Preserved central cholinergic functioning to transcranial magnetic stimulation in de novo patients with celiac disease

Abstract

Background Celiac disease (CD) is now viewed as a systemic disease with multifaceted clinical manifestations. Among the extra-intestinal features, neurological and neuropsychiatric symptoms are still a diagnostic challenge, since they can precede or follow the diagnosis of CD. In particular, it is well known that some adults with CD may complain of cognitive symptoms, that improve when the gluten-free diet (GFD) is started, although they may re-appear after incidental gluten intake. Among the neurophysiological techniques, motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) can non-invasively probe in vivo the excitation state of cortical areas and cortico-spinal conductivity, being also able to unveil preclinical impairment in several neurological and psychiatric disorders, as well as in some systemic diseases affecting the central nervous system (CNS), such as CD. We previously demonstrated an intracortical disinhibition and hyperfacilitation of MEP responses to TMS in newly diagnosed patients. However, no data are available on the central cholinergic functioning indexed by specific TMS measures, such as the short-latency afferent inhibition (SAI), which might represent the neurophysiological correlate of cognitive changes in CD patients, also at the preclinical level. Methods Cognitive and depressive symptoms were screened by means of the Montreal Cognitive Assessment (MoCA) and the 17-item Hamilton Depression Rating Scale (HDRS), respectively, in 15 consecutive de novo CD patients and 15 healthy controls. All patients were on normal diet at the time of the enrolment. Brain computed tomography (CT) was performed in all patients. SAI, recorded at two interstimulus intervals (2 and 8 ms), was assessed as the percentage amplitude ratio between the conditioned and the unconditioned MEP response. Resting motor threshold, MEP amplitude and latency, and central motor conduction time were also measured. Results The two groups were comparable for age, sex, anthropometric features, and educational level. Brain CT ruled out intracranial calcifications and clear radiological abnormalities in all patients. Scores at MoCA and HDRS were significantly worse in patients than in controls. The comparison of TMS data between the two groups revealed no statistically significant difference for all measures, including SAI at both interstimulus intervals. Conclusions Central cholinergic functioning explored by the SAI of the motor cortex resulted to be not affected in these de novo CD patients compared to age-matched healthy controls. Although the statistically significant difference in MoCA, an overt cognitive impairment was not clinically evident in CD patients. Coherently, to date, no study based on TMS or other diagnostic techniques has shown any involvement of the central acetylcholine or the cholinergic fibers within the CNS in CD. This finding might add support to the vascular inflammation hypothesis underlying the so-called “gluten encephalopathy”, which seems to be due to an aetiology different from that of the cholinergic dysfunction. Longitudinal studies correlating clinical, TMS, and neuroimaging data, both before and after GFD, are needed.

A comprehensive review of transcranial magnetic stimulation in secondary dementia

“…The TMS group included 4 studies on NPH (Zaaroor et al, 1997;Chistyakov et al, 2012;Nardone et al, 2019a;Agrawal et al, 2021), 11 on MS (Cucurachi et al, 2008;Mori et al, 2011Mori et al, , 2013Canham et al, 2015;Hofstadt-van Oy et al, 2015;Nantes et al, 2016;Chalah et al, 2018Chalah et al, , 2019Chaves et al, 2019Chaves et al, , 2021a, 6 on CD and other immune-mediated disorders (Pennisi et al, 2014;Bella et al, 2015;Pennisi et al, 2017;Tokimura et al, 2020;Fisicaro et al, 2021b;Lanza et al, 2021), 5 on endocrine disorders (Ozata et al, 1996;Rizzo et al, 2008;Terranova et al, 2016;Fried et al, 2017Fried et al, , 2019, 13 on liver and renal diseases (Meyer et al, 1991;Nolano et al, 1997;Córdoba et al, 2003;Battaglia et al, 2005;Cerri et al, 2010;McDonald et al, 2010;Dubbioso et al, 2016;Golaszewski et al, 2016;Nardone et al, 2016b;Groiss et al, 2019;Hassan et al, 2019;Stezin et al, 2019;Dubbioso et al, 2020), 9 on nutritional and alcohol-related disorders (Wu and Chu, 1996;Oishi and Mochizuki, 1999;…”

“…The TMS group included 4 studies on NPH ( Zaaroor et al, 1997 ; Chistyakov et al, 2012 ; Nardone et al, 2019a ; Agrawal et al, 2021 ), 11 on MS ( Cucurachi et al, 2008 ; Mori et al, 2011 , 2013 ; Canham et al, 2015 ; Hofstadt-van Oy et al, 2015 ; Nantes et al, 2016 ; Chalah et al, 2018 , 2019 ; Chaves et al, 2019 , 2021a , b ), 6 on CD and other immune-mediated disorders ( Pennisi et al, 2014 ; Bella et al, 2015 ; Pennisi et al, 2017 ; Tokimura et al, 2020 ; Fisicaro et al, 2021b ; Lanza et al, 2021 ), 5 on endocrine disorders ( Ozata et al, 1996 ; Rizzo et al, 2008 ; Terranova et al, 2016 ; Fried et al, 2017 , 2019 ), 13 on liver and renal diseases ( Meyer et al, 1991 ; Nolano et al, 1997 ; Córdoba et al, 2003 ; Battaglia et al, 2005 ; Cerri et al, 2010 ; McDonald et al, 2010 ; Dubbioso et al, 2016 ; Golaszewski et al, 2016 ; Nardone et al, 2016b ; Groiss et al, 2019 ; Hassan et al, 2019 ; Stezin et al, 2019 ; Dubbioso et al, 2020 ), 9 on nutritional and alcohol-related disorders ( Wu and Chu, 1996 ; Oishi and Mochizuki, 1999 ; Ravaglia et al, 2002 ; Misra et al, 2003 ; Atanassova et al, 2004 ; Di Lazzaro et al, 2004 ; Nardone et al, 2006 , 2010b , 2016a ), 7 on infectious or inflammatory diseases ( Misra and Kalita, 1998 ; Kalita and Misra, 2002 ; Lo and Ratnagopal, 2007 ; Volz et al, 2016 ; Nardone et al, 2019b ; Ortelli et al, 2021 ; Versace et al, 2021 ), 5 on sleep disorders (…”

Cerebral hemodynamic changes to transcranial Doppler sonography in celiac disease: A pilot study

“…GFD ( Bella et al, 2015 ; Pennisi et al, 2017b ). Overall, these studies suggest a global pattern of intracortical and intercortical “hyperexcitable celiac brain,” which partially recovers with a long lasting GFD ( Lanza et al, 2018 , 2021 ; Fisicaro et al, 2021 ). Translationally, this hyperexcitability to TMS may represent the neurophysiological correlate of the hyperdynamic circulation to TCD, although, at this stage, an association only and not a causal or reciprocal effect can be postulated.…”

“…In severe patients, fortunately today more and more rare, an overt dementing disorder may manifest (Collin et al, 1991;Hu et al, 2006;Lurie et al, 2008;Casella et al, 2012). In this scenario, transcranial magnetic stimulation (TMS), an electrophysiological technique that may non-invasively assess and monitor different neurological and neuropsychiatric disorders (Cantone et al, 2020(Cantone et al, , 2021Fisicaro et al, 2020;Di Lazzaro et al, 2021), even those without clear clinical manifestations (Lanza et al, 2020a,b), has been recently applied to CD patients, both at diagnosis (Pennisi et al, 2014;Lanza et al, 2021) and after a short-or long-term GFD (Bella et al, 2015;Pennisi et al, 2017b). Overall, these studies suggest a global pattern of intracortical and intercortical "hyperexcitable celiac brain, " which partially recovers with a long lasting GFD (Lanza et al, 2018(Lanza et al, , 2021Fisicaro et al, 2021).…”

“…In this scenario, transcranial magnetic stimulation (TMS), an electrophysiological technique that may non-invasively assess and monitor different neurological and neuropsychiatric disorders (Cantone et al, 2020(Cantone et al, , 2021Fisicaro et al, 2020;Di Lazzaro et al, 2021), even those without clear clinical manifestations (Lanza et al, 2020a,b), has been recently applied to CD patients, both at diagnosis (Pennisi et al, 2014;Lanza et al, 2021) and after a short-or long-term GFD (Bella et al, 2015;Pennisi et al, 2017b). Overall, these studies suggest a global pattern of intracortical and intercortical "hyperexcitable celiac brain, " which partially recovers with a long lasting GFD (Lanza et al, 2018(Lanza et al, , 2021Fisicaro et al, 2021). Translationally, this hyperexcitability to TMS may represent the neurophysiological correlate of the hyperdynamic circulation to TCD, although, at this stage, an association only and not a causal or reciprocal effect can be postulated.…”