Decreased thickness of the retinal nerve fiber layer (RNFL) may reflect retinal neuronal-ganglion cell death. A decrease in the RNFL has been demonstrated in Alzheimer’s disease (AD) in addition to aging by optical coherence tomography (OCT). Twenty-three mild-AD patients and 28 age-matched control subjects with mean Mini-Mental State Examination 23.3 and 28.2, respectively, with no ocular disease or systemic disorders affecting vision, were considered for study. OCT peripapillary and macular segmentation thickness were examined in the right eye of each patient. Compared to controls, eyes of patients with mild-AD patients showed no statistical difference in peripapillary RNFL thickness (
Alzheimer’s disease (AD), the most common cause of dementia, afflicts 67 of every 1000 persons over age 65. Its prevalence and incidence increase exponentially with age [
AD is characterized by a decline in cognitive function, loss of learning and memory, and the formation of neuritic plaques and neurofibrillary tangles, primarily in the cerebral cortex [
The retina is a projection of the brain, and a number of similarities between AD pathology and several distinct retinal degenerations have been described [
The RNFL reportedly thins with aging [
Currently it is thought that retinal ganglion cell (RGC) loss in AD might result from amyloid deposits in the eye and/or retina. Amyloid-beta plaques as well as oligomers have been reported in postmortem retinal tissue from patients with AD and in a mouse model of AD, as well as in human retinal tissue
Diagnosis and progression of AD, especially early cases, are complicated because of imprecise neuropsychological testing, sophisticated but expensive neuroimaging techniques, and invasive sampling of cerebrospinal fluid [
OCT is a reliable noninvasive technique, routinely used in ophthalmology to visualize and quantify the layers of the retina. OCT enables quantitative cross-sectional imaging of the RNFL and macular volume. A recent study published by our group [
The goal of the present study was to examine in detail peripapillary and macular segmentation in order to determine which is the earliest thinned area in patients with mild AD which may be used, in the future, as a predictive tool.
To select patients, we reviewed the Database of the Memory Unit of the Hospital Clinico San Carlos in Madrid (Spain), consisting of a total of 2635 patients. First, we excluded the patients with a Global Deterioration Scale (GDS) over 4 and then those with a mood or psychiatric disorder. Next, we took into account 87 patients with mild AD. These patients, according to the National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association and the Diagnostic and Statistical Manual of Mental Disorders IV, had mild cognitive impairment according to the Clinical Dementia Rating scale. Then ophthalmic medical records of these patients were reviewed, excluding patients who were previously diagnosed with an ophthalmological pathology (glaucoma or suspected glaucoma, media opacity, and retinal diseases). After this analysis, 29 patients with AD satisfied all the requirements to participate in the study (GDS over 4 and free of ocular disease and systemic disorders affecting vision in their medical record). Of the 29 mild-AD patients and 37 age-matched control subjects selected (normal MMSE scores), 6 mild-AD patients and 9 age-matched control subjects were subsequently excluded due to posterior pole pathology including macular degeneration, drusen, suspicion of glaucoma, glaucoma, epiretinal membrane, or cataract that prevented ocular examination. Because of this selection, 23 patients with mild AD and 28 age-matched control subjects were considered for the study. Informed consent was obtained from both groups. The research followed the tenets of the Declaration of Helsinki, and the protocol was approved by the local ethics committee.
For the ophthalmological part of the study, the right eye of each patient was analyzed. All participants met the following inclusion criteria: being free of ocular disease, AREDS Clinical Lens Standards <2, retinal drusen, and systemic disorders affecting vision; having a best corrected VA of 20/40; having a ±5 spherocylindrical refractive error; and having intraocular pressure of less than 20 mmHg. For screening, all AD patients and control subjects underwent a complete ophthalmologic examination, including assessment of VA, refraction, anterior segment biomicroscopy, applanation tonometry (Perkins MKII tonometer, Haag Streit-Reliance Medical, Switzerland), dilated fundus examination, and OCT. The RNFL thickness and macular thickness were measured by OCT Model 3D OCT-1000 (Topcon, Japan) after pupil dilatation. The RNFL thickness was scanned 3 consecutive times per patient in each area studied. The mean values were considered for statistical analysis. All tests were performed by the same optometrist (ESG) under the same conditions. These tests were selected considering that in this developmental stage of the disease the results were not influenced by the patient’s cognitive impairment.
The peripapillary RNFL thickness parameters evaluated in this study were average thickness (360° measurement), thickness for each 12-o’clock hour position with the 3-o’clock position as nasal, 6-o’clock position as inferior, 9-o’clock position as temporal, and 12-o’clock position as superior. Macular RNFL thickness data were displayed in three concentric rings centered in the foveola that were distributed as follows: a central macular ring, 1 mm away from the fovea; an inner macular ring, 3 mm away from the fovea; and an outer macular ring, 6 mm away from the fovea. As a result, the total area studied made up a 6 mm macular map. In addition, the inner and outer rings were each divided into four quadrants (superior, inferior, nasal, and temporal) (Figure
OCT report of retinal nerve fiber layer (RNFL) thickness analysis. (a) Peripapillary OCT. The thickness for each 12-o’clock hour position with the 3-o’clock position as nasal, 6-o’clock position as inferior, 9-o’clock position as temporal, and 12-o’clock position as superior was evaluated. (b) Macular OCT. Diagram showing the concentric rings and quadrants considered for analysis of the macular RNFL thickness and measurements automatically provided by the analyzer.
The data are reported as mean values ± SD. The differences between mild AD and control eyes were analyzed using the Mann-Whitney test. Data for the statistical analysis were introduced and processed in a SPSS 19.0 (SPSS Inc©, Inc, Chicago, IL, USA). A
Demographic and clinical data for the mild-AD patients and control group are shown in Table
Demographic and clinical data of the study groups.
AD | Control |
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( |
( | ||
Age |
79.3 ± 4.6 | 72.3 ± 5.1 | 0.274 |
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Gender | |||
Male | 9 | 9 | 0.615 |
Female | 14 | 19 | |
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Race | Caucasian | Caucasian | |
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MMSE |
23.3 ± 3.1 | 28.2 ± 1.9 | 0.001 |
Range (17–29) | Range (25–31) |
RNFL thickness and total macular volume.
Retinal area of study | AD group |
Control group |
% RNFL decrease |
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Peripapillary thickness ( |
Sector 1 | 101.2 ± 24.4 | 100.0 ± 16.9 | 1.24 | 0.790 |
Sector 2 | 96.8 ± 20.8 | 100.4 ± 14.4 | −3.62 | 0.618 | |
Sector 3 | 80.1 ± 22.9 | 90.8 ± 16.0 | −11.85 | 0.084 | |
Sector 4 | 60.5 ± 18.3 | 65.4 ± 10.3 | −7.60 | 0.464 | |
Sector 5 | 73.7 ± 12.7 | 68.3 ± 11.3 | 7.83 | 0.173 | |
Sector 6 | 101.4 ± 23.7 | 99.3 ± 19.0 | 2.02 | 0.790 | |
Sector 7 | 119.4 ± 19.1 | 116.3 ± 21.9 | 2.62 | 0.756 | |
Sector 8 | 111.7 ± 21.6 | 114.5 ± 24.5 | −2.48 | 0.564 | |
Sector 9 | 66.3 ± 18.2 | 67.5 ± 16.5 | −1.80 | 0.877 | |
Sector 10 | 60.7 ± 13.8 | 57.3 ± 9.6 | 5.99 | 0.464 | |
Sector 11 | 77.0 ± 20.6 | 78.5 ± 14.7 | −1.96 | 0.94 | |
Sector 12 | 101.3 ± 27.1 | 110.7 ± 15.8 | −8.45 | 0.335 | |
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Foveal thickness ( |
Fovea | 221.2 ± 21.6 | 243.7 ± 24.8 | −9.24 | 0.015 |
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Inner macular quadrant ( |
Superior area | 283.4 ± 11.1 | 294.9 ± 18.1 | −3.91 | 0.002 |
Inferior area | 279.8 ± 18.1 | 295.8 ± 13.5 | −5.40 | 0.002 | |
Nasal area | 285.6 ± 17.2 | 300.1 ± 15.1 | −4.83 | 0.007 | |
Temporal area | 273.1 ± 12.7 | 285.2 ± 14.6 | −4.22 | 0.002 | |
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Outer macular quadrant ( |
Superior area | 245.4 ± 12.5 | 252.1 ± 13.7 | −2.65 | 0.084 |
Inferior area | 242.8 ± 17.4 | 245.2 ± 13.9 | −0.99 | 0.531 | |
Nasal area | 263.7 ± 12.1 | 267.5 ± 19.1 | −1.41 | 0.110 | |
Temporal area | 228.0 ± 18.8 | 238.5 ± 12.3 | −4.43 | 0.009 | |
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Total macular volume (mm3) | 7.1 ± 0.3 | 7.3 ± 0.3 | 9.34 | 0.024 |
Mean data of RNFL thickness against eye quadrants assessed with optical coherence tomography (OCT). (a) Peripapillary segmentation retinal nerve fiber layer, (b) Central macular ring (1 mm away from the fovea). (c) Inner macular ring (3 mm away from the fovea). (d) Outer macular ring (6 mm away from the fovea).
Although the differences were not significant in any of the sectors, it was shown that peripapillary sectors 2, 3, 4, 8, 9, 11, and 12 were thinner in the mild-AD patients than in controls; in peripapillary sectors 1, 5, 6, 7, and 10 the retina in mild-AD patients was thicker with respect to the control (Figure
The total macular volume was significantly reduced in mild-AD patients in comparison with control subjects (
Alzheimer’s dementia syndromes, like all neurodegenerative diseases, lack objective disease- and stage-specific biomarkers [
Thinning of the RNFL has been found in several neurological diseases, such as Parkinson’s disease [
In the present work, we compare the peripapillary RNFL segmentation thickness, macular thickness, and the total macular volume in mild-AD patients and age-matched control subjects. One of the relevant issues of the study was that the sample analyzed here was homogeneous in that (i) all patients had recently been diagnosed as having mild AD (GDS 4, Reisberg scale [
Widespread axonal degeneration in the optic nerve was found in a postmortem study of patients with AD [
There is controversy on the reduction of the peripapillary RNFL thickness measured by OCT in AD. A reduction in the thickness of all peripapillary RNFL quadrants as measured by OCT has been reported [
Most authors, although working in more advanced stages of disease (MMSE > 23.7), agree that the peripapillary RNFL thinning is significant in the superior and inferior sectors [
Reactive astrogliosis in the brain is a well-known feature of AD, but its role in AD is not well understood. Reactive astrogliosis tends to be focal in AD. Reactive astrocytes are intimately associated with amyloid plaques or diffuse amyloid deposits. Astrocytes surround them with dense layers of processes as if forming miniature scars around them, perhaps to wall them off and act as neuroprotective barriers [
In the same way, retinal neurodegenerative diseases are also associated with chronic microglial activation and neuroinflammation. In the degenerating retina, endogenous signals activate microglial cells, leading to their local proliferation, migration, enhanced phagocytosis, and secretion of cytokines, chemokines, and neurotoxins. These immunological responses and the loss of limiting control mechanisms may contribute significantly to retinal tissue damage and proapoptotic events in retinal neurodegeneration [
In the present study, the analysis of the OCT values of both peripapillary and macular RNFL thickness in patients with mild AD (MMSE = 23.7) showed that only in the macula was there a significant thickness reduction compared to aged-matched controls. Our data, taken together with those reported in the literature, move us to propose the hypothesis that the first affected area of the retina in mild AD is the macular area, where, due to the arrangement of the multilayer bodies of the ganglion cells, the decrease is easier to detect.
Subsequently, as the neurodegeneration progresses, a significant decline in peripapillary RNFL thickness will become apparent. The study of the peripapillary segmentation reveals, in a more accurate way, the changes that occur in RNFL thickness in relation to the macular-thickness changes. In this sense, our patients with mild AD differed with respect to controls, although without reaching statistical significance; perhaps due to the early stage of the disease. In addition, the increase in peripapillary thickness in our mild-AD patients may indicate the existence of an inflammatory process that would lead to neurodegeneration of the peripapillary fibers. More extensive studies should be conducted to test these findings.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by the Ophthalmological Network OFTARED (RD12-0034/0002: Prevención, Detección Precoz y Tratamiento de la Patología Ocular Prevalente Degenerativa y Crónica)