Introduction Normal brain function requires appropriate provision of oxygen, glucose, and other nutrients. This requirement is fulfilled through continuous adjustment of cerebral blood flow (CBF), the process also known as neurovascular coupling (NVC). Therefore, impairment of the resting CBF or impairment of NVC in the brain may be responsible for the development of vascular cognitive deficits in aging. A novel method, Dynamic Retinal Vessel Analysis (DVA) allows evaluation of NVC responses in the retinal circulation in response to photoreceptor stimulation. Considering that human retina shares similar embryologic origins with the central nervous system, this approach may provide a novel and non‐invasive tool to screen subjects at risk for development of vascular cognitive impairment. In this study, we hypothesize that examination of retinal vessels may provide a proxy measure of the microcirculatory health of the brain. We test whether the arterio‐venous ratio (AVR) and NVC measured in the retina correlate with age, cognitive function, central and cerebrovascular hemodynamics. Methods For our study, we enrolled 44 healthy adults 23–86 years of age. DVA and static vessel analysis was performed using a mydriatic retinal camera to determine retinal NVC and AVR. Transcranial Doppler Sonography (TCD) was used to assess resting CBF velocity and pulsatility in the middle cerebral artery (MCA). Pulse Waveform Analysis was used to measure central hemodynamic pressures. and stiffness (augmentation index, AIx) was calculated from these results. Cognitive performance was assessed using Cambridge Neuropsychological Cognitive Test Automated Battery (CANTAB), specifically, Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) tests. Spearman’s correlation between variables was used for statistical analysis. Results Retinal NVC showed negative (rho=−0.48, p=0.02), and MCA pulsatility showed positive (rho=0.69, p<0.01) correlation with aortic pulse pressure. Neither of these vascular parameters correlated with central arterial stiffness (AIx). Older age was associated with decreased cognitive performance: total errors on PAL test (PALTEA28, rho=0.49, p<0.01),mean latency to the correct response during DMS (DMSMLAD, rho=0.46, p<0.01), and correct responses in DMS (DMSPC rho=−0.43, p<0.01). AVR correlated negatively with PALTEA28 (rho=−0.48, p<0.01) and positively with DMSPC (rho=0.64, p<0.01), retinal arteriolar dilation correlated negatively with DMSMLAD (rho=−0.32, p=0.04). Conclusions Our results demonstrate that age‐related changes in the macrocirculation lead to the maladaptation and decreased reactivity of retinal microcirculation. The association between retinal‐, and brain hemodynamics, together with cognitive performance suggests that the retinal microcirculation may reflect the health of the cerebral microcirculation.
Background It is predicted that by the year 2030 every 5 th American will be >65 years of age. There is growing importance to understand age‐associated changes that lead to vascular cognitive impairment (CI) and dementia. Normal brain function is critically dependent on moment‐to‐moment adjustment of cerebral blood flow (CBF) to neuronal activity, the process also known as neurovascular coupling (NVC). It is now well established that diminished NVC, specifically in cerebral microvasculature, plays a causal role in CI in animal models of aging, however, little is known about the effects of aging on NVC responses and their role in cognitive decline in human subjects. Transcranial Doppler (TCD) ultrasound is currently employed as an important tool to measure NVC responses in larger cerebral vessels in response to cognitive stimulation in humans, however, TCD does not provide direct information about the diameter of measured cerebral vessels and it is not clear whether same changes are applicable to cerebral microcirculation. Since human retina shares similar embryologic origins with central nervous system, studying NVC responses in the retinal vessels using Dynamic Vessel Analysis (DVA) may provide another important tool to study changes in cerebral microcirculation with aging. In this study, our goal was to investigate age‐related changes of NVC responses in macro‐ and microcirculation and their association with cognitive decline. Methods For our study, we enrolled 23 healthy adult volunteers of 26–80 years of age (Y: n=10, <40 y.o.; and A: n=12, >65 y.o.). NVC responses in cerebral macrocirculation were measured using TCD in the middle cerebral artery (MCA) during cognitive stimulation with N‐back task. CBF velocity was evaluated as a percent change of the flow during 2‐back test relative to 0‐back test. DVA was performed on the right eye of each subject using a mydriatic retinal camera and change of diameter relative to baseline in the pair of retinal artery and vein was measured during and after three consecutive 20s flicker/80s recovery intervals. NVC measurements were adjusted to mean arterial pressure. Results In agreement with current knowledge, we observed age‐dependent decline in cognitive performance during N‐back test (98.8±0.4% correct answers in Y vs 91.1±2.1% in A, p<0.002), and our data showed that these changes were accompanied by a decrease in CBFv in large cerebral vessels such as MCA (0.84±0.11‰/mmHg in Y vs 0.41±0.13‰/mmHg in A, p= 0.02). We have also observed that aging impaired NVC responses in retinal vessels evidenced by near‐significant decrease in maximal arterial dilation (0.37±0.06‰/mmHg in Y vs 0.18±0.06‰/mmHg in A, p=0.055) and pronounced arterial constriction (0.43±0.07‰/mmHg in Y vs 0.11±0.03‰/mmHg in A, p=0.0005). Summary Our results indicate that cognitive performance in healthy aged individuals is associated with impairment of NVC responses in cerebral macro‐ and microcirculation. DVA may be a useful tool for detailed assessment of vascular function and for early detection of individuals at risk for VCID. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Abstract Cognitive impairment and dementia are major medical, social, and economic public health issues worldwide with significant implications for life quality in older adults. The leading causes are Alzheimer’s disease (AD) and vascular cognitive impairment/dementia (VCID). In both conditions, pathological alterations of the cerebral microcirculation play a critical pathogenic role. Currently, the main pathological biomarkers of AD—β-amyloid peptide and hyperphosphorylated tau proteins—are detected either through cerebrospinal fluid (CSF) or PET examination. Nevertheless, given that they are invasive and expensive procedures, their availability is limited. Being part of the central nervous system, the retina offers a unique and easy method to study both neurodegenerative disorders and cerebral small vessel diseases in vivo. Over the past few decades, a number of novel approaches in retinal imaging have been developed that may allow physicians and researchers to gain insights into the genesis and progression of cerebromicrovascular pathologies. Optical coherence tomography (OCT), OCT angiography, fundus photography, and dynamic vessel analyzer (DVA) are new imaging methods providing quantitative assessment of retinal structural and vascular indicators—such as thickness of the inner retinal layers, retinal vessel density, foveal avascular zone area, tortuosity and fractal dimension of retinal vessels, and microvascular dysfunction—for cognitive impairment and dementia. Should further studies need to be conducted, these retinal alterations may prove to be useful biomarkers for screening and monitoring dementia progression in clinical routine. In this review, we seek to highlight recent findings and current knowledge regarding the application of retinal biomarkers in dementia assessment.
Abstract Carotid artery stenosis (CAS) is a consequence of systemic atherosclerotic disease affecting the aging populations of the Western world. CAS is frequently associated with cognitive impairment. However, the mechanisms contributing to the development of vascular cognitive impairment (VCI) associated with CAS are multifaceted and not fully understood. In addition to embolization and decreased blood flow due to the atherosclerotic lesion in the carotid artery, microcirculatory dysfunction in the cerebral circulation also plays a critical role in CAS-related VCI. To better understand the microvascular contributions to cognitive decline associated with CAS and evaluate microvascular protective effects of therapeutic interventions, it is essential to examine the structural and functional changes of the microvessels in the central nervous system (CNS). However, there are some limitations of in vivo brain vascular imaging modalities. The retinal microvasculature provides a unique opportunity to study pathogenesis of cerebral small vessel disease and VCI, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. Similar microvascular pathologies may manifest in the brain and the retina, thus ocular examination can be used as a noninvasive screening tool to investigate pathological changes in the CNS associated with CAS. In this review, ocular signs of CAS and the retinal manifestations of CAS-associated microvascular dysfunction are discussed. The advantages and limitation of methods that are capable of imaging the ocular circulation (including funduscopy, fluorescein angiography, Doppler sonography, optical coherence tomography [OCT] and optical coherence tomography angiography [OCTA]) are discussed. The potential use of dynamic retinal vessel analysis (DVA), which allows for direct visualization of neurovascular coupling responses in the CNS, for understanding microvascular contributions to cognitive decline in CAS patients is also considered.
