Improvement of Retinal Capillary Function After High-Speed Circuit Resistance Training in Healthy Older Adults

To determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) and its relation to cognitive function in healthy older people without known cognitive impairment following an 8-week high-speed circuit resistance training program (HSCT).

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Improvement of Retinal Capillary Function After HighSpeed Circuit Resistance Training in Healthy Older Adults Hong Jiang, MD, PhD, Joseph F. Signorile, PhD, Ava-Gaye Simms, MBBS, Jianhua Wang, MD, PhD Background: To determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) and its relation to cognitive function in healthy older people without known cognitive impairment following an 8-week high-speed circuit resistance training program (HSCT). Methods: Eleven subjects in the HSCT group and 7 agematched nontraining controls (CON) were recruited. The HSCT group trained 3 times per week for 8 weeks, whereas CON performed no formal training. One eye of each subject from both groups was imaged at baseline and 8-week follow-up. Retinal blood flow (RBF) was measured using a retinal function imager, and retinal capillary density (RCD, expressed as fractal dimension Dbox) was measured using optical coherence tomography angiography. RCF was defined as the ratio of RBF to RCD. Cognitive function was assessed during both visits using the NIH Toolbox Fluid Cognition Battery. Results: RCF was 2.07 ± 0.64 nL$s21$Dbox21 (mean ± SD) at baseline, and significantly increased to 2.59 ± 0.54 nL$s21$Dbox21 after training (P = 0.0003) in the HSCT group, reflecting an increase of 25%. The changes of RBF were not related to the changes of RCD in the HSCT group (r = 20.18, P = 0.59). There was no significant change of RCF in the CON group (P = 0.58). In the HSCT group, the Pattern Comparison Processing Speed Test and Fluid Cognition Composite Score were significantly increased after HSCT (P = 0.01). Furthermore, the changes in Flanker Inhibitory Control and Attention Test (FLNK) were positively correlated to increases in RCF (r = 0.77, P = 0.005). Department of Ophthalmology (HJ, JW, A-GS), Bascom Palmer Eye Institute, Department of Neurology (HJ), University of Miami Miller School of Medicine, Miami, Florida; and Department of Kinesiology and Sports Sciences (JFS), University of Miami, Miami, Florida. Supported by NIH Center Grant P30 EY014801, NINDS 1R01NS111115-01 (J. Wang), the Ed and Ethel Moor Alzheimer’s Disease Research Program (Florida Health, 20A05, to H. Jiang), UM Provost Pilot Study Award (PRA 2022-2555, J. F. Signorile, H. Jiang, and J. Wang) and a grant from Research to Prevent Blindness. The authors report no conflicts of interest. Address correspondence to Hong Jiang, MD, PhD, Miller School of Medicine, Bascom Palmer Eye Institute, University of Miami, 1638 NW 10th Avenue, McKnight Building—Room 202A, Miami, FL 33136; E-mail: [e-mail] 180 Conclusions: This is the first prospective study to demonstrate that the increased RCF after HSCT was related to improved cognition in cognitively normal older adults. Journal of Neuro-Ophthalmology 2023;43:180–184 doi: 10.1097/WNO.0000000000001679 © 2022 by North American Neuro-Ophthalmology Society A ging and cardiovascular disease play a role in vascular alterations, especially microcirculation (1). Cerebral microvascular diseases contribute to age-related cognitive impairment (ACI) in older adults (2); hence, microcirculation is a promising vascular factor for ACI risk stratification and prediction (3). Cerebral and retinal microcirculation, with their comparable embryologic origin, share similar physiological and anatomic features (4); therefore, alterations in retinal microcirculation reflect similar changes in cerebral microvasculature (5). Indeed, the retinal microvasculature has been used as a proxy in studying cerebral vascular abnormalities (5). Furthermore, age-related decline of blood flow velocity and microvessel density has been well documented in normal subjects (1). Physical activity and fitness are important modulators of vascular aging and may therefore help expand individual health span. Indeed, accumulating evidence indicates that physical exercises could improve cognitive function in older adults (6). Because of the relationship between cardiovascular and brain health, aerobic-based training has been studied extensively in older adults with and without dementia (6). Compared with typical steady-state aerobic-based training programs, high-speed circuit training (HSCT) can maximize cardiovascular benefits (7). Our previous study showed improved retinal blood supply and retinal tissue perfusion after HSCT (8). The goal of the present study was to evaluate the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) and its relation to cognitive function Jiang et al: J Neuro-Ophthalmol 2023; 43: 180-184 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution in healthy older people without known cognitive impairment after an 8-week HSCT program. METHODS The study was approved by the institutional review board for human research at the University of Miami, and informed consent was obtained from each participant. Participants with systemic or cerebral diseases such as stroke, heart failure, autoimmune diseases, malignancy, uncontrolled hypertension, and diabetes were excluded. In addition, those with ocular diseases such as glaucoma, macular degeneration, dense cataracts, a refractive error greater than 26 diopters (D) or +6 D, or other ocular problems were also excluded. Eighteen older people (age . 65 years) with no known cognitive impairment were recruited at the Department of Kinesiology and Sports Sciences at the University of Miami. The participants were randomly assigned to 2 groups: Eleven in the HSCT group were trained 3 times per week for 8 weeks, and 7 agematched nontraining controls (CON) did not receive any formal training. The details of HSCT were reported previously (9). Briefly, all exercise sessions occurred in the morning. After 10 minutes of a movement-specific warm-up, 10–12 repetitions were performed on the 10 computerized pneumatic machines in the circuit. Minimal recovery time was provided between exercises. Each subject completed one set of each exercise with the alterations of upper and lower body exercise. The subject was instructed to move “as quickly as possible” during the concentric phase of each exercise and performed a controlled eccentric. The machines’ digital displays were used to detect the plateaus in power, which determined when the subject should progress to the next level. When the power reached a plateau within 5% of the previous day’s performances, the load was increased by 5% until the next power plateau. One circuit was performed in week one; then, 2 circuits were performed in Week 2. Thereafter, 3 circuits were performed for the remainder of the 8 weeks. Retinal blood flow (RBF) was measured using the retinal function imager (RFI, Optical Imaging Ltd, Rehovot, Israel). The device and measurement have been wellreported in the literature and intensively reviewed (10). The RFI system is a fundus camera equipped with a highspeed digital camera and a stroboscopic flash lamp system to capture retinal blood flow. The motion of the red blood cells was used to track the blood flow, and subsequently, blood flow velocity was calculated. To calculate the blood flow supplying the macular region, all blood flow measurements in the arterioles and venules crossing a 2.5-mm circle centered on the macular were summed (Fig. 1) (8). The blood flow was measured separately in arterioles and venules, then the average blood flow between arterioles and venules was used to represent RBF. Jiang et al: J Neuro-Ophthalmol 2023; 43: 180-184 FIG. 1. RCF measurements at baseline and 8-week followup. RCF was significantly increased after 8-week HSCT training, whereas RCF in the CON group did not show a significant difference. Bars = standard error. CON, control group; HSCT, high-speed circuit training; RCF, retinal capillary function. Retinal capillary density (RCD) was measured using an AngioVue optical coherence tomography angiography (OCTA, AngioVue, Optovue, Inc, Fremont, CA). The system and its measurement have been well-documented in the literature (9). The image protocol and analysis of RCD have also been described previously (9). An angio retina of the 3- · 3-mm scan protocol was used to scan the macula centered on the fovea. Angiographic enface images of the total retinal vascular network were exported and analyzed using fractal analysis (9). The retinal vascular network (RVN) slab defined the vessels from the inner limiting membrane (ILM) to the outer plexiform layer (OPL). After a series of image processing procedures, including removal of the large vessels with a diameter $25 mm, small vessels were analyzed in the annulus from 0.6 to 2.5 mm. Because the foveal avascular zone is about 0.6 mm in the center of the fovea, the annulus from 0.6 to 2.5 mm encompassed the small vessels and most capillaries in calculating RCD. The box-counting method was used in fractal analysis to yield Dbox to represent RCD. To determine the efficacy of the capillary bed in transporting blood, RCF was calculated as RBF (unit: nL/s) divided by RCD (expressed as Dbox). Therefore, the unit of RCF is nL/s/Dbox, meaning retinal blood flow volume per second per unit of capillaries. One eye of the subject in each group was imaged at baseline and 8-weeks. Because a reduction of retinal microvascular density was related to an increase in systolic blood pressure (11), the measurement was performed after a resting period (at least 24 hours) after the participant finished the training. Cognitive function was assessed during both visits using the NIH Toolbox Fluid Cognition Battery (9): Dimensional Card Sort Test (DCCS, executive function, and task shifting), Flanker Inhibitory Control and Attention Test (FLNK, executive function, and attention), Picture Sequence Memory Test (PSM, episodic memory), Pattern 181 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Cognitive function at baseline and 8-week follow-up. A. In the HSCT group, the pattern comparison were significantly increased after HSCT (P = 0.01). B. There were no changes in PAT and FCS in the CON (P . 0.05). CON, control group; FCS, fluid cognition composite score; HSCT, high-speed circuit training; PAT, processing speed test. Comparison Processing Speed Test (PAT, processing speed), and List Sorting Working Memory Test (LSWM, working memory). Age-adjusted scale scores were used for comparative analyses. Descriptive statistics and data analyses were conducted using a statistical software package (SPSS for Windows 26.0; SPSS Inc, Chicago, IL). Student t-tests were used to determine whether differences existed in the continuous variables between baseline and follow-up. A x2 test was used to test for differences in categorical variables between groups. Pearson correlations were used to determine the relationships between cognition tests and ocular variables. P , 0.05 was considered significant. RESULTS There were no significant differences in age, sex, blood pressure, and educational levels between groups (P . 0.05). In addition, no significant differences in risk factors (i.e., diabetes, hypertension, dyslipidemia, and cardiovascular diseases) were found between groups (P . 0.05). RCF was 2.07 ± 0.64 nL$s21$Dbox21 (mean ± SD) at baseline and significantly increased to 2.59 ± 0.54 nL$s21$Dbox21 after training (P = 0.0003) in the HSCT group, reflecting an increase of 25%. The changes of RBF were not related to the changes of RCD in the HSCT group (r = 20.18, P = 0.59). Furthermore, there was no significant change of RCF in the CON group (P = 0.58) (Fig. 1). In the HSCT group, the PAT and Fluid Cognition Composite Score (FCS) were significantly increased (P = 0.01); but no significant improvements were observed in the controls (Fig. 2). Furthermore, as illustrated in Figure 3, the 182 changes in FLNK were positively correlated to increases in RCF (r = 0.77, P = 0.005). DISCUSSION To the best of our knowledge, this is the first study to demonstrate increased RCF after a short term of HSCT. Moreover, the changes of RCF were correlated with the improved score of the Flanker Inhibitory Control and Attention Test, indicating RCF could be used to monitor the effect of HSCT on cognitive functions, such as attention and executive function. This finding may also increase the understanding of the effect of HSCT on microvasculature not only in the retina but also in the brain. The capillary bed is a critical site for providing oxygen and nutrition to the tissue. Traditionally, the capillary bed FIG. 3. Relation between changes of RCF and changes in FLNK. The changes of RCF were related to the changes of FLNK in the HSCT group after 8-week HSCT training. FLNK, flanker Inhibitory control, and attention test; HSCT, highspeed circuit training; RCF, retinal capillary function. Jiang et al: J Neuro-Ophthalmol 2023; 43: 180-184 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution has been shown to maintain the relation between tissue blood flow (i.e., the capacity for blood flow transportation) and oxygenation (i.e., the ability to facilitate the crossing of oxygen from the blood to the tissue) (12). To provide sufficient oxygen to the tissue, blood flow needs to maintain a certain threshold, which allows the extraction of oxygen to meet the needs of the tissues. Furthermore, the tissue receives more oxygen and nutrition if the blood flow increases. Although capillary regrowth may take some time, increased blood flow may ease the burden of insufficient oxygenation. In the present study, RCD did not alter whereas RBF increased after 8 weeks of HSCT, which facilitated the increased RCF to provide more oxygen and nutrition to the tissue by the increased RBF. It is worth noting that this study did not measure the capacity of the capillary to deliver oxygen, which is part of the capillary function; rather, the improved cognition observed in the HSCT group seems to be related to the benefit of increased RCF, which eventually promotes tissue oxygenation. This hypothesis is also supported by our previous study, which demonstrated improved tissue perfusion (i.e., blood flow per unit of tissue volume) was related to improved cognitive function after HSCT (9). Furthermore, the improved RCF after HSCT was found to be because of increased retinal blood flow (8), and a relatively stable retinal capillary network density (9). This result is consistent with previous reports that higher physical activity levels were associated with enlarged central retinal arteriolar (CRAE) diameter equivalents (13), indicating HSCT may facilitate the opening of retinal arterioles to allow more blood flow into the capillary bed in response to the higher metabolic demands. One underlying mechanism could be increased release of nitric oxide because of exercise. Nitric oxide is responsible for relaxing smooth muscle cells and vasodilation (14). Moreover, retinal arteriolar narrowing has been associated with increased cardiovascular risks such as hypertension (15), strokes (16), or even dementia (17). Hence, the HSCT-induced improved RCF may indicate its potential in counteracting microvascular alteration and development of small vessel disease because of aging. Aging plays a role in capillary dysfunction. The increased capillary tortuosity, twisting, thickened capillary basement membrane, and pericyte loss were found in the human brain (18), and in the retina (19). The decline of retinal microvascular density and tissue perfusion were found during aging (1), and the reduced rate of retinal blood flow is consistent with age-related blood flow decline (2). The individual variability of retina capillary density noted after the short-HSCT (9), may be because of different baseline status of age-related retinal capillary alteration. Interestingly, the change in retinal blood flow was not correlated with retinal capillary density. We believe that retinal capillary function, the ratio of retinal blood flow, and retina capillary density may be more reprehensive of the microvascular changes after exercise. Jiang et al: J Neuro-Ophthalmol 2023; 43: 180-184 Moreover, the improved RCF was correlated with FLNK in this group of healthy older adults with no known cognitive impairment. The improved FLNK indicates improved executive function and attention after this short-term HSCT training. The score of PAT and FCS were also improved, although they were not correlated with RCF. This indicates that HSCT may improve cognitive function not only through increased RCF, but also other mechanisms such as increased level of brain-derived neurotrophic factor, which is believed to modulate normal human hippocampal aging (20). There are limitations that may have affected the results of this pilot study. First, the sample size was small, because this study was designed to test the concept if the RCF changes after HSCT in older adults; nevertheless, our result showed improved RCF after HSCT. Second, the short training and follow-up period in this study may have been insufficient to optimize results; therefore, future large sample studies using longer intervention periods are suggested. In summary, this is the first prospective pilot study to demonstrate that the increased RCF after HSCT was related to improved attention in older adults without known cognitive impairment. As part of the cerebrovascular bed, retinal microvascular changes, such as RCF, are a promising vascular biomarker that can be used to optimize cardiovascular risk stratification and treatment monitoring in primary and secondary prevention. 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