Limbic Network Derangement Mediates Unawareness of Apathy in Mild Cognitive Impairment due to Alzheimer’s Disease: Clues from [¹⁸F]FDG PET Voxel-Wise Analysis

Article type: Research Article

Authors: Kreshpa, Wendy^a | Raffa, Stefano^{b; e} | Girtler, Nicola^{a; b} | Brugnolo, Andrea^{a; b} | Mattioli, Pietro^{a; b} | Orso, Beatrice^a | Calizzano, Francesco^a | Arnaldi, Dario^{a; b} | Peira, Enrico^c | Chincarini, Andrea^c | Tagliafico, Luca^{b; d} | Monacelli, Fiammetta^{b; d} | Calcagno, Pietro^{a; b} | Serafini, Gianluca^{a; b} | Gotta, Fabio^{a; b} | Mandich, Paola^{a; b} | Pretta, Stefano^b | Del Sette, Massimo^b | Sofia, Luca^e | Sambuceti, Gianmario^{b; e} | Morbelli, Silvia^{f; g} | Schenone, Angelo^{a; b} | Massa, Federico^{a; b; 1} | Pardini, Matteo^{a; b; 1; *} | Dementia Disease Management Team of the IRCCS Ospedale Policlinico San Martino, Genoa²

Collaborators: Argenti, Lucia | Biffa, Gabriella | Bosinelli, Francesca | Bozzo, Giulia | Castellan, Lucio | Castellini, Paola | Colombo, Barbara | Gandoglia, Ilaria | Giacomini, Gabriele | Lombardo, Lorenzo | Losa, Mattia | Mancini, Raffaele | Murialdo, Alessandra | Nencioni, Alessio | Nozza, Paolo | Origone, Paola | Pelagotti, Virginia | Roccatagliata, Luca

Affiliations: [a] Department of Neuroscience, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy | [b] IRCCS Ospedale Policlinico San Martino, Genoa, Italy | [c] National Institute of Nuclear Physics (INFN), Genoa section, Genoa, Italy | [d] Department of Internal Medicine (DIMI), University of Genoa, Italy | [e] Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy | [f] Department of Medical Science, Università degli studi di Torino, Turin, Italy | [g] Nuclear Medicine Unit, Città della Salute e della Scienza di Torino, Turin, Italy

Correspondence: [*] Correspondence to: Prof. Matteo Pardini, MD, PhD, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Daneo 3, 16132 Genoa, Italy. Tel.: +39 0105557040; E-mail: matteo.pardini@hsanmartino.it.

Note: [1] These authors collaborated equally to this work as last authors.

Note: [2] Collaborators of the Dementia Disease Management Team of the IRCCS Ospedale Policlinico San Martino, Genoa, Italy: Lucia Argenti, Gabriella Biffa, Francesca Bosinelli, Giulia Bozzo, Lucio Castellan, Paola Castellini, Barbara Colombo, Ilaria Gandoglia, Gabriele Giacomini, Lorenzo Lombardo, Mattia Losa, Raffaele Mancini, Alessandra Murialdo, Alessio Nencioni, Paolo Nozza, Paola Origone, Virginia Pelagotti, Luca Roccatagliata.

Abstract: Background:Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. Objective:To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. Methods:We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). Results:DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Conclusions:Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.

Keywords: Alzheimer’s disease, apathy, awareness, dementia, [¹⁸F]FDG PET, mild cognitive impairment

DOI: 10.3233/JAD-240430

Journal: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 475-485, 2024