Impact of Obstructive Sleep Apnea in the Evolution of Alzheimer Disease. Role of Hypoxia and Sleep Fragmentation
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 144
- 试验地点
- 2
- 主要终点
- Change from baseline in cognitive scores on the Disease Assessment Scale-cognitive at 12 months in patients with mild AD with and without OSA.
研究概览
简要总结
Alzheimer's Disease (AD) is the most prevalent neurodegenerative disease, manifested as an initial deficit of episodic memory that evolves into a global cognitive and psychosocial dysfunction and which prevalence is increasing around the world. Sleep disturbance is frequent since early stages of the disease and sleep fragmentation had been demonstrated increase the production of amyloid peptide (AB) (main pathological hallmark) in non-demented population. Obstructive Sleep Apnea (OSA), which consist in intermittent hypoxia and sleep fragmentation, is a major health problem with multiple systemic effects and it's very prevalent in AD. However, the influence of this comorbidity on the cognitive evolution of AD patients remains unknown. The investigation of neurobiological markers and sleep recording may reveal potential mechanisms of neurodegeneration and explain the influence of sleep fragmentation and/or hypoxia on cognitive decline.
To fill those gaps, investigators will perform a multidisciplinary and translational project to assess the progression of symptoms in AD patients, diagnosis of sleep disturbance and new biomarkers of progression of the disease.
The present proposal is going to be developed by coordination of different expertises that will be range from the clinical research conducted by a medical neurologist, to the animal model and most molecular work, to be done by an experimented group in mouse work.
详细描述
As AD and OSA have a bidirectional relationship, OSA causes cerebral hypoxia and sleep fragmentation favouring the deposition of AB and AD causes alterations in sleep quality, investigators will develop a comprehensive project with human patients and an animal model of AD with sleep fragmentation (SF) and intermittent hypoxia (IH).
Investigators prospectively will study consecutive patients with new diagnosis of mild probable Alzheimer's Disease by a neurologist. Investigators will define Alzheimer's Disease according to National Institute of Aging-Alzheimer's Association criteria (NIA-AA).
All patients undergo routine neuropsychological battery, sleep polysomnography and actigraphy registry, brain MRI, lumbar puncture and blood biochemistry.
Neuropsychological battery The following assessments will be used at baseline and at 12 months: Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog), Mini-Mental State Exam (MMSE), Hachinski Scale, Digit Wechsler Adult Intelligence Scale(WAIS- III); Stroop Color-Word Interference Test (Stroop); Verbal fluency test; Trail Making Test (TMT) A and B; California verbal learning test (CVLT), Rey-Osterrieth Complex Figure Test (RCFT), Cornell depression scale, neuropsychiatric inventory, caregiver burden scale and EuroQol Test.
CSF Cerebrospinal fluid will be obtained by lumbar punction at 8 am, after overnight fasting. Amyloid beta 42 (AB42), tau and phosphotau will be measured using enzyme-linked immunoabsorbent assay (ELISA)(INNOTEST, Innogenetics). The cut-off will be based on prior studies of our laboratory. Also, ELISA will be employed to detect the levels of hypoxia-inducible factor 1-alpha (HIF-1alpha vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the cerebrospinal fluid (CSF).
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 50 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients diagnosed of mild probable AD according to NIA-AA criteria (MMSE>20).
- •Informed Consent Form signed by the patient (and/or if applicable the legal representative if different from the responsible caregiver) and the responsible caregiver.
- •The patient has a knowledgeable and reliable caregiver who will accompany the patient to all clinic visits during the study.
- •Absence of visual and hearing problems that, in the investigator's judgement, difficult for compliance with the study procedures.
排除标准
- •Previous diagnosis of OSA.
- •Severe Alzheimer's disease, other types of dementia or patients with mild Alzheimer's disease with current acetylcholinesterase inhibitors or memantine treatment.
- •Presence of any previously diagnosed sleep disorder: narcolepsy, insomnia, chronic lack of sleep.
- •Having serious comorbidities: cancer, excessive intake of alcohol (>280 gr/week), severe depression, severe renal or hepatic insufficiency, severe cardiac or respiratory failure.
- •Currently receiving an investigational drug or device.
- •Patient or family declining to take part.
- •Disabling drowsiness not justifiable by any other cause.
- •The patient has MRI evidence of hydrocephalus, stroke, a space-occupying lesion, cerebral infection or any clinically significant central nervous system disease other than AD.
- •The patient suffers from mental retardation, organic mental disorders, or mental disorders due to a general medical condition (DSM-IV-TR™ criteria).
- •The patient has an untreated vitamin B12 or folate deficiency that is considered clinically significant, or has clinical and laboratory evidence of untreated thyroid disease. Patients with vitamin B12 or folate deficiency may be enrolled in the study provided they have been on a supplement therapy for >3 months prior to the Screening Visit and are stable. Patients with thyroid disease may be enrolled in the study provided they are stable and euthyroid.
- •Patient on betablockers, antidepressants, neuroleptics, hypnotics, or they have been removed 15 days before conducting polysomnography (PSG).
结局指标
主要结局
Change from baseline in cognitive scores on the Disease Assessment Scale-cognitive at 12 months in patients with mild AD with and without OSA.
时间窗: One year
For this objective we will recruit consecutively 72 patients with OSA and another 72 patients without OSA from the same population of patients with mild initial AD. We will use extensive neuropsychological battery at baseline and at 12 month and polysomnography (PSG) to select both groups of patients at baseline.
次要结局
- Differential pattern of biomarkers at baseline in in patients with mild AD with and without OSA.(One year)
研究者
Ferran Barbe
PhD
Sociedad Española de Neumología y Cirugía Torácica