In this study, we compared retinal peripapillary perfusion density and microvascular density alterations by OCTA in AD and MCI patients with normal cognitively subjects. Besides that, we also estimated the effect of MAP and MOPP to interpret the progression of AD, which could be considered as confounding factors. Our data indicated that macular parameters (inner ring of macula, outer ring of macula), ONH parameters (inner ring of ONH, outer ring of ONH) and FAZ presented significant correlation with MMSE while the central section of macular and ONH presented no significant correlation with MMSE. In terms of MOPP and MAP, although the value of MAP showed significant difference among three groups, MAP showed no significant correlation with MMSE in Pearson’s and linear regression analyses. On the other hand, the value of MOPP showed no significant difference among three groups, which showed significant correlation with MMSE in Pearson’s and univariate linear regression analyses.
Studies from the association between elevated blood pressure (BP) and AD pathology indicated that the impact of BP has been still controversial. A number of evidence conducted that there was no association between late life hypertension and brain Aβ deposition[20–22]. However, some conflictual findings revealed that hypertension was associated with accelerated Aβ accumulation. Those variable results might be explained by findings from the following aspects: some data came from normal cognitively people and some research studied patients with reduced cognitive ability. Besides that, the diagnosis and measurement of hypertension also differed in those studies. Given the heterogeneity between studies, it should be difficult to make a meaningful analysis for the association between blood pressure and AD. The present study was partly consistent with previous research, reporting that the statistical difference in MAP did not markedly affect the association between MMSE and MAP. While the value of MOPP has shown different results: MOPP showed apparent relevance with MMSE although no significant difference was reached in primary values. One explanation for changes in MAP was that MAP depended on SBP and DBP regulation while MOPP depended on measurement of MAP and IOP, so MOPP might be more ideal than MAP to estimate the relevance between ocular vascular perfusion and the progression of AD. To the best of our knowledge, there has been few studies on changes of MOPP in patients with worsen cognitive decline. The majority of those research focused on the relationship between MOPP fluctuation and ocular ischemic disease with the optic nerve defect including diabetic retinopathy, glaucoma, non-arteritic anterior ischemic optic neuropathy (NAAION) [24–26]. MOPP has been shown strong association with the prevalence of those ocular disease. Thus MOPP might offer additional information to estimate the risk of cognitive decline and prediction of rates of neurodegeneration worsening.
A number of studies have also found that the presence of OCTA changes in patients developing neurodegenerative damage. Previous analysis has reported that the area of the FAZ was much larger in AD or MCI patients than the controls[15, 16, 27]. Our OCTA data demonstrated a markedly enlargement of the FAZ in AD cohorts, which is in line with previous reports. Besides, we noted that the area of FAZ was much greater in AD group than the MCI group, while we found no significant difference in FAZ area between MCI group and NC group. The enlargement of the FAZ has been regarded as an important signal for retinal capillary occlusion and retinal ischemia, Furthermore, we exhibited a significant correlation between FAZ and MMSE, so our data suggested that FAZ size might be an indicator for progression of cognitive impairment. Whereas Wu et al found significant difference in FAZ area in MCI patients comparing with control group, which is inconsistent with our findings. There may be various possible explanations for this discrepancy. First, the differences may be attributable to the small sample size, and the area of FAZ varies considerably between individuals in the study. Second, data obtained by different OCTA devices may not have good consistency due to various algorithms.
In terms of other OCTA data, previous studies demonstrated a decrease in retinal vessel density and increase in FAZ area in AD patients[15, 29]. Our observation exhibited similar differences in vessel densities centered on macular region in the dementia phase of MCI and AD patients. Based on our findings, we found the obvious decrease of vessel density in all retinal areas (center/inner/outer ring of the macula, center/inner/outer around the ONH) in AD group compared with the NC group. In contrast to the reduction of vessel density in all retinal areas, some researcher indicated the opposite result: they found vessel density in all retinal areas statistically significant higher in AD patients than the control. We assessed the explanation for those unexpected alterations might lie in the inflammatory reaction in the development of AD accompanied with Aβ accumulation. Supposing that inflammatory process in the onset stage of AD with ischemic and hypoxic damage might result in retinal vasoconstriction increasing, which would be detected by OCTA and documented as visible retinal vessel density. With the progress of AD, chronic inflammation and Aβ accumulation might cause loss of retinal microvasculature and the decrease in vessel density. Considering the significant differences in vessel density around macular and ONH between the cognitive impairment and the normal cognitive individuals, we also found correlations between MMSE and OCTA parameters, including FAZ, the inner/outer ring of the macula and the inner/outer ring of ONH, while no significant correlation was found in center of macula and center of ONH area. The univariate linear regression analysis was similar with the Pearson’s correlation data, except the center of macula and center of ONH area showed no association with MMSE, other OCTA parameters were correlated with MMSE significantly. However, only FAZ and outer ring of ONH showed statistical association with MMSE and the other OCTA parameters lost associations after multiple linear regression analysis. The possible explanations for the lack of this association might attribute to the distribution of the value of MMSE. Outcomes on calculation in MMSE and MoCA varied across individuals and placed a high load on personal abilities including language, education stratification. Although MoCA test seemed to fare better than MMSE in detecting cognitive impairment clinically, the MoCA score in our study exhibited obvious fluctuations and hardly normalization, so we chose MMSE score to represent the dementia phrase.
To the best of our knowledge, few studies have investigated OCTA features and ocular perfusion pressure in cognitive impairment patients simultaneously. Our study characterized the thorough OCTA descriptive indicators in participants with early and development stage of cognitive impairment. We explored vascular involvement in AD development extensively by analyzing MOPP and MAP.
We acknowledge some limitations to this study. This was a single-center, cross-sectional trial with a limited number of samples. It is necessary to conduct a larger number of subjects and follow-up study to confirm our findings. And due to the algorithms of OCTA, artifacts cannot be avoided. Furthermore, this only measure the central foveal area of 4.5×4.5mm, which may be limited in detecting early microvascular changes in outer region. PET scanning provided rather sensitive visualization of Aβ accumulation in vivo, which might be compared with OCTA parameters and MOPP in the future.
In summary, we found a significant lower retinal vessel density around macular and ONH regions in AD versus NC participants. We also discovered FAZ and outer ring of ONH showed strong association with MMSE score in multiple linear regression analysis, suggesting those two parameters could be possible biomarker for predicting the onset of AD clinically. No significant association was found between ocular perfusion indicators(MOPP/MAP) and MMSE in multiple linear regression analysis, however, we confirmed the significant difference among three groups and MOPP showed moderate association with MMSE in Pearson correlation and univariate linear regression analysis. Further in vivo studies are needed to understand the pathologic mechanistic insights into ocular vascular involvement in AD clinical process.