Clinical and Biological Effects of Citrus-phytochemicals in Subjective Cognitive Decline.
Condition: Subjective Cognitive Decline
MeSH terms: Cognitive Dysfunction
Study type: Interventional

Summary: 
      Subjective cognitive decline (SCD) is receiving increasing attention as a risk factor for
      incident dementia due to AD. SCD manifests prior to the onset of clinical impairment, and as
      such could serve as a potential target population for early intervention trials. The
      pathogenesis of AD is complex and involves a dysregulation of the neuroendocrine immune (NEI)
      system, a network of signaling molecules, such as neurotransmitters, hormones and cytokines.
      As a result, it may be unlikely that cognitive decline may be mitigated by drugs acting on a
      single specific target. Plant extracts acting at different levels of the NEI regulation could
      represent appealing therapeutic strategies for cognitive decline. Citrus-derived
      phytochemicals, like auraptene and naringenin, showed antioxidant, anti-inflammatory, and
      neuroprotective effects in preclinical studies of AD mouse models and preservation of
      cognition in elderly without cognitive impairment. This is a pilot randomized controlled
      trial to determine clinical and biological effects of Citrus-phytochemicals in individuals
      with SCD. Participants will be randomized to receive Citrus-phytochemicals standardized in
      auraptene and naringenin or placebo for 9 months. Cognitive tests and blood-based biological
      markers will be done at baseline and at the end of treatment as outcome measures.
    

Detailed description: 
      Background: Alzheimer's disease (AD) is a neurodegenerative disorder which represents a major
      health issue and financial burden for health care systems around the world. The impact will
      further increase over the next decades due to increasing life expectancies. AD leads to
      progressive and irreversible disturbances of cognition and functional abilities. AD is the
      fifth-leading cause of death among those age 65 and older and is also a leading cause of
      disability and poor health. Due to the absence of a cure against AD, the public health
      priority has focused more recently on improvement of cognitive performance in older age and,
      possibly, prevention of cognitive decline. Subjective cognitive decline (SCD) in older adults
      is increasingly recognized as a potential indicator of non-normative cognitive decline and
      eventual progression to dementia. Longitudinal studies in SCD showed an up to 4.5-fold
      increased risk for progression to mild cognitive impairment. SCD has also been characterized
      by pathological changes of the brain associated with AD. These findings suggest that SCD may
      be an early clinical marker for AD, making an ideal target to test preventive interventions.
      Several nutraceuticals have displayed over the years the ability or potential to improve
      cognitive impairment. Among these, auraptene (AUR) and naringenin (NAR) are natural bioactive
      compounds derived from peels of Citrus fruits, with a strong preclinical rationale for
      cognitive enhancement. In fact, preclinical studies showed that they have anti-inflammatory,
      antioxidant, and neuroprotective effects in mouse brain and, specifically, in AD mouse
      models. These effects are mediated by a number of neuropeptides, growth factors, hormones,
      and cytokines, which are components of the neuroendocrine and immune (NEI) system, a complex
      network of communication, which showed altered functioning in ageing and neurodegenerative
      diseases.

      The capacity of some nutraceutical in restoring and remodelling the NEI response at both
      neuroendocrine and immune level, could represent a new strategy in order to reach healthy
      ageing and prevent cognitive decline in the elderly. This perspective is supported by the
      results of a randomized, placebo-controlled, double blind study of 84 older adults, in which
      administration of AUR for 24 weeks showed significantly higher percentage of improvement in
      the immediate memory in the AUR group compared to the placebo.

      Specific aims: This is a pilot randomized controlled trial to determine the cognitive and
      biological effects of Citrus peels extracts standardized in auraptene and naringenin, in
      individuals with SCD.

      Specific aim 1. The investigators will enrol 80 individuals with SCD randomized into two
      groups of treatments, i.e. control and Citrus peels extracts. Cognitive assessment will be
      carried out at baseline and after 9 months of treatment, in order to evaluate the effect on
      cognition.

      The investigators hypothesize that treatment group has an improvement in cognition compared
      to placebo group.

      Specific aim 2. To evaluate the biological effects of the Citrus peels extracts treatment on
      the NEI system, through blood samples taken at baseline, and after 9 months of treatment.

      The investigators hypothesize that treatment group has an improvement in the NEI functions as
      indicated by biological markers (increase of the growth factors, reduction of stress hormones
      levels, reduction of inflammation) compared to placebo group.
    

Intervention name(s): Extracts of citrus peels standardized in AUR and NAR (phytocomplex).
Intervention type(s): Dietary Supplement
Intervention description(s): One capsule a day for 9 months
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Citrus-phytochemicals, auraptene, naringenin; subjective cognitive decline, randomized, efficacy; cognitive tests, R-BANS, interleukins, Interleukin-8