Cerebral Haemodynamic Changes During Cognitive Testing: a Functional Transcranial Doppler (fTCD) Study
Conditions: Mild Cognitive Impairment, Alzheimer Disease, Vascular Dementia, Healthy Controls
Sponsor: University of Leicester

 
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Cerebral Haemodynamics During Cognitive Testing 
 
CEREBRAL HAEMODYNAMIC CHANGES DURING COGNITIVE TESTING: A 
FUNCTIONAL TRANSCRANIAL DOPPLER (fTCD) STUDY 
Sponsor Reference No: 0613 
Ethics Ref: 203853 
Date and Version No:  
Version 3, 1st June 2017 
 
Chief Investigator: 
 
Professor Thompson G Robinson 
Head of Department and Professor of Stroke Medicine, Department 
of Cardiovascular Sciences, University of Leicester 
 
Investigators:  
 
Dr Victoria Haunton 
Consultant 
in 
Geriatric 
Medicine 
and 
General 
Internal 
Medicine/Honorary Senior Lecturer, University Hospitals of Leicester 
NHS Trust/Department of Cardiovascular Sciences, University of 
Leicester 
 
Professor Ronney Panerai 
Emeritus Professor, Department of Cardiovascular Sciences, 
University of Leicester 
 
 
Dr Hari Subramaniam 
Honorary Senior Lecturer, Department of Health Sciences, University 
of Leicester and  
Consultant Psychiatrist, Mental Health Services for Older 
People, Leicestershire Partnership NHS Trust  
 
Dr Lucy Beishon 
Academic Clinical Fellow 
Department of Cardiovascular Sciences, University of Leicester 
 
 
 
 
 
 

 
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Cerebral Haemodynamics During Cognitive Testing 
 
Sponsor: 
 
 
University of Leicester 
Funder: 
 
 
University of Leicester 
 
Confidentiality Statement 
All information contained within this protocol is regarded as, and must be kept confidential.  No 
part of it may be disclosed by any Receiving Party to any Third Party, at any time, or in any form 
without the express written permission from the Chief Author/Investigator and / or Sponsor. 
Authors 
 
Dr Victoria Haunton BM MD DGM MRCP(Geriatric Medicine)  
Consultant in Geriatric Medicine and General Internal Medicine/Honorary Senior Lecturer  
University Hospitals of Leicester NHS Trust/Department of Cardiovascular Sciences, University of 
Leicester 
Phone:  
+44(0) 116 252 5802 
Email:  
vjh12@le.ac.uk  
 
Professor Thompson G Robinson BMedSci MD FRCP 
Head of Department and Professor of Stroke Medicine, Honorary Consultant Physician  
Department of Cardiovascular Sciences, University of Leicester, UK 
Phone:  
+44(0) 116 252 3187 
Email:   
tgr2@le.ac.uk 
 
Professor Ronney Panerai BSc MSc PhD 
Emeritus Professor 
Department of Cardiovascular Sciences, University of Leicester, UK 
Phone:  
+44(0) 116 252 3130 
Email:   
rp9@le.ac.uk  

 
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Cerebral Haemodynamics During Cognitive Testing 
 
Signature Page 
 
Chief Investigator Name: 
          _________________________________________ 
Chief Investigator signature: 
  _________________________________________ 
Date: 
                                                       _________________________________________ 
  
 
Sponsor Representative Name: 
_________________________________________ 
Sponsor Representative signature: 
_________________________________________ 
Date: 
                                                       _________________________________________ 
  
 
Principal Investigator Name: 
        _________________________________________ 
Principal Investigator signature: 
_________________________________________ 
Date: 
                                                       _________________________________________  
 
 
 

 
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TABLE OF CONTENTS 
1. 
AMENDMENT HISTORY ............................................................................................................... 6 
2. 
SYNOPSIS ................................................................................................................................... 7 
3. 
ABBREVIATIONS ......................................................................................................................... 9 
4. 
BACKGROUND AND RATIONALE ................................................................................................. 11 
5. 
OBJECTIVES .............................................................................................................................. 15 
5.1 
Primary Objective ........................................................................................................... 15 
5.2 
Secondary Objectives ..................................................................................................... 15 
6. 
STUDY DESIGN ......................................................................................................................... 16 
6.1 
Summary of Trial Design ................................................................................................ 16 
6.2 
Primary and Secondary Endpoints/Outcome Measures .................................................. 16 
7. 
ELIGIBILITY CRITERIA ................................................................................................................. 17 
7.1 
 Overall Description of Trial Participants ......................................................................... 17 
7.2 
Recruitment Process....................................................................................................... 17 
7.3 
Inclusion Criteria ............................................................................................................. 19 
7.4 
Exclusion Criteria ............................................................................................................ 21 
8. 
STUDY PROCEDURES ................................................................................................................. 22 
8.1 Informed Consent and Assessment of Capacity ................................................................. 22 
8.2 TCD window insonation check ............................................................................................ 24 
8.3 
Collection of demographic data ....................................................................................... 24 
8.4 
TCD Assessment ............................................................................................................ 26 
8.5 
Follow-up measurements ................................................................................................ 27 
8.6 
Definition of End of Trial .................................................................................................. 27 
8.7 
Discontinuation/Withdrawal of Participants from Study Treatment .................................. 27 
8.8  
Source Data .................................................................................................................... 28 
9. 
TREATMENT OF TRIAL PARTICIPANTS .......................................................................................... 29 
9.1 
 Storage of Study Equipment of Related Apparatus ........................................................ 29 
9.2 
Clinical Care ................................................................................................................... 29 

 
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9.3 Incidental findings………………………………………………………………………………….29 
10. sAFETY REPORTING ................................................................................................................... 30 
10.1 Definitions......................................................................................................................... 30 
10.2 Reporting procedures for All Adverse Events ................................................................... 31 
10.3 Reporting Procedures for Serious Adverse Events ........................................................... 32 
11. STATISTICS ............................................................................................................................... 33 
11. 1Statistical analysis ............................................................................................................ 33 
11.2 Sample size calculation .................................................................................................... 33 
12. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................................................... 34 
13. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURE .......................................................... 35 
14. CODES OF PRACTICE AND REGULATION ...................................................................................... 36 
14.1 Ethics ............................................................................................................................... 36 
14.2 Sponsor Standard Operating Procedures ......................................................................... 36 
14.3 Declaration of Helsinki ...................................................................................................... 36 
14.4 ICH Guidelines for Good Clinical Practice......................................................................... 36 
14.5 Approvals ......................................................................................................................... 36 
14.6 Participant Confidentiality ................................................................................................. 37 
15. DATA HANDLING AND RECORD KEEPING ..................................................................................... 38 
15.1Data Extraction .................................................................................................................. 38 
15.2Data Analysis .................................................................................................................... 38 
16. STUDY GOVERNANCE ................................................................................................................ 39 
17. FINANCING AND INSURANCE ..................................................................................................... 40 
18. PUBLICATION POLICY ................................................................................................................ 41 
19. REFERENCES ............................................................................................................................ 42 
20. APPENDIX A: EXPECTED EVENTS NOT SUBJECT TO EXPEDITED REPORTING ...................................... 46 
21. APPENDIX B: ADDENBROOKE’S COGNITIVE EXAMINATION-iii......................................................... 47 
22. appendix C: EDINBURGH HANDEDNESS INVENTORY....................................................... 53 
 

 
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1. 
AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued 
Author(s) of changes 
Details 
of 
Changes 
made 
 
0.1 
15/10/2015 
Dr V Haunton 
Pre-sponsor 
approval 
version 
 
0.2 
14/02/2017 
Dr L Beishon 
Revision of recruitment 
strategy, updated 
protocol details 
 
0.3 
02/03/2017 
Dr L Beishon 
Sponsor changes made 
 
1 
06/03/2017 
Dr L Beishon 
Sponsor approved 
version 
 
2 
03/04/2017 
Dr L Beishon 
Revision following REC 
review 
 
3 
01/06/2017 
Dr L Beishon 
Major amendment to 
recruitment strategy 

 
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2. 
SYNOPSIS 
 
Study Title 
Cerebral Haemodynamic Changes During Cognitive Testing: A Functional Transcranial Doppler 
(fTCD) study 
Internal ref. 
no. 
 
 
 
Trial Design 
Prospective, observational, case-control study 
Trial 
Participants 
Healthy Control Subjects, Patients with Mild Cognitive Impairment, Patients with Vascular 
Dementia and Patients with Alzheimer’s Dementia  
Planned 
Sample Size 
11 Healthy Control Patients, 11 Patients with Mild Cognitive Impairment, 11 Patients with 
Vascular Dementia and 11 Patients with Alzheimer’s Dementia 
Follow-up 
duration 
None 
Planned Trial 
Period 
7 Months 
Primary 
Objective 
To compare the beat-to beat cerebral blood flow velocity (CBFv) between patients with Mild 
Cognitive Impairment (MCI), patients with Vascular Dementia (VascD), patients with 
Alzheimer’s Dementia (AlzD) and age-, gender- and blood pressure (BP)-matched healthy 
control (HC)  subjects during performance of the Addenbrooke’s Cognitive III (ACE-III) 
examination 
 
Secondary 
Objectives 
1) To investigate whether performance of the Addenbrooke’s Cognitive III Examination 
is associated with differences in other beat-to-beat cerebral haemodynamic 
parameters, specifically autoregulation index (ARI), between MCI patients, VascD 
patients, AlzD patients, and age-, gender- and BP-matched HC subjects. 
2) To assess the acceptability and feasibility of this protocol in patients with cognitive 
impairment in clinical practice.  
3) To assess the reproducibility of measurements in cognitively impaired patient group 
at 3 months from initial measurement 
 
Outcome 
Measure 
This is not an intervention study, and therefore it would not be appropriate to assess the 
classical primary and secondary outcome measures such as death and disability for this study. 
However, we intend to evaluate the following relevant outcomes: 
1. The percentage of recruited subjects (HC, MCI patients, VascD patients and AlzD 
patients) able to comply with the full measurement protocol. 
2. The percentage of measurements rejected because of aspects related to data quality 
during the analysis protocol, with recorded reasons. 
3. Overall, the percentage of recruited subjects (healthy controls, MCI patients, VascD 
patients and AlzD patients) in whom values for the following parameters can be 
derived: 

 
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• 
% change of CBFv at baseline in response to performance of the ACE-III  
Cognitive Examination 
• 
Autoregulation index (using the Tiecks model and from the phase, gain and  
coherence). 

 
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3. 
ABBREVIATIONS 
ACE-III 
Addenbrooke’s Cognitive Examination 
AE 
Adverse event 
AlzD 
Alzheimer’s Dementia 
AR  
Adverse reaction 
ARI  
Autoregulation Index 
BP 
Arterial Blood Pressure 
CA 
Cerebral Autoregulation 
CBF 
Cerebral Blood Flow 
CBFv 
Cerebral Blood Flow Velocity 
CI 
Chief Investigator 
CPP 
Cerebral Perfusion Pressure 
CrCP 
Critical Closing Pressure 
CRF 
 
Case Report Form 
CRO  
Contract Research Organisation 
CT 
 
Clinical Trials 
CVR 
 
Cerebrovascular Resistance 
CVRi 
 
Cerebrovascular Resistance Index 
dCA 
 
Dynamic Cerebral Autoregulation 
EC 
 
Ethics Committee (see REC) 
ECG 
 
Electrocardiogram 
EHI 
 
Edinburgh Handedness Inventory 
EtCO2 
 
End-Tidal Partial Pressure of Carbon Dioxide 
FFT 
 
Fast Fourier Transform 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
GPI 
Gosling’s Pulsatility Index 
HC 
Healthy Control 
HR  
Heart Rate 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ISF  
Investigator Site File 
LRI 
Leicester Royal Infirmary 
MCA 
Middle Cerebral Artery 
MCI 
Mild Cognitive Impairment 
NVC 
Neurovascular Coupling 
NHS 
National Health Service 
NICE 
National Institute for Health and Care Excellence 

 
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NRES 
National Research Ethics Service  
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PIL/S 
Participant/ Patient Information Leaflet/Sheet 
RAP 
Resistance Area Product 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TCD 
Transcranial Doppler Ultrasound 
TFA 
Transfer Function Analysis 
TMF 
Trial Master File 
UK 
United Kingdom 
VMR 
Vasomotor Reactivity 
VascD 
Vascular Dementia 
 

 
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4. 
BACKGROUND AND RATIONALE 
Dementia is a syndrome which comprises an acquired decline in memory and other cognitive 
functions(s) in an alert (non-delirious) person that is sufficiently severe to affect daily life.  It is the 
most common neurodegenerative disorder in the United Kingdom (UK); 850,000 people currently 
live with dementia in the UK, and that number is expected to rise to more than 1 million within the 
next 5 years [Alzheimer’s Society 2014].  The annual cost to the UK of dementia is £23.6 billion 
[Alzheimer’s Society 2014].  The most common type of dementia in the population (55%) is 
Alzheimer's dementia (AlzD), which is characterised pathologically by neuronal loss and the presence 
of amyloid plaques and tau neurofibrillary tangles.  AlzD typically has an insidious onset and a slow 
progression.  There are several diagnostic criteria, and commonly used criteria include; Diagnostic 
and Statistical Manual of Mental Disorders (DSM-IV) classification of neurocognitive disorders 
[American Psychiatric Association 2000], ICD-10 classification [World Health Organisation, 1992], and 
the National Institute on Aging-Alzheimer’s Association (NIA/AA) criteria [McKhann, 2011].  The 
recently published DSM-V criteria have re-classified dementia as major and mild neurocognitive 
disorders [Simpson, 2014]. Vascular dementia (VascD) is the second commonest form of dementia 
(15%), and is suggested by the presence of vascular risk factors.  The key pathological processes are 
subcortical white matter ischaemia and/or multiple cerebral infarcts.  The onset is often abrupt, and 
the progression stepwise and irregular; cognitive deficits are often less uniform than those of 
Alzheimer's dementia.  Vascular dementia is diagnosed according to NINDS-AIREN criteria [Roman et 
al 1993].  Mild cognitive impairment (MCI) affects up to 20% of older adults and describes a set of 
symptoms rather than a specific medical condition or disease.  A person with MCI has subtle 
problems with one or more of the following: day-to-day memory, planning, language, attention and 
visuospatial skills [McDade et al 2015].  MCI clinically may comprise a group of heterogeneous 
conditions and may have differing aetiologies [Petersen 2004]. MCI can be diagnosed using the 
criteria set out by the   International Working Group on Mild Cognitive Impairment [Winblad et al 
2004].  Although MCI significantly increases the risk of developing dementia [Busse et al 2006], at 
present it is not possible to accurately predict which patients with MCI will progress to dementia.   
 
In recent times, our knowledge regarding the pathogenic mechanisms of dementia has changed 
considerably.  In contrast to previous thoughts about the pure neurodegenerative nature of AlzD, it 
is now well established that vascular dysfunction and haemodynamic disturbances play a role in 
ALzD, as well as in VascD [Sabayan et al 2012]; with several epidemiological studies reporting an 
association between vascular risk factors (e.g. hypertension, hyperlipidaemia, type 2 diabetes 
mellitus) and AlzD [Viswanathan et al 2009].  Furthermore, post-mortem examinations have shown 
that the brains of AlzD patients contain cerebrovascular pathologies [Cacabelos et al 2003, Gorelick 

 
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2004].  Research studies investigating the vascular contributions to cognitive decline have generally 
reported cerebral hypoperfusion [Keage et al 2012, Sabayan et al 2012], and it is thought that this 
hypoperfusion affects cellular health which in turn triggers neurodegenerative pathways [Ruitenberg 
et al 2005, Kalaria 2010]. 
 
Cerebral haemodynamics can be studied using techniques such as functional magnetic resonance 
imaging (fMRI), positron emission tomography (PET) or single-photon emission computed 
tomography (SPECT).  However, these techniques are expensive, in the case of SPECT involve 
radiation, and there are feasibility issues which are particularly problematic for older populations, 
including the need to lie still for prolonged periods and to have no metal implants.  Transcranial 
Doppler Ultrasonography (TCD) is a simple, non-invasive imaging modality with high temporal 
resolution which allows for continuous and bilateral recording of cerebral blood flow velocity 
(CBFv) through the major cerebral arteries [Aaslid et al, 1982].  Measurements can be taken at rest, 
or during brain activation tasks such as sensorimotor functions or cognitive tasks.  TCD 
measurement preformed during such brain activation tasks is commonly referred to as functional 
TCD (fTCD), and is the assessment of blood flow in response to a specific cognitive stimulus or 
mental operation, a concept known as neurovascular coupling (NVC).  Although the exact 
mechanisms of NVC continue to be explored and evaluated, it is thought that cerebral activation 
triggers a haemodynamic response involving neurons, astrocytes, vascular cells and local 
metabolites [Carmignoto et al 2010, Girouard et al 2006]. Cerebral blood flow (CBF) is also strongly 
influenced by the arterial partial pressure of carbon dioxide (PaCO2) which also modulates the 
effectiveness of cerebral autoregulation (CA), defined as the ability of the brain to maintain a 
relatively constant CBF in response to significant changes in cerebral perfusion pressure (CPP).  CA 
is improved by hypocapnia and impaired by hypercapnia [Aaslid et al 1989, Paulson et al 1990].  It 
has been shown that CA can be reliably assessed by evaluating CBF responses to changes in PaCO2, 
such as those induced by hypo- and hyperventilation respectively [Dineen et al, 2010]. This concept 
is known as assessing vasomotor (or CO2) reactivity (VMR).   
 
In addition to studying CBFv, NVC and VMR, by using transfer function analysis (TFA) further 
haemodynamic data can be obtained and calculated using TCD and beat-to-beat blood pressure 
monitoring.  These data include coherence, phase, gain, autoregulatory index (ARI), critical closing 
pressure (CrCP) and resistance area product (RAP).   By examining the transfer of BP fluctuations to 
CBF as a measure of CA, TFA makes it possible to examine the effect of changes in arterial blood 
pressure (BP) on CBFv.  It quantifies the extent to which the input signal, BP, is reflected in the 
output signal, CBFv, and was first proposed by Giller in 1990.  The parameter which tests the 

 
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linearity between the input and output signals at each frequency is called the coherence, with 
values of coherence ranging between zero and one. Values of coherence approaching one indicate 
a perfect linear relationship between input and output (i.e. CBFv and BP).  Although there is 
currently no consensus on the threshold at which good coherence is assumed, many studies have 
adopted a coherence of ≥ 0.5 to accept the relationship as significant [Panerai et al 1998, Panerai et 
al 2006].  Phase is equivalent to the shift in radians from 0 to 2π (or degrees from 0° to 360°) that 
would be required to align input (BP) with output (CBFV) at a given frequency, and so gives an 
indication of the relative timing of the two signals.  The magnitude of the phase response may be 
an indicator of the integrity of the autoregulatory response; phase is positive in intact CA (CBFv 
recovers faster than changes in BP) and it tends to zero in impaired CA when CBFv tends to follow 
BP, during steady-state conditions [Panerai et al 1998, Birch et al 1995].  Gain is the ratio of the 
amplitude of the output signal to the input signal, and so indicates the magnitude of change in 
CBFv that is due to a change in BP.  Although gain alone is not a reliable measure of CA, an increase 
in gain suggests that CA is impaired, whereas a low gain indicates an efficient CA [Giller 1990, Van 
Beek et al 2008].   
The time domain approach in TFA is used to extract information about the CA mechanism from the 
analysis of mean BP, CBFv, heart rate (HR) and end-tidal partial pressure of carbon dioxide (EtCO2) 
with respect to time.  In 1995 Tiecks et al derived a set of equations and curves based on the CBFV 
response to a sudden fall in induced by thigh cuff deflation. These equations and curves allow for 
the calculation of an autoregulatory index (ARI) from 0 to 9, where 0 represents absence of 
autoregulation i.e. CBF dependent on CPP, (a ‘pressure-passive relationship’) and 9 represents best 
measurable autoregulation.  ‘Normal’ autoregulation is represented by an ARI of 5±1.  Other 
parameters obtainable in the time domain may also provide useful information regarding the 
integrity of dCA, including CrCP and RAP.  CrCP is expressed in mmHg and is defined as the arterial 
pressure below which small vessels collapse and forward blood flow becomes zero, which in the 
cerebral circulation is equivalent to the sum of ICP and the contributions of vascular smooth muscle 
tone [Panerai 2003]. RAP is expressed in mmHg.s/cm and is an index of cerebrovascular resistance, 
which is equal to the total cerebrovascular resistance x cross-sectional area of the vessel [Evans et 
al 1988]. 
 
A meta-analysis of twelve TCD studies in AlzD and VascD [Sabayan et al 2012], reported significantly 
lower CBFv in patients with ALzD and VascD in comparison to healthy control subjects. CFBv was 
especially low in patients with VascD.  In MCI, although there are limited data available, no 
significant differences in CBFv have been observed between MCI patients and healthy controls, 
unless restricting to amnestic MCI [Keage et al 2012].   

 
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Four studies which have used fTCD to investigate cerebral haemodynamic responses to brain 
activation in patients with dementia have reported conflicting findings; two found that individuals 
with AlzD had attenuated blood flow responses to cognitive demand, and two found no differences 
between dementia patients and controls.  These studies used visual stimulation [Asil et al 2005, 
Gucuyener et al 2010, Rosengarten et al 2001], and a whispered verbal task, a thumb opposition task 
and a design discrimination task [Matteis et al 1998]. 
 
Cognitive testing with standardised assessment tools such as the Mini Mental State Examination, 
Montreal Cognitive Assessment and Addenbrooke’s-III Cognitive Examination (ACE-III) is a key 
component of the formal diagnosis of dementia, yet the effects of these tests on cerebral blood flow 
and haemodynamics is unknown.  The ACE-III [Hsieh et al 2013] is a widely used, validated, cognitive 
screening tool recommended for use by health practitioners and researchers in patients over 50 
years old with suspected dementia.  The ACE-III is available for free.  The copyright is held by 
Professor John Hodges, ARC Federation Fellow and Professor of Cognitive Neurology at Neuroscience 
Research Australia, who is happy for the test to be used in clinical practice and research projects.   
 
This protocol has been used successfully by this group to examine changes in CBFv in 40 healthy 
volunteers from the University of Leicester. The data from this analysis has been presented at an 
international conference and is currently undergoing peer review for publication. Therefore, this 
protocol has demonstrated feasibility in a healthy population and warrants further investigation for 
the utility in a patient population.  
 
Therefore, the proposed study will investigate and compare the beat-to beat cerebral blood flow 
velocity (CBFv) between patients with Mild Cognitive Impairment (MCI), patients with Vascular 
Dementia (VascD), patients with Alzheimer’s Dementia (AlzD) and age-, gender- and blood pressure 
(BP)-matched healthy control (HC)  subjects during performance of the Addenbrooke’s Cognitive III 
(ACE-III) examination.  The proposed study will also investigate whether performance of the 
Addenbrooke’s Cognitive III Examination is associated with differences in other beat-to-beat cerebral 
haemodynamic parameters, specifically autoregulation index (ARI), between MCI patients, VascD 
patients, AlzD patients, and age-, gender- and BP-matched HC subjects. 

 
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5. 
OBJECTIVES 
 
5.1 Primary Objective 
 
To compare the beat-to beat cerebral blood flow velocity (CBFv) between patients with Mild 
Cognitive Impairment (MCI), patients with Vascular Dementia (VascD), patients with Alzheimer’s 
Dementia (AlzD) and age-, gender- and blood pressure (BP)-matched healthy control (HC)  subjects 
during performance of the Addenbrooke’s Cognitive III (ACE-III) examination 
 
 
5.2 Secondary Objectives 
  
1) To investigate whether performance of the Addenbrooke’s Cognitive III Examination is 
associated with differences in other beat-to-beat cerebral haemodynamic parameters, 
specifically autoregulation index (ARI), between MCI patients, VascD patients, AlzD patients, 
and age-, gender- and BP-matched HC subjects. 
2) To assess the acceptability and feasibility of this protocol in patients with cognitive impairment 
in clinical practice.  
3) To assess the reproducibility of measurements in cognitively impaired patient group at 3 
months from initial measurement 
 
 
 

 
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6. 
STUDY DESIGN 
 
6.1 Summary of Trial Design 
 
This is a prospective, observational, case-control study. 
 
Each participant will be required to attend the Cardiovascular Research Laboratory, Level 5, 
Windsor Building, University Hospitals of Leicester NHS Trust, for one Transcranial Doppler 
Assessment lasting approximately 90 minutes. 
 
6.2 Primary and Secondary Endpoints/Outcome Measures 
 
This is not an intervention study, and therefore it would not be appropriate to assess the classical 
primary and secondary outcome measures such as death and disability for this study. However, we 
intend to evaluate the following relevant outcomes: 
1) The percentage of recruited subjects (HC, MCI patients, VascD patients and AlzD patients) 
able to comply with the full measurement protocol. 
2) The percentage of measurements rejected because of aspects related to data quality 
during the analysis protocol, with recorded reasons. 
3) Overall, the percentage of recruited subjects (healthy controls, MCI patients, VascD 
patients and AlzD patients) in whom values for the following parameters can be derived: 
• 
% change of CBFv at baseline in response to performance of the ACE-III Cognitive Examination 
• 
Autoregulation index (using the Tiecks model and from the phase, gain and coherence). 
 
 
 
 

 
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7. 
ELIGIBILITY CRITERIA  
 
7.1  Overall Description of Trial Participants 
Patients with MCI, Patients with VascD and Patients with AlzD, together with age-, gender- 
and BP matched healthy volunteer control subjects (HC)  will be recruited to enable the 
complete data analysis of 11 MCI Patients, 11 VascD Patients, 11 ALzD Patients and 11 HCs. 
 
7.2 Recruitment Process 
Patient recruitment at the site will only commence once the research team has ensured 
that the following approval/essential documents are in place: 
• 
Research Ethics Committee (REC) approval 
• 
HRA approval 
• 
Final Sponsorship approval 
• 
NHS Trust Research and Development Department (R&D) approval 
• 
Signed delegation of duties and responsibilities logs 
Suitable MCI patients, AlzD patients and VascD patients will be identified at the specialist 
memory clinics at Leicester Partnership NHS Trust, and in the stroke and geriatric 
outpatient clinic at University Hospitals of Leicester NHS Trust, according to a study-specific 
list of inclusion and exclusion criteria (detailed in next section).  We will also be using Join 
Dementia Research (JDR) as a recruitment tool. This is an online self-registration service 
that enables volunteers with memory problems or dementia, carers of those with memory 
problems or dementia and healthy volunteers to register their interest in taking part in 
research. The purpose of JDR is to allow such volunteers to be identified by researchers as 
potentially eligible for their studies. Researchers can then contact volunteers, in line with 
the volunteers' preferred method of contact, to further discuss potential inclusion. 
Eligibility screening will be conducted by the specialist nurses or consultants who are part 
of the direct clinical care team. They will only refer potential participants who meet the 
eligibility criteria and who have capacity to consent to the researcher. The researcher will 
not access patients’ medical records until formal written consent has been obtained. 
Participants recruited from Join Dementia Research will be screened by the researcher 
through discussion with the participant and their carers, friends or relatives, or GP surgery 

 
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to ensure they meet the study specific inclusion and exclusion criteria. Participants will only 
be referred to the researcher if the direct care team, based on the patient’s cognitive 
functioning and clinical assessment determine that the patient will have capacity to 
consent to the study. Capacity will then be assessed formally by the researcher at the initial 
stage of information provision and at the formal consent process after a cooling off period 
of up to 7 days. These patients will be introduced to the researcher by the responsible 
clinical physician or specialist nurse for the provision of further study specific information, 
in the form of Participant (Patient) Information Leaflet. After provision of study specific 
information, the researcher will assess the patient’s capacity in accordance with the Mental 
Capacity Act 2005. This is a 2 stage process where firstly, there must be a concern that the 
patient may lack capacity (in this case due to cognitive impairment). When the study 
information is provided to participants, it will be assessed in 4 steps. Firstly, the ability to 
understand the information, secondly to weigh up the information, thirdly to retain the 
information, and finally be able to communicate the decision back to the researcher. This 
initial discussion and assessment will take place at the outpatient memory clinic and stroke 
clinic at the LPT and UHL respectively, or through the participant’s preferred contact 
method if recruiting from Join Dementia Research.  
 
Age-, gender-, BP-matched HC will be recruited from University of Leicester departmental 
volunteers, patients’ relatives and friends, and by poster advertisement (using Research 
Participant Poster) displayed in outpatient clinics at the University Hospital of Leicester 
(UHL) NHS Trust. Care will be taken to ensure that the HC are matched to the patients in 
terms of age, gender, and medical co-morbidities. HC will be provided with a volunteer 
specific information leaflet (Participant (Volunteer) Information).  
 
After study specific information has been provided to the patients or volunteers, the 
researcher’s contact details will be provided at the end of the PIS and the patient or 
volunteer will be able to contact the researcher directly if they wish to participate in the 
study.  
Participants who contact the researcher to be included in the study will be made an 
appointment to attend the Cerebral Haemodynamics in Ageing and Stroke Medicine 
(CHIASM) laboratory at the Leicester Royal Infirmary to undergo formal consent using the 
Participant (Patient or Volunteer) Consent Form. At this point, the researcher will then 
explain the nature and purpose of the research again and answer any questions that the 

 
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participant, may have. Capacity will be re-assessed at this time using the process described 
above and in accordance with the principles of the Mental Capacity Act 2005.  
Formal consent will then be obtained as detailed in Section 8 and the participant will be 
enrolled into the study. 
All participants will have their travel expenses reimbursed. 
 
If a patient or volunteer expresses an interest in the study at the initial stage but does not 
make contact with the researcher within 7 days, a follow-up reminder letter (Patient 
Follow-up Letter) will be sent to the patient through the direct care team with the 
researcher’s contact details.  
 
7.3 Inclusion Criteria 
• 
Informed volunteer consent, patient consent  
• 
Male or female, aged between 18 and 100 years of age 
• 
Able (in the Investigator’s opinion) and willing to comply with all study requirements  
• 
Willing to allow his or her General Practitioner (GP) to be notified of participation in the 
study 
• 
Good understanding of written and verbal English 
 
Healthy Controls-specific Inclusion Criteria 
 
• 
No evidence of subjective or objective memory impairment on cognitive testing 
• 
No major medical co-morbidity (outlined in detail in the exclusion criteria) or 
medication use that could adversely affect cognition 
 
MCI Patient-specific Inclusion Criteria 
Clinical diagnosis of MCI made by a specialist* in a patient who fulfils the established 
clinical consensus criteria for MCI [NIA/AA 2011] specifically: 
• 
Concern regarding a change in cognition compared to the person’s previous 
level, by the patient and/or informant 

 
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• 
Objective evidence of impairment of one or more cognitive domains, greater 
than expected for age, and educational background, over time if repeated 
measures are available.  
• 
Preserved independence of functional abilities and minimal to no impairment 
on complex instrumental functions 
• 
Not demented 
 
Vascular Dementia Specific Inclusion Criteria 
Clinical diagnosis of VascD made by a specialist* in a patient who fulfils the NINDS-AIREN 
criteria for VascD, specifically: 
• 
Cerebrovascular disease defined by the presence of focal signs on neurological 
examination consistent with stroke and evidence of cerebrovascular disease on brain 
imaging. 
• 
One or more of: 
o Onset of dementia within 3 months of a diagnosed stroke 
o Abrupt deterioration in cognitive function 
o Fluctuating, stepwise progression of cognitive deficits 
 
 
Alzheimer’s Dementia Specific Inclusion Criteria 
Clinical Diagnosis of AlzD made by a specialist* in a patient who fulfils the NIA/AA criteria for 
Probable AlzD, specifically: 
• 
Meets the criteria for dementia 
o The memory impairment and cognitive deficits cause significant impairment in 
social or occupational functioning, and represent a significant decline from a 
previous level of functioning, not explained by a delirium or a major psychiatric 
disorder 
o Impairment of at least two cognitive domains 
• 
Insidious or gradual onset 
• 
Clear history of worsening cognition by report or observation  

 
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• 
The initial and most prominent cognitive deficits are evident on history and 
examination in one of the following domains: 
o Amnestic: impaired learning and recall of recently learned information 
o Non amnestic: language/visuospatial/executive dysfunction 
• 
No evidence of substantial cerebrovascular disease, core features of dementia with 
lewy bodies, features of frontotemporal dementia, prominent features of semantic 
variant primary progressive aphasia, evidence of active neurological disease, a non-
neurological co-morbidity or medication that could affect cognition 
 
 
*A specialist being defined as a psychiatrist or a geriatrician, or a specialist mental health nurse 
with a specific interest or expertise in cognitive disorders. 
 
 
 
7.4 Exclusion Criteria 
• 
Male or Female, aged under 18 years 
• 
Unable (in the Investigator’s opinion) or unwilling to comply with any study 
requirements 
• 
Female participants who are pregnant, lactating or planning pregnancy during the 
course of the study 
• 
Major co-morbidity likely to affect cerebral autoregulation; severe respiratory disease, 
carotid artery stenosis, atrial fibrillation, severe cardiac failure (left ventricular ejection 
fraction <20%), extreme frailty or multi-morbidity.  

 
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8. 
STUDY PROCEDURES 
8.1 Informed Consent and Assessment of Capacity  
 
Following provision of study specific information, the potential research participant 
(Volunteer or Patient) will be able to contact the researcher with the contact details provided 
to confirm willingness to participate in the study. At this time an appointment will be made 
to attend the Leicester Royal Infirmary to undergo formal consent and capacity assessment 
as outlined below.  
Participant consent form must be in place before the undertaking of any research project-
specific assessments, using the current version (Participant (Volunteer or Patient) Consent 
Form) which has been approved by the National Research Ethics Service and the local Trust 
Research and Development Department.  Written and verbal versions of the current 
approved Participant (Volunteer or Patient Information Leaflet, Participant (Patient or 
Volunteer) Consent Form or will be presented detailing no less than: the exact nature of the 
study; the implication and constraints of the protocol; the known side effects and any risks 
involved in taking part. It will be clearly stated that the participant is free to withdraw from 
the study at any time for any reason without prejudice to future care, and with no obligation 
to give the reason for withdrawal.  
At the time of consent, the researcher will re-assess the patient’s capacity in accordance with 
the Mental Capacity Act 2005. This is a 2 stage process where firstly, there must be a concern 
that the patient may lack capacity (in this case due to cognitive impairment). When the study 
information is provided to participants, it will be assessed in 4 steps. Firstly, the ability to 
understand the information, secondly to weigh up the information, thirdly to retain the 
information, and finally be able to communicate the decision back to the researcher. This 
initial discussion and assessment will take place at the outpatient memory clinic and stroke 
clinic at the LPT and UHL respectively.  
The person who obtains consent and performs the capacity assessment must be suitably 
qualified and experienced, and have been authorised to do so by the Chief/Principal 
Investigator (CI/PI), as detailed on the Delegation of Authority and Signature log for the 
study. The original signed Informed Consent form will be retained at the study site within the 
Investigator Site File (ISF). A copy of the signed Informed Consent form will be given to 

 
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participants and a copy retained in the participant’s medical notes For HC volunteers, the 
original signed copy will be retained within the ISF, and a copy provided to the volunteer. 
 
A letter will be sent to the volunteer’s and patient’s GP informing them of their participation 
in the study (GP Information Leaflet (Volunteer or Patient)). 
 
Process for Consent in Volunteers 
 
We will only invite volunteers who have capacity to give us consent in this research study. All 
potential volunteers will be recruited from departmental volunteers, patient’s relatives and 
friends and by poster advertisement in the outpatient clinics at the University Hospitals of 
Leicester (UHL) NHS Trust. The researcher will explain the details of the research study and 
provide a Participant (Volunteer) Information Leaflet. The researcher will answer any 
questions or concerns that the volunteer has regarding participation in the study.  
 
Volunteers will be allowed up to seven days to consider the information, and the opportunity 
to question the Investigator, their GP or other independent parties to decide whether they 
wish to participate in the study.  Written informed consent will then be obtained by means of 
Volunteer dated signature and dated signature of the person who presented and obtained 
the informed consent.  
 
Prior to the study, we will also ensure that the volunteer is aware that he/she is free to 
withdraw from the study at any time for any reason. However, should this situation occur the 
research team would like to keep all the health information and data that has been collected 
so far for the final analysis. This will be clearly stated in both the Participant (Volunteer) 
Information Leaflet and Participant (Volunteer) Consent Form.  
 
 
Process for Consent in Patients  
 
We will only invite patients who have capacity to give us consent in this research study. All 
potential participants will be approached initially by the responsible clinical physician, who 
will undertake the eligibility screening and subsequently introduced to the research team 
member(s). The research team member(s) will explain the details of the research study and 

 
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provide a Participant (Patient) Information Leaflet.   The researcher will answer any questions 
or concerns that the Participant (Patient) has regarding participation in the study. 
 
The Participant (Patient) will be provided with the researcher’s contact details, to allow up to 
7 days to consider the information, and have the opportunity to question the Investigator, 
their GP or other independent parties to decide whether they wish to participate in the 
study. Written informed consent will then be obtained by means of participant dated 
signature and dated signature of the person who presented and obtained the informed 
consent. Capacity will be assessed as described above in accordance with the Mental 
Capacity Act 2005. If the patient expressed an interest in the study at the initial stage but did 
not make contact with the researcher, a follow-up reminder letter (Patient Follow-up Letter) 
will be sent to the patient through the direct care team with the researcher’s contact details.  
 
Prior to the study, we will ensure that the participant is aware that he/she is free to 
withdraw from the study at any time for any reason. However, should this situation occur we 
would like to keep all the health information and data that has been collected so far for the 
final analysis. This will be clearly stated in both the Participant (Patient) Information Leaflet 
and Participant (Patient) Consent Form.  
 
 
8.2 TCD window insonation check 
Once a consent form has been signed, and before collecting baseline information on 
demographics, medical history, medications, and handedness, participants will undergo a 
brief Transcranial Doppler Ultrasound (TCD) check to ensure they have adequate acoustic 
temporal windows (inadequacy rates of 5-37% well documented in the literature) [Itoh et al 
1993, Bos et al 2007, Marinoni et al 1997]. 
 
 
8.3 Collection of demographic data  
Baseline demographic data will be collected from the participants as detailed below: 
 
Healthy controls 
• 
Demographics 
Date of birth, gender, height, weight, and ethnicity will be recorded 

 
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• 
Medical History 
Details of any relevant history of disease or surgical interventions will be recorded 
Smoking status and weekly alcohol intake will be recorded 
• 
Current Medications 
Details of any prescription or over the counter medications will be recorded 
• 
Handedness 
Determined using the Edinburgh Handedness Inventory 
 
Patients with MCI, VascD and AlzD 
• 
Demographics 
Date of birth, gender, height, weight, and ethnicity will be recorded.  
• 
Medical History  
Details of any relevant history of disease or surgical interventions will be recorded 
Smoking status and weekly alcohol intake will be recorded 
Any family history of dementia will be recorded 
• 
Current Medications 
Details of prescription medication or over the counter medications will be recorded, 
including the use of any anti-dementia drugs  
• 
Handedness 
Determined using the Edinburgh Handedness Inventory [Oldfield et al, 1971] 
 
In addition, the patient’s medical records will be reviewed to extract the following 
information: 
• 
Results and significant findings from Computerised Tomography (CT) head/Brain Magnetic 
Resonance Imaging (MRI), if undertaken 
• 
Results and details of any previous cognitive testing 
• 
Date of diagnosis of MCI, VascD or AlzD 

 
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8.4 TCD Assessment  
For all subjects, all assessments will be undertaken in a dedicated cardiovascular research 
laboratory at Leicester Royal Infirmary (LRI), which is at a controlled temperature (20-24⁰C) and 
is free from distraction. Participants will be asked to refrain from heavy meals, strenuous 
exercise, alcohol, smoking and caffeine for four hours prior to attending the research 
laboratory.  The subject will sit on an examination couch. Baseline casual BP will be calculated 
as a mean of three supine brachial BP readings using a validated UA767 BP monitor.  Beat-to-
beat non-invasive BP will be recorded continuously using the Finometer cuff device (Finapres 
Medical Systems; Amsterdam, The Netherlands) attached to the middle finger of the non-
dominant hand.  R-R interval will be recorded using a 3-lead ECG. End-tidal partial pressure of 
carbon dioxide (EtCO2) will be monitored using small nasal cannulae placed at the base of the 
nose (Salter Labs, ref 4000) attached to a capnograph (Capnocheck Plus) to monitor the 
breathing. Simultaneous bilateral insonation of the middle cerebral arteries (MCAs) will be 
performed using TCD with 2MHz probe using a Viasys Companion III, with the subject either 
sitting or lying supine on a couch (in the case of difficult to insonate windows). The vessel will 
be located via the temporal bone window, and identified as the MCA by the waveform, its 
depth, velocity, and the direction of flow. All parameters will be simultaneously recorded onto 
a computer software system (PHYSIDAS), providing data for subsequent off-line analysis.  A 
head frame will be used to secure the ultrasound probes in position and to minimise their 
movement. Once satisfactory signals have been obtained, four recordings will be made: 
1) A 5 minute baseline recording during which the patient sits quietly with their eyes 
open 
2) A recording during which the participant undertakes the Attention, Memory, and 
Fluency tasks of the ACE-III Cognitive Examination.   
3) A recording during which the participant undertakes the language tasks of the 
ACE-III Cognitive Examination.   
4) A recording during which the participant undertakes the visuospatial ability, and 
final memory tasks, of the ACE-III Cognitive Examination. 
During the recordings the internal plethysmography servo-adjust of the Finometer will be 
switched off, but this will be switched back on in between each recording to allow for accurate 
calibration of BP.  A brachial BP will also be taken in between each recording using the same 
validated UA767 BP monitor as at the beginning of the baseline assessment. Recordings 2, 3 
and 4 will each begin and end with a period of 1 minute baseline recording where the 

 
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participant sits quietly with their eyes open. An event marker will be used to mark the start of 
each individual question of the ACE-III, so that these can be identified within the recordings. 
Each individual question will be followed by a period of 1 minute rest, to allow CBFv to return 
to baseline levels. In order to ensure that visually impaired participants are not placed at a 
disadvantage during the cognitive examination, enlarged versions of the pictures contained 
within the ACE-III will be provided on A4 laminated cards. 
 
8.5 Follow-up measurements 
A sub-set of 11 Participants will be invited to return after 3 months to repeat the study 
measurement to assess for reproducibility. This will be stated explicitly on the consent form 
(Volunteer and Patient consent forms), but participants can decline to be contacted at this 
time, and can withdraw from the study at any time.  
 
8.6 Definition of End of Trial 
The end of trial is the date of the last visit of the last participant.  
At the end of the study, both healthy controls and patients will receive a written letter, in plain 
English, summarising the study findings and conclusions.  
 
8.7 Discontinuation/Withdrawal of Participants from Study Treatment  
Each participant has the right to withdraw from the study at any time and without giving a 
reason.  A decision to withdraw at any time, or a decision not to take part, will not affect the 
standard of care that participant receives. In addition, the investigator may discontinue a 
participant from the study at any time if the investigator considers it necessary for any of the 
following reason: 
• 
An inability to comply with study procedures 
• 
Consent withdrawn 
• 
Loss of capacity 
In the case of withdrawal in the healthy control group, they will be replaced to ensure that 
there are 11 healthy control subjects with complete data analysis. 
All of the above will be recorded in the case report form (CRF). 

 
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Prior to the study, we will ensure that the participant is aware that he/she is free to withdraw 
from the study at any time for any reason. However, should this situation occur we would like 
to keep all the health information and data that has been collected so far for the final analysis. 
This will be clearly stated in both the Participant (Patient and Volunteer) Information Leaflet 
and Participant (Patient and Volunteer) Consent Form.  
 
8.8 Source Data 
Source documents are original documents, data, and records from which participants’ CRF 
data are obtained. These include, but are not limited to, hospital records (from which medical 
history and previous and concurrent medication may be summarised into the CRF), clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence.  
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. 
there is no other written or electronic record of data).  
All documents will be stored safely in confidential conditions. On all study-specific documents, 
other than the signed consent, the participant will be referred to by the study participant 
number/code, not by name.  

 
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9. 
TREATMENT OF TRIAL PARTICIPANTS 
9.1  Storage of Study Equipment of Related Apparatus 
All study specific equipment is stored in a research-dedicated lab, and the Department of 
Medical Physics, University of Leicester is responsible for the service and maintenance of the 
equipment.  
 
9.2 Clinical Care 
Throughout the study, patients with MCI, VascD and AlzD will continue to receive standard 
clinical care. 
 
9.3 Incidental Findings 
Any unexpected or incidental findings in Volunteers of Patients, such as, high blood pressure, 
abnormal heart rhythm, undiagnosed cognitive impairment (volunteers), cerebral blood flow 
velocity suggestive of intracranial pathology or carotid artery stenosis will be reported to the 
patient or volunteer’s GP for further investigation. This will only be with the patient or 
volunteer’s permission and written consent (Participant (Patient or Volunteer) Consent Form), 
and is expressly stated in the Participant (Patient or Volunteer) Information Sheet.  
 
 
 

 
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10. 
SAFETY REPORTING  
10.1 Definitions 
Adverse Event (AE) 
An AE or adverse experience is: 
Any untoward medical occurrence in a patient or clinical investigation participant, which does 
not necessarily have to have a causal relationship with his/her treatment.  
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the study, whether or not 
considered related to the study.  
 
Adverse Reaction (AR) 
All untoward and unintended responses related to the study.  
All cases judged by either the reporting medically qualified professional or the sponsor as 
having a reasonable suspected causal relationship to the study qualify as adverse reactions.  
 
Severe Adverse Events (SAE) 
To ensure no confusion or misunderstanding of the difference between the terms “serious” 
and “severe”, which are not synonymous, the following note of clarification is provided: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious”, which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a participant’s life or functioning. Seriousness (not severity) serves 
as a guide for defining regulatory reporting obligations.  
 
Serious Adverse Event or Serious Adverse Reaction (SAR) 
A serious adverse event or reaction is any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening 

 
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NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant 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 inpatient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect 
• 
Other important medical events* 
*Other events that may not result in death, are not life threatening, or do not require 
hospitalisation, may be considered a serious adverse event when, based upon appropriate 
medical judgement, the event may jeopardise the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
 
Expected Serious Adverse Events/Reactions 
Serious adverse events are common in dementia. For a full list of expected SAE that are not 
subject to expedited reporting, investigators should refer to Appendix A.  
 
Suspected Unsuspected Serious Adverse Events/Reactions (SUSAR) 
A serious adverse event, the nature or severity of which is not consistent with a diagnosis of 
dementia. 
 
10.2 Reporting procedures for All Adverse Events 
All AEs occurring during the study observed by the investigator or reported by the participants, 
whether or not attributed to study, will be recorded on the CRF. 
The following information will be recorded: description, date of onset and end date, severity, 
assessment of relatedness to study, other suspect device and action taken.  Follow-up 
information should be provided as necessary.  
AEs considered related to the study as judged by a medically qualified investigator or the 
sponsor will be followed until resolution or the event is considered stable.  All related AEs that 
result in a participant’s withdrawal from the study or are present at the end of the study, 
should be followed up until a satisfactory resolution occurs. 

 
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It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity 
to require the participant’s removal from the study. A participant may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE.  If either of 
these occurs, the participant must undergo an end of study assessment and be given 
appropriate care under medical supervision until symptoms cease or the condition becomes 
stable. 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = 
severe.   
The relationship of AEs to the study will be assessed by a medically qualified investigator.  
 
10.3 Reporting Procedures for Serious Adverse Events 
All SAEs, must be reported to the Sponsor within one working day of discovery or notification 
of the event.  The Sponsor will perform an initial check of the information and ensure that it is 
reviewed at the next R&D Management meeting.  All SAE information must be recorded on an 
SAE form and sent to the Sponsor using the appropriate reporting form and the contact details 
on there. Additional information received for a case (follow-up or corrections to the original 
case) needs to be detailed on a new SAE form which must be sent to the Sponsor using the 
appropriate reporting form and the contact details on there.  
The Sponsor will report all SUSARs to the Research Ethics Committee concerned. Fatal or life-
threatening SUSARs must be reported within 7 days and all other SUSARs within 15 days. The CI 
will inform all investigators concerned of relevant information about SUSARs that could 
adversely affect the safety of participants. 
In addition to the expedited reporting above, the CI shall submit once a year throughout the 
study or on request an Annual Report to the Ethics Committee which lists all SAEs / SUSARs 
that have occurred during the preceding 12 months. 
Only SAEs that occur during the fTCD study will be reported to the sponsor. After this, the 
Patient or Volunteer, ceases to be involved in the study.  
 
 
 
 

 
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11. 
STATISTICS 
11. 1Statistical analysis 
The null hypothesis being tested is that: 
(a) cerebral haemodynamic parameters, including CBFv and ARI, and any alterations related to 
the performance of the ACE-III Cognitive Examination are not significantly different 
between MCI, VascD, AlzD patients and HC subjects. 
All normally distributed continuous variables will be described as mean (SD) and 
continuous variables with skewness as median (IQR). Comparison between baseline data 
for MCI patients, VascD patients, AlzD patients and HC will be made using Student t-tests 
for normally distributed data, or by appropriate non-parametric test, with Bonferroni 
correction applied to multiple comparisons. Repeated measures ANOVA will be adopted to 
test for the effect of performance of the ACE-III Cognitive Examination on CBFv and ARI 
between MCI patients, VascD patients, AlzD patients and HC subjects.  
 
11.2 Sample size calculation 
A formal sample size calculation was not possible for this study therefore a realistic number of 
participants has been selected based on previous experience of similar research studies by Dr 
Haunton, Professor Robinson and Professor Panerai.  
However, to detect a change of 2 units in autoregulation Index (ARI) and to calculate the 
required sample size we followed the technique as previously described by others (Brodie FG 
et al, 2009). For this study a sample of 11 patients per intervention group will allow the 
detection of a difference between groups (MCI patients, VascD patients, AlzD patents and HC 
subjects) in the ARI of 2 units with 80% power at the 5% significance level.   
 
 
 

 
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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  
Direct access will be granted to authorised representatives from the Sponsor, host institution 
and the regulatory authorities to permit trial-related monitoring, audits and inspections. 

 
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13. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURE 
  
The study will be conducted in accordance with the current approved protocol, ICH GCP, 
relevant regulations and standard operating procedures. 
The University of Leicester, as the study Sponsor, operates a risk based monitoring system to 
which this study will be subject.  
 

 
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14. 
CODES OF PRACTICE AND REGULATION  
14.1 Ethics 
All informed consent taken from MCI patients, VascD patients, AlzD patients and HC subjects 
will be taken following GCP guidelines. 
JDR is funded by Department of Health working in partnership with the charities Alzheimer 
Scotland, Alzheimer’s Research UK and Alzheimer’s Society and is Health Research Authority 
(HRA) endorsed. The online service and all associated documentation, methods of contacting 
volunteers and handling of data, were reviewed by a specially convened HRA committee which 
included experts in research ethics, data protection and information governance. Formal 
endorsement was issued by the HRA in a letter dated 20 May 2014. 
 
14.2 Sponsor Standard Operating Procedures 
All relevant Sponsor Standard Operating Procedures will be followed to ensure that this study 
complies with all relevant legislation and guidelines. 
 
14.3 Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformity with the current 
revision of the Declaration of Helsinki (last amended October 2008). 
 
14.4 ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in full conformity with relevant 
regulations and with the ICH Guidelines for GCP. 
 
14.5 Approvals 
Once Sponsor authorisation has been confirmed, the protocol, informed consent form, 
participant information sheet and any proposed advertising material will be submitted to an 
appropriate Research Ethics Committee (REC), HRA, and host institution(s) for written 
approval. 
Once Sponsor authorisation has been confirmed, the investigator will submit and, where 
necessary, obtain approval from the above parties for all substantial amendments to the 
original approved documents. 
 

 
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14.6 Participant Confidentiality 
The trial staff will ensure that the participants’ anonymity is maintained. The participants will 
be identified only by initials and a participant’s ID number on the CRF and any electronic 
database. All documents will be stored securely and only accessible by trial staff and 
authorised personnel. The study will comply with the Data Protection Act, which requires data 
to be anonymised as soon as it is practical to do so.  
 

 
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15. 
DATA HANDLING AND RECORD KEEPING 
 
15.1Data Extraction 
As supportive evidence of the diagnosis of MCI, VascD and AlzD, results and significant 
findings from Computerised Tomography (CT) head/Brain Magnetic Resonance Imaging 
(MRI), if undertaken, will be recorded on the CRF. 
Other information which will be extracted from the medical notes and recorded on the CRF 
include results and details of any previous cognitive testing, and the date of diagnosis of 
MCI, VascD or AlzD. 
 
 
15.2Data Analysis 
All other parameters recorded, including CBFv, heart rate, BP, and ETCO2 will be 
simultaneously recorded onto a computer system (PHYSIDAS), providing data for 
subsequent analyses. Off-line analyses will be undertaken using software designed by the 
University of Leicester’s Medical Physics Group.  
 
 
15.3 Data Management 
All parameters (signals) that are collected during the measurement will be saved using a 
coded filename. The name and other identifying detail will NOT be included in any study 
data electronic file.  
All files will be encrypted and stored on a password secured computer/laptop, which will 
have restricted access by members who are authorised on the authorisation log.  
 

 
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16. 
STUDY GOVERNANCE 
The trial management group, which consists of the CI, co-applicants, and other research staff, 
will meet monthly to monitor study progress, and recruitment targets. As this is a 
prospective observational study and is not a therapeutic study, a data safety monitoring 
committee is not required.  
 
 
 

 
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17. 
FINANCING AND INSURANCE 
In this study, Dr Haunton, Professor Robinson and Professor Panerai will supervise the 
researcher who is responsible for patient recruitment, data collection and analysis. Dr 
Haunton will take a lead role in preparing the experimental procedures.  Dr Subramaniam 
will take responsibility for guiding patient recruitment.  Professor Panerai will supervise data 
analysis, and Professor Robinson will also have a key role in the interpretation of results in 
terms of physiology and clinical relevance.  
In this study, the extra assessments on patients will be carried out by the researcher, and all 
the equipment to be used is provided, serviced and maintained by the Department of 
Medical Physics, University of Leicester. No other patient related costs will be incurred by the 
project in addition to the routine care provided from the University Hospitals of Leicester 
NHS Trust or Leicestershire Partnership Trust. 
 
 
 
 

 
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18. 
PUBLICATION POLICY 
On all publications, the funding body will be acknowledged, and each author will be required 
to disclose details of their own involvement/contribution in the study (specific publication).  
 
 

 
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19. 
REFERENCES 
Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow 
velocity in basal cerebral arteries. J.Neurosurg. 1982;57:769-74 
 
Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. 
Stroke 1989; 20: 45-52 
 
Alzheimer’s Society (2014a). Dementia UK: second edition.  London: Alzheimer’s Society. 
 
American Psychiatric Association. (2000). Diagnostic and Statistical Manual Of Mental Disorders: 
DSM-IV-Tr. Washington, Dc, American Psychiatric Association. 
 
Asil T, Uzuner N.  Differentiation of vascular dementia and Alzheimer disease: a functional 
transcranial Doppler ultrasonographic study.  J Ultrasound Med 2005; 24: 1065-1070 
 
Birch AA, Dirnhuber MJ, Hartley-Davies R, Iannotti F, Neil-Dwyer G. Assessment of autoregulation 
by means of periodic changes in blood pressure. Stroke 1995;26:834-7 
 
Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM. Transcranial Doppler hemodynamic 
parameters and risk of stroke: the Rotterdam study. Stroke 2007; 38: 2453-8 
 
Brodie FG, Atkins ER, Robinson TG, Panerai RB. Reliability of dynamic cerebral autoregulation 
measurement using spontaneous fluctuations in blood pressure. Clinical Science 2009; 116: 513-
520 
 
Busse A, Angermeyer MC, Riedel-Heller SG.  Progression of mild cognitive impairment to dementia: 
a challenge to current thinking.  Br J Psychiatry. 2006 ;189: 399-404 
 
Cacebelos R, Fernandez-Novoa L, Lombardi V, Corzo L, Pichel V, Kubota Y.  Cerebrovascular risk 
factors in Alzheimer’s disease: brain haemodynamics and [haracogenomic implications.  Neurol Res 
2003; 25: 567-580 
Carmignoto G, Gomez-Gonzalo M. The Contribution of Astrocyte Signalling to Neurovascular 
Coupling. Brain Res Rev 2010; 63: 138-148 
 
Carmignoto G, Gomez-Gonzalo M. The contribution of astrocyte signalling to neurovascular 
coupling. Brain Res Rev 2010; 63: 138-148 
 
Dineen NE, Brodie FG, Robinson TG, Panerai RB. Continuous estimates of dynamic cerebral 
autoregulation during transient hypocapnia and hypercapnia. J Appl Physiol 2010; 108(3): 604-13 
 
Evans DH, Levene MI, Shortland DB, Archer LN. Resistance index, blood flow velocity, and 
resistance-area product in the cerebral arteries of very low birth weight infants during the first 
week of life. Ultrasound Med.Biol. 1988;14:103-10 
 

 
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Giller CA. The frequency-dependent behavior of cerebral autoregulation. Neurosurgery 
1990;27:362-368 
 
Girouard H, Iadecola C. Neurovascular Coupling in the Normal Brain and in Hypertension, Stroke 
And Alzheimer’s Disease. J Appl Physiol 2006; 100: 328-335 
 
Gorelick PB.  Risk factors for vascular dementia and Alzheimer’s disease.  Stroke.  2004; 35: 2620-
2622 
 
Gucuyener DO, Yenilmez C, Ayranci U, Ozdemir F, Uzuner N, Ozkan S, Kaptanoglu C, Ozdemir G. An 
analysis of changes in cerebral blood flow velocities in depressive pseudo-dementia and Alzheimer 
disease patients.  Neurologist. 2010; 16: 358-363 
 
Hsieh S., Schubert S., Hoon C., Mioshi, E., Hodges J.R., Validationodthe Addenbrooke’s Cognitive 
Examination Iii In Frontotemporal Dementia And Alzheimer’s Disease.  Dement Geriatr Cogn Disord 
2013; 36: 242-250 
 
Itoh T, Matsumoto M, Handa N, Maeda H, Hougaku H, Hashimoto H, Etani H, Tsukamoto Y, T. 
Kamada.  Rate of successful recording of blood flow signals in the middle cerebral artery using 
transcranial Doppler sonography. Stroke 1993; 24: 1192–1195 
 
Kalaria RN: Vascular basis for brain degeneration: faltering controls and risk factors for dementia.  
Nutr Rev 2010; 68: S74-S87 
 
Keage HAD, Churches OF, Kohler M, Pomeroy D, Luppino, Bartolo ML, Elliott S.  Cerebrovasculat 
Function in Aging and Dementia: A Systematic Revie of Transcranial Doppler Studies.  Dement 
Geraitr Cogn Disord Extra 2012; 2: 258-270 
 
Marinoni M, Ginanneschi A, Forleo P, Amaducci L.  Technical limits in transcranial Doppler 
recording: Inadequate acoustic windows.  Ultrasound Med Biol 1997; 23: 1275–1277 
 
Matteis M, Sivestrini M, Troisi E, Bragoni M, Vernieri F,Caltagirone C.  Cerebral haemodynamic 
patterns during stimuli tasks in multi-infarct and Alzheimer types of dementia.  Acta Neurol Scand 
1998; 97: 374-380 
 
McDade EM, Petersen RC. Mild Cognitive Impairment: Prognosis And Treatment. 
Http://Www.Uptodate.Com/Index. Accessed Aug 13th 2015 
 
McKhann, GM et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from 
the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer's disease. The Journal of the Alzheimer’s Association. 2011; 7: 263-269.  
 
Oldfield, R. C. The assessment and analysis of handedness: The Edinburgh inventory. 
Neuropsychololgia 1971; 9: 97-113. 
 

 
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Panerai RB, Rennie JM, Kelsall AWR, Evans DH. Frequency-domain analysis of cerebral 
autoregulation from spontaneous fluctuations in arterial blood pressure. Medical and Biological 
Engineering and Computing 1998; 36: 315-322 
 
Panerai RB. The critical closing pressure of the cerebral circulation. Med.Eng Phys. 2003; 25: 621-
632 
 
Panerai RB, Eames PJ, Potter JF. Multiple coherence of cerebral blood flow velocity in humans. Am J 
Physiol 2006; 291: 251-259 
 
Paulson OB, Strandgaard S, Edvinson L. Cerebral autoregulation. Cerebrovasc Brain Metb Rev 1990: 
2; 161-192 
 
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004: 256(3):183-94 
 
Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo 
JM, Brun A, Hofman A, et Al. Vascular Dementia: Diagnostic Criteria For Research Studies. Report of 
the NINDS-AIREN International Workshop. Neurology 1993; 4392): 250-260 
 
Rosengarten B, Aldinger C, Kaufmann A, Kaps M.  Comparison of visually evoked peak systolic and 
end diastolic blood flow velocity using a control system approach.  Utrasound Med Biol 2001; 27: 
1499-1503 
 
Ruitenberg A, deb Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM.  
Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam study.  Ann Neurol 2005; 57: 
789-794 
 
Sabayana B, Jansena S, Oleksika AM, van Oschc MJP, van Buchemc MA, van Vlieta P, de Craena 
AJM, Westendorpa RGJ.  Cerebrovascular hemodynamics in Alzheimer's disease and vascular 
dementia: A meta-analysis of transcranial Doppler studies.  Ageing Research Reviews.  2012; 11(2): 
271–277 
 
Simpson, J. DSM-5 and Neurocognitive Disorders. Journal of the American Academy of Psychiatry 
and the Law Online. 2014, 42 (2) 159-164 
 
Tiecks FP, Lam AM, Aaslid R, Newell DW. Comparison of static and dynamic cerebral autoregulation 
measurements. Stroke 1995; 26: 1014-1019 
 
Van Beek A, Claasen J, Rikkert M, Jansen R. Cerebral autoregulation: an overview of current 
concepts and methodology with special focus on the elderly. JCBFM 2008; 28: 1071-1085 
 
Winblad B, Palmer K,Kivipelto M, Jelic V, Fratiglioni L, Wahlund L-O, Nordberg A, Backman L, Albert 
M, Almkvist O, Arai H, Basun H, Blennow K, Deleon M, Decarli C, Erkinjuntti T, Giocobini E, Graff C, 
Hardy J, Jacki C, Jormi A, Rtchie K, Van Duijn C, Viserri P, Petersen RC. Mild cognitive impairment – 
beyond controversies, towards a consensus: report of the International Working Group on Mild 
Cognitive Impairment.  Journal of Internal Medicine 2004; 256: 240-246 

 
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World Health Organisation. The ICD-10 Classification of Mental and Behavioural Disorders. Clinical 
descriptions and diagnostic guidelines. WHO Library Cataloguing in Publication Data. 1992: 45-57.  

 
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20. 
APPENDIX A: EXPECTED EVENTS NOT SUBJECT TO EXPEDITED REPORTING 
 
Acute Coronary Syndromes 
Agitation 
Angina 
Anorexia 
Anxiety 
Constipation 
Delirium 
Depression 
Dysphagia 
Electrolyte disturbance 
Fall 
Fatigue 
Gastrointestinal disturbance 
Hallucinations 
Incontinence, faecal 
Incontinence, urinary 
Infections 
Institutionalisation / Admission to care home 
Intracerebral Haemorrhage 
Loss of ability to function or care for self 
 
 
Myocardial infarction 
Nausea 
Personality change 
Peripheral Vascular Disease 
Renal impairment 
Sedation 
Seizure 
Sexual dysfunction 
Sleep disturbance 
Stroke 
Transient ischemic attack 
Urinary retention 
Urinary tract infection 
Violent behaviour 
Visual loss 
Vomiting 
Weakness 
Weight loss 
 
 
 

 
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21. 
APPENDIX B: ADDENBROOKE’S COGNITIVE EXAMINATION-III 
 
 

 
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22. 
APPENDIX C: EDINBURGH HANDEDNESS INVENTORY 
Please indicate with a check () your preference in using your left or right hand in the following tasks. 
Where the preference is so strong you would never use the other hand, unless absolutely forced to, put 
two checks ().  
If you are indifferent, put one check in each column (   |  ). 
Some of the activities require both hands. In these cases, the part of the task or object for which hand 
preference is wanted is indicated in parentheses. 
Task / Object 
Left Hand 
Right Hand 
1. Writing 
 
 
2. Drawing 
 
 
3. Throwing 
 
 
4. Scissors 
 
 
5. Toothbrush 
 
 
6. Knife (without fork) 
 
 
7. Spoon 
 
 
8. Broom (upper hand) 
 
 
9. Striking a Match (match) 
 
 
10.  Opening a Box (lid) 
 
 
Total checks: 
LH =  
RH =  
Cumulative Total 
CT = LH + RH =  
Difference 
D = RH – LH =  
Result 
R = (D / CT) × 100 =  
Interpretation: 
(Left Handed: R < -40) 
(Ambidextrous: -40 ≤ R ≤ +40) 
(Right Handed: R > +40) 
 

 
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