18F-FDG PET, cognitive functioning, and CSF biomarkers in patients with obstructive sleep apnoea before and after continuous positive airway pressure treatment

Journal of Neurology https://doi.org/10.1007/s00415-022-11182-z ORIGINAL COMMUNICATION 18 F‑FDG PET, cognitive functioning, and CSF biomarkers in patients with obstructive sleep apnoea before and after continuous positive airway pressure treatment Mariana Fernandes1 · Luisa Mari2 · Agostino Chiaravalloti3,4 · Barbara Paoli1 · Marzia Nuccetelli5 · Francesca Izzi2 · Maria Pia Giambrone2 · Riccardo Camedda3 · Sergio Bernardini5 · Orazio Schillaci3,4 · Nicola Biagio Mercuri2,6 · Fabio Placidi1,2 · Claudio Liguori1,2 Received: 14 February 2022 / Revised: 7 May 2022 / Accepted: 10 May 2022 © The Author(s) 2022 Abstract Introduction Dysregulation of cerebral glucose consumption, alterations in cerebrospinal fluid (CSF) biomarkers, and cognitive impairment have been reported in patients with obstructive sleep apnoea (OSA). On these bases, OSA has been considered a risk factor for Alzheimer’s disease (AD). This study aimed to measure cognitive performance, CSF biomarkers, and cerebral glucose consumption in OSA patients and to evaluate the effects of continuous positive airway pressure (CPAP) treatment on these biomarkers over a 12-month period. Methods Thirty-four OSA patients and 34 controls underwent 18F-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET), cognitive evaluation, and CSF analysis. A subgroup of 12 OSA patients treated with beneficial CPAP and performing the 12-month follow-up was included in the longitudinal analysis, and cognitive evaluation and 18F-FDG PET were repeated. Results Significantly reduced glucose consumption was observed in the bilateral praecuneus, posterior cingulate cortex, and frontal areas in OSA patients than controls. At baseline, OSA patients also showed lower β-amyloid42 and higher phosphorylated-tau CSF levels than controls. Increased total tau and phosphorylated tau levels correlated with a reduction in brain glucose consumption in a cluster of different brain areas. In the longitudinal analysis, OSA patients showed an improvement in cognition and a global increase in cerebral 18F-FDG uptake. Conclusions Cognitive impairment, reduced cerebral glucose consumption, and alterations in CSF biomarkers were observed in OSA patients, which may reinforce the hypothesis of AD neurodegenerative processes triggered by OSA. Notably, cognition and brain glucose consumption improved after beneficial CPAP treatment. Further studies are needed to evaluate the long-term effects of CPAP treatment on these AD biomarkers. Keywords Obstructive sleep apnoea · Positron emission tomography · Cognition · Cerebrospinal fluid · Continuous positive airway pressure * Claudio Liguori 1 Department of Systems Medicine, Sleep Medicine Centre, University of Rome “Tor Vergata”, Rome, Italy 2 Neurology Unit, University Hospital of Rome “Tor Vergata”, Rome, Italy 3 Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy 4 IRCCS Neuromed, Pozzilli, Italy 5 Department of Clinical Biochemistry and Molecular Biology, University of Rome “Tor Vergata”, Rome, Italy 6 IRCSS Santa Lucia Foundation, Rome, Italy Introduction Obstructive sleep apnoea (OSA) is the most frequent sleep-disordered breathing (SDB) and is highly prevalent in middle-aged and older adults [1]. OSA is characterised by repetitive episodes of upper airway obstruction, leading to apnoea and hypopnoea events, intermittent hypoxia, and sleep fragmentation [2, 3]. OSA is a risk factor for several morbidities [1, 4–8] and is associated with the risk of cognitive impairment [9]. Recent evidence suggests that OSA may also be a risk factor for Alzheimer’s disease (AD) neurodegeneration [10–13], given that it alters cerebral 13 Vol.:(0123456789) Journal of Neurology β-amyloid metabolism and promotes neuroinflammation and oxidative stress [3, 10–19]. However, in contrast to other proven risk factors for the development of AD, OSA can be treated in clinical practice through the use of continuous positive airway pressure (CPAP), which significantly improves OSA symptoms [20]. Decreased cerebrospinal fluid (CSF) levels or documentation of plaque deposition of β-amyloid42 (Aβ42), reduced cortical temporo-parietal 18F-fluoro-2-deoxy- d -glucose uptake ( 18 F-FDG) on positron emission tomography (PET), and increased CSF levels of total-tau (t-tau) and phosphorylated-tau (p-tau) have been considered biomarkers of AD neuropathology and are currently used to support AD diagnosis in both clinical practice and research [21–24]. These biomarker alterations appear early during the course of the AD pathology, usually before brain magnetic resonance imaging (MRI) structural changes. Accordingly, they have been validated in providing early high diagnostic accuracy during the work-up for AD [25]. In the recent past, pathological modifications of CSF biomarkers have already been described in patients with OSA, with or without subtle cognitive impairment [10, 14–16, 26–29]. Conversely, fewer 18F-FDG PET brain studies have been performed in patients with OSA and included very small groups of patients. These studies documented a significant modification of 18F-FDG uptake in different brain areas, in particular, glucose hypometabolism in the bilateral prefrontal areas, praecuneus, left hippocampus, and left anterior cingulate cortex, among others [30–32]. One of the more recent studies reported that despite the presence of subtle memory impairment, OSA patients displayed a significant reduction in cerebral glucose consumption in the praecuneus, cingulate, parieto-occipital, and prefrontal cortices [33]. However, studies evaluating brain glucose consumption using 18F-FDG PET in OSA patients remain limited, and the possible effects of prolonged CPAP treatment were not evaluated, since the longitudinal studies were set at a 3-month follow-up [30–33]. Finally, previous studies evaluating patients with OSA analysed CSF and PET data obtained weeks or months after the diagnosis of OSA. Therefore, the present study aimed to comprehensively measure cognition, CSF biomarkers, and cerebral glucose uptake by 18F-FDG PET in middle-aged adult patients with moderate to severe OSA (apnoea–hypopnoea index [AHI] ≥ 15/h) during the diagnostic work-up of the sleep disorder. A subgroup of patients was also followed for a period of 12 months and repeated cognitive testing and brain 18F-FDG PET. Moreover, to better understand the direction of the biomarker changes obtained at baseline, associations between the measured CSF biomarkers of AD pathology (tau proteins and Aβ42), cerebral glucose uptake and cognitive performance were analysed. 13 Methods Participants and study procedures Middle-aged adult patients with OSA who were admitted to the Sleep Medicine Centre at the Neurology Unit of the University Hospital of Rome “Tor Vergata” were recruited between January 2016 and September 2018. All patients underwent a standard sleep medicine visit, polysomnographic recording (PSG), physical and neu (...truncated)