Effects of Palmitoylethanolamide Combined with Luteoline on Frontal Lobe Functions, High Frequency Oscillations, and GABAergic Transmission in Patients with Frontotemporal Dementia

Article type: Research Article

Authors: Assogna, Martina^{a; b} | Casula, Elias Paolo^{a; c} | Borghi, Ilaria^a | Bonnì, Sonia^a | Samà, Domenico^b | Motta, Caterina^a | Di Lorenzo, Francesco^a | D’Acunto, Alessia^a | Porrazzini, Francesco^a | Minei, Marilena^a | Caltagirone, Carlo^a | Martorana, Alessandro^b | Koch, Giacomo^{a; d; *}

Affiliations: [a] Santa Lucia Foundation, IRCCS, Rome, Italy | [b] Tor Vergata Policlinic, Rome, Italy | [c] Department of Clinical and Movement Neurosciences, University College London, United Kingdom | [d] eCampus University, Novedrate, Italy

Correspondence: [*] Correspondence to: Prof. Giacomo Koch, MD, PhD, Non Invasive Brain Stimulation Unit, Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Fondazione S. Lucia, Via Ardeatina, 306-00179 Rome, Italy. Tel.: +39 0651501181; E-mail: g.koch@hsantalucia.it.

Abstract: Background:Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD. Objective:Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients. Methods:Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mg×2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity. Results:Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range. Conclusion:PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission.

Keywords: Brain inflammation, behavioral symptoms, EEG, executive functions, frontotemporal dementia, GABA activity, transcranial magnetic stimulation

DOI: 10.3233/JAD-200426

Journal: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1297-1308, 2020