Striatal Dopamine Transmission in Individuals With Isolated Rapid Eye Movement Sleep With Atonia: a Search for Precursor Biomarker for Neurodegeneration
Condition: REM Sleep Behavior Disorder; Neurodegenerative Diseases
MeSH terms: Neurodegenerative Diseases; REM Sleep Behavior Disorder; Nerve Degeneration; Mental Disorders
Study type: Observational [Patient Registry]

Summary: 
      Background:

      Previous studies have confirmed that most patients with idiopathic REM sleep behaviour
      disorder (iRBD) eventually develop neurodegenerative diseases. In addition, REM sleep without
      atonia (RSWA), a hallmark of RBD feature, is a significant predictor of development of
      neurodegenerative diseases in patients with iRBD. Some preliminary studies have implied that
      isolated RSWA in the absence of RBD symptoms may also indicate neurodegeneration. However,
      this speculation needs to be confirmed by more refined study with sophisticated measures in
      both RSWA and markers of neurodegeneration

      Objectives: 1) to determine the differences in striatal dopamine transmission and other
      markers of neurodegeneration among individuals with isolated RSWA and healthy controls; 2) to
      examine the correlation of severity of RSWA with striatal dopamine transmission.

      Design: Case-control study

      Setting: Community-based sample

      Participants: 1) iRBD first degree relatives with isolated RSWA (n=18) 2) iRBD first degree
      relatives without isolated RSWA (n=18) 3) Community-based health controls without isolated
      RSWA (n=18)

      Main outcome measures:

        1. The dopamine transmission as measured by triple-tracer PET/ CT imaging protocol
           including 18F-DOPA, 11C-Raclopride and 18F-FDG images;

        2. Brain glucose metabolism and neurocognitive measures;

        3. Severity of EMG activity during REM sleep
    

Detailed description: 
      In the past two decades, a number of studies have confirmed that most patients with
      idiopathic RBD will eventually develop neurodegenerative diseases, especially
      α-synucleinopathies. Previous studies, including our preliminary data, suggested that RSWA is
      a marker of predicting the conversion of neurodegenerative diseases in idiopathic RBD. In
      other words, RSWA is an early marker of neurodegeneration in patients with idiopathic RBD.
      However, a number of individuals who are absent of any RBD symptoms (including patients with
      α-synucleinopathies, also have RSWA, which is described to have isolated RSWA. Only a few
      studies have attempted to understand the clinical importance and predictive prognosis of
      isolated RSWA. These preliminary studies suggest that isolated RSWA in healthy subjects may
      be a silent biomarker of neurodegeneration. However, these preliminary findings need to be
      replicated and confirmed by more refined study with dopamine neurotransmission neuroimaging.

      This proposed study will enrich the limited scientific literature of the potential
      pathogenesis and progression of isolated RSWA. By using an ongoing family study, we have
      screened a number of individuals with isolated RSWA, who are the first degree relatives of
      patients with RBD and are presumed to have a higher risk of neurodegeneration. Based on the
      existing sample, the current study will provide the first neuroimaging data on isolated RSWA
      to test the hypothesis that isolated RSWA, even in the absence of RBD symptoms, is an early
      marker of neurodegeneration. Individuals with isolated RSWA are expected to show dopamine
      dysfunction when compared with individuals without RSWA. If we confirm this hypothesis, the
      findings in the current study will extend our understanding of the spectrum of RBD and RSWA.
      The potential implication of our findings is that asymptomatic RSWA, especially in the
      presence of family history, will harbour the neurodegenerative progression. The results will
      pave the way for future prospective follow up to determine the course of neurodegeneration.
      From an etiological understanding, it will help to expand the understanding of the evolution
      course of synucleinopathy neurodegeneration. From an interventional angle, this study will
      have significant implication for developing a longer prevention window for neuroprotective
      trial.

      The inclusion criteria for the subjects:

      iRBD first degree relatives with isolated RSWA

        1. First degree relatives of patients with iRBD;

        2. Age 45 years or above;

        3. Absence of dream enactment behaviors;

        4. A total score on REM Sleep Behavior Questionnaire (RBDQ-HK) less than 19, which is the
           cut-off suggestive of a diagnosis of RBD;

        5. Presence of RSWA as measured by v-PSG; RSWA is defined as the percentage of increased
           EMG activity (phasic or tonic) at least 10% during REM sleep for any channel.

        6. for those individuals with moderate to severe obstructive sleep apnea (apnea-hypopnea
           index, AHI > 15/hour), effective CPAP treatment should be documented and a second night
           of V-PSG is required to determine RSWA.

      Community-based health controls without isolated RSWA:

        1. No family history of RBD;

        2. Age- and sex- matched with isolated RSWA subjects

        3. Absence of dream enactment behaviors;

        4. A score of RBDQ-HK less than 19;

        5. Absence of RSWA as measured by v-PSG;

        6. for those individuals with moderate obstructive sleep apnea (AHI > 15/hour), effective
           CPAP treatment should be documented and a second night of V-PSG is required to determine
           RSWA.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Subjects will be identified and recruited from our previous cohort.
      
Keywords: REM Sleep Without Atonia; Dopamine transmission; Neurodegeneration