Impaired Retinal Capillary Function in Patients With Alzheimer Disease.

BACKGROUND: Extensive evidence indicates that vasculopathy, especially the level of microcirculation, contributes to neurodegeneration in Alzheimer disease (AD). However, it is not easy to directly monitor cerebral microcirculation. The retinal microvasculature has been proposed as a surrogate measure to study cerebral vascular changes. Indeed, decreased retinal microvascular network densities were reported in patients with AD. We sought to determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) in patients with AD. METHODS: Twenty patients (age 60-84 years, mean ± SD: 72.8 ± 7.7 years) with AD and 14 age-matched cognitively normal controls (CN, age 62-81 years, mean ± SD: 68.6 ± 6.7 years.) were recruited. There were no differences in vascular risk factors, including smoking, hypertension, hyperlipidemia, Type 2 diabetes, and cardiovascular disease, between the groups. One eye of each subject in both groups was imaged. 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. RESULTS: RCF was 1.62 ± 0.56 nl/s/Dbox (mean ± SD) in the AD group, which was significantly lower than that (2.56 ± 0.25 nl/s/Dbox, P < 0.01) in the CN group. The change of RCF in the AD group represented 28% lower than in the CN group. RCF was significantly and positively correlated with RBF in the AD group (r = 0.98, P < 0.05) and in the CN group (r = 0.65, P < 0.05). CONCLUSIONS: Our study is the first to demonstrate impaired retinal capillary function in patients with AD. The alteration of RCF was mainly due to decreased retinal blood flow, which is transferred by the capillary network. The RCF may be developed as a biomarker of impaired cerebral microcirculation in patients with AD.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Retinal Microvascular Alterations as the Biomarkers for Alzheimer Disease: Are We There Yet?

BACKGROUND: Alzheimer disease (AD) is a heterogeneous and multifactorial disorder with an insidious onset and slowly progressive disease course. To date, there are no effective treatments, but biomarkers for early diagnosis and monitoring of disease progression offer a promising first step in developing and testing potential interventions. Cerebral vascular imaging biomarkers to assess the contributions of vascular dysfunction to AD are strongly recommended to be integrated into the current amyloid-ß (Aß) [A], tau [T], and neurodegeneration [(N)]-the "AT(N)" biomarker system for clinical research. However, the methodology is expensive and often requires invasive procedures to document cerebral vascular dysfunction. The retina has been used as a surrogate to study cerebral vascular changes. There is growing interest in the identification of retinal microvascular changes as a safe, easily accessible, low cost, and time-efficient approach to enhancing our understanding of the vascular pathogenesis associated with AD. EVIDENCE ACQUISITION: A systemic review of the literature was performed regarding retinal vascular changes in AD and its prodromal stages, focusing on functional and structural changes of large retinal vessels (vessels visible on fundus photographs) and microvasculature (precapillary arterioles, capillary, and postcapillary venules) that are invisible on fundus photographs. RESULTS: Static and dynamic retinal microvascular alterations such as retinal arterial wall motion, blood flow rate, and microvascular network density were reported in AD, mild cognitive impairment, and even in the preclinical stages of the disease. The data are somewhat controversial and inconsistent among the articles reviewed and were obtained based on cross-sectional studies that used different patient cohorts, equipment, techniques, and analysis methods. CONCLUSIONS: Retinal microvascular alterations exist across the AD spectrum. Further large scale, within-subject longitudinal studies using standardized imaging and analytical methods may advance our knowledge concerning vascular contributions to the pathogenesis of AD.

Long-term brain fog and cognitive impairment in previously hospitalized COVID-19 patients.

OBJECTIVES: Limited research exists on COVID-19 associated brain fog, and on the long-term cognitive and psychiatric sequelae in racially and ethnically diverse patients. We characterize the neuropsychological sequelae of post-acute COVID-19 in a diverse cohort and investigate whether COVID-19 clinical severity remains associated with brain fog and cognitive deficits approximately 2 years post infection. METHODS: A cross-sectional study of patients with a history of COVID-19 hospitalization (March-September 2020). COVID-19 clinical severity was indexed using the National Early Warning Score 2 and a comprehensive neuropsychological tele-battery was administered 2 years post discharge. Pearson's r correlations assessed association, while independent sample t-tests examined group differences. Significant outcomes were further analyzed using multiple regression and ANCOVAs, adjusting for key covariates. RESULTS: In 41 adult patients (19 female, 30 Hispanic, 13 Black, mean age of 65 (SD = 15), COVID-19 level of severity was associated with greater number of endorsed brain fog symptoms (Pearson's r = .34, 95% CI [.04, .59]), worse overall cognitive functioning (global cognition: r = -.36, 95% CI [-.61, -.05]) and reduced performance on an attention and working memory task (digit span backwards: r = -.41, 95% CI [-.66, -.09]) at 2-year follow-up. Brain fog symptoms most associated with COVID-19 severity included difficulty focusing (r = .46, 95% CI [.18, .67]), detached (r = .41, 95% CI [.12, .64]) and feeling sleepy (r = .40, 95% CI [.11, .63]). Patients' cognitive performance was generally below average (global cognition z-score: M = -.96, SD = .66), with group differences based on sex and ethnicity evidenced on individual cognitive tests. DISCUSSION: This study emphasizes the importance of continued research on the long-term effects of COVID-19 infection on neuropsychological outcomes, particularly among underrepresented, health-disparate groups. Greater understanding of these associations could improve detection and treatment of those at increased risk of cognitive decline or impairment.

Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer's disease.

Mesenchymal stem cell (MSC) administration is a novel and promising therapeutic approach for Alzheimer's disease (AD). Focusing on an intervention easily translatable into clinical practice, we administered allogeneic bone marrow-derived MSCs intravenously in a mouse model of AD (3xTg-AD). We systematically evaluated the effects of a single-dose and multiple-doses of MSCs in young and old mice (5 or 10 months old), comparing the short-term and long-term effects after 1, 2, or 7 months of treatment. A single dose of MSCs in young mice attenuated neuroinflammation 1 and 7 months after injection, whereas multiple-doses did not show any effect. Multiple-doses of MSCs (administered at 5 to 12 mo, or 10 to 12 mo) reduced the ß-secretase cleavage of the amyloid precursor protein, although levels of Aß-42 did not change. Most interestingly, multiple doses of MSCs affected tau hyperphosphorylation. MSCs administered in young mice for 7 months decreased the pathological tau phosphorylation at T205, S214, and T231. MSCs administered in old mice for 2 months decreased tau phosphorylation at S396. Our findings show how different timing and frequency of MSC injections can affect and modulate several aspects of the AD-like neuropathology in the 3xTg-AD mouse model, strengthening the concept of fine-tuning MSC therapy for Alzheimer's disease.

Retinal tissue hypoperfusion in patients with clinical Alzheimer's disease.

BACKGROUND: It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer's disease. The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer's disease (CAD). METHODS: Twenty-four CAD patients and 19 cognitively normal (CN) age-matched controls were recruited. A retinal function imager (RFI, Optical Imaging Ltd., Rehovot, Israel) was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea. Blood flow volumes of arterioles (entering the macular region) and venules (exiting the macular region) of the supplied area were calculated. Macular blood flow was calculated as the average of arteriolar and venular flow volumes. Custom ultra-high-resolution optical coherence tomography (UHR-OCT) was used to calculate macular tissue volume. Automated segmentation software (Orion, Voxeleron LLC, Pleasanton, CA) was used to segment six intra-retinal layers in the 2.5 mm (diameter) area centered on the fovea. The inner retina (containing vessel network), including retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL) and outer plexiform layer (OPL), was segmented and tissue volume was calculated. Perfusion was calculated as the flow divided by the tissue volume. RESULTS: The tissue perfusion in CAD patients was 2.58 ± 0.79 nl/s/mm3 (mean ± standard deviation) and was significantly lower than in CN subjects (3.62 ± 0.44 nl/s/mm3, P <  0.01), reflecting a decrease of 29%. The flow volume was 2.82 ± 0.92 nl/s in CAD patients, which was 31% lower than in CN subjects (4.09 ± 0.46 nl/s, P <  0.01). GCIPL tissue volume was 0.47 ± 0.04 mm3 in CAD patients and 6% lower than CN subjects (0.50 ± 0.05 mm3, P < 0.05). No other significant alterations were found in the intra-retinal layers between CAD and CN participants. CONCLUSIONS: This study is the first to show decreased retinal tissue perfusion that may be indicative of diminished tissue metabolic activity in patients with clinical Alzheimer's disease.

Impaired retinal microcirculation in patients with Alzheimer's disease.

The goal of this study was to determine the retinal blood flow rate (BFR) and blood flow velocity (BFV) of pre-capillary arterioles and post-capillary venules in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Forty patients (20 AD and 20 MCI) and 21 cognitively normal (CN) controls with a similar age range (± 5 yrs) were recruited. A retinal function imager (RFI) was used to measure BFRs and BFVs of arterioles and venules in the macular region. The thickness of the ganglion cell-inner plexiform layer (GCIPL) was measured using Zeiss Cirrus optical coherence tomography. Macular BFRs in AD group were 2.64 ± 0.20 nl/s (mean ± standard deviation) in arterioles and 2.23 ± 0.19 nl/s in venules, which were significantly lower than in MCI and CN groups (P < 0.05). In addition, BFRs in MCI were lower than in CN in both arterioles and venules (P < 0.05). The BFV of the arterioles was 3.20 ± 1.07 mm/s in AD patients, which was significantly lower than in CN controls (3.91 ± 0.77 mm/s, P = 0.01). The thicknesses of GCIPL in patients with AD and MCI were significantly lower than in CN controls (P < 0.05). Neither BFV nor BFR in arterioles and venules was related to age, GCIPL thickness, mini mental state examination (MMSE) score and disease duration in patients with AD and MCI (P > 0.05). The lower BFR in both arterioles and venules in AD and MCI patients together with the loss of GCIPL were evident, indicating the impairment of the two components in the neurovascular-hemodynamic system, which may play a role in disease progression.