PET Imaging in MCI Following ADT for PCa
Condition: Prostate Cancer; Mild Cognitive Impairment
MeSH terms: Prostatic Neoplasms; Cognitive Dysfunction
Study type: Observational

Summary: 
      Mild cognitive impairment (MCI) with ageing is thought in part to be related to reduced serum
      sex hormones which is well-recognized, especially in females, but poorly understood.
      International studies assessing hormone replacement therapy (HRT) to prevent/reduce MCI are
      ongoing. MCI leads to morbidity, reduced quality of life and substantial healthcare costs.
      The commonest therapeutically induced reduction in sex hormone level in men is treatment of
      prostate cancer (PCa). PCa is androgen dependent and androgen deprivation therapy (ADT)
      suppressing testosterone to castrate levels is key therapy for advanced disease. About one
      million men worldwide have received ADT for PCa, mostly using luteinising hormone releasing
      hormone agonists (LHRHa) although oral oestrogens were used in the past; eventually perhaps
      4% of Caucasians may be castrated. MCI as a side effect of castration in men remains poorly
      researched. This study aims to demonstrate that pathological changes occur in the brains of a
      significant proportion of prostate cancer patients subjected to ADT that correlate with MCI
      symptoms. Highlighting the pathological changes of MCI should improve understanding and
      interventions for slowing/preventing MCI in PCa survivors. Brain scans employing positron
      emission tomography (PET) imaging technique will be used to detect the presence of
      pathological changes in the brain that relate to ADT induced MCI. MCI will be assessed by
      neuropsychological assessments (standard paper-based questionnaires and online) and its
      neural basis will be investigated using magnetic resonance imaging (MRI).
    

Detailed description: 
      In males, MCI with aging is thought in part to be related to reduction in serum androgen
      level and international studies are on-going to prevent age-related cognitive decline using
      androgen replacement therapy. Reduction in cognitive function often leads to morbidity and
      reduction in quality of life. The commonest therapeutically induced reduction in sex hormone
      level in men is in the treatment of prostate cancer. As prostate cancer is androgen dependent
      for growth, androgen-deprivation therapy (ADT) to suppress serum testosterone level to
      castration levels (< 1.7mM) is the key therapeutic intervention for advanced disease. Up to 1
      million men worldwide are estimated to have been prescribed ADT for prostate cancer, mostly
      using luteinising hormone releasing hormone agonists (LHRHa). ADT is now also used to treat
      some early prostate cancer and as early asymptomatic prostate cancer is increasingly being
      diagnosed and treated following screening with serum prostate-specific antigen (PSA)
      measurement, estimates suggest that eventually up to 4% of all Caucasians will be castrated,
      some of them remaining on ADT for as long as 10 years or more. ADT is associated with
      considerable adverse effects, including MCI. Up to 69% of men showed MCI after six to nine
      months of ADT, with a decline in at least one cognitive area, most commonly visuospatial
      ability and executive function. Little work has been done to quantify MCI due to ADT,
      understand the mechanism, predict which patients will be affected and determine ways of
      reducing this side effect.

      Establishing the presence of pathophysiology in ADT induced MCI first is important due to the
      lack of understanding of the underlying mechanism. A plausible scientific approach in this
      regard appears to be the use of the brain's immunological response to pathology using a PET
      imaging ligand for activated microglia. Brain microglia have been demonstrated to be highly
      responsive to brain injury and are rapidly activated in an attempt to envelope/ contain the
      focal pathology. When activated, brain microglia have been shown to express the translocator
      protein (TSPO). The 18 kilo-Dalton (KDa) translocator protein (TSPO) formerly known as the
      peripheral benzodiazepine receptor (PBR) is widely expressed in the body but is particularly
      enriched up to 20 to 50 fold in steroid synthesising tissues. High TSPO expression has also
      been reported in immune cells such as macrophages and monocytes and TSPO is a
      well-characterised marker of neuroinflammation. PET imaging ligands have been developed for
      TSPO and used successfully for researching a range of brain disorders. While such imaging
      does not provide mechanistic information of the underlying pathology, except for the
      exasperation of frank neuro-inflammation, it does offer a generic sensitive bio-marker for
      demonstrating the presence of an on-going active pathology
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        A total of 12 prostate cancer patients on ADT with LHRHa will be recruited for the imaging
        part of the study; six patients having significant cognitive impairment attributable to
        LHRHa and six patients without cognitive impairment.
      
Biospecimen description: 
      Blood samples for determining TSPO (Ala147Thr) polymorphism, testosterone and estrogen
      hormone levels
    
Keywords: Prostate cancer; Androgen Deprivation Therapy; Mild Cognitive Impairment