Study to Detect Dendritic Cell Recruitment in Human Retina

This methods development pilot study is intended to determine if human phagocytic cells labeled with the near-infrared dye ICG in the periphery can subsequently be detected in association with retinal pathology in two cohorts of participants: 1) patients with Dry AMD with geographic atrophy (GA), N = 2-6; and 2) patients diagnosed with either mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or with mild AD, N = 2-6. Conversely, it is hypothesized that these cells will be largely absent in healthy control participants (N = 2-3). For both disease conditions, retinal pathology includes inclusions that contain amyloid plaques, areas of retinal thinning and neuronal loss, damage to the RPE and choroid, and changes in vascular structure. Accumulation of ICG-labeled cells should be seen close to the border(s) of GA in the Dry AMD participants. The imaging results for each participant will be reviewed by the study team to modify the imaging approach for the next participant. A maximum of fifteen (15) subjects will be recruited for participation, and a maximum of 3 of these participants will be healthy control participants without any retinal pathology.

Inclusion criteria

• All Study Participants

• Male or female and between the ages of 55 to 80 years old (inclusive)
• Participants are determined by the qualified investigator to be medically stable and able to understand and agree to comply with the study procedures and report for scheduled study visits.
• Participants have adequate hearing, vision, and language skills to provide informed consent and to cooperate with all retinal imaging, cognitive testing, interviews and other medical procedures as specified in the protocol. Hearing augmentation (i.e., hearing aids) are allowed.
• Participants are able to reliably communicate with study personnel about adverse events (AEs) and concomitant medications.
• Provide signed written informed consent according to institutional guidelines. Participants with mild AD must be able to provide assent and be accompanied by a relative or caregiver who is empowered to provide written consent.
• Permitted medications stable for at least 1 month prior to screening. In particular:

• Participants may take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past year).
• Healthy Elderly Participants

• MMSE score > 27
• CDR score = 0
• No current or past history of first-degree relative(s) with either a diagnosis of AD or suspected AD, and no subjective memory impairment with persisting worries.
• If any such test results are available, no APOE e4 allele positivity or abnormal beta-amyloid protein aggregation as assessed by blood plasma, PET imaging or CSF analyses.
• No evidence of any retinal/ocular diseases, other than myopia or hyperopia
• No evidence of any neurological / neurodegenerative diseases
• Participants with Dry AMD with GA

• MMSE score > 27
• CDR score = 0
• Advanced non-neovascular stage AMD, as determined by qualified neuro-ophthalmologist or retinal specialist
• No evidence of choroidal neovascularization (CNV) in study eye - current or historical
• Best Corrected Visual Acuity (BCVA) ≥ 20/80
• Low-luminance visual acuity deficit, defined as the difference between BCVA and LLVA > 5 letters
• Cumulative GA lesion size 1.27 mm2 (approximately ≥ 0.5 disc area (DA)) and ≤ 10.16 mm2 (approximately ≤ 4.0 DA). Standard DA is equivalent to 2.54 mm2 on the retina.
• Participants with Dry AMD who are not (yet) being treated with a complement system inhibitor (intravitreal injections).
• Participants with Mild Cognitive Impairment (MCI) due to AD or mild AD

• MMSE score > 21
• CDR score between 0.5 and 1.0
• MoCA total score > 18 and < 26 at screening
• Positive prior biomarker evidence of Alzheimer's disease (blood plasma marker(s), PET imaging, or CSF assays), by review of available medical records
• A clinical diagnosis of either mild cognitive impairment (MCI) due to AD, or mild AD, from qualified specialist or from a memory disorders clinic or center
• Participants must have a study partner (i.e., family member, close friend, or caregiver) who can attend study appointments with them.
• Because this study does not include any form of therapeutic intervention, participants' concurrent enrollment in other clinical trials for MCI or AD is allowed, including those that involved the use of investigational drugs. Relevant information about other studies in which individuals are participating (e.g., study name, sponsor) will be made available and recorded on their case report forms (CRFs).

Exclusion criteria

• Medical History

• Participants with a history of any anaphylactic reactions to drugs
• Participants with a history of allergic reaction to ICG
• Participants with a history of iodine sensitivity and/or allergic reaction to iodine
• Participants with a history of a clinically significant hepatic disease
• Participants with a Modified Hachinski Ischemia Scale (MHIS) score > 2
• Participants with a known hypersensitivity to tropicamide eye drops or other anticholinergic medications
• Participants with histories of other ocular or neurologic disease that could affect the results including, but not limited to, diabetic retinopathy or glaucoma.
• Geriatric Depression Scale Short Form (GDS-S 15 Items) score > 6.
• Target Disease Exceptions

• Any participant diagnosed to have an autoimmune disorder, including but not limited to

• Psoriasis
• Lupus
• Rheumatoid arthritis
• Crohn's disease
• Multiple sclerosis
• Alopecia areata
• Any participant who has any unstable cardiovascular (included uncontrolled hypertension), pulmonary, or GI disease.
• 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.
• Participants who, in the investigator's opinion, have any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol including (but not limited to):

• History of myocardial infarction within the past six (6) months or unstable or severe cardiovascular disease including angina or CHF with symptoms at rest.
• Uncontrolled hypertension (i.e., systolic BP > 170 or diastolic BP > 100)
• Uncontrolled (A1C>7) or insulin requiring diabetes.
• 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
• Concurrent Medications

• Any participant who is immunocompromised at screening including taking medications that are systemic immunosuppressives including corticosteroids but not NSAIDS
• Any participant currently prescribed a biologic immunosuppressive therapy or having taken such therapy in the prior 3 months, including

• abatacept (Orencia)
• adalimumab (Humira)
• anakinra (Kineret)
• certolizumab (Cimzia)
• etanercept (Enbrel)
• golimumab (Simponi)
• infliximab (Remicade)
• ixekizumab (Taltz)
• natalizumab (Tysabri)
• rituximab (Rituxan)
• secukinumab (Cosentyx)
• tocilizumab (Actemra)
• ustekinumab (Stelara)
• vedolizumab (Entyvio)
• Monoclonal antibodies
• basiliximab (Simulect)
• daclizumab (Zinbryta)
• Regular (daily) use of narcotics or antipsychotic medications. Low doses for off-label use may be permitted, as determined by the principal investigator's clinical judgment and if stable for 4 weeks prior to screening.
• New use of anti-Parkinsonian medications (e.g., sinemet, amantaine, bromocriptine, pergolide and selegiline) within 2 months prior to screening. Low doses for off-label use may be permitted, as determined by the principal investigator's clinical judgment and if stable for 2 months prior to screening.
• New use of anti-convulsants (e.g., phenytoin, phenobarbital, carbamazepine) within 2 months prior to screening. Low doses for off-label use may be permitted, as determined by the principal investigator's clinical judgment and if stable for 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.
• Initiation or change in dose of an antidepressant within 4 weeks prior to screening (use of stable doses of antidepressants for at least 4 weeks prior to screening is acceptable)
• Any participant currently or previously treated for Dry AMD with a complement system inhibitor.
• Physical and Laboratory Test Findings at Screening

• Any participant, in the clinical judgement of the qualified investigator, with uncontrolled hypertension, abnormal systolic BP, or abnormal heart rate at screening (e.g., repeated diastolic measurements ≥ 96 mmHg).
• Any participant with either of the following hepatic test abnormalities at screening:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the institutional ULN
• Total Bilirubin > 2 times the institutional ULN
• Any participant with P-Amylase or Lipase values > 2 times the ULN at screening
• Any participant at screening with insulin-dependent diabetes mellitus or HbA1C ≥ 6.5%
• Abnormal liver function test laboratory results, as determined by screening visit (pre-ICG infusion) safety lab tests
• Any participant at screening with pathologic renal findings as defined by the presence of calculated glomerular filtration rate (GFR) (creatinine clearance) ≤45 ml/min/1.73m2 (2021 revision of CKD-EPI formula for GFR estimate)
• Any participant at screening with any of the following hematologic abnormalities:

• Hemoglobin < 10g/dL
• WBC < 3.0 x 103/mm3
• Platelet count < 100,000/mm3
• Any participant who has a known infection with a human immunodeficiency virus, hepatitis B virus, or hepatitis C virus.
• Any participant with a positive urine drug screen with no concomitant medication to justify the results.