Sleep apnoeas may represent a reversible risk factor for amyloid-β pathology

doi:10.1093/brain/awx281 BRAIN 2017: 140; 1–5 | e75 LETTER TO THE EDITOR Sleep apnoeas may represent a reversible risk factor for amyloid-b pathology Claudio Liguori,1,2 Agostino Chiaravalloti,3 Francesca Izzi,1,2 Marzia Nuccetelli,4 Sergio Bernardini,4 Orazio Schillaci,3 Nicola Biagio Mercuri1,2,5 and Fabio Placidi1,2 Correspondence to: Claudio Liguori, MD Sleep Medicine Centre Neurophysiopathology Unit Department of Systems Medicine University of Rome “Tor Vergata” Viale Oxford 81 00133 Rome, Italy E-mail: Sir, Obstructive sleep apnoea (OSA) is a condition with increasing prevalence and frequently diagnosed in middleage and elderly subjects (Heinzer et al., 2015). OSA has been widely associated with the risk of cognitive impairment (Vaessen et al., 2015), and recently with the pathological alteration of cerebral amyloid-b42 dynamics (Osorio et al., 2014; Ju et al., 2016; Liguori et al., 2017). Therefore, OSA may represent a risk factor for Alzheimer’s disease neurodegeneration (Osorio et al., 2014; Ju et al., 2016; Liguori et al., 2017). However, it is a condition easily treated by continuous positive airway pressure (CPAP), which usually restores brain structure changes and cognitive impairment (Canessa et al., 2011). A 57-year-old male complaining of snoring, subjective sleep impairment, daytime sleepiness, and nocturia was visited at our Sleep Medicine Centre. The patient also reported memory and attention deficits, although he had already performed the neuropsychological tests, the results of which were normal. Therefore, once admitted at our Sleep Medicine Centre he underwent: (i) Polysomnography (PSG), performed as previously reported (Pierantozzi et al., 2016). Briefly, the montage consisted of two electroculographic channels, three electromyographic channels (chin and anterior tibialis muscles) and eight EEG channels (F4, C4, O2, A2, F3, C3, O1, A1). Oronasal flow, thoracic and abdominal movements (plethysmography), pulsoximetry and electrocardiography measured the cardiorespiratory parameters. PSG was scored according to the international standard criteria of the American Academy of Sleep Medicine (Iber et al., 2007). (ii) Brain MRI, performed with a 1.5 T superconductive system (OptimaTM MR450w, GE Medical System). Head-coil was used and standard sequences were obtained in axial planes with 3-mm slice thickness. (iii) Neuropsychological tests, counting the Mental Deterioration Battery, which is a standardized and validated neuropsychological battery including cognitive tests pertaining to the elaboration of verbal and visuospatial materials (Carlesimo et al., 1996). (iv) Lumbar puncture, performed in the decubitus position with an atraumatic needle, between 8:00 and 9:30 am, 2 h after morning awakening. Blood specimens were also obtained at the same time as the lumbar puncture procedure. CSF samples were collected in polypropylene tubes using standard sterile techniques Advance Access publication October 25, 2017 ß The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: 1 Sleep Medicine Centre, Neurophysiopathology Unit, Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy 2 Neurology Unit, Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy 3 Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy 4 Clinical Biochemistry and Molecular Biology, University of Rome “Tor Vergata”, Rome, Italy 5 IRCCS Fondazione Santa Lucia, Rome, Italy e75 | BRAIN 2017: 140; 1–5 Taking all the exams into account, PSG showed the impairment of sleep efficiency coupled with the mild reduction of stage 3 of non-REM and REM sleep (Fig. 1). Notably, the apnoea-hypopnoea index (AHI) was 39.7/h. Brain MRI appeared unremarkable (Fig. 2). Lumbar puncture showed pathological CSF levels of amyloid-b42 and normal CSF concentrations of t-tau, p-tau and orexin (Fig. 1). Notably, at that time both t-tau/amyloid-b42 (0.57) and amyloid-b42/amyloid-b40 (0.03) ratios were suggestive of Alzheimer’s disease pathology. However, amyloid-PET resulted normal and 18F-FDG-PET did not show focal hypometabolisms (Fig. 2). At the end of the diagnostic work-up, the patient started CPAP treatment and was admitted at follow-up. Every 6 months he repeated the neuropsychological tests, which remained normal. At 1-year follow-up, considering the recovery of subjective cognitive deficits and the resolution of daytime sleepiness and subjective sleep impairment, the patient repeated PSG, which showed the improvement of sleep efficiency and continuity and the increase of stage 3 non-REM and REM sleep (Fig. 1) associated with the reduction of AHI to 2.7/h. The patient also repeated lumbar puncture, which documented normal CSF t-tau and p-tau levels, the increase of CSF amyloid-b40 concentrations and, unexpectedly, the recovery to normal CSF concentrations of amyloid-b42 (Fig. 1). Moreover, both t-tau/amyloid-b42 (0.17) and amyloid-b42/amyloid-b40 (0.09) ratios recovered to values not suggestive of Alzheimer’s disease pathology. Finally, CSF orexin levels decreased, although they remained in the normal range (Fig. 1). This emblematic case shows the normalization of cerebral amyloid-b dynamics after CPAP therapy in a patient affected by OSA and subjective cognitive impairment (SCI). Consistently, both the CSF indices suggestive of Alzheimer’s disease pathology (t-tau/amyloid-b42 and amyloid-b42/amyloid-b40) before starting CPAP, recovered to normal values 1 year after CPAP treatment. Both OSA and SCI actually represent conditions considered at risk for the development of Alzheimer’s disease (Osorio et al., 2014; Ju et al., 2016; Liguori et al., 2017; Rabin et al., 2017). On the one hand, OSA has been related to the alteration of cerebral amyloid-b dynamics, since both the reduction of CSF amyloid-b42 levels and the increase of amyloid-b brain deposition have been documented in OSA patients (Osorio et al., 2014; Ju et al., 2016; Liguori et al., 2017). On the other hand, SCI is a condition associated with both CSF amyloid-b42 pathological levels and increased cerebral b-amyloid deposits in crucial brain regions for Alzheimer’s disease pathology (Colijn and Grossberg, 2015). Therefore, it is possible to hypothesize that OSA and SCI may represent preclinical stages of Alzheimer’s disease, in which biomarker changes occur in a very early stage of neurodegeneration. Nowadays, substantial efforts are being spent trying to identify and possibly treat Alzheimer’s disease at the preclinical or mild stages of neurodegeneration. It was recently hypothesized that OSA may be considered as a preclinical Alzheimer’s disease condition in which CPAP treatment may stop or, in an optimistic suggestion, reverse amyloid-b pathology (Liguori et al., 2017). The present report showed the pathological reduction of CSF amyloid-b42 concentrations and the alteration (...truncated)