14. Appendices

Appendix A: Consent Form 1: Use of clinical information for research purposes

CONSENT FORM 1
Title of research study:
A pilot study on the utility of CSF and blood biomarkers in the delineation of the aetiopathology of cognitive impairment and in the prediction of conversion of mild cognitive impairment to dementia.
Part 1: Use of clinical information for research purposes

This study and this consent form have been explained to me. My doctor has answered all my questions to my satisfaction. I believe I understand what will happen if I agree to be part of this study.

I have read, or had read to me, this consent form. I have had the opportunity to ask questions and all my questions have been answered to my satisfaction. I freely and voluntarily agree to be part of this research study, though without prejudice to my legal and ethical rights. I have received a copy of this agreement.

I hereby consent to the use of anonymised information from my medical records at St. James’s hospital for the purposes of the above research study – this includes but is not limited to, my medical history and the results of laboratory investigations, diagnostic imaging and neuropsychological tests. I understand that I may be asked to undergo some brief additional neuropsychological tests as part of this study.

PARTICIPANT’S NAME:                      ____________________________________

PARTICIPANT’S SIGNATURE:            ____________________   Date:____________ 

Date on which the participant was first furnished with this form:
___________

Where the participant is capable of comprehending the nature, significance and scope of the consent required, but is physically unable to sign written consent, signatures of two witnesses present when consent was given by the participant to a registered medical practitioner will be provided.

Name of first witness:    ____________________    Signature: ______________________

Name of second witness:____________________Signature: ______________________ 

Statement of investigator’s responsibility: I have explained the nature, purpose, procedures, benefits, risks of, or alternatives to, this research study. I have offered to answer any questions and fully answered such questions. I believe that the participant understands my explanation and has freely given informed consent.

Physician’s signature_____________________       Date:__________________

 (Keep the original of this form in the participant’s medical record, give one copy to the participant, keep one copy in the investigator’s records)

Appendix B: Consent Form 2: Blood tests for biomarkers and albumin.

CONSENT FORM 2

Title of research study:
A pilot study on the utility of CSF and blood biomarkers in the delineation of the aetiopathology of cognitive impairment and in the prediction of conversion of mild cognitive impairment to dementia.

Part 2: Blood tests for biomarkers and albumin (blood protein) level.
This study and this consent form have been explained to me. My doctor has answered all my questions to my satisfaction. I believe I understand what will happen if I agree to be part of this study.

I have read, or had read to me, this consent form. I have had the opportunity to ask questions and all my questions have been answered to my satisfaction. I freely and voluntarily agree to be part of this research study, though without prejudice to my legal and ethical rights. I have received a copy of this agreement.

I hereby consent to provide blood samples for biomarker testing and a sample to allow for measurement of albumin (blood protein) in my blood, as part of the above study. I understand the results are for research purposes only and will not be made available to me during the course of the study.

PARTICIPANT’S NAME:                      ____________________________________

PARTICIPANT’S SIGNATURE:            ____________________  

Date:____________

Date on which the participant was first furnished with this form:

___________

Where the participant is capable of comprehending the nature, significance and scope of the consent required, but is physically unable to sign written consent, signatures of two witnesses present when consent was given by the participant to a registered medical practitioner will be provided.

Name of first witness:    ____________________    Signature: ______________________

Name of second witness:____________________Signature: ______________________

Statement of investigator’s responsibility: I have explained the nature, purpose, procedures, benefits, risks of, or alternatives to, this research study. I have offered to answer any questions and fully answered such questions. I believe that the participant understands my explanation and has freely given informed consent.

Physician’s signature:_____________________      Date:__________________

 (Keep the original of this form in the participant’s medical record, give one copy to the participant, keep one copy in the investigator’s records)

Appendix C: Consent Form 3: Blood test for Genotyping.

CONSENT FORM 3

Title of research study:
 A pilot study on the utility of CSF and blood biomarkers in the delineation of the aetiopathology of  cognitive impairment and in the prediction of conversion of mild cognitive impairment to dementia.
Part 3: Blood tests for genetic markers (APOE)

This study and this consent form have been explained to me. My doctor has answered all my questions to my satisfaction. I believe I understand what will happen if I agree to be part of this study.

I have read, or had read to me, this consent form. I have had the opportunity to ask questions and all my questions have been answered to my satisfaction. I freely and voluntarily agree to be part of this research study, though without prejudice to my legal and ethical rights. I have received a copy of this agreement.

I hereby consent to provide blood samples for genetic testing as part of the above study. I understand the results are for research purposes only and will not be made available to me during the course of the study.

PARTICIPANT’S NAME:                      ____________________________________

PARTICIPANT’S SIGNATURE:            ____________________  

Date:____________

Date on which the participant was first furnished with this form: ___________

Where the participant is capable of comprehending the nature, significance and scope of the consent required, but is physically unable to sign written consent, signatures of two witnesses present when consent was given by the participant to a registered medical practitioner will be provided.

Name of first witness:    ____________________    Signature: ______________________

Name of second witness:____________________Signature: ______________________

Statement of investigator’s responsibility:

I have explained the nature, purpose, procedures, benefits, risks of, or alternatives to, this research study. I have offered to answer any questions and fully answered such questions. I believe that the participant understands my explanation and has freely given informed consent.

Physician’s signature:_____________________      Date:   __________________

 (Keep the original of this form in the participant’s medical record, give one copy to the participant, keep one copy in the investigator’s records)

Appendix D: Consent Form 4: Lumbar puncture for biomarker testing

CONSENT FORM 4
Title of research study:
A pilot study on the utility of CSF and blood biomarkers in the delineation of the aetiopathology of cognitive impairment and in the prediction of conversion of mild cognitive impairment to dementia.
Part 4: Lumbar puncture for biomarker testing

This study and this consent form have been explained to me. My doctor has answered all my questions to my satisfaction. I believe I understand what will happen if I agree to be part of this study.

I have read, or had read to me, this consent form. I have had the opportunity to ask questions and all my questions have been answered to my satisfaction. I freely and voluntarily agree to be part of this research study, though without prejudice to my legal and ethical rights. I have received a copy of this agreement.

I hereby consent to undergo lumbar puncture to provide a sample of spinal fluid for biomarker testing as part of the above study.  The risks and benefits of taking part in this procedure have been explained. I understand that the results of the biomarker tests are for research purposes only and will not be made available to me during the course of the study.

PARTICIPANT’S NAME:                      ____________________________________

PARTICIPANT’S SIGNATURE:            ____________________   Date:____________

Date on which the participant was first furnished with this form: ___________

Where the participant is capable of comprehending the nature, significance and scope of the consent required, but is physically unable to sign written consent, signatures of two witnesses present when consent was given by the participant to a registered medical practitioner will be provided.

Name of first witness:    ____________________    Signature: ______________________

Name of second witness:____________________Signature: ______________________

Statement of investigator’s responsibility:

I have explained the nature, purpose, procedures, benefits, risks of, or alternatives to, this research study. I have offered to answer any questions and fully answered such questions. I believe that the participant understands my explanation and has freely given informed consent.

Physician’s signature:_____________________      Date:   __________________

 (Keep the original of this form in the participant’s medical record, give one copy to the participant, keep one copy in the investigator’s records)

Appendix E:  NINCDS-ADRDA criteria for Probable Alzheimer’s disease (McKhann et al., 1984)

I. Criteria for the clinical diagnosis of PROBABLE Alzheimer’s disease
Dementia established by clinical examination and documented by the Mini-Mental Test; Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological tests;
Deficits in two or more areas of cognition;
Progressive worsening of memory and other cognitive functions;
No disturbance of consciousness;
Onset between ages 40 and 90, most often after age 65; and
Absence of systemic disorders or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition

II. The diagnosis of PROBABLE Alzheimer’s disease is supported by:
Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perceptions (agnosia);
Impaired activities of daily living and altered patterns of behavior;
Family history of similar disorders, particularly if confirmed neuropathologically; and
Laboratory results of:
Normal lumbar puncture as evaluated by standard techniques,
Normal pattern or non-specific changes in EEG, such as increased slow-wave activity, and
Evidence of cerebral atrophy on CT with progression documented by serial observation

III. Other clinical features consistent with the diagnosis of PROBABLE Alzheimer’s disease, after exclusion of causes of dementia other than Alzheimer`s disease, include:
Plateaus in the course of progression of the illness;
Associated symptoms of depression, insomnia, incontinence, delusions, illusions, hallucinations, catastrophic verbal, emotional, or physical outbursts, sexual disorders, and weight loss;
Other neurologic abnormalities in some patients, especially with more advanced disease and including motor signs such as increased muscle tone, myoclonus, or gait disorder;
Seizures in advanced disease; and
CT normal for age

IV. Features that make the diagnosis of PROBABLE Alzheimer’s disease uncertain or unlikely include:
Sudden, apoplectic onset;
Focal neurologic findings such as hemiparesis, sensory loss, visual field deficits, and in coordination early in the course of the illness; and Seizures or gait disturbances at the onset or very early in the course of the illness.

Appendix F: PATIENT INFORMATION LEAFLET

Patient Information Leaflet

Title of study

 A pilot study on the utility of CSF and blood biomarkers in the delineation of the aetiopathology of cognitive impairment and in the prediction of conversion of mild cognitive impairment to dementia.

Introduction

The Memory Clinic in St. James’s provides assessment for people who are having problems with their memory or other areas of thinking (cognition). Sometimes mild cognitive problems progress to a point where they begin to interfere with everyday activities – this is what we call ‘dementia’. In some cases, Alzheimer’s disease, a progressive disease of the brain, is responsible for these symptoms and the fact that they progress to dementia. It can be difficult, in the clinic, to predict which cognitive problems are caused by Alzheimer’s disease and which patients will develop dementia.

This is especially difficult when the cognitive problems are mild or when the patient is young (under 65 years). The Cognitive Clinic in St James Hospital also provides assessment for younger patients presenting with cognitive and neurological problems where the presenting symptoms can be atypical or unusual and the diagnosis can be unclear. Being more certain of the diagnosis would mean that medical treatments and other useful interventions could be introduced earlier.

This study will explore whether measuring the levels of certain proteins (called ‘biomarkers’) in the spinal fluid of people with cognitive problems is helpful in predicting who will develop dementia and whether the underlying cause is Alzheimer’s disease.

Because the results of these biomarker tests vary depending on what laboratory carries out the test and what country the patient is from, we would like to develop a reliable test, specifically for Irish patients, which would be carried out in our hospital laboratory.

To do this we are inviting Irish people aged ≥ 65years but < 90 years, with a diagnosis of possible Alzheimer’s Disease or Mild Cognitive Impairment (MCI), or cognitive impairment diagnosed at a younger age (≥ 45years but  < 65 years) to allow us to take a sample of their blood and/or spinal fluid for testing. We will compare the results of these tests with tests on patients from other Irish clinics who have no cognitive impairments.

If we can show that the results of these biomarker tests are useful, we will be able to make this test available to people with memory complaints on a routine basis in our clinic.

This research study is part of a large EC funded project called BIOMARKAPD, which aims to develop blood and spinal fluid tests to help in the diagnosis of Alzheimer's disease.

Procedures:
To participate in this study, you must:
Be attending the Memory clinic or Cognitive Clinic in St James Hospital. 
Be aged ≥ 65 years but < 90 years and have a diagnosis of possible Alzheimer’s disease (following assessment in clinic)
Be aged ≥ 65 years but < 90 years and have a diagnosis of mild cognitive impairment (MCI) (following assessment in clinic)
Be aged ≥ 45 years but < 65 years and presenting with cognitive symptoms where
the underlying cause is uncertain.

You will have had all the normal tests the Memory Clinic or Cognitive Clinic provides and be given your diagnosis or possible diagnosis.

If you agree, you will have a blood test and lumbar puncture for spinal fluid. These will be tested for the biomarkers described above. These tests will be carried out when your first become involved in the study.  They can then be repeated annually or until a definite diagnosis can be made in the clinic.

Because these tests are experimental and we cannot yet guarantee their accuracy in Irish people, you will not be given the results of these tests – they are used for research purposes only.

You will also be asked to give consent for a blood test to test for a gene (called a susceptibility gene) that can put some people at a slightly higher risk of developing Alzheimer’s disease. The test is for research purposes only and the results of the test are not provided to you.

You will also be asked to consent for a sample of blood to be taken to measure a protein in your blood called albumin and this sample will be taken in conjunction with the spinal tap, so proteins in your blood and spinal fluid can be measured together.  

You may be asked to do some extra psychological tests relating to memory, cognition or mood. These will be done in the Memory Clinic or the Cognitive Clinic, in St James Hospital.

Bloods and spinal fluid samples will be stored safely and anonymously in St. James's Hospital until measured for biomarkers. Some of your blood or spinal fluid samples may be sent to another collaborating laboratory in Europe as part of the BIOMARKAPD study to help with validation and standardisation of the testing. BIOMARKAPD is a larger European Study involving many countries. As part of BIOMARKAPD, some of your blood and spinal fluid sample may be sent to an approved biobank facility in Luxembourg for the development of new tests for Alzheimer's disease. Your samples will be anonymised so that you will not be identified at any time.

Some of your blood and spinal fluid samples may be stored for up to 10 years. Some of your stored sample may be used at a later date for other research tests or studies; if that is the case, research permission to use your sample will be sought again from the Ethics Committee.

Benefits:

There are no direct benefits to participating in the study. However, your participation and contribution of blood and/or spinal fluid samples may help in the development of a diagnostic test for Alzheimer’s disease.

Risks:

The only potential risk as a result of taking part in this study, is related to the procedure for taking a sample of your spinal fluid.

Procedure: LUMBER PUNCTURE

What is a lumber puncture?
A lumber puncture is a procedure to take a sample of fluid( CSF) that surrounds your brain and spine. It is produced continuously and so the small sample that is taken will be replaced very rapidly by your body. This is an out-patient procedure and is commonly performed in hospitals. On the day of the procedure you will come to the hospital and remain for a few hours only, and can return home later that day.

How is the test performed?
The spinal fluid is collected by passing a needle into the lower part of your back. You may be lying on your side on a bed or occasionally the lumber puncture is done sitting up.

The area around your lower back is cleaned with an antiseptic, this can feel a little cold and wet on your skin. A local anaesthetic or numbing medicine (just like you might have had at the dentist) is  injected under the skin with a small needle  to numb the area so the procedure will not be  too uncomfortable. As the local anaesthetic is injected you may experience a stinging sensation for a few seconds.

The doctor will then pass a needle through the skin into the spinal canal to collect a small amount of fluid, about a teaspoon amount. You may feel a slight pushing or pressure sensation. Sometimes a pain is felt down your leg, this is normal and nothing to worry about and should stop after a few minutes once the needle is removed, but if it persists tell the doctor.

The entire procedure takes about 15- 20 minutes. Afterwards you will remain lying down for about 30 minutes to rest. You will be advised to drink plenty of fluids after the procedure and to take things easily for a few days afterwards.

What are the Risks:
As with all medical procedures, there are possible complications. In general, these are quite uncommon.

Headache:
Up to 4% of patients report headache, called an LP- headache, after the test and this usually develops 1-2 days after the procedure.  If this happens, it can be troublesome and the headache is usually worse with standing and eases on lying down. Therefore if this does occur you should lie down and rest as much as possible and drink plenty of fluids as this will help with the headache. It should settle in 24 hours but if this persist or is severe you should contact your doctor or the hospital for advice.

Backache:
Some people experience some discomfort in their lower back at the site where the needle was introduced. This usually is mild and settles quickly. Painkillers such as paracetamol may be helpful.

Infection:
Infection at the site of the sample collection, or in the cerebrospinal fluid, is an extremely rare complication as the procedure is carried out using sterile technique with sterile, single-use equipment.

Bleeding:
There is a very small risk of a bleed in the spinal canal or on the outside of the brain. If you are taking Warfarin or other blooding thinning medications (anticoagulants) this can increase your risk of bleeding and this bleeding in the spinal canal could lead to paralysis. The doctor will review your medications prior to the procedure, in particular medications to thin the blood or prevent clots and if you are taking a medication that is contraindicated, you will not have the procedure.
The blood sample taken afterwards is the same as any other blood test and may cause some bruising or mild discomfort at the site.

Exclusion from participation:
You most definitely must not have the Lumbar Puncture carried out if you are on Warfarin or Heparin or any of the newer Anticoagulant (anti-clotting) drugs like  Dagabatrin (Pradaxa)

Alternative treatment:
You do not have to be a part of this study to be treated in the Memory Clinic or Cognitive Clinic, St James Hospital.

Confidentiality:
Your identity will remain confidential. Your name will not be published and will not be disclosed to anyone outside the hospital.  The samples of blood and. or spinal fluid you provide will be coded with a unique patient identification number.

Compensation:
Your doctors are covered by standard medical malpractice insurance. Nothing in this document restricts or curtails your rights.

Voluntary Participation:
You have volunteered to participate in this study. You may quit at any time. If you decide not to participate, or if you quit during the study, you will not be penalised and will not give up any benefits which you had before entering the study. The care provided to you in the clinic you are attending will not be compromised in any way.

Stopping the study:
It is important to understand that your doctor or the sponsoring company may stop your participation in the study at any time without your consent.

Permission:
This study has hospital Research Ethics Committee approval
           
Further information:
Please Contact: 01-4284531

Appendix H: Patient Eligibility Screening Form (ESF)

Patient Eligibility Screening Form (ESF)

Category Allocation:                                                                                                 (tick correct box)

>65 but <90 years, diagnosed with possible/ mild Alzheimer’ Disease.

> 65 but <90 years with mild cognitive impairment (MCI).                           

>45 but <65 years with cognitive deficits/ early onset neurodegeneration.