Multicenter Study on Sleep and Circadian Alterations as Objective Markers of Mild Cognitive Impairment and Alzheimer’s Disease Reveals Sex Differences

Article type: Research Article

Authors: Guarnieri, Biancamaria^{a; b; *} | Maestri, Michelangelo^c | Cucchiara, Federico^{d; e} | Lo Gerfo, Annalisa^c | Schirru, Alessandro^c | Arnaldi, Dario^{f; g} | Mattioli, Pietro^{f; g} | Nobili, Flavio^{f; g} | Lombardi, Gemma^h | Cerroni, Gianluigi^{a; b} | Bartoli, Antonella^{a; b} | Manni, Raffaeleⁱ | Sinforiani, Elena^j | Terzaghi, Michele^{i; k} | Arena, Maria Grazia^l | Silvestri, Rosalia^m | La Morgia, Chiara^{n; o} | Di Perri, Maria Caterina^m | Franzoni, Ferdinando^p | Tognoni, Gloria^c | Mancuso, Michelangelo^c | Sorbi, Sandro^{h; q} | Bonuccelli, Ubaldo^c | Siciliano, Gabriele^c | Faraguna, Ugo^{d; r} | Bonanni, Enrica^c

Affiliations: [a] Center of Sleep Medicine, Villa Serena Hospital, Città S. Angelo, Pescara, Italy | [b] Villaserena Foundation for the Research, Città S. Angelo, Pescara, Italy | [c] Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy | [d] SONNOLab, Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy | [e] Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy | [f] Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy | [g] IRCCS Ospedale San Martino, Genoa, Italy | [h] IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy | [i] Sleep and Epilepsy Unit, IRCCS Mondino Foundation, Pavia, Italy | [j] Neuropsychology/Alzheimer's Disease Assessment Unit, IRCCS Mondino Foundation, Pavia, Italy | [k] Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy | [l] Center for Cognitive Disorders and Dementias, Alzheimer's Disease Assessment Unit, UOC of Neurology and Neuromuscular Disorders, AOU Policlinico, ``G. Martino'', University of Messina, Messina, Italy | [m] Sleep Medicine Center, UOSD of Neurophysiopathology and Movement Disorders, AOU Policlinico ``G.~Martino'', Department of Clinical and Experimental Medicine, University of Messina, Italy | [n] IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy | [o] Department of Biomedical and Neuromotor Sciences, University of Bologna Bologna, Italy | [p] Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy | [q] Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy | [r] Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy

Correspondence: [*] Correspondence to: Biancamaria Guarnieri, MD, Center of Sleep Medicine, Villa Serena Hospital, Villaserena Foundation for the Research, Viale L. Petruzzi 42, 65013 Città S. Angelo, Pescara, Italy. Tel.: +39 3926907880; E-mails: bmariaguarnieri@villaserena.it; bmariaguarnieri@hotmail.it

Abstract: Background:Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. Objective:To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. Methods:Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. Results:Wake after sleep onset (WASO) was higher (p < 0.001) and sleep efficiency (SE) lower (p = 0.003) in MCI, and Sleep Regularity Index (SRI) was lower in AD patients compared to controls (p = 0.004). SE was lower in male AD compared to female AD (p = 0.038) and SRI lower in male AD compared to male controls (p = 0.008), male MCI (p = 0.047), but also female AD subjects (p = 0.046). Mesor was significantly lower in males in the overall population. Age reduced the dissimilarities for WASO and SE but demonstrated sex differences for amplitude (p = 0.009) in the overall population, controls (p = 0.005), and AD subjects (p = 0.034). The confusion-matrices showed good predictive power of actigraphic data. Conclusion:Actigraphic data could help identify disease or health status. Sex (possibly gender) differences could impact on neurodegeneration and disease trajectory with potential clinical applications.

Keywords: Alzheimer’s disease, circadian rhythms, confusion matrix, mild cognitive impairment, sex differences, sleep disturbances, sleep parameters, sleep regularity index, wearable activity tracker

DOI: 10.3233/JAD-200632

Journal: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1707-1719, 2020