Pathophysiology of Neurodegeneration in Late-life Depression (AV45+THK)
Condition: Major Depressive Disorder
MeSH terms: Nerve Degeneration; Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2

Summary: 
      Late-life depression has been frequently associated with cognitive impairment. Several
      meta-analyses consistently suggested that a history of depression approximately doubles an
      individual's risk for developing dementia later in life. Neurodegeneration may play an
      important component in late-life depression. The pathophysiology behind the link between
      late-life depression and the subsequent development of dementia largely remains unclear, and
      should be heterogeneous. This highlights the need to identify specific neurodegenerative
      pathways involved in late-life depression, which will facilitate research on mechanisms and
      new treatments in the future.

      The recently published the National Institute on Aging and the Alzheimer Association (NIA-AA)
      criteria might provide new insights and frameworks to explore the patterns of
      neurodegenerative process in elderly depressed patients and to categorize them into different
      biomarker-based groups. In the present project, the investigators will recruit 40 patients
      with lifetime major depressive disorder, and 20 non-depressed cognitively normal comparison
      subjects. Alzheimer's disease pathology (A) was determined by measuring Aβ deposition by F-18
      AV-45 PET, and neurodegeneration (N) was established by measuring hippocampal volume using
      MRI. Individuals were categorised as A-N-, A+N-, A+N+, or suspected non-Alzheimer's disease
      pathophysiology (A-N+, SNAP). All subjects will further undergo F-18-THK-5351 image study to
      detect underlying tau pathology. By doing this, the investigators will elucidate the
      neurodegenerative pathophysiology behind the link between depressive disorder and the
      subsequent development of dementia.
    

Detailed description: 
      Visit 1, Screening assessments (Day 1)

      The purpose is to determine eligibility for the proposed study. Screening period may take
      place over several days to one week after the first visit. Screening assessments will
      include:

        1. Study explanations and obtainment of informed consent;

        2. Inclusion and exclusion Criteria;

        3. Demographics, medical history, and concomitant medications;

        4. Clinical characteristic of MDD;

        5. Safety measurements include vital sign, ECGs and laboratory tests. In addition, a
           pregnancy test will be performed at screening for females who are of childbearing
           potential (not for subjects with postmenopause period). A resting ECG and laboratory
           tests will be taken during the period of the study visit or had been done within 3
           months before study visit.

        6. Fertile females must avoid becoming pregnant 30 days after administration of F-18 AV-45
           and 18F-THK-5351.The investigators will advise fertile females to use adequate
           contraceptive methods during this period, e.g., established use of oral, injected or
           implanted hormonal methods of contraception; placement of an intrauterine device (IUD)
           or intrauterine system (IUS); barrier methods: condom with spermicidal
           foam/gel/film/cream or occlusive cap(diaphragm or cervical/vault caps) with spermicidal
           foam /gel /film /cream. In addition, a pregnancy test will be performed at screening for
           females who are of childbearing potential (the test must be negative).This test is not
           applicable for female subjects with postmenopausal period; permanently sterilized (eg,
           bilateral tubal occlusion [which includes tubal ligation procedures as consistent with
           local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or
           otherwise be incapable of pregnancy.

        7. Cognitive function assessment includes MMSE, CDR and comprehensive neurocognitive
           battery.

      Visit 2, Image study (Month 1±14 days) F-18 AV-45 PET study will be conducted for all
      subjects. PET data will be acquired using SIMENS PET/CT or PET/MRI scanner. For PET/CT
      protocol, a dynamic brain PET scan will be started simultaneously with the injection of F-18
      AV-45 PET after a low-dose CT scan for patient positioning and attenuation correction.
      Instead of PET/CT, the investigators will also consider PET/MRI for better soft tissue
      contrast and limited radiation exposure for multiple scan session. However, the attenuation
      map delineated from MRI is not consistent, and the delicate PET/MRI protocol is still under
      evaluation. Vital sign will be checked before and at the end of the image study for all
      subjects. Subjects will be continuously observed for signs of adverse events or serious
      adverse events. Each study participant (or their caregiver if applicable) will be contacted
      by phone approximately 7-14 days after the PET imaging study or at the next follow-up visit
      of outpatient department to confirm their well-being and query them about any new adverse
      events. Study-emergent AEs will be monitored till resolution or relatively stable state.

      Visit 3, Image study (Month 1±14 days) All participants will receive F-18-THK-5351 PET image
      study. PET data will be acquired using SIMENS PET/CT or PET/MRI scanner. For PET/CT protocol,
      a dynamic brain PET scan will be started simultaneously with the injection of F-18-THK-5351
      after a low-dose CT scan for patient positioning and attenuation correction. Instead of
      PET/CT, the investigators will also consider PET/MRI for better soft tissue contrast and
      limited radiation exposure for multiple scan session. However, the attenuation map delineated
      from MRI is not consistent, and the delicate PET/MRI protocol is still under evaluation.
      Vital sign will be checked before and after the image study. Safety measurements include ECG,
      and clinical labs will be performed at the end of the image study for all subjects. Subjects
      will be continuously observed for signs of adverse events or serious adverse events. Each
      study participant (or their caregiver if applicable) will be contacted by phone approximately
      7-14 days after the PET imaging study or at the next follow-up visit of outpatient department
      to confirm their well-being and query them about any new adverse events. Study-emergent AEs
      will be monitored till resolution or relatively stable state.
    

Intervention name(s): F-18 AV-45; F-18-THK-5351
Intervention type(s): Drug; Drug
Intervention description(s): In the present project, the investigators will recruit 40 patients with lifetime major depressive disorder, and 20 non-depressed cognitively normal comparison subjects. Alzheimer's disease pathology (A) was determined by measuring Aβ deposition by F-18 AV-45 PET.; In the present project, the investigators will recruit 40 patients with lifetime major depressive disorder, and 20 non-depressed cognitively normal comparison subjects. All subjects will further undergo F-18-THK-5351 image study to detect underlying tau pathology. By doing this, the investigators will elucidate the neurodegenerative pathophysiology behind the link between depressive disorder and the subsequent development of dementia.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: late-life depression; major depressive disorder; Alzheimer's disease dementia; neurodegeneration; amyloid plague, tau protein