Clinical Trial on Dementia, Alzheimer Disease, Mild Cognitive Impairment, Amyloid Angiopathy, Macular Ischemia - Clinical Trials Registry

Study Overview

Status

Completed

Conditions

Detailed Description

Alzheimer disease dementia (ADD) is the most common neurodegenerative disease dementia in elderly population associated with the accumulation of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles (NFTs). Diagnostic biomarkers reflecting underlying amyloid or tau pathology of ADD have actively been developed. Of these, amyloid or tau positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) Aβ1-42 or phosphorylated tau are representative biomarkers for ADD. However, these tend to be expensive, invasive, or available only in a tertiary hospital or a specialized laboratory. Alternative biomarkers which are inexpensive, less invasive, and highly available could be needed.

Patients with ADD commonly show visuospatial dysfunction which is mainly attributed to damage of parieto-occipital or temporo-occipital visual pathway. In addition, previous studies using optical coherence tomography (OCT) which is a useful tool measuring retinal nerve fiber layer thickness (RNFLT), macula ganglion cell/inner plexiform layer thickness (GC/IPLT) reported impaired pregeniculate afferent visual pathway, for example, reduction of RNFLT and loss of retinal ganglionic cells (RGCs) in patients with ADD.

The retina and brain have the same embryological origin. These were branched off from the forebrain, so the brain and retina have similar anatomic and physiologic traits of the vasculature. In line with this, several studies using laser doppler ultrasonography, or retinal function imager (RFI) revealed narrowed central retinal vein and decreased its blood velocity, or low blood flow rate of retinal arterioles and venules in patients with mild cognitive impairment (MCI) and ADD. The authors suggested that in patients with ADD, accumulation of Aβ in the vessel walls could cause disruption of basement membrane and endothelium, leading to the decreased vascular lumen and density of retinal vessel. Indeed, postmortem study revealed accumulated Aβ inside or around RGCs in AD.

OCTA can clearly visualize not only the specific layers of retinal vasculatures, including superficial, middle, and deep capillary plexuses, but also choroidal vessels with a high resolution and in a reproducible manner, without contrast agent. A few prior studies using OCTA reported enlarged foveal avascular zone (FAZ) and decrease of retinal vascular density and choroidal thickness in ADD or MCI compared to controls. On the other hand, the others showed no differences in FAZ area and vessel density between them.

In this study, the investigators first evaluated structural and microvascular changes of retina and the microvascular change of macula and optic disc in patients with clinically diagnosed ADD, MCI and cognitively normal controls using OCT and OCTA. Then, to investigate whether impaired pregeniculate visual pathway is truly associated with underlying amyloid pathology, the investigators further investigated those OCT and OCTA parameters in each subgroup with positive or negative amyloid biomarker.

Study Type

Observational

Enrollment (Actual)

117

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Korea, Republic of
- - Busan, Korea, Republic of, 49241
    - Pusan National University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Neurologic Clinic of Pusan National University Hospital

Description

Inclusion Criteria:

Clinical and pathologic diagnosis of ADD or MCI as well as cognitively unimpaired control (CU) from the Neurologic Clinic of Pusan National University Hospital

Exclusion Criteria:

Patient not within the ages of 50-90 years old
Patient with glaucoma, macular degeneration, retinal vascular disease including diabetic retinopathy, retinal vein occlusion
Intraocular pressure (IOP) ≥ 21 mmHg
Dense corneal or ocular media opacity
History of ocular trauma or associated ocular disease
Astigmatism ≥ 3.0 diopter or spherical equivalent ≥ 6.0 diopter
Best corrected visual acuity (BCVA) < 20/40
Any ocular surgery except uncomplicated cataract extraction
Uncontrolled hypertension and diabetes

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Observational Models: Cohort
Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort
Dementia Patients with Alzheimer disease dementia (ADD) fulfilled the NIA-AA core clinical criteria for probable ADD and Aβ positive according to ATN classification scheme. Aβ positive refers to Aβ pathology (CSF Aβ1-42 < 631.8 pg/ml or positive amyloid deposits on 18F-flutemetamol PET by visual inspection).
MCI (Mild cognitive impairment) Patients with mild cognitive impairment (MCI) met the Petersen's criteria.
CU (Cognitively unimpaired control) CU consisted of cognitively unimpaired subjects whose cognition (as defined by the Seoul Neuropsychological Screening Battery (SNSB)) was within normal limits.
Aβ positive Aβ positive refers to Aβ pathology (CSF Aβ1-42 < 631.8 pg/ml or positive amyloid deposits on 18F-flutemetamol PET by visual inspection).
Aβ negative Aβ negative was within normal limits.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SD-OCT imaging Time Frame: Through study completion, measured at enrollment and analyzed from September 2019 to July 2021	Measuring macular GC/IPLT (μm) and cimcumpapillary RNFLT (μm). The average, minimum, and 6 sectoral (superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal) GC/IPLT (μm) values are obtained. The average, 4 sectoral (temporal, superior, nasal, and inferior), and 12 clock-hour circumpapillary RNFLT (μm) are obtained. Multiple measurements will not be aggregated, but analyzed respectively.	Through study completion, measured at enrollment and analyzed from September 2019 to July 2021
SD-OCTA imaging Time Frame: Through study completion, measured at enrollment and analyzed from September 2019 to July 2021	Acquiring microvasculature images of macular (6 × 6 mm^2 scan) and optic disc areas (4.5 × 4.5 mm^2 scan). The average vessel density (VD, mm/mm^2) and perfusion density (PD, %) were automatically measured in the Early Treatment of Diabetic Retinopathy Study (ETDRS) grid with values shown in the nine subfields, central, inner, outer and full region. The software calculated the area (mm^2), perimeter (mm), and circularity (defined as 4πA/P^2, where A was the area and P was the perimeter) of foveal avascular zone (FAZ). A circularity closer to 0 means an irregular shape, and closure to 1 indicates a circular shape. Multiple measurements will not be aggregated, but analyzed respectively.	Through study completion, measured at enrollment and analyzed from September 2019 to July 2021

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic performance Time Frame: Through study completion, analyzed from July 2021 to July 2022	Diagnostic performance of OCT and OCTA parameters according to underlying Aβpathology. Receiver operating characteristic (ROC) curves were drawn by plotting sensitivity against 1-specificity, and areas under ROC curves (AUCs) were used to evaluate the diagnostic performance of continuous OCT/OCTA variables. Ideal cut-off points were derived using the Youden index	Through study completion, analyzed from July 2021 to July 2022
Correlations Time Frame: Through study completion, analyzed from July 2021 to July 2022	Correlations between MMSE score and all of OCT/OCTA parameters were expressed as Pearson's or Spearman's rank correlation coefficients to account for the normal or non-normal distribution of the parameters, respectively. OCT/OCTA parameters including as follows; macular GC/IPLT (μm): average, minimum, and 6 sectoral (superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal) GC/IPLT cimcumpapillary RNFLT (μm): verage, 4 sectoral (temporal, superior, nasal, and inferior), and 12 clock-hour circumpapillary RNFLT Macular vessel density (VD, mm/mm^2) & perfusion density (PD, %) : VDs and PDs of central, parafoveal (nasal, temporal, superior, inferior), perifoveal (nasal, temporal, superior, inferior), and total Optic disc perfusion density (%) and flux index (from 0 to 1) : nasal, temporal, superior, inferior	Through study completion, analyzed from July 2021 to July 2022

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Pusan National University Hospital

Investigators

Principal Investigator: Eun-Joo Kim, MD, PhD, Department of Neurology, Pusan National University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2019

Primary Completion (Actual)

July 31, 2021

Study Completion (Actual)

July 31, 2021

Study Registration Dates

First Submitted

June 23, 2022

First Submitted That Met QC Criteria

July 24, 2022

First Posted (Actual)

July 26, 2022

Study Record Updates

Last Update Posted (Actual)