Atlas of Retinal Imaging in Alzheimer's Study

Recruiting

• Conditions: Mild Cognitive Impairment; Mild Dementia; Alzheimer Disease; Cognitive Change; Aging
• Interventions: Other: Retinal Imaging; Other: Pupillometry; Other: Contrast Sensitivity; Diagnostic Test: Neuropsychological Evaluation; Genetic: APOE genotyping; Other: blood draw; Other: Gait Assessment; Other: Actigraphy

• Registration Number: NCT03862222
• Lead Sponsor: University of Rhode Island

Brief Summary

The Atlas of Retinal Imaging in Alzheimer's (ARIAS) study is a 5-year study examining the natural history of retinal imaging biomarkers associated with disease risk, disease burden, and disease progression in Alzheimer's disease (AD). The objective of this project is to create a 'gold standard' reference database of structural anatomic and functional imaging of the retina, in order to enable the identification and development of both sensitive and reliable markers of AD risk and/or progression. Our ultimate goal is to develop a new screening protocol that identifies changes related to AD 10-20 years before AD is clinically visible.

Detailed Description

This will be a longitudinal, within-participants prospective natural history study. Participants will be recruited on the basis of serial referrals to the memory disorders centers at all three investigative sites, as well as by Institutional Review Board (IRB)-approved radio, social media and print advertisements. All participants will meet inclusion/exclusion criteria for one of the four (4) participant groups. All participants will be recruited into the study over a 24-month enrollment period. Once enrollment closes, participants will be followed for 3 years, with examinations at one of the four study locations at baseline, 12 months post-enrollment, 24 months post-enrollment, and 36 months post-enrollment. All exam and testing procedures are described below. All retinal imaging will be completed on an FDA-approved clinical OCT imaging system by trained study personnel (with quality assurance and participant safety managed by two Co-Principal Investigator (PI)'s and their staff). Pupillometry and contrast sensitivity vision testing will rely on FDA-approved and commercially widely available devices and standard clinical procedures. All techniques are well-known to both PI's, and these techniques have been in regular use by their clinical research and/or clinical care groups for the past 6+ years.

During the screening visit a cheek swab will be obtained to determine apolipoprotein (APOE) genotype. Enrollment and group assignment will be established once the genotyping results are received (i.e., approximately 55 minutes following cheek swab, and by the end of each screening visit), at which point individuals who meet enrollment criteria will be scheduled for their baseline visit. PIs may choose to include disclosure of APOE genotyping results in their location-specific protocol, if they have the appropriate clinical resources and local IRB approval for disclosure procedures. Genotyping results will not be released to participants or their physicians except through the process of an IRB approved, site-specific protocol for disclosure.

At each study visit (i.e., baseline, 12 months, 24 months, and 36 months) participants will undergo an eye examination and screening for ophthalmic disease, a medical screening exam, vital signs, neuropsychological assessment, a blood sample for measurement of plasma biomarkers, and a full retinal imaging exam. All participants will be asked to provide consent to allow review of medical records, including relevant imaging (including both clinical reports and Digital Imaging and Communications in Medicine (DICOM) image files for computerized tomography (CT)/ magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) neuroimaging) and cerebrospinal fluid (CSF) biomarker evidence of AD, if available. Additional clinical and experimental endpoints will include measures of gait, sleep quality, social and psychological health, and pupillometry. Assessment of sleep architecture (i.e., actigraphy measures) will be collected via wearable trackers over the course of a 2-week period following the baseline and 36-month study visits. A subset of participants, in each of the subject groups, will be asked to take an over-the-counter herbal supplement (Longvida curcumin; Verdure Sciences, Inc., www.longvida.com) for two days prior to their baseline exams.

Study Timeline

• Study First Submitted: 2019-02-28
• Study First Submitted QC: 2019-02-28
• Study First Posted: 2019-03-05
• Study Start: 2019-12-16
• Status Verified: 2020-10
• Last Update Submitted: 2020-10-17
• Last Update Posted: 2020-10-20
• Primary Completion: 2021-12
• Study Completion: 2025-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 330

Inclusion Criteria

Not provided

Exclusion Criteria

• · Patients with histories of other ocular or neurologic disease that could affect the results, such as unusually high refractive errors ( > or < 5.0 diopters native spherical equivalent), age related macular degeneration, diabetic retinopathy, hypertensive retinopathy, retinal vascular disease, glaucoma, optic nerve disease, cystic macular edema, large cataracts or corneal disease that may preclude visualization of the retinal fundus, substantial ocular media opacity, and/or intraocular surgery within 90 days of any study visit will be excluded.

  • History of severe brain injury or other known neurologic disease or insult, which, as described by medical records, and/or as determined by the PI's clinical judgment, has resulted in lasting cognitive sequelae that would confound the assessment and staging of potential neurodegenerative disease.
  • Geriatric Depression Scale Short Form (GDS-S 15 Items) score > 6.
  • Poorly controlled major depression or another psychiatric disorder within the past year.
  • History of alcohol or substance abuse and/or dependence within the past 2 years (DSM-V criteria).
  • History of schizophrenia or a history of psychotic features, agitation or behavioral problems within the last 3 months, which could lead to difficulty complying with the protocol.
  • Participants who, in the investigator's opinion, will not comply with study procedures.
  • Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol including:
  • History of systemic cancer within the past 5 years (non-metastatic skin cancers are acceptable).
  • History of clinically significant liver disease, coagulopathy, or vitamin K deficiency within the past 2 years.
  • History of myocardial infarction within the past six (6) months or unstable or severe cardiovascular disease including angina or congestive heart failure (CHF) with symptoms at rest.
  • History of stroke(s) with lasting impairment to vision or the visual system, coagulopathy, uncontrolled hypertension (i.e., systolic BP > 170 or diastolic BP > 100) and uncontrolled or insulin requiring diabetes. Blood pressure will be recorded on the day of each examination.
  • Evidence of enlarged ventricles and/or normal pressure hydrocephalus on review of medical records or inspection of CT/MRI of the brain based on previous clinical diagnosis (MRI) as noted in their neurological history
  • History of Parkinson's disease, Parkinsonism due to multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Shy Drager Syndrome (SDS) or other neuro-degenerative dementias
  • History of symptoms of narrow-angle glaucoma (warning signs include eye pain, restricted vision, blurred vision)
  • History of elevated intraocular pressure, or medical record evidence of intraocular pressure > 20 mm Hg
  • Regular (daily) use of narcotics or antipsychotic medications.
  • New use of anti-Parkinsonian medications (e.g., sinemet, amantaine, bromocriptine, pergolide and selegiline) within 2 months prior to screening.
  • New use of anti-convulsants (e.g., phenytoin, phenobarbital, carbamazepine) within 2 months prior to screening.
  • New use of centrally active beta-blockers, narcotics, methyldopa and clonidine within 4 weeks prior to screening.
  • New use of neuroleptics or narcotic analgesics within 4 weeks prior to screening.
  • New and chronic use of long-acting benzodiazepines or barbiturates within 4 weeks prior to screening.
  • Use of short-acting anxiolytics or sedative-hypnotics more frequently than 2 times per week within 4 weeks prior to screening (note: sedative agents should not be used within 72 hours of the baseline and follow-up visits).
  • Initiation or change in dose of an antidepressant lacking significant cholinergic side effects within the 4 weeks prior to screening (use of stable doses of antidepressants for at least 4 weeks prior to screening is acceptable)
  • An anticholinergic burden score of >3 on the Anticholinergic Cognitive Burden Scale (see appendix item 9.19).
  • Known hypersensitivity to anticholinergic medications, including tropicamide eye drops.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Cognitively normal - low risk	Pupillometry	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - low risk	Contrast Sensitivity	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - low risk	Actigraphy	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - low risk	blood draw	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - high risk	Retinal Imaging	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
Cognitively normal - high risk	Contrast Sensitivity	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
Cognitively normal - high risk	Neuropsychological Evaluation	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
mild cognitive impairment	APOE genotyping	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
mild dementia	Neuropsychological Evaluation	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.
Cognitively normal - low risk	Retinal Imaging	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - low risk	APOE genotyping	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - high risk	Gait Assessment	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
Cognitively normal - high risk	Actigraphy	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
mild cognitive impairment	Pupillometry	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
Cognitively normal - low risk	Gait Assessment	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - low risk	Neuropsychological Evaluation	Adults aged 55-80 without subjective memory complaints, family history of Alzheimer's disease, or genetic risk for Alzheimer's disease.
Cognitively normal - high risk	APOE genotyping	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
mild dementia	Pupillometry	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.
mild dementia	Contrast Sensitivity	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.
mild dementia	APOE genotyping	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.
mild dementia	Gait Assessment	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.
Cognitively normal - high risk	Pupillometry	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
Cognitively normal - high risk	blood draw	Adults aged 55-80 with subjective memory complaints, first degree family history of Alzheimer's disease, and at least one copy of the APOE E4 gene, a risk gene for Alzheimer's disease
mild cognitive impairment	Neuropsychological Evaluation	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
mild dementia	Actigraphy	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.
mild cognitive impairment	Retinal Imaging	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
mild cognitive impairment	Contrast Sensitivity	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
mild cognitive impairment	Gait Assessment	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
mild cognitive impairment	blood draw	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
mild cognitive impairment	Actigraphy	Adults aged 55-80 who have a confirmed diagnosis of mild cognitive impairment.
mild dementia	Retinal Imaging	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.
mild dementia	blood draw	Adults aged 55-80 with mild dementia due to probable Alzheimer's disease.

Primary Outcome Measures

Name	Time	Method
Structural retinal biomarkers assessed with OCT	5 years	RNFL volume
Metabolic retinal biomarkers assessed with OCT	5 years	macular pigment optical density (MPOD)
vascular retinal biomarkers assessed with OCT-A	5 years	area of blood non-flow

Secondary Outcome Measures

Name	Time	Method
processing speed, attention	5 years	Digit Symbol Substitution Task (DSST)
physiological	5 years	gait assessment (timed get up and go + timed get up and go dual task)
general cognition	5 years	Repeatable Battery for the Assessment of Neuropsychological Status - Update (RBANS-U)
language	5 years	Redden Lab Speech/Language Task
memory	5 years	Free and Cued Selective Reminder Task (FCSRT)

Trial Locations

Locations (4)

Butler Hospital; 🇺🇸 Providence, Rhode Island, United States

St. Anthony's Hospital; 🇺🇸 Saint Petersburg, Florida, United States

University of Rhode Island; 🇺🇸 Kingston, Rhode Island, United States

Morton Plant Hospital; 🇺🇸 Clearwater, Florida, United States