Multimodal Ocular Imaging in Neurodegeneration

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two of the most common types of age-related neurodegenerative disorders. Identifying at-risk patients and gauging disease progression in a non-invasive manner would be invaluable. Early and correct diagnosis is crucial for coordinating supportive care, patient expectations, caregiver arrangements and family planning. In addition, as treatments become available, beginning therapy early in the disease before symptoms become severe will be important. Multimodal ocular imaging (MOI) includes an ophthalmic (eye) exam and eye photographs to evaluate different layers of the retina, which is the light sensing layer of the eye. Newer technologies make it possible to visualize the disease process occurring in AD and FTD by using MOI to look at the retina, since the retina is fundamentally an outward extension of the brain itself. This study will attempt to correlate signs of disease in the retina, as determined by MOI, with plaque buildup in the brain as seen by imaging. This will demonstrate the sensitivity and specificity of MOI for diagnosing AD and FTD in a noninvasive manner.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Frontotemporal Dementia; Alzheimer Dementia
• Intervention / Treatment: Device: Spectral-Domain Optical Coherence Tomography (SD-OCT); Device: Magnetic Resonance Imaging (MRI); Device: Positron Emission Tomography (PET); Diagnostic test: Comprehensive Ophthalmic Examination; Device: Fundus Photography

• Study Type: Observational
• Enrollment (Actual): 16

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 43 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients are recruited with mid-to-late stage AD and FTD, as well as age-matched healthy controls, using the extensive database of research participants maintained by the Michigan Alzheimer's Disease Center (MADC).

Description

Inclusion Criteria:

• Subjects with dementia must have known diagnosis of Alzheimer's dementia (AD) or frontotemporal dementia (FTD)
• Subjects with dementia must have Moderate/severe dementia as preferentially defined by a documented MoCA score of less than 17, or by MMSE score of less than 17, within the last 12 months
• Individuals with no evidence of AD or FTD as age-matched controls.

Exclusion Criteria:

• Preexisting retinal or optic nerve disorder including macular degeneration, diabetic retinopathy, retinal dystrophy, and glaucoma
• Anterior segment abnormalities of the eye limiting ocular imaging (e.g. corneal disorders, dense cataract).
• Use of medications with known effects on the retina or optic nerve (e.g. hydroxychloroquine, ethambutol).
• Pregnant or lactating women.
• Prisoners.
• Subjects with advanced dementia who cannot be independently and reliably positioned at the ocular imaging device for reliable imaging.
• Subjects with contraindications to magnetic resonance (MR) imaging, including pacemakers or claustrophobia.
• Evidence of large vessel stroke or mass lesion identified on MR imaging.
• Subjects limited by participation in research procedures involving ionizing radiation.
• Subjects who are already participating in another clinical study or clinical trial
• Participants with a clinically significant or unstable medical or surgical condition that, in the opinion of any of the investigators, might preclude safe completion of the study or might affect the results of the study. These include conditions causing significant central nervous system or autonomic dysfunction, such as congestive heart failure, recent (<6 months) myocardial infarction, thrombocytopenia (<50 x 10(9)/L), immunosuppressed state, severe uncontrolled hypertension, severe cardiopulmonary disease, severe anemia (hemoglobin <8g/dl), severe liver or kidney disease (creatinine >2.3 mg/dl) uncontrolled diabetes mellitus (HgbA1c >10g%), alcoholism, malignant neoplasms, amyloidosis, uncontrolled hypothyroidism, unstable peripheral neuropathies, concurrent infections, orthopedic problems that compromise mobility and activities of daily living, severe cerebrovascular accidents (causing symptoms such as hemiplegia, aphasia and non-dominant parietal lobe syndrome), history of exposure to neurotoxins or neuroactive drugs, or parkinsonism due to drugs (including neuroleptics, alpha-methyldopa, reserpine, metoclopramide).

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy Control; Healthy controls will undergo a single magnetic resonance imaging (MRI) and PET (positron emission tomography) scan of the brain. In addition, all healthy controls will receive a comprehensive ophthalmic examination as well as undergo photography and imaging of the eye.	Device: Spectral-Domain Optical Coherence Tomography (SD-OCT); Each participant in this study will undergo Optical coherence tomography (OCT), a non-invasive imaging test of the eye, one time. OCT uses light waves to take cross-section pictures of the retina, which are generated using scattered light waves.; Other Names: Imaging of the Eye; Device: Magnetic Resonance Imaging (MRI); Each participant in this study will undergo a single Magnetic resonance imaging (MRI) scan, a scanning technique for creating detailed images of the human body. The scan uses a magnetic field and radio waves to generate images of the brain.; Device: Positron Emission Tomography (PET); Each participant in this study will undergo a single Positron emission tomography (PET) scan of the brain. PET is a nuclear medicine functional imaging technique that is used to observe metabolic processes in the brain as an aid to the diagnosis of disease using the combination of a radioactive tracer, camera, and a computer.; Diagnostic test: Comprehensive Ophthalmic Examination; Each participant in this study will receive one comprehensive eye examination which will be performed by a licensed ophthalmologist at the University of Michigan. This examination will include the assessment of the participant's visual acuity, a slit lamp examination which will look at the anterior and posterior tissues of the eye including the retina using various lights and lenses, and intraocular pressures.; Other Names: Comprehensive Eye Examination; Device: Fundus Photography; Each participant in this study will undergo fundus photography of each eye. Fundus photography involves the use of a retinal camera coupled with a low power microscope to capture photographs of the retina.; Other Names: Photography of the Eye
Alzheimer's Dementia; Subjects with Alzheimer's Dementia will undergo a single magnetic resonance imaging (MRI) and PET (positron emission tomography) scan of the brain. In addition, all subjects with Alzheimer's Dementia will receive a comprehensive ophthalmic examination as well as undergo photography and imaging of the eye.	Device: Spectral-Domain Optical Coherence Tomography (SD-OCT); Each participant in this study will undergo Optical coherence tomography (OCT), a non-invasive imaging test of the eye, one time. OCT uses light waves to take cross-section pictures of the retina, which are generated using scattered light waves.; Other Names: Imaging of the Eye; Device: Magnetic Resonance Imaging (MRI); Each participant in this study will undergo a single Magnetic resonance imaging (MRI) scan, a scanning technique for creating detailed images of the human body. The scan uses a magnetic field and radio waves to generate images of the brain.; Device: Positron Emission Tomography (PET); Each participant in this study will undergo a single Positron emission tomography (PET) scan of the brain. PET is a nuclear medicine functional imaging technique that is used to observe metabolic processes in the brain as an aid to the diagnosis of disease using the combination of a radioactive tracer, camera, and a computer.; Diagnostic test: Comprehensive Ophthalmic Examination; Each participant in this study will receive one comprehensive eye examination which will be performed by a licensed ophthalmologist at the University of Michigan. This examination will include the assessment of the participant's visual acuity, a slit lamp examination which will look at the anterior and posterior tissues of the eye including the retina using various lights and lenses, and intraocular pressures.; Other Names: Comprehensive Eye Examination; Device: Fundus Photography; Each participant in this study will undergo fundus photography of each eye. Fundus photography involves the use of a retinal camera coupled with a low power microscope to capture photographs of the retina.; Other Names: Photography of the Eye
Frontotemporal Dementia; Subjects with Frontotemporal Dementia will undergo a single magnetic resonance imaging (MRI) and PET (positron emission tomography) scan of the brain. In addition, subjects with Frontotemporal Dementia will receive a comprehensive ophthalmic examination as well as undergo photography and imaging of the eye.	Device: Spectral-Domain Optical Coherence Tomography (SD-OCT); Each participant in this study will undergo Optical coherence tomography (OCT), a non-invasive imaging test of the eye, one time. OCT uses light waves to take cross-section pictures of the retina, which are generated using scattered light waves.; Other Names: Imaging of the Eye; Device: Magnetic Resonance Imaging (MRI); Each participant in this study will undergo a single Magnetic resonance imaging (MRI) scan, a scanning technique for creating detailed images of the human body. The scan uses a magnetic field and radio waves to generate images of the brain.; Device: Positron Emission Tomography (PET); Each participant in this study will undergo a single Positron emission tomography (PET) scan of the brain. PET is a nuclear medicine functional imaging technique that is used to observe metabolic processes in the brain as an aid to the diagnosis of disease using the combination of a radioactive tracer, camera, and a computer.; Diagnostic test: Comprehensive Ophthalmic Examination; Each participant in this study will receive one comprehensive eye examination which will be performed by a licensed ophthalmologist at the University of Michigan. This examination will include the assessment of the participant's visual acuity, a slit lamp examination which will look at the anterior and posterior tissues of the eye including the retina using various lights and lenses, and intraocular pressures.; Other Names: Comprehensive Eye Examination; Device: Fundus Photography; Each participant in this study will undergo fundus photography of each eye. Fundus photography involves the use of a retinal camera coupled with a low power microscope to capture photographs of the retina.; Other Names: Photography of the Eye

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of Retinal Thinning	Imaging of the eye will be used to measure differences in retinal thickness between subjects with Alzheimer's Dementia, Frontotemporal Dementia, and healthy age-matched controls.	45 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of Amyloid Plaque	Fundus autofluorescence (FAF) will be used to detect the presence of lipofuscin	45 Minutes
Presence of Brain Pathology	MRI of the brain will be performed in order to determine if pathology observed on neuroimaging correlates quantitatively and/or qualitatively with retinal thickness.	60 Minutes
Presence of Brain Metabolism	PET scanning of the brain will be performed in order to determine if brain metabolism observed on neuroimaging correlates quantitatively and/or qualitatively with retinal thickness.	180 Minutes
Presence of Macular Vascular Anomalies	Imaging of the eye will be used to measure differences in vascular density between subjects with Alzheimer's Dementia, Frontotemporal Dementia, and healthy age-matched controls.	45 Minutes

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Principal Investigator: Cagri G. Besirli, MD PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2019
• Primary Completion (Actual): April 3, 2019
• Study Completion (Actual): April 3, 2019

Study Registration Dates

• First Submitted: October 5, 2018
• First Submitted That Met QC Criteria: October 5, 2018
• First Posted (Actual): October 9, 2018

Study Record Updates

• Last Update Posted (Actual): March 28, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Retina; Dementia; FTD
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Tauopathies; Language Disorders; Communication Disorders; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Dementia; Alzheimer Disease; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Nerve Degeneration
• Other Study ID Numbers: HUM00146956

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD Data may be shared if requests to the PI are made, a reasonable plan is proposed, and Data Use agreements are put in place.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No