Multimodal Retinal Imaging in the Detection and Follow-up of Alzheimer's Disease (RetAD)

• ClinicalTrials.gov Identifier: NCT03466177
• Recruitment Status: Unknown
• First Posted: March 15, 2018
• Last Update Posted: March 15, 2018
• Sponsor: Universitaire Ziekenhuizen Leuven
• Information provided by (Responsible Party): Universitaire Ziekenhuizen Leuven

Study Description

Brief Summary:

Because of a shared ontogenic origin, the retina displays similarities to the brain and spinal cord in terms of anatomy, functionality, response to insult, and immunology. Hence, the retina can be approached as an integral part of the central nervous system. The occurence of ocular manifestations in several neurodegenerative pathologies, such as Alzheimer's disease and Parkinson's disease, accentuates the strong relationship between eye and brain. Particularly retinal changes can present a substrate for cerebral changes in these disorders. Offering a 'window to the brain', the transparent eye enables non-invasive imaging of these changes in retinal structure and vasculature. In this project, the potential of retinal biomarkers for e.g. Alzheimer's will be explored with the aim to overcome some of the hurdles in the current management of these pathologies, mainly the lack of techniques for patient screening and early diagnosis. The aim of this clinical trial is to correlate the retinal biomarkers for Alzheimer's with neuro-imaging, and cognitive function. Integrating the results will yield non-invasive retinal biomarkers for clinical research, screening, and follow-up of disease progression in various neurodegenerative disorders.

Condition or disease	Intervention/treatment
Alzheimer Disease; Alzheimer Dementia; Mild Cognitive Impairment; Dementia	Diagnostic Test: Non-invasive, multimodal retinal imaging; Diagnostic Test: Cerebral imaging; Diagnostic Test: Neuropsychiatric testing; Diagnostic Test: Venous blood sampling

Detailed Description:

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide. A growing number of people are surviving into their 80s-90s and the number of AD patients projected to nearly triple in the next three decades, affecting 80-90 million people worldwide by 2040. As such, AD will become the third cause of death for older people, just behind cardiovascular disease and cancer. In contrast to the latter, AD cannot be prevented, slowed or cured. AD represents an enormous socio-economic burden and has become a trillion dollar disease. Despite decades of intensive research, diagnosis and treatment remain challenging for AD. A string of recent failures in clinical trials for AD drugs has pointed out that our understanding of the disease is still far from complete. More in detail, three major reasons underlying this treatment gap have been identified:

i. The lack of techniques for patient screening and early diagnosis. ii. The incomplete understanding of the complex interplay of pathological processes that underlie AD.

iii. The many hurdles between drug discovery and approval.

With this study, the investigators propose a novel way to address these needs, by using the retina as a model organ to study the central nervous system (CNS). Many of the hallmark cerebral pathophysiological processes of AD have also been observed in the retina. Unlike the rest of the CNS, the retina can be visualized directly, with an imaging resolution up to 100x higher than PET and MRI scans. Using these high-resolution imaging tools such as Optical Coherence Tomography (OCT), studies have demonstrated microvascular changes and neuro-retinal thinning in AD patients. Pilot data show that retinal Aβ can be visualized non-invasively solely based on the intrinsic hyperspectral signature of aggregated amyloid deposits. Non-invasive retinal imaging (e.g., fundus photography, OCT, hyperspectral imaging (HSI)) - which are all available at affordable cost -, could therefore represent novel means for identifying patients at risk, for longitudinal follow-up of disease progression in AD patients, and for research in a quest for more effective treatments.

This is an open-label longitudinal biomarker study without investigational medicinal product in subjects in different stages of the AD spectrum.

The data that we will collect consist of amyloid imaging, MRI, blood, genetic, general health and cognitive data, as well as visual acuity, ocular biomicroscopy and funduscopy, fundus photographs, hyperspectral retinal images, Optical Coherence Tomography (OCT) retinal images and OCT angiography (OCT-A) retinal images. Subjects will be followed longitudinally. In the current study the investigators will primarily investigate the potential of non-invasive, multimodal retinal imaging for the early detection of Alzheimer's disease and for the evaluation of disease progression. This will be done in comparison with amyloid imaging and neuropsychological evaluations.

The investigators will build a longitudinal database of ocular, systemic, neuro-psychiatric, MRI and PET imaging parameters of Aβ-positive and Aβ-negative patients with different stages of cognitive impairment. This database will be used to provide proof-of-concept that retinal biomarkers provide an early, accurate and non-invasive tool for AD detection and follow-up. All data will be collected in a database for statistical analysis.

Study Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 90 participants
• Observational Model: Cohort
• Time Perspective: Cross-Sectional
• Target Follow-Up Duration: 2 Years
• Official Title: Multimodal Retinal Imaging in the Detection and Follow-up of Alzheimer's Disease
• Estimated Study Start Date: April 1, 2018
• Estimated Primary Completion Date: December 31, 2018
• Estimated Study Completion Date: December 31, 2020

Groups and Cohorts

Group/Cohort	Intervention/treatment
Ab+ AD patients; amyloid positive Alzheimer's Disease patients; Venous blood sampling Hematology and chemistry; Genotyping: apolipoprotein E (apoE) polymorphism Cerebral imaging; Brain MRI MPRAGE volumetric MRI, en FLAIR and Gradient Echo sequence; 18F-Flutemetamol PET CT; Neuropsychiatric testing Auditory Verbal Learning Test (AVLT) Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Raven's Progressive Matrices (RPM) Mini Mental State Examination (MMSE) Neuropsychiatric Inventory (NPI) Cornell Scale for Depression in Dementia (CSDD); Ocular examination Visual acuity, biomicroscopy, funduscopy Fundus pictures, including hyperspectral imaging OCT + angio-OCT (Non-invasive, multimodal retinal imaging)	Diagnostic Test: Non-invasive, multimodal retinal imaging; Ocular exam including the application of different non-invasive ocular imaging techniques; Diagnostic Test: Cerebral imaging; amyloid-PET and MRI; Diagnostic Test: Neuropsychiatric testing; neuropsychiatric test battery; Diagnostic Test: Venous blood sampling; fasting laboratory tests and apoE genotyping
Ab+ Mild Cognitive Impairment (MCI) patients; amyloid positive Mild Cognitive Impairment patients; Venous blood sampling Hematology and chemistry; Genotyping: apoE polymorphism Cerebral imaging; Brain MRI MPRAGE volumetric MRI, en FLAIR and Gradient Echo sequence; 18F-Flutemetamol PET CT; Neuropsychiatric testing Auditory Verbal Learning Test (AVLT) Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Raven's Progressive Matrices (RPM) Mini Mental State Examination (MMSE) Neuropsychiatric Inventory (NPI) Cornell Scale for Depression in Dementia (CSDD); Ocular examination Visual acuity, biomicroscopy, funduscopy Fundus pictures, including hyperspectral imaging OCT + angio-OCT (Non-invasive, multimodal retinal imaging)	Diagnostic Test: Non-invasive, multimodal retinal imaging; Ocular exam including the application of different non-invasive ocular imaging techniques; Diagnostic Test: Cerebral imaging; amyloid-PET and MRI; Diagnostic Test: Neuropsychiatric testing; neuropsychiatric test battery; Diagnostic Test: Venous blood sampling; fasting laboratory tests and apoE genotyping
Ab+ cognitively intact volunteers; amyloid positive cognitively intact volunteers; Venous blood sampling Hematology and chemistry; Genotyping: apoE polymorphism Cerebral imaging; Brain MRI MPRAGE volumetric MRI, en FLAIR and Gradient Echo sequence; 18F-Flutemetamol PET CT; Neuropsychiatric testing Auditory Verbal Learning Test (AVLT) Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Raven's Progressive Matrices (RPM) Mini Mental State Examination (MMSE) Neuropsychiatric Inventory (NPI) Cornell Scale for Depression in Dementia (CSDD); Ocular examination Visual acuity, biomicroscopy, funduscopy Fundus pictures, including hyperspectral imaging OCT + angio-OCT (Non-invasive, multimodal retinal imaging)	Diagnostic Test: Non-invasive, multimodal retinal imaging; Ocular exam including the application of different non-invasive ocular imaging techniques; Diagnostic Test: Cerebral imaging; amyloid-PET and MRI; Diagnostic Test: Neuropsychiatric testing; neuropsychiatric test battery; Diagnostic Test: Venous blood sampling; fasting laboratory tests and apoE genotyping
Ab- cognitively intact volunteers; amyloid negative cognitively intact volunteers; Venous blood sampling Hematology and chemistry; Genotyping: apoE polymorphism Cerebral imaging; Brain MRI MPRAGE volumetric MRI, en FLAIR and Gradient Echo sequence; 18F-Flutemetamol PET CT; Neuropsychiatric testing Auditory Verbal Learning Test (AVLT) Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Raven's Progressive Matrices (RPM) Mini Mental State Examination (MMSE) Neuropsychiatric Inventory (NPI) Cornell Scale for Depression in Dementia (CSDD); Ocular examination Visual acuity, biomicroscopy, funduscopy Fundus pictures, including hyperspectral imaging OCT + angio-OCT (Non-invasive, multimodal retinal imaging)	Diagnostic Test: Non-invasive, multimodal retinal imaging; Ocular exam including the application of different non-invasive ocular imaging techniques; Diagnostic Test: Cerebral imaging; amyloid-PET and MRI; Diagnostic Test: Neuropsychiatric testing; neuropsychiatric test battery; Diagnostic Test: Venous blood sampling; fasting laboratory tests and apoE genotyping

Outcome Measures

Primary Outcome Measures :

1. Retinal biomarkers for AD: specificity [ Time Frame: 2 years ]
   To evaluate the diagnostic performance of selected ocular biomarkers for Alzheimer's disease
2. Retinal biomarkers for AD: sensitivity [ Time Frame: 2 years ]
   To evaluate the diagnostic performance of selected ocular biomarkers for Alzheimer's disease
3. Retinal biomarkers for AD: number needed to image [ Time Frame: 2 years ]
   To evaluate the diagnostic performance of selected ocular biomarkers for Alzheimer's disease
4. Retinal biomarkers for AD: area under the curve (AUC) [ Time Frame: 2 years ]
   To evaluate the diagnostic performance of selected ocular biomarkers for Alzheimer's disease
5. Retinal biomarkers for AD: receiver operating characteristic (ROC) [ Time Frame: 2 years ]
   To evaluate the diagnostic performance of selected ocular biomarkers for Alzheimer's disease

Secondary Outcome Measures :

1. Retinal biomarkers for AD: quantification of cerebral Aβ load by non-invasive retinal imaging against the cerebral Aβ load measured by cerebral imaging [ Time Frame: 2 years ]
   To deliver a proof-of-concept for the use of retinal biomarkers to quantitatively measure cerebral Aβ load by comparing the results of cerebral imaging (Standard Uptake Value ratio (SUVr) on amyloid-PET) with the results of retinal hyperspectral imaging (area of retinal Aβ detected, in µm²)
2. Retinal biomarkers for AD: disease progression by measuring the change from baseline at 2 years [ Time Frame: 2 years ]
   To deliver a proof-of-concept for the use of retinal biomarkers to follow Alzheimer's disease progression by measuring the change from baseline at 2 years and to compare the results of the cerebral imaging and neuropsychiatric tests with the results from the selected retinal biomarkers for AD at different time points (t0, t 6 months, t 12 months, t 18 months, t 24 months)

Biospecimen Retention:   Samples With DNA

Venous blood samples for genotyping of the apoE polymorphism

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Sampling Method: Probability Sample

Study Population

Cfr. eligibility criteria

Criteria

Inclusion Criteria:

• Between ≥ 50 and ≤ 85 years of age.
• In the opinion of the investigator, the patient is in stable medical condition and willing and able to perform study procedures.
• Patient is fluent in written and verbal Dutch.
• Patient is capable of giving informed consent.

Exclusion Criteria:

• Patient has a history or current evidence of a neurological disorder, which, in the opinion of the primary investigator, may contribute to the subject's cognitive impairment.
• Patient has a history of large-vessel stroke or evidence of a large-vessel infarction or other focal lesions on baseline MRI scan, which may contribute to the cause of the memory impairment in the opinion of the investigator. Vascular white matter lesions or other signs of microangiopathy will not be considered an exclusion.
• Patient has a history of malignancy ≤ 5 years prior to signing informed consent, except for patients who have undergone potentially curative therapy with no evidence of recurrence for 1 year, and who are deemed at low risk for recurrency by her/his treating physician.
• Patient is currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent.
• Subject has any magnetizable metal prostheses, implants or foreign objects that could pose a hazard during MRI scans.
• Patient has a known history of ocular diseases other than the exception of cataract and/or wearing glasses/contact lenses.

Contacts and Locations

Contacts

Contact: Sophie Lemmens, MD; +3216332387; sophie.1.lemmens@uzleuven.be

Locations

Belgium

UZ Leuven; Recruiting

Leuven, Vlaams Brabant, Belgium, 3000

Contact: Ingeborg Stalmans, Phd 003216332372 ingborg.stalmans@uzleuven.be

Contact: Sien Boons, Optometrist 003216340391 sien.boons@uzleuven.be

Sponsors and Collaborators

Universitaire Ziekenhuizen Leuven

Investigators

• Principal Investigator: Ingeborg Stalmans, MD PhD; UZ Leuven/KU Leuven

  Study Documents (Full-Text)

Documents provided by Universitaire Ziekenhuizen Leuven:

Study Protocol  [PDF] October 27, 2017

More Information

Additional Information:

• Responsible Party: Universitaire Ziekenhuizen Leuven
• ClinicalTrials.gov Identifier: NCT03466177
• Other Study ID Numbers: S60932
• First Posted: March 15, 2018
• Last Update Posted: March 15, 2018
• Last Verified: January 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Universitaire Ziekenhuizen Leuven:

Alzheimer's disease; Dementia; Mild cognitive impairment; Optical coherence tomography; Hyperspectral imaging; Multimodal retinal imaging

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Cognitive Dysfunction; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders