Narcolepsy Protect Against Alzheimer's Disease?
Condition: Narcolepsy; Amyloid Pathology
MeSH terms: Alzheimer Disease; Narcolepsy; Amyloidosis
Study type: Interventional

Summary: 
      Links between orexin and amyloid processes have been underlined recently. During the
      Alzheimer's process an upregulation of the orexin mechanism has been observed. The
      pathophysiological mechanism of narcolepsy type 1 is linked to orexin deficiency. Thus, the
      investigators hypothesized that patients with narcolepsy may be protected from amyloid brain
      lesions, hallmarks of the Alzheimer's process. To test this hypothesis, the investigators
      analyzed the brain amyloid load measured by PET-scan amyloid brain imaging in patients with
      narcolepsy type 1 compared to controls without cognitive deficits.
    

Detailed description: 
      The lack of innovative treatments in Alzheimer' disease (AD) is due to the non-understanding
      of the pathological process. The investigators need to include the latest concept of the
      sleep-wake/circadian kinetics of proteins in the brain, the new theory of the wash-out of
      pathological proteins via the brain glymphatic system during sleep and act at an early stage.
      New pathways are opened to better understand proteinopathies' processes and to propose new
      therapeutics interventions. The variations of the production/clearance curves of amyloid in
      the cerebrospinal fluid (CSF) during circadian rhythms and sleep-wake cycles have been
      demonstrated in in vivo metabolism experimentations. Suprachiasmatic nucleus damages due to
      AD may induce circadian regulation dysfunction and secondary sleep/wake cycle alterations.
      Key sleep/wake cycle neuromediators (Orexin-A, melatonin) are involved in the regulation of
      brain amyloid levels. The influence of orexin-A signaling on Aβ metabolism in animals and
      humans was recently highlighted. In rats, orexin-A release shows a 24-h fluctuation similar
      to that of brain interstitial fluid Aβ. In transgenic mice that overexpress amyloid precursor
      protein (APP), brain interstitial fluid Aβ concentration increases during wakefulness and
      after orexin-A infusion. Conversely, it decreases during sleep and after infusion of an
      orexin-A receptor antagonist6. In transgenic mice that overexpress APP/presenilin1 (PS1), in
      which the orexin gene is knocked out, a reduction of Aβ pathology was found, possibly caused
      by changes in sleep time. Orexin-A is linked to Aβ42 in AD and an increase of CSF orexin-A is
      observed in AD vs. controls, possibly related to sleep deterioration and neurodegeneration.

      The narcolepy with cataplexy type 1 is the only disease with a specific orexin deficiency.
      Montpellier team have previously underlined in 15 patients with narcolepsy type 1 a normal
      level of Aβ42 in the CSF. The clinical expertise of the narcolepsy center suggested that the
      frequency of AD in old narcoleptic patients is low. The hypothesis was that patients with
      narcolepsy type 1 may be protected from amyloid brain lesions, hallmarks of the Alzheimer's
      process. The objective was to determine whether the brain amyloid load by PET-scan18 F-AV-45
      measured with a semi-quantitative analysis (mean cortical SuVr) is lower in patients with
      narcolepsy type 1 older than 65 years-old than in cognitively normal age- and gender-matched
      controls.
    

Intervention name(s): PET-scan18F-AV-45; PET-scan18F-AV-45
Intervention type(s): Device; Device
Intervention description(s): The PET-scan18F-AV-45 is a PET-scan dedicated to analyze the amyloid load in the brain with the AV45 tracer by the measurement of the mean cortical SuVr; PET-scan18F-AV-45 already done in another protocol MEMENTO-AMYging
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: Narcolepsy; Alzheimer; Orexin; Amyloid; PET-amyloid imaging