Dr. Sagnik Sen, S18926, Dr. Pradeep Sharma, Dr. Radhika Tandon, Dr. Rohit Saxena
Introduction
Alzheimer’s disease (AD) is the most common dementia in the world and its incidence and prevalence are projected to double by 2050. Although conventionally Alzheimer’s has been diagnosed clinically using cognitive battery and neuroimaging like MRI and PET, efforts are ongoing to detect Alzheimer’s in the preclinical asymptomatic stage so that treatment or preventive strategies could be started at an earlier stage. In this regard, optical coherence tomography (OCT) has been studied over the past decade with some fruitful results. Our study evaluated a group of early stage Alzheimer’s patients using ocular tests for structural imaging and electrophysiology to detect changes suggestive of disease.
Methodology
A total of 15 Alzheimer’s patients were included in the study after being referred to our tertiary care centre from the Neurology department where they were screened for dementia using the Mini Mental State Examination. The inclusion criteria was best corrected visual acuity better than 6/12, intraocular pressure less than 18, wilfulness to participate and cooperation towards tests. The Global Deterioration Scale was used to determine the disease severity. 15 age matched controls were selected randomly from the outpatient department patients and included only after ruling out any ocular, neurological or cardiovascular diseases. All subjects underwent extensive ophthalmological examination including visual acuity, intraocular pressure, colour vision, contrast sensitivity, anterior segment and posterior segment examination. Any subject found to have posterior segment pathology which may result in OCT or electrophysiological changes were excluded. Spectral domain OCT using Cirrus HD-OCT 4000 (Carl Zeiss Meditec, US) was performed to detect the retinal nerve fibre layer (RNFL) thickness with the Optic nerve 200×200 program and the ganglion cell layer (GCL) thickness and macular volume using the Macular 520×128 program. Sensitivity was kept at 50% for the effective data collection. MetrovisionMonpack 3 vision monitor system was used to perform multifocal electroretinogram (mfERG) and pattern visual evoked response (pVER) for all patients. mfERG P1, N1 and N2 waves were evaluated. pVER P100 wave was evaluated. Descriptive statistics in the form of Mean ± Standard Deviation was used to analyse normally distributed variables. Pearson’s correlation coefficient were used to determine any correlations among variables and the strength of such correlations. Data was considered significant when 2-tailed p value was <0.05.
Results
The study evaluated 60 eyes of 15 patients and 15 controls. The demographic characteristics of the sample population is given in Table 1. The mean age of AD patients was 59.8 ± 6 .24 years (range 45-72). The median MMSE score in AD patients was 16 (range 10-23). The median duration of disease was 2.25 years (range 6 months-3.5 years).
Table 1: Demographic characteristics of AD cases and Healthy control subjects (mean ± SD)
| AD cases (n=15) | Healthy controls (n=15) | P value | |
| Age | 59.8 ± 6.24 | 60.7 ± 7.96 | 0.73 |
| Sex (M/F) | 8/7 | 6/9 | – |
| BCVA (logMAR) | 0.183 ± 0.14 | 0.125 ± 0.13 | 0.25 |
| IOP(mm Hg) | 14.67 ± 2.84 | 14.87 ± 2.6 | 0.84 |
| Contrast sensitivity | 1.4 ± 0.16 | 1.85 ± 0.1 | <0.001 |
| Median | |
| Disease duration (years) | 2.25 |
| Mini Mental State Examination score | 16 |
Mean BCVA of patients was 0.183 ± 0.14, which was essentially normal. Mean contrast sensitivity was significantly reduced in the AD cases (1.4 ± 0.16) according to the Pelli-Robson chart. The anterior segment, intraocular pressure, fundus examination and colour vision were within normal limits in all subjects. Visual fieldswere evaluated for all cases and found normal. The RNFL, GCL thicknesses and the Macular volume measured using SD-OCT have been shown in Table 2. The electrophysiological data analysed in the subjects has been recorded in Table 3. RNFL and GCL thinning was observed in AD patients along with significant electrophysiological abnormalities (p<0.001).
Table 2: Mean ± SD of SD-OCT parameters of nerve fiber layer, ganglion cell layer and macular volume
| Cases (n=30) | Controls (n=30) | P value | |
| Average nerve fibre layer thickness (um) | 73.43 ± 12.74 | 86.04 ± 11.42 | <0.001 |
| Average ganglion cell layer thickness (um) | 63.69 ± 14.77 | 84.99 ± 7.27 | <0.001 |
| Macular volume (cumm) | 8.98 ± 0.84 | 9.75 ± 0.42 | 0.001 |
Table 3: Mean ± SD of amplitudes of mfERG and pattern VER waves
| Cases (n=30) | Controls (n=30) | P value | |
| Average P1 amplitude (nV) | 896.26 ± 239.67 | 1135.33 ± 234.83 | <0.001 |
| Average N1 amplitude (nV) | -471.87 ± 119.07 | -609.01 ± 108.51 | <0.001 |
| Average N2 amplitude (nV) | -705.41 ± 209.66 | -1040.57 ± 224.89 | <0.001 |
| p100 amplitude (µV) | 7.62 ± 2.97 | 11.04 ± 2.89 | 0.015 |
| Average P1 implicit time (ms) | 48.57 ± 4.3 | 44.95 ± 2.05 | <0.001 |
| Average N1 implicit time (ms) | 28.47 ± 4.53 | 2.44 ± 2.57 | <0.001 |
| Average N2 implicit time (ms) | 65.28 ± 4.6 | 63.32 ± 5.2 | <0.001 |
| p100 latency (ms) | 120.01 ± 6.99 | 108.36 ± 4.84 | <0.001 |
The structural and functional changes of the retina and optic nerve were correlated with each other (Table 4). RNFL thickness changes significantly correlated directly with mfERG amplitude changes and inversely with implicit time. RGCL had a weaker yet significant correlation with the functional parameters. Pattern VER amplitude correlated directly with RNFL, RGCL changes and mfERG amplitudes significantly. Pattern VER latency correlated inversely with RNFL thickness and mfERG amplitude.
Table 4: Summary of correlation of structural and functional changes in the retina and optic nerve in AD patients
| r | P value | |
| Average RNFL thickness | ||
| Average P1 amplitude | 0.65 | <0.001 |
| Average N1 amplitude | 0.54 | 0.002 |
| Average N2 amplitude | 0.534 | 0.002 |
| Average N2 implicit time | -0.384 | 0.036 |
| P100 amplitude | 0.737 | <0.001 |
| P100 latency | -0.368 | 0.046 |
| Average RGCL thickness | ||
| Average P1 amplitude | 0.374 | 0.042 |
| Average N1 implicit time | -0.377 | 0.04 |
| P100 amplitude | 0.474 | 0.008 |
| P100 amplitude | ||
| Average P1 amplitude | 0.48 | 0.007 |
| Average N1 amplitude | 0.495 | 0.005 |
| Average N2 amplitude | 0.426 | 0.019 |
| Average N2 implicit time | -0.719 | <0.001 |
| P100 latency | ||
| Average P1 amplitude | -0.397 | 0.03 |
Discussion
Several studies have evaluated the RNFL using time domain and spectral domain OCT machines and found global thinning in Alzheimer’s patients.[1] [2] [3]Cheung et al evaluated the GCL separately and found thinning of the average GCL thickness in the macula.[4]Moschos et al evaluated the RNFL along with mfERG changes in AD patients and found a diffuse retinal electrical dysfunction, but they did not study the correlations between the different parameters.[5]Pattern VER has been found to be deranged in early stages of AD and it may represent an impairment in the anterior visual pathway function.[6]No study till date has evaluated the correlation between the structural and functional impairment present in Alzheimer’s patients. Our study has observed that there is a conclusive evidence of correlation between the structural degeneration and the functional impairment of the neural component of the eye in AD patients and these tests may help in evaluation of mild cognitive impairment cases in future.
References
- Iseri PK, Altinas O, Tokay T, Yuksel N. Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. J Neuroophthalmol. 2006;26: 18-24
- Paquet C, Boissonnot M, Roger F, Dighiero P, Gil R, Hugon J. Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. NeurosciLett. 2007; 420: 97-99
- Gunes A, Demirci S, Tok L, Tok O, Demerci S. Evaluation of retinal nerve fiber layer thickness in Alzheimer’s disease using spectral-domain optical coherence tomography. Turk J Med Sci 2014;44
- Cheung, Carol Yim-lui et al. Retinal Ganglion Cell Analysis Using High-Definition Optical Coherence Tomography in Patients with Mild Cognitive Impairment and Alzheimer’s Disease. J Alz Dis. 2015;45:45-56,
- Moschos MM, Markopoulos I, Chatziralli I, Rouvas A, Papageorgiou SG, Ladas I et al. Structural and functional impairment of the retina and optic nerve in Alzheimer’s disease. CurrAlzh Res. 2012;9:782-788
- Krasodomska K, Lubinski W, Potemkowski A, Honczarenko K. Pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) in the early stages of Alzheimer’s disease. Doc Ophthalmol. 2010;121:111-121
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