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PET Imaging in MCI Following ADT for PCa

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ClinicalTrials.gov Identifier: NCT02061345
Recruitment Status : Suspended (Preliminary data analysis)
First Posted : February 12, 2014
Last Update Posted : August 15, 2016
Sponsor:
Information provided by (Responsible Party):
Imperial College London

Brief 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).

Condition or disease
Prostate Cancer Mild Cognitive Impairment

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


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Study Type : Observational
Estimated Enrollment : 12 participants
Observational Model: Case Control
Time Perspective: Cross-Sectional
Official Title: A PET Imaging Study to Detect the Presence of Activated Microglia in the Brains of Prostate Cancer Patients Who Develop Mild Cognitive Impairment Following Androgen Deprivation Therapy
Study Start Date : April 2014
Estimated Primary Completion Date : December 2016
Estimated Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Group/Cohort
MCI
Prostate cancer patients having mild cognitive impairment (MCI) attributable to ADT with LHRHa
Control
Prostate cancer patients on ADT with LHRHa not having mild cognitive impairment



Primary Outcome Measures :
  1. PET biomarker uptake [ Time Frame: Single time-point ]
    The outcome measure is the increased uptake of 11-Carbon Peripheral Benzodiazepine Receptor-28 ([11C]PBR28) biomarker by activated microglia of patients demonstrating significant MCI with the primary endpoint of [11C]PBR28 uptake measured as a standardized uptake value (SUV)


Secondary Outcome Measures :
  1. PET biomarker volume of distribution [ Time Frame: Single time-point ]
    Secondary endpoint is the [11C]PBR28 total volume of distribution (VT)


Other Outcome Measures:
  1. Cognitive impairment [ Time Frame: Single time-point ]
    Association of cognitive and neuropsychiatric impairments following ADT with structural and/or functional brain connectivity


Biospecimen Retention:   Samples With DNA
Blood samples for determining TSPO (Ala147Thr) polymorphism, testosterone and estrogen hormone levels


Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.
Criteria

Inclusion Criteria:

  1. Prostate cancer patients between the ages 50 to 80 years on ADT with LHRHa for for 3 months up to a year.
  2. Able to give written informed consent.
  3. Able to lie still for up to 90 minutes for a PET scan.
  4. Not claustrophobic and so able to undergo an MRI scan.

Exclusion Criteria:

  1. Patients with a known history of organic brain disorders and associated dementia, delirium and other specific neuropsychiatric conditions, including stroke and head injury.
  2. Patients who are clinically assessed as having MCI prior to starting ADT.
  3. Patients with a medical prognosis of less than 3 months.
  4. Patients who are claustrophobic.
  5. Patients who have any metal implanted in their body e.g. heart pacemaker, cochlear implant or any other electronic device.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02061345


Locations
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United Kingdom
Imperial College Healthcare NHS Trust
London, United Kingdom, W6 8RF
Sponsors and Collaborators
Imperial College London
Investigators
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Principal Investigator: Paul D Abel Imperial College London

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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT02061345     History of Changes
Other Study ID Numbers: 13HH0558
First Posted: February 12, 2014    Key Record Dates
Last Update Posted: August 15, 2016
Last Verified: February 2016

Keywords provided by Imperial College London:
Prostate cancer
Androgen Deprivation Therapy
Mild Cognitive Impairment

Additional relevant MeSH terms:
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Prostatic Neoplasms
Cognitive Dysfunction
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs