Blood-based lipidomic signature of severe obstructive sleep apnoea in Alzheimer's disease

Background: Obstructive sleep apnoea (OSA) is the most frequent form of sleep-disordered breathing in patients with Alzheimer’s disease (AD). Available evidence demonstrates that both conditions are independently associated with alterations in lipid metabolism. However, it is unknown whether the expression of lipids is diferent between AD patients with and without severe OSA. In this context, we examined the plasma lipidome of patients with suspected OSA, aiming to identify potential diagnostic biomarkers and to provide insights into the pathophysiological mechanisms underlying the disease. Methods: The study included 103 consecutive patients from the memory unit of our institution with a diagnosis of AD. The individuals were subjected to overnight polysomnography (PSG) to diagnose severe OSA (apnoea-hypopnea index ≥30/h), and blood was collected the following morning. Untargeted plasma lipidomic profling was performed using liquid chromatography coupled with mass spectrometry. Results: We identifed a subset of 44 lipids (mainly phospholipids and glycerolipids) that were expressed diferently between patients with AD and severe and nonsevere OSA. Among the lipids in this profle, 30 were signifcantly correlated with specifc PSG measures of OSA severity related to sleep fragmentation and hypoxemia. Machine learning analyses revealed a 4-lipid signature (phosphatidylcholine PC(35:4), cis-8,11,14,17-eicosatetraenoic acid and two oxidized triglycerides (OxTG(58:5) and OxTG(62:12)) that provided an accuracy (95% CI) of 0.78 (0.69–0.86) in the detection of OSA. These same lipids improved the predictive power of the STOP-Bang questionnaire in terms of the area under the curve (AUC) from 0.61 (0.50–0.74) to 0.80 (0.70–0.90). Conclusion: Our results show a plasma lipidomic fngerprint that allows the identifcation of patients with AD and severe OSA, allowing the personalized management of these individuals. The fndings suggest that oxidative stress and infammation are potential prominent mechanisms underlying the association between OSA and AD.Government of Catalonia, Department of Health (PERIS 2019 SLT008/18/00050) and “Fundació La Marató TV3” (464/C/2014) to GPR. The Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades), co-fnanced by FEDER funds from the European Union “A way to build Europe” (grant RTI2018-099200-B-I00), the IRBLleida-Diputació de Lleida (PIRS2021), and the Government of Catalonia: Agency for Management of University and Research Grants (2017SGR696) to RP. FD was supported by the Agency for Management of University and Research Grants and the European Social Fund (FI_B100153). IRBLleida is a CERCA Program of the Government of Catalonia

Decrease in sleep depth is associated with higher cerebrospinal fluid neurofilament light levels in patients with Alzheimer's disease

STUDY OBJECTIVES: The majority of studies investigating the association between sleep and Alzheimer's disease (AD) biomarkers have been performed in healthy participants. Our objective was to investigate the association between sleep and several biomarkers that reflect distinct aspects of AD physiopathology. METHODS: The cohort included 104 individuals with mild-moderate AD. The participants were submitted to one-night polysomnography, and cerebrospinal fluid was collected in the following morning to measure the selected biomarkers associated with amyloid deposition, tau pathology, neurodegeneration, axonal damage, synaptic integrity, neuroinflammation, and oxidative damage. RESULTS: There was a positive correlation between neurofilament light (NF-L) and the time spent in stage 1 of non-rapid eyes movement (NREM) (N1) sleep and a negative correlation between this marker and the time spent in stage 3 of NREM (N3) sleep. Accordingly, we observed that deep sleep was associated with lower levels of NF-L, whereas light sleep increased the probability of having higher levels of this marker. Furthermore, chitinase-3-like-1 (YKL-40) was negatively correlated with sleep efficiency, the time spent in stage 2 of NREM (N2) sleep, and the time spent in N3 sleep. Conversely, there was a positive correlation between N3 sleep and the oxidative protein damage markers N-ε-(carboxyethyl)lysine and N-ε-(malondialdehyde)lysine. CONCLUSIONS: There were significant correlations between sleep parameters and AD biomarkers related to axonal damage and neuroinflammation, such as NF-L and YKL-40. A lack of deep sleep was associated with higher levels of NF-L. This highlights a potential role for NF-L as a biomarker of sleep disruption in patients with mild-moderate AD in addition to its role in predicting neurodegeneration and cognitive decline

Plasma and Cerebrospinal Fluid Lipidomic Signature of Alzheimer’s Disease Diagnosis and Progression

L’objectiu era determinar el lipidoma plasmàtic i de LCR i el dany oxidatiu proteic associat a la patologia de malaltia d'Alzheimer (MA) i la seva progressió. Es va utilizar tècniques de cromatografia combinada amb espectrometria de masses per analitzar mostres de 290 individus. Els lípids més associats a la patologia amiloide eren de les classes PL, SM i TG. SM30:1 a LCR es va asociar amb la patologia tau, i al plasma FAHFA(34:0) i PC(O-34:3) es van associar amb Ttau. Els èters de TG van mostrar poder predictiu pel que fa a la progressió i la velocitat de progressió. Ni en el LCR ni en el plasma els marcadors de dany oxidatiu proteic es van associar a la patologia de la MA o la progressió. Finalment, els lípids neutrals podrien tenir un paper important en els processos patològics de progressió de l'AD i, afectar el temps fins a la progressió.El objetivo era determinar el lipidoma plasmático y de LCR y el daño oxidativo proteico asociado a la patología de enfermedad de Alzheimer (EA) y su progresión. Se utilizó técnicas de cromatografía combinada con espectrometría de masas para analizar muestras de 290 individuos. Los lípidos más asociados a la patología amiloide eran de las clases PL, SM y TG. SM30:1 en LCR se asoció con la patología tau, y en el plasma FAHFA(34:0) y PC(O-34:3) se asociaron con Ttau. Los éteres de TG mostraron poder predictivo en cuanto a progresión y velocidad de progresión. Ni en el LCR ni en el plasma los marcadores de daño oxidativo proteico se asociaron a la patología de la EA o la progresión. Por último, los lípidos neutrales podrían desempeñar un papel importante en los procesos patológicos de progresión del EA y, afectar el tiempo hasta la progresión.Our objective was to determine plasma and CSF lipids and oxidative protein damage markers associated with Alzheimer’s disease (AD) pathology and progression from mild cognitive impairment to AD. Lipidome and oxidative protein damage markers were determined by chromatography coupled to mass spectrometry for 290 subjects (AD, MCI, control). In CSF and plasma, the lipids most associated with amyloid pathology were from PL, SM, and TG classes. Our CSF data related SM30:1 to tau pathology, and in plasma the levels of FAHFA(34:0) and PC(O-34:3) were associated with pathological levels of Ttau in CSF. Both our CSF and plasma data indicated that ether-linked TGs have predictive power regarding progression and rate of progression. Neither in CSF nor in plasma were the levels of oxidative protein damage markers associated with AD pathology, or progression. Finally, neutral lipids could play an important role in pathological processes of AD progression and, affect time to progression

Plasma and cerebrospinal fluid nonenzymatic protein damage is sustained in Alzheimer's disease

Background: Oxidative stress is considered to play an important role in the pathogenesis of Alzheimer's disease (AD). It has been observed that oxidative damage to specific protein targets affecting particular functional networks is one of the mechanisms by which oxidative stress contributes to neuronal failure and consequently loss of cognition and AD progression. Studies are lacking in which oxidative damage is measured at both systemic and central fluid levels and in the same cohort of patients. We aimed to determine the levels of both plasma and cerebrospinal fluid (CSF) nonenzymatic protein damage in patients in the continuum of AD and to evaluate the relation of this damage with clinical progression from mild cognitive impairment (MCI) to AD. Methods: Different markers of nonenzymatic post-translational protein modification, mostly from oxidative processes, were detected and quantified in plasma and CSF by isotope dilution gas chromatography‒mass spectrometry using selected ion monitoring (SIM-GC/MS) for 289 subjects: 103 AD, 92 MCI, and 94 control subjects. Characteristics of the study population such as age, sex, Mini-mental state examination, CSF AD biomarkers, and APOE ϵ4, were also considered. Results: Forty-seven (52.8%) MCI patients progressed to AD during follow-up (58 ± 12.5 months). After controlling for age, sex, and APOE ϵ4 allele, plasma and CSF concentrations of protein damage markers were not associated with either diagnosis of AD or MCI. The CSF levels of nonenzymatic protein damage markers were associated with none of the CSF AD biomarkers. In addition, neither in CSF nor in plasma were the levels of protein damage associated with the MCI to AD progression. Conclusion: The lack of association between both CSF and plasma concentrations of nonenzymatic protein damage markers and AD diagnosis and progression suggests that oxidative damage in AD is a pathogenic mechanism specifically expressed at the cell-tissue level, not in extracellular fluids

The circadian rest-activity pattern predicts cognitive decline among mild-moderate Alzheimer's disease patients

Background:Alterations in circadian rhythms are present in the presymptomatic stage of Alzheimer’s disease (AD),possibly contributing to its pathogenesis. However, it is unknown whether such alterations are associated withworse outcomes once individuals are diagnosed with symptomatic disease. We aimed to evaluate the associationbetween the circadian rest-activity pattern and AD-related features in patients with mild-moderate AD.Methods:We assessed the circadian rest-activity pattern of consecutive patients with mild-moderate AD throughactigraphy for 14 days. Cerebrospinal fluid was obtained to determine the levels of important pathological markersincluding amyloid-beta protein (Aβ42), phosphorylated tau (P-tau), total tau (T-tau), and neurofilament light (NF-L).Neuropsychological evaluation was conducted at the beginning of the study and after 12 months of follow-up.Linear regression models were performed considering the global population and Aβ42+ patients only.Results:The cohort included 100 patients with mild-moderate AD. The median age [p25;p75] was 76.0 [73.0;80.0]years and 63.0% were female. Older age (effect size [SE] of 0.324 [0.096];p= 0.001) and male sex (0.780 [0.193];p=0.001) were associated with increased fragmentation and decreased synchronization of the rhythm, respectively.After adjusting for age, sex, and season of the year, increased levels of T-tau (effect size [95% CI] of 0.343 [0.139 to0.547];p= 0.001) and NF-L (0.444 [0.212 to 0.676];p= 0.001) were associated with a higher amplitude of the rest-activity rhythm. Increased fragmentation of the rhythm at baseline was associated with greater cognitive declineafter one year of follow-up independent of age, sex, T-tau/Aβ42 ratio, educational level, and season of the year (−0.715 [−1.272 to−0.157];p= 0.013). Similar findings were obtained considering only the Aβ42+ patients.Conclusions:Our results suggest a potential role of the circadian rest-activity pattern in predicting the cognitivedecline of patients with mild-moderate AD. Further studies are warranted to confirm these findings and toelucidate whether there is causality among the observed associations.Generalitat of Catalonia, Department of Health (PERIS 2019 SLT008/18/00050)and“Fundació La Marató TV3”(464/C/2014) to GPR. Co-financed by FEDERfunds from the European Union (‘A way to build Europe’). IRBLleida is aCERCA Programme/Generalitat of Catalonia. FD was supported by Agencyfor Management of University and Research Grants (FI_B100153