. The x-axis is the inter-stimulus interval (ISI) between the conditioning and the test shock. The y-axis is the size of the conditioned response expressed as a percentage of the response size produced by the test shock given alone. The dotted line at 100% represents the size of unconditioned MEP response. Each point represents a mean value; error bars indicate standard deviation.

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 slightly more severe than our patients (Liepert et al., 2001; Di Lazzaro et al., 2002). Liepert et al. (2001) described a reduced ICI in ‘mildly-tomoderately affected AD patients’ utilizing paired-TMS delivered in a conditioning-test design. In the work by Di Lazzaro et al. (2002), despite the reduction of ICI was considered not strongly significant ðP , 0:05Þ; a clear decrease of cortical excitability was shown via short latency afferent inhibition of motor cortex. The impairment of other TMS measures of cortical excitability, including the RMT and the absolute MEP amplitude, has been also described in different populations of AD (Alagona et al., 2001; de Carvalho et al., 1997; Di Lazzaro et al., 2002; Ferreri et al., 2003; Liepert et al., 2001;

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Fig. 5. Examples of traces demonstrating the effect of galantamine on the time course of the intracortical excitability of a representative AD patient tested before (A) and 2 h later the drug assumption (B). The top traces show the response to the test stimulus alone. Each trace is the average of eight sweeps. TMS artefacts correspond to the vertical bar at constant and variable positions, respectively.

Pepin et al., 1999; Pennisi et al., 2002). In contrast, we observed that the early loss of ICI was not accompanied to relevant changes in RMT and absolute MEP amplitude, apparently at odd with most of previous papers (Alagona et al., 2001; de Carvalho et al., 1997; Di Lazzaro et al., 2002; Ferreri et al., 2003; Pepin et al., 1999). This apparent discrepancy could be interpreted if we consider that our patients represent a clinical and demographic homogeneous population of EOAD (see Table 1). On the contrary, in previous studies mild, moderate and even severe AD individual patients were often intermixed (Alagona et al., 2001; de Carvalho et al., 1997; Pepin et al., 1999; Perretti et al., 1996; Pennisi et al., 2002), and patients with both a long disease duration (more than 2 year) and/or a late-onset were often included in the same analysis (Alagona et al., 2001;

Di Lazzaro et al., 2002; Ferreri et al., 2003; Pepin et al., 1999). In our EOAD patients a dramatic decrease of ICI, but an unchanged RMT coexists. It is feasible that mechanisms related to RMT are initially preserved, but then progressively involved in the further progression of AD (Alagona et al., 2001; de Carvalho et al., 1997; Pepin et al., 1999; Pennisi et al., 2002). If, in fact, RMT reflects mostly the level of neuronal membrane excitability, being sensitive to drugs blocking voltage-gated membrane channels (Hallett, 2000; Kobayashi and Pascual-Leon, 2003; Ziemann et al., 1996), the changes in RMT described in late stages of AD could represent an important electrophysiological index of a diffuse neuronal and axonal loss. Differently, paired-pulse TMS seems to reflect the complex interaction of neurotransmitter synaptic activity. In particular, ICI is commonly attributed to the activation of intracortical GABAergic neurons (Hallett, 2000; Kujirai et al., 1993; Ziemann et al., 1996), being affected by drugs able to modulate intracortical synaptic activities (Ziemann et al., 1996). Therefore, we may speculate that an altered ICI reflects subtle early synaptic alterations of mildly affected AD patients. Our findings have also suggested that these changes may be ascribed, at least in part, to an impaired endogenous cholinergic transmission. In fact, the tertiary alkaloid galantamine, widely used as a first-choice treatment in AD patients, modified acutely the motor cortex excitability in AD. A single oral dose of the drug was consistently able to recover the physiological inhibition in EOAD patients. Noticeably, galantamine is not only a competitive AchEI, but also an allosteric modulator of nicotinic acetylcholine receptors (Lilienfeld, 2002; Santo et al., 2002). Hence, we might suggest that the large alteration in ICI, observed in EOAD, could partially depend on a defect of cholinergic transmission impinging on GABAergic interneurons in cortical layers. A large body of evidence has shown that cholinergic receptors, largely expressed by hippocampal interneurons (Frazier et al., 2003), promote IPSPS. In addition, the GABAergic inhibition to the layer V pyramidal neurons is enhanced via the activation of alpha4 beta2 (and alpha 7) nicotinic receptors (Alkondon and Albuquerque, 2004). Nevertheless, considering that complex neurotransmitter changes in areas other than primary motor cortex (M1) are plausible in AD, the described galantamine-mediated effect on ICI cannot be attributed unequivocally to a pre- or postsynaptic interactions with muscarinic or nicotinic binding sites in motor cortex. In other words, agents facilitating cholinergic transmission in structures such as basal ganglia and non-motor frontal circuitries might give rise to secondary modulation of ICI. The other aspect of our work was the comparison of EOAD with FTD, a well-defined different form of earlyonset dementia, whose TMS features have been little studied. Differently from AD, FTD patients exhibited

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a preserved ICI. So far, ICI is considered a sensitive, although not disease-specific, TMS parameter able to detect even minimal changes in intracortical inhibitory mechanisms (Hallett, 2000; Kobayashi and Pascual-Leon, 2003). The absence of significant ICI changes in FTD patients should imply that intracortical inhibitory circuits may be little involved in this disease. Which mechanisms underlie this clear-cut difference between EOAD and FTD patients? The different extension of cortical atrophy may represent the most parsimonious explanation. This does not apply, however, to our patients, whose cortical degeneration was negligible. An alternative hypothesis suggests that in the preclinical or initial phases of AD, the peculiar damage is mostly ‘dysfunctional’, attaining the fine modulation of intra-cortical circuitry. Global corticocortical disconnection may occur in AD representing the primary anatomical substrate for dementia (Hof et al., 1997). Indeed, interneuronal elements connecting pyramidal neurons are likely the target of subtle pathological changes, as supported by the prominent deposition of neurofibrillary tangles in long association pathways. As known, ascending fibres (Deschenes et al., 1979; Gil and Amitai, 1996), intracortical horizontal fibres (ChagnacAmitai and Connors, 1989a,b; Connors et al., 1988; Gil and Amitai, 1996), and recurrent fibres (Deschenes et al., 1979) may concurrently activate cortical neurons. Hence, inhibitory GABAergic interneurons might virtually affect all types of cortical cells (Chagnac-Amitai and Connors, 1989a; McCormick et al., 1985) inducing a powerful inhibitory effect on pyramidal cell firing initiation (Somogyi et al., 1998). In this perspective, the modification of ICI observed in AD, but not FTD, may reflect the cortico-cortical disconnection reported in this pathology, whereas the lack of modification in motor cortical excitability found in FTD may be attributed to a preservation of intracortical inhibitory circuits affecting the motor cortex. In conclusion, we suggest that the use of TMS, a technique able to explore the central motor pathway (Hallett, 2000; Kobayashi and Pascual-Leon, 2003; Rossini et al., 1994), may be helpful in the assessment of early differential diagnosis between EOAD and FTD. We, therefore, propose that the distinctive profile of ICI found in these two pathological conditions, can be considered as an auxiliary, not invasive, functional test that could be easily added to the clinical follow-up of dementias, so far based upon neuropsychological, genetic and neuroimaging data.

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

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