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
Conditions: Prostate Cancer, Mild Cognitive Impairment
Sponsor: Imperial College London

 
Version 4, 18-09-2014 
 
STUDY PROTOCOL 
 
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 
 
COMPLIANCE 
This study will be conducted in accordance with the principles of Good Clinical 
Practice (GCP). It will also be conducted in compliance with the protocol, Data Protection Act 
and other regulatory requirements, as appropriate. 
 
AUTHORISATION 
Professor Paul Abel (Chief Investigator) is authorised to sign the final protocol and 
protocol amendments:  
 
ADMINISTRATION 
 
Chief Investigator 
Professor Paul D Abel* 
Department of Surgery and Cancer 
Faculty of Medicine 
Imperial College London (Hammersmith Hospital Campus) 
Du Cane Road 
London,  
W12 0NN 
 
T: 020 8383 2268 
F: 020 8383 2431 
p.abel@imperial.ac.uk 
 
Principal Investigator 
Dr. Azeem Saleem** 
 
Co-investigators 
Professor Pat Price* 
Professor Basant Puri* 
Prof. David Sharp*** 
Dr. Adam Hampshire*** 
Dr. Jilka Sagar*** 
Dr. Syed Imran Ali Shah* 
Professor Terry Jones*** 
Professor Richard Wassersug*** 
 
*Imperial College London and Imperial College Healthcare NHS Trust, London, UK 
**Imanova Centre for Imaging Studies 
*** Imperial College Computational, Cognitive and Clinical Neuroimaging Laboratory 
*** UC Davis, USA 
***University of British Columbia, Vancouver, Canada 

 
Version 4, 18-09-2014 
 
 
CONTENTS 
 
List of Abbreviations 
Study Design 
Scientific Rationale 
Objectives of the study 
 
Primary Objective 
 
Secondary Objectives 
Outcome measures 
Patient recruitment 
Inclusion Criteria 
Exclusion Criteria 
Sample Size 
Treatment of Patients 
Medications 
Radiotherapy 
Procedures 
Stage 11 (Screening) 
 
Neuropsychological Assessment 
Determination of TSPO polymorphism 
 
Blood Hormone Assays 
Stage 2 
Cognitive assessment 
Blood Analyses 
Brain Imaging 
 
PET Scan 
 
MRI Scan 
Statistics and Data Analysis 
End of Study 
Withdrawal of patients 
Clinical Queries 
Incidental Clinical Findings 
Adverse Events Definitions 
Reporting Procedure for Adverse Events 
Regulatory Issues 
 
Ethical Approval 
 
ARSAC Certification 
 
Consent 
 
Confidentiality 
 
Indemnity 
 
Sponsor 
 
Funding 
 
Audit 
 
 
 
 
Formatted: Indent: Left:  1.27 cm

 
Version 4, 18-09-2014 
 
 
 
LIST OF ABBREVIATIONS 
 
ADL 
 
Activities of daily living 
ADT 
 
Androgen deprivation therapy 
AE 
 
Adverse event 
CANTAB 
Cambridge neuropsychological test automated battery 
EDTA  
Ethylenediamine tetracetic acid 
FBC 
 
Full blood count 
FBP 
 
Filtered back projection 
fMRI 
 
Functional magnetic resonance imaging 
ICHT  
Imperial College Healthcare NHS trust 
KDa 
 
Kilo-dalton 
LHRHa 
Luteinising hormone releasing hormone agonists 
LVLS  
Last visit of the last subject 
mBq 
 
Millibecquerel 
MCI 
 
Mild cognitive impairment 
mM 
 
Millimolar 
MRI  
 
Magnetic resonance imaging 
OSEM  
Ordered subset expectation maximisation 
PET 
 
Positron emission tomography 
PIS 
 
Patient information sheet 
ROI 
 
Region of interest 
SAE 
 
Serious adverse event 
SHBG  
Sex hormone-binding globulin 
SPM 
 
Statistical parametric mapping 
SUV 
 
Standardised uptake value 
TSPO  
Translocator protein 
VT 
 
Total volume of distribution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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STUDY DESIGN 
To compare quantitative [11C]PBR28 positron emission tomography (PET) imaging in 
patients with clinically significant androgen deprivation therapy (ADT) associated mild 
cognitive impairment (MCI) with an age and treatment matched cohort with no MCI. 
Six patients reporting and assessed to have significant ADT related MCI and who are 
subsequently shown to have the genetic polymorphism demonstrating high [11C]PBR28 
binding will be scanned. Comparison of these data will be made with scans of 6 age and 
treatment matched patients with no evidence of MCI who again are shown to express high 
affinity 18 kDa TSPO/Peripheral benzodiazepine receptors.  
MCI will be assessed by neuropsychological and cognitive assessments (standard 
paper and computer-based) questionnaires and online) and its neural basis will be 
investigated using magnetic resonance imaging (MRI). 
 
SCIENTIFIC RATIONALE  
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 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 18KDa 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, 

 
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except for the exacerbation of frank neuro-inflammation, it does offer a generic sensitive bio-
marker for demonstrating the presence of an on-going active pathology.  
 
OBJECTIVES OF THE STUDY 
This is a pilot study to determine if there is an increase in uptake of the [11C]PBR28 PET 
biomarker in patients who have been clinically assessed to have ADT induced MCI.  
 
Primary Objective 
• 
To demonstrate, using a PET imaging bio marker of activated microglia (TSPO), the 
presence of regional or global pathological changes in the brain that relate to hormonal 
cancer therapy induced MCI. 
 
Secondary Objectives 
• 
To provide insight into possible mechanisms of hormonal therapy induced MCI i.e. 
association of cognitive and neuropsychiatric impairments following ADT with structural 
and/or functional brain connectivity. 
• 
To design and provide a power calculation for a subsequent comprehensive and 
mechanistic based molecular imaging study of hormonal therapy induced MCI. 
 
OUTCOME MEASURES 
The outcome measure is the increased uptake of [11C]PBR28 biomarker by activated 
microglia of patients demonstrating significant MCI with the primary endpoint of [11C]PBR28 
uptake measured as a standardised uptake value (SUV). and secondary endpoint as the 
[11C]PBR28 total volume of distribution (VT). 
 
PATIENT RECRUITMENT 
Patients will be recruited from the uro-oncology follow-up clinics of Imperial College 
Healthcare NHS trust (ICHT). The potential participants will be identified and approached in 
the clinic by their treating consultants. The consultants will then refer interested patients to a 
member of the research team to give details of the study. 
Before a patient is entered into the study, written informed consent will be obtained. 
When obtaining consent from a patient, the study and the patient information sheet (PIS) will 
be introduced in full by a member of the research team and then consent taken. Patients will 
be allowed at least 24 hours to consider participation but they may take as long as they wish 
before making a decision.  
The participants will be asked about any previous radiotherapy. Their medical notes 
will be reviewed for the same purpose and in the case of any concern, a direct check will be 
made with the radiotherapy department. Participants will be asked about any scans they 
have had in the last year and their medical notes and computerised radiology record will also 
be reviewed for the same. 
 
Inclusion Criteria 
1. Prostate cancer patients between the ages 50 to 80 years on ADT with LHRHa for at 
least 3 months and up to a year. 
2. Able to give written informed consent. 
3. Suitable for insertion of an arterial line. 
4.3. 
Able to lie still for up to 90 minutes for a PET scan. 

 
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5.4. 
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 with a known history of Raynaud’s disease, thromboangiitis obliterans. 
3.2. 
Patients who are clinically assessed as having MCI prior to starting ADT. 
4.3. 
Patients with a medical prognosis of less than 3 months survival. 
5.4. 
Patients who are claustrophobic. 
6.5. 
Patients who have any metal implanted in their body e.g. heart pacemaker, 
cochlear implant or any other electronic device. 
 
Sample size 
A total of 12 prostate cancer patients on ADT with LHRHa will be recruited for the 
imagingPET scanning part of the study; six patients having significant cognitive impairment 
attributable to LHRHa and six patients without cognitive impairment. This grouping will 
screening will be based on a detailed clinical history taken from the patient and/or their 
partners where applicable and detailed neuropsychological assessment. As part of 
screening, Ppatients will also be required to undergo a screening blood test to determine 
their genetic predisposition to high TSPO binding. Only those patients having the genetic 
polymorphism for high [11C]PBR28 uptake will continue to the next stage of the study. 
Therefore dependent on the incidence of polymorphism in the population (likely 25-50%) it is 
envisaged that 2-4 times the number of patients will be needed to be recruited at the 
screening stage. Also keeping in mind that some patients may withdraw following 
recruitment to the second phase of the study for several reasons such as disease 
progression, more patients will need to be recruited in both study groups initially to get the 
final sample size of 12 PET scanned patients to complete this pilot study. 
 
TREATMENT OF PATIENTS 
This is not a treatment study and the study will not interfere with the patient’s on-
going anticancer therapy. Patients will continue the same therapy for as long as it is deemed 
appropriate by their treating consultant. 
 
Medications 
This is not a treatment study. All medications will be recorded and continued 
throughout the study unless the responsible physician decides otherwise. Any additional 
treatment that the responsible physician feels is appropriate is permitted. 
 
Radiotherapy 
The treating physician might start the patient on radiotherapy at any time if there is 
any indication; this will not interfere with the study. 
 
PROCEDURES 
 
STAGE 1 
 
Stage 1 will include clinical history and neuropsychological assessment (paper and 
computer-based and online). Blood tests for determining TSPO (Ala147Thr) polymorphism 

 
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and sex hormone levels, full blood count (FBC) and coagulation profile will also be done 
atduring this stage. All stage 1 procedures will be carried out at the uro-oncology clinics of 
Charing Cross hospitalICHT on routine follow-up visits. Based on results from Stage 1, 
eligible patients will be invited to proceed to the next stage of the study. 
 
Neuropsychological assessment 
Neuropsychological functions will be assessed by using a battery of paper-based 
standard neuropsychological questionnaires and online computerised detailed remote 
tracking of cognition and emotion. via CBSTrials.com. The paper and computer-based and 
online assessments will be administered to patients. and their spouse or partner where 
available.  
The detailed neuropsychological battery will be used to assess current verbal and 
nonverbal reasoning ability, cognitive flexibility, inhibition, set shifting, executive functions, 
working memory, verbal recall, associative learning and recall. 
Online assessments will be completed by the patients and their spouse or partner at 
home. For the internet-based cognitive testing, participants and their family members  will 
receive an email reminding them that it is time to be tested. Clicking on the email link will 
take them directly into the set of cognitive tests. They will then be presented with the tests 
one after the other in a pre-set sequence. When all tests are completed, they will be 
navigated to a simple end page. Additional exclusion criteria will be used for this component 
of the study. Participants having internet access at home will be enrolled. 
Based on clinical history and neuropsychological assessments, patients will be 
grouped into two arms, (1) those having significant MCI due to ADT and (2) those without 
evidence of MCI.  
Determination of TSPO polymorphism 
 
For determining TSPO (Ala147Thr) polymorphism, 10ml venous blood will be 
collected in EDTA tubes and the sample will be sent for analysis to the Hematology 
department, Hammersmith hospital within 72 hours of collection. Only those patients shown 
to have the genetic polymorphism demonstrating expression of high affinity 18 kDa 
TSPO/Peripheral  benzodiazepine receptor for binding the PET imaging marker[11C]PBR28. 
will progress to stage 2.  
Hormone levels 
A venous blood sample (10ml) for measurement of hormones (testosterone and 
oestradiol) will be obtained. 
Coagulation Profile and FBC 
A coagulation profile (PT, APTT) and a full blood count (FBC) will also be performed 
to ensure that the subject is eligible for an arterial cannulation.  
 
STAGE 2 
Stage 2 will involve arterial cannulation and research imaging of the brain to be 
undertaken at the Imanova Centre for Imaging Studies. Patients will be registered at the 
Hammersmith hospital before the imaging session and then will undergo a brain PET scan 
and a brain MRI scan on the same day at the same visit.  
 
Arterial Cannulation 
An arterial line will be inserted for blood sampling during the PET scan. In case of 
failure to insert an arterial line, we will either not go ahead with the PET scan or we may 

 
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decide to scan without arterial lines if preliminary results are available for us to get 
meaningful data without arterial cannulation.  
 
 
PET Scan 
During the PET scanning session, an x-ray topogram will be performed to localise the 
area to be scanned. This will be followed by a CT scan localised to the area to be scanned 
for attenuation and scatter corrections followed by administration of [11C]PBR28 and 
dynamic PET imaging for 90 minutes. Target dose of [11C]PBR28 will be 400MBq. 
Continuous and discrete arterial blood samples will be taken throughout the duration of the 
[11C]PBR28 scans for measurement of total plasma and whole blood radioactivity and for 
radiolabelled metabolites. The total amount of blood withdrawn during the course of the PET 
scanning would be about 135 ml (75ml for continuous arterial blood sampling (15min @5 
ml/min) + 57ml for discrete sampling for a 90min scan =  132 ml).  
 PET images will be reconstructed using the filtered back projection (FBP) and 
ordered subset expectation maximisation (OSEM) algorithms. Regions of interest (ROIs) will 
be defined outlining the area of interest and will be applied to the dynamic [11C]PBR28 data 
to generate mean voxel radioactivity for the full duration of the scan. Time activity curves for 
the full duration of the scan corrected for radioactive decay and normalized for injected 
radioactivity will be generated. Tissue uptake parameters including but not limited to SUV 
and VT will be calculated. [11C]PBR28 input function derived from the time course of arterial 
blood radioactivity will be used to model and obtain VT.  
In the case of [11C]PBR28 preparation failure, the PET scan will be done later on the 
same day if feasible, or on another day. Patients will be informed beforehand that there is up 
to a 5% scan failure rate. 
  
MRI Scan 
A structural MRI scan will be performed for neuroanatomical interpretation of the PET 
scan. No contrast material will be used. Checks will again be made before scanning to 
ensure that no patient has any MRI-incompatible metallic object in his body. Additionally, 
rest and task-activated fMRI measures will be performed and the total scan time will be one 
hour approximately. 
 
STATISTICS AND DATA ANALYSIS  
This is a pilot study with a sample size for PET and MRI studies limited to 12 
patients. The kinetically acquired PET data, requiring accompanying arterial blood sampling, 
will be processed to provide parametric images of the ligand’s binding potential or 
equilibrium distribution volume. Statistical parametric mapping (SPM) of the quantitative 
images of binding potential or equilibrium distribution volumes of [11C]PBR28 will be used to 
identify regional effectsdifferences in ligand binding between the two patient arms and of the 
combined data from the two groups against fMRI measures and cognitive scores. This will 
inform the design of a future more comprehensive and definitive study and likely identify 
underlying mechanisms which could then be further investigated. Data and all appropriate 
documentation will be stored for a minimum of 10 years after the completion of the study.  
 
END OF STUDY 
The study will be considered ‘closed’ at the last visit of the last subject (LVLS).  
 

 
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WITHDRAWAL OF PATIENTS 
Every patient has the right to withdraw consent for participation in the study at any 
time. A patient may withdraw, or be withdrawn, from trial participation for the following 
reasons: 
1. Intercurrent illness which prevents participation. 
2. Withdrawal of consent. 
3. Any alteration in the patient’s condition which justifies the discontinuation in the 
clinician’s opinion. 
 
CLINICAL QUERIES 
Clinical queries should be directed to the Chief Investigator who will direct the query 
to the appropriate person. 
 
INICIDENTAL CLINICAL FINDINGS 
The scans in this study are not aimed at diagnosing medical disorders. However, 
there is a small probability of incidental findings in the structural MRI scans and the 
attenuation CT scans of the PET-CT scan performed as part of the study.  Therefore all  
scans will be reviewed soon after acquisition by an Imperial College Healthcare NHS Trust 
consultant radiologist and incidental findings reported to the CI. The CI will arrange for any 
such patient to be seen in clinic for counselling about the incidental finding(s) and, if consent 
is given, inform the patient’s GP for further action. 
ADVERSE EVENTS DEFINITIONS  
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.  
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that:  
• 
Results in death  
• 
Is life-threatening – refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe  
• 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital anomaly or birth defect  
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations. Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious.  
REPORTING PROCEDURES FOR ADVERSE EVENTS 
All adverse events should be reported. Depending on the nature of the event the 
reporting procedures below should be followed. Any questions concerning adverse event 
reporting should be directed to the Chief Investigator in the first instance. Any adverse 
events arising as a result of the radiotracer administration will be reported to Imanova as per 
the Imanova standard operating procedures. 

 
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Non serious AEs  
All such events, whether expected or not, should be recorded.  
 
Serious AEs  
An SAE form should be completed and faxed to the Chief Investigator within 24 
hours. However, relapse and death due to prostate cancer and hospitalisations for elective 
treatment of a pre-existing condition do not need reporting as SAEs.  
All SAEs should be reported to the ‘name of REC’ where in the opinion of the Chief 
Investigator, the event was:  
• 
‘related’, i.e. resulted from the administration of any of the research procedures; and  
• 
‘unexpected’, i.e. an event that is not listed in the protocol as an expected 
occurrence. 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the 
Chief Investigator becoming aware of the event, using the NRES SAE form for non-IMP 
studies. The Chief Investigator must also notify the Sponsor of all SAEs.   
Contact details for reporting SAEs 
Professor Paul D Abel 
Department of Surgery and Cancer 
Faculty of Medicine 
Imperial College London (Hammersmith Hospital Campus) 
Du Cane Road 
London,  
W12 0NN 
 
T: 020 8383 2268 
F: 020 8383 2431 
p.abel@imperial.ac.uk 
 
 
REGULATORY ISSUES 
 
Ethics Approval  
The Chief Investigator will obtain approval from the London Queen Square Research 
Ethics Committee. The Chief Investigator will require a copy of the Trust R&D approval letter 
before accepting participants into the study. The study will be conducted in accordance with 
the recommendations for physicians involved in research on human subjects adopted by the 
18th World Medical Assembly, Helsinki 1964 and later revisions. Except in the case of 
urgent safety measures, any amendments to the protocol should be approved by the 
sponsor, prior to submission to the ethics committee. Upon receiving ethical approval, any 
amendment must receive further Trust approval, before being implemented at site. In the 
case of an urgent safety measure, the sponsor and REC should be informed as soon as 
possible following the amendment.  
 

 
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ARSAC Certification 
Approval from the Administration of Radioactive Substances Advisory Committee 
(ARSAC) at the National Radiation Protection Board to administer radioactivity has been 
obtained for the study.  Radiotracer prescription will be signed by the ARSAC holder or an 
authorized delegated investigator. 
Consent 
Consent to enter the study will be sought from each participant only after a full 
explanation has been given, an information leaflet offered and time allowed for 
consideration. Signed participant consent must be obtained. The right of the participant to 
refuse to participate without giving reasons must be respected. After the participant has 
entered the study, the clinician remains free to give alternative treatment to that specified in 
the protocol at any stage if he/she feels it is in the participant’s best interest, but the reasons 
for doing so should be recorded. In these cases the participants remain within the study for 
the purposes of follow-up and data analysis. All participants are free to withdraw at any time 
without giving reasons and without prejudicing further treatment. 
 
Confidentiality 
All information collected during the course of the research will be kept strictly 
confidential. The Chief Investigator will preserve the confidentiality of participants taking part 
in the study and is registered under the Data Protection Act. In addition, all procedures for 
handling, processing, storage and destruction of data are compliant with the Data Protection 
Act. No individual patients will be identified when the results of the trial are published. 
 
Indemnity  
Imperial College London holds negligent harm and non-negligent harm insurance 
policies which apply to this study. Imperial College Healthcare NHS Trust holds standard 
NHS Hospital Indemnity and insurance cover with NHS Litigation Authority for NHS Trusts in 
England, which apply to this study. 
  
Sponsor  
Imperial College London is the main research sponsor for this study. For further 
information regarding the sponsorship conditions, please contact the Head of Regulatory 
Compliance at: 
Joint Research Compliance Office  
Imperial College London and Imperial College Healthcare NHS Trust 
Room 5L10C, 5th Floor Lab Block 
Charing Cross Hospital, Fulham Palace Road 
London, W6 8RF 
Tel: 0203 311 0204  
Fax: 020 311 0203  
  
Funding  
The funding for the research will be provided by a joint Imanova / BRC grant. Dr SIA 
Shah is funded by an IC commonwealth scholarship.  
 
Audits  

 
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The study may be subject to inspection and audit by Imperial College London under 
their remit as sponsor and other regulatory bodies to ensure adherence to GCP and the 
NHS Research Governance Framework for Health and Social Care (2nd edition).  
  
STUDY MANAGEMENT 
The day-to-day management of the study will be co-ordinated by the Chief 
Investigator.  
  
PUBLICATION POLICY  
The results from the study will be analysed and published in a journal article. The 
results will also form part of a doctoral thesis. All publications will acknowledge the 
participating institutions and clinicians. 
 
REFERENCES  
1. Sharifi N, et al. An update on androgen deprivation therapy for prostate cancer. 
Endocrine-Related Cancer 2010;17:305-15. 
2. Alibhai SMH, et al. Impact of androgen-deprivation therapy on cognitive function in 
men with nonmetastatic prostate cancer. J Clin Oncol 2010;28:5030-7. 
3. LeBlanc ES, et al. Hormone replacement therapy and cognition. JAMA 
2001;285:1489-99. 
4. Nelson CJ, et al. Cognitive effects of hormone therapy in men with prostate cancer: a 
review. Cancer 2008;113:1097-106. 
5. Moffat SD et al. Longitudinal assessment of serum free testosterone concentrations 
predicts memory performance and cognitive status in elderly men. J Clin Endocrinol 
Metab. 2002;87:5001-7. 
6. Canat X, et al. Distribution profile and properties of peripheral-type benzodiazepine 
receptors on human hemopoietic cells. Life Sci;1993:52:107-18. 
7. Bik-Multanowski M, et al. Routine use of CANTAB system for detection of 
neuropsychological deficits in patients with PKU. Molecular genetics and metabolism 
2011;102:210-3. 
8.7. 
Okello A, et al. Microglial activation and amyloid deposition in mild cognitive 
impairment: a PET study. Neurology 2009;72:56-62. 
9.8. 
Hampshire A et al. Hypoconnectivity and hyperfrontality in retired american 
football players. Scientific Reports 2013 
10.9. 
Hampshire A et al. Fractionating human intelligence. Neuron 2012;76:1225-
37. 
11.10. 
Bonnelle V et al. Default mode network connectivity predicts sustained 
attention deficits after traumatic brain injury. J Neuroscience 2011:31:13442-51.