Optical Coherence Tomography in Cerebral Amyloidosis
Conditions: Alzheimer Disease, Dementia Alzheimers, Dementia, Lewy Body Disease, Dementia, Lewy Body, Mild Cognitive Impairment
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 
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Protocol Full Title prospective observational trial: 
Optical coherence tomography in cerebral amyloidosis 
 
 
Protocol Acronym/short title: 
OCT in cerebral amyloidosis (“OCT in cerebrale amyloidose”) 
 
Version and date of protocol: 
v1.1 
17-04-2016 
 
 
Sponsor: 
 
Name: UZLeuven 
Address: Herestraat 49, 3000 Leuven 
 
Principal Investigator: 
Name: prof. dr. Evelien Vandewalle 
Address: Kapucijnenvoer 33, campus Sint-Rafaël, dienst oftalmologie, 3000 Leuven 
Telephone: +32 16 34 25 09 
Email: evelien.vandewalle@uzleuven.be 
 
 
Sub-investigator: 
 
Name: prof. dr. Ingeborg Stalmans 
Address: Kapucijnenvoer 33, campus Sint-Rafaël, dienst oftalmologie, 3000 Leuven 
Telephone: +32 16 33 23 72 
Email: ingeborg.stalmans@uzleuven.be 
 
Name: prof. dr. Rik Vandenberghe 
Address: Herestraat 49, dienst neurologie, 3000 Leuven  
Telephone: +32 16 3 44280 
Email: rik.vandenberghe@uzleuven.be 
 
 
 
 
 

29/04/2016
29/04/2016

 
 
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Table of Contents 
1. 
Study Synopsis ................................................................................................................................. 4 
2. 
Background and rationale ............................................................................................................... 6 
3. 
Trial objectives and Design .............................................................................................................. 7 
4. 
Selection and withdrawal of subjects .............................................................................................. 8 
4.1 Inclusion criteria ........................................................................................................................ 8 
4.2 Exclusion criteria ....................................................................................................................... 8 
4.3 Expected duration of trial .......................................................................................................... 8 
5. 
Trial Procedures .............................................................................................................................. 8 
6. 
Assessment of efficacy .................................................................................................................... 9 
7. 
Assessment of Safety ...................................................................................................................... 9 
8. 
Statistics .......................................................................................................................................... 9 
8.1 Sample size ................................................................................................................................ 9 
8.2 Analysis .................................................................................................................................... 10 
9. 
Quality assurance .......................................................................................................................... 10 
10. 
Direct access to source data and documents ........................................................................... 10 
11. 
Ethics and regulatory approvals ............................................................................................... 10 
12. 
Data Handling ........................................................................................................................... 11 
13. 
Data Management ................................................................................................................... 11 
14. 
Translational research .............................................................................................................. 11 
15. 
Publication Policy ..................................................................................................................... 11 
16. 
Insurance/Indemnity ................................................................................................................ 12 
17. 
Financial Aspects ...................................................................................................................... 12 
18. 
References ................................................................................................................................ 12 
 
 
 

 
 
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1. Study Synopsis  
 
 
Title of clinical trial 
 
 
Optical coherence tomography in cerebral amyloidosis 
Protocol Short Title/Acronym 
 
OCT in cerebral amyloidosis (“OCT in cerebrale 
amyloidose”) 
Sponsor name 
 
UZLeuven 
Principal Investigator 
 
Prof. Dr. Evelien Vandewalle  
Medical condition or disease under 
investigation 
 
Community-recruited cognitively intact older adults 
(Control), patients with Alzheimer’s Disease (AD), 
Lewy Body Dementia (LBD) and Mild Cognitive 
Impairment (MCI) 
Purpose of clinical trial 
 
To explore the distribution of novel optical coherence 
tomography (OCT) parameters in patients with 
different subtypes of dementia, MCI patients with or 
without positive amyloid scan and cognitively intact 
older adults and to evaluate the diagnostic value of 
these parameters. 
Primary objective 
 
Relative distribution of retinal and choroidal 
thickness, flow index and vessel density in the 
different subpopulations. 
Secondary objective (s) 
 
- Diagnostic performance of the aforementioned 
parameters to distinguish the different 
subpopulations. 
- The association between these parameters and the 
presence of cardiovascular risk factors. 
Trial Design 
 
Observational, cross-sectional 
Endpoints 
 
The diagnostic performance of retinal and choroidal 
thickness, flow index and vessel density to classify 
between amyloid positive vs amyloid negative 

 
 
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controls, amyloid-positive vs amyloid negative MCI, 
AD and DLBD. 
 
 
Sample Size 
 
 
85 
-15 amyloid-positive and 15 amyloid-negative 
 
cognitively intact controls (55-80 years) 
 
- 15 amyloid-positive and 15 amyloid-
 
negative MCI patients 
 
- 15 patients in the dementia stage of AD 
 
- 10 patients with LBD 
 
Summary of eligibility criteria 
 
Confirmed diagnosis of MCI, AD, LBD or absence of 
dementia (cfr 4.1 inclusion criteria) 
 Capable and willing to participate 
Maximum duration of treatment of a Subject 
 
/ 
Version and date of final protocol 
 
V1.1 17-04-2016 
Version and date of protocol amendments 
 
 
 
 
 
 
 
 
 
 
 

 
 
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2. Background and rationale 
 
Being a direct extension of the central nervous system and the only place in the human body where 
the vessels of the central circulation can be visualized directly, the eye provides a unique window to 
investigate the central circulatory system. Several studies have demonstrated that retinal blood vessels 
show structural and functional alterations in patients with dementia. These measurements are based 
on fundus pictures and are hence limited to the larger retinal vessels.   
Until recently, intravenous injection of a contrast agent was necessary to visualize the retinal 
microvasculature in detail. While indispensable for the diagnosis of some ocular vascular diseases 
(arterial/venous occlusion, neovascularization,…) the invasiveness of fluorescein angiography (and the 
risk of an allergic reaction) limits its use as a screening tool to detect alterations in the microvascular 
network of the retina and choroid. 
 
Optical coherence tomography (OCT) is a non-invasive diagnostic tool capable of generating cross-
sectional coupes of the retina and choroid. Novel algorithms allow to render a 3-dimensional model of 
the ocular microcirculation based merely on the motion contrast of the circulating blood. Since OCT is 
fast, easy to perform and completely non-invasive, this technique lends itself for screening purposes. 
The proposed study aims to investigate whether retinal or choroidal vascular parameters measured 
using OCT could be useful to identify different subpopulations of cognitive intact, MCI and dementia 
patients. 
 
Figure 1. OCT camera 

 
 
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Figure 2. OCT angiography 
3. Trial objectives and Design 
 
In this observational study, we aim to evaluate whether changes in the retinal and choroidal 
circulation, as assessed by OCT are correlated with the degree and subtype of dementia and with the 
presence or absence of a positive amyloid scan. 
For this purpose, patients with established AD and LBD, as well as amyloid positive and amyloid 
negative MCI and aged matched cognitively intact patients will be included in this cross-sectional 
study. 
 
 
 

 
 
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4. Selection and withdrawal of subjects 
 
4.1 Inclusion criteria 
- Cognitively intact healthy controls will be recruited from an ongoing community-recruited 
longitudinal cohort of cognitively intact older adults (55-85 years, S51125) who all have undergone 
amyloid PET at the baseline visit in the context of study S51125. Half of the subjects will be amyloid-
positive and half will be amyloid-negative. In the context of study S51125 these subjects receive two-
yearly neuropsychological assessment. 
- MCI patients (Petersen et al., 2004 criteria) will be recruited from an ongoing memory-clinic 
recruited longitudinal cohort of patients with amnestic mild cognitive impairment who participate in 
study S55892. All subjects have undergone an amyloid PET at the baseline study in the context of 
study S55892. Half of the subjects will be amyloid-positive and half will be amyloid negative. 
- Clinically probable AD subjects (NINCDS-AIREN criteria) will be recruited from the memory clinic UZ 
Leuven (MMSE 12-28). Subjects will be recruited only if they are capable of providing written 
informed consent. 
-Clinically probable LBD (McKeith et al. criteria, 2005) will be recruited from the memory clinic UZ 
Leuven (MMSE 12-28). Subjects will be recruited only if they are capable of providing written 
informed consent. 
- Capable and willing to participate 
4.2 Exclusion criteria 
- Personal medical history of retinal neovascularization  
- Unable or unwilling to give consent 
4.3 Expected duration of trial 
10 minutes per person 
 
5. Trial Procedures 
 
1. Informed consent: AD en LDB patients will be accompanied by a personal study partner who 
will verify and sign whether the purpose, course and voluntary nature of the trial has been 
explained to the patient in a clear and understandable language, prior to signing the 
informed consent. 

 
 
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2. Medical questionnaire assessing personal medical history of cardiovascular diseases and 
cardiovascular risk factors. When necessary, the Electronic Health Record as well as treating 
physicians might be consulted to complete the questionnaire. 
3. Basic non-invasive ophthalmic examination: visual acuity, slit lamp assessment of the 
anterior and posterior segments, lens grading and non-dilated fundus photography 
4. OCT: Macula centered cube followed by optic disc centered cube, for both eyes 
Each scan takes approximately 2.5 seconds. 
5. Retinal and choroidal thickness and motion decorrelation will be measured using the 
provided software. 
6. The diagnostic performance of these OCT parameters to classify between amyloid positive vs 
amyloid negative controls, amyloid-positive vs amyloid negative MCI, AD and DLBD will be 
evaluated. 
 
 
 
6. Assessment of efficacy 
/ 
 
7. Assessment of Safety 
 
The power and frequency of the light source used by the fundus camera and by the spectral-domain 
OCT are completely harmless for the human retina and cause no subjective discomfort. The OCT device 
uses a faint light at the near-infrared spectrum that can barely be perceived by the human eye. 
Pupillary dilatation is not required. 
 
8. Statistics 
8.1 Sample size 
As of now, there is no data available on the distribution of flow index or vessel density in the 
population. This exploratory study is aimed to provide data on the distribution of these parameters in 
the healthy and diseased population. For this purpose, we will recruit 15 amyloid-positive and 15 
amyloid-negative cognitively intact controls, 15 amyloid-positive and 15 amyloid-negative MCI, 15 
clinically probable AD in an early stage and 10 clinically probable LBD. 

 
 
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8.2 Analysis 
Demographics and measured parameters will be analyzed with descriptive statistics (mean ± standard 
deviation). Image analysis for the OCT will be performed with the software provided by the 
manufacturer. To evaluate the diagnostic performance of these parameters in distinguishing between 
subcategories, ‘receiver operating characteristic’ (ROC) curves with ‘area under the curve’ (AUC) 
analysis will be used. Logistic regression models will be used to assess the association between 
retinal/choroidal vascular parameters and cardiovascular risk factors. Statistical significance will be 
based on two-sided P-values of <0.05. All statistical analyses will be performed using SPSS 20.0 for Mac 
(SPSS Inc., Chicago, IL, USA). 
 
9. Quality assurance 
 
To assure maximal quality and reproducibility, the trial protocol will be followed rigorously. 
 
10. 
Direct access to source data and documents 
 
Demographics and disease-related parameters (functional assessment, biochemistry and imaging) 
will be retrieved from the electronic medical health record. When not available, additional tests will 
not be performed. 
 
11. 
Ethics and regulatory approvals 
 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (2008), 
the principles of GCP and in accordance with all applicable regulatory requirements. This protocol 
and related documents will be submitted for review to Ethics Committee of the University 
Hospitals Leuven. 
The Study will be conducted only on the basis of prior informed consent by the Subjects to 
participate in the Study. We shall obtain a signed informed consent form (ICF) for all patients prior 
to their enrollment and participation in the Study in compliance with all applicable laws, 

 
 
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regulations and the approval of the (local) Ethics Committee, if required. We shall retain such ICFs 
in accordance with the requirements of all applicable regulatory agencies and laws. 
 
12. 
Data Handling 
 
We shall treat all information and data as confidential and shall not disclose such information to any 
third parties or use such information for any purpose other than the performance of the Study. The 
collection, processing and disclosure of personal data, will comply with applicable personal data 
protection and the processing of personal data (Directive 95/46/EC and Belgian law of December 8, 
1992 on the Protection of the Privacy in relation to the Processing of Personal Data). We will protect 
the data from disclosure outside the research according to the terms of the research protocol and the 
informed consent document. The subject’s name or other identifiers will be stored separately from 
their research data and replaced with a unique code to create a new identity for the subject. 
 
13. 
Data Management 
 
Volunteers will be matched to an anonymous identifier. Data will be recorded electronically in a 
spreadsheet. Images will be exported and permanently removed from the diagnostic device. 
 
14. 
Translational research 
 
No biological material will be collected/shipped/stored/used for the study 
 
15. 
Publication Policy 
 
Any publication will be submitted to all co-authors and sponsors for review at least thirty (30) days 
prior to submission or disclosure. Sponsor shall have the right to delay the projected publication for a 

 
 
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period of up to three (3) months from the date of first submission to the Sponsor in order to enable 
the Sponsor to take steps to protect its intellectual property rights and know-how.  
16. 
Insurance/Indemnity 
 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
Sponsor shall assume, even without fault, the responsibility of any damages incurred by a Study Patient 
and linked directly or indirectly to the participation to the Study, and shall provide compensation 
therefore through its insurance. 
 
17. 
Financial Aspects 
 
Volunteers will not be charged with the cost of the additional examinations. 
No commercial interests to declare. 
18. 
References 
 
1. Patton, Niall, et al. "Retinal vascular image analysis as a potential screening tool for 
cerebrovascular disease: a rationale based on homology between cerebral and retinal 
microvasculatures." Journal of anatomy 206.4 (2005): 319-348. 
2. Cheung, Carol Yim-lui, et al. "Microvascular network alterations in the retina of patients with 
Alzheimer's disease." Alzheimer's & Dementia 10.2 (2014): 135-142. 
3. Huang, David, et al. "Optical coherence tomography." Science 254.5035 (1991): 1178-1181. 
4. Spaide, Richard F., James G. Fujimoto, and Nadia K. Waheed. "Optical Coherence 
Tomography Angiography." Retina 35.11 (2015): 2161-2162.