Purpose: The development of biomarkers for Alzheimer pathology makes it possible to recognize Alzheimer Disease (AD) before the onset of the cognitive and neuropsychiatric clinical phenotype. Electroretinogram (ERG) is a diagnostic test that measures the electrical activity generated by neural and non-neuronal cells in the retina in response to a light stimulus. Pattern ERG (PERG) stimulates the retina with alternating black/white bars while full-field flash ERG measures the massed bioelectrical response of the retina under dark-adapted and light-adapted conditions. Additionally, the photopic negative response (PhNR) is a slow negative component of the full-field ERG that has been shown to be specific for retinal ganglion cell (RGC) activity. Because patients with prodromal (early) AD with minimal cognitive impairment have abnormalities in RGCs as measured by ERG, we hypothesize that patients with preclinical AD whom are asymptomatic, will exhibit a significant reduction in the PERG N95-wave and PhNR amplitudes measured by ERG to detect earlier pathology of RGC function.
Methods: We prospectively enrolled participants aged 60-100 with preclinical AD and cognitively healthy adults (control), classified after medical, neuropsychological, ophthalmic and cerebrospinal fluid Aß42/pTau ratio examination. Standard PERG and full-field ERG were performed in 24 eyes of 12 patients with the preclinical stage of AD and compared to 24 eyes of 12 normal healthy controls. Recorded data were statistically analyzed using Welch’s t-test and Spearmen’s correlation.
Results: PERG and full-field ERG detected RGC dysfunction in preclinical AD. In PERG examination, increased N95-wave implicit times (P<0.05) and amplitude reduction in N95-waves (P<0.01) were observed indicating delayed responsiveness and degeneration of RGCs respectively. Mean full-field Photopic Negative Response (PhNR) amplitudes decreased significantly in preclinical AD compared to controls (P < 0.01), suggesting RGC degeneration. PhNR amplitude was also moderately correlated to CSF ratio of beta-amyloid (Aß42)/hyperphosphorylated Tau (pTau) (R2 = 0.50, p=0.003) which may be associated with early deposition of Aß42 and pTau.
Conclusions: The present study demonstrated retinal ganglion cell dysfunction in patients with preclinical AD as measured by PERG and full-field PhNR. Our findings suggest that electrophysiology may serve as a reliable and non-invasive means of assessing AD even prior to the onset of cognitive deficits.