Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-ß (Aß) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aß clearance have fueled a debate as to whether Aß is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aß clearance trials provide critical evidence to support the role of Aß in AD pathogenesis and suggest that targeting Aß clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aß targeting therapies, and provide perspectives on early intervention, adequate Aß removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-ß and Prevents Alzheimer's Disease-Type Pathology and Cognitive Deficits.

Deficiencies in the clearance of peripheral amyloid ß (Aß) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aß is decreased in AD. However, the exact mechanism of Aß clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aß. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aß in vivo and in vitro. Moreover, enhancing blood monocyte Aß phagocytosis by improving energy metabolism alleviated brain Aß deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aß phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Biomarkers of aging.

Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.

A meta-analysis of the effectiveness of Yangxue Qingnao granules for the treatment of chronic cerebral circulation insufficiency.

OBJECTIVE: Yangxue Qingnao granules (YXQNG), which translates to granules that tonify the blood and clear liver heat, are widely available in China for the treatment of Chronic Cerebral Circulation Insufficiency (CCCI). This systematic review aimed to evaluate the effectiveness and safety of YXQNG in treating CCCI. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, Embase, the Chinese National Knowledge Infrastructure, and the Wanfang Database were searched from their inception to February 2019. Randomized controlled trials of YXQNG used alone or in combination with other drugs against a placebo, with no intervention or used with other drugs in CCCI patients were identified. The reviewers identified studies, extracted data, and assessed the quality of the evidence, independently and in duplicate. The Cochrane risk of bias assessment tool was used for quality assessment. RESULTS: A total of 31 RCTs and 2,877 patients were selected. The meta-analysis indicated that the ratio between the combined RR of the total effective rate and the 95% confidential interval (95% CI) was 1.21 (1.17, 1.26). The combined MD of transcranial Doppler (TCD) detecting carotid artery, vertebral artery, and basilar artery blood flows (95% CI), respectively, were 8.84 (5.83, 11.85), 4.72 (3.71, 5.73), and 3.89 (3.03, 4.76). The combined MD of plasma viscosity and fibrinogen, respectively, were -0.35 (-0.40, -0.30) and -0.81 (-1.12, -0.50). Serious adverse effects were not reported in all the included trials. CONCLUSION: This systematic review revealed that YXQNG could increase cerebral blood flow in patients with CCCI and improve their symptoms, with no serious adverse effects. Since the literature reviewed was affected by factors such as lower quality of the included studies, the systematic evaluation's conclusion is not very reliable. Thus, more rigorously designed trials are needed.

Limbic encephalitis associated with AMPA receptor and CRMP5 antibodies: A case report and literature review.

AIMS: AMPA receptor (AMPAR) and CRMP5 antibodies are relatively uncommon in limbic encephalitis, and patients with both antibodies are rare. We recently treated such a patient, but the patient died after active treatment. To further understand this disease, we conducted a case report and literature review. DISCUSSIONS: To date, five encephalitis patients, including our patient, have been found to be positive for AMPAR and CRMP5 antibodies. The male-to-female ratio of the reported cases is 4:1, and the age range is 26 and 62 years old. All five patients presented with various neuropsychiatric symptoms, including insomnia, abnormal behavior, seizures, extrapyramidal symptoms, and autonomic dysfunction. Four patients had tumors (three invasive thymomas and one suspected lymphoma), and three cases died within a short period of time. No tumor was detected in one of the patients during the follow-up period; however, after active treatment, the outcome was poor, and the patient developed cachexia. One patient had good response to immunotherapy and tumor therapy and successfully returned to work. CONCLUSIONS: The prognosis of encephalitis associated with AMPAR and CRMP5 antibodies is worse than that of the encephalitis associated with AMPAR antibodies alone. The most likely cause is that this encephalitis is more likely to be accompanied by malignant tumors, leading to a poor prognosis. In addition, it may also be due to some synergistic mechanisms between the two antibodies. Further studies aimed at the prognosis of this type of encephalitis are warranted.

Natural Course of Clinically Isolated Syndrome: A Longitudinal Analysis Using a Markov Model.

Clinically isolated syndrome (CIS) refers to the initial clinical episode with symptoms suggestive of multiple sclerosis (MS). Due to limited number of long-term follow-up studies, progression pattern from CIS to more advanced stages remains unclear. In the current study, we constructed a Markov model to simulate the natural course of CIS. The model estimated the probabilities of transition from CIS to more advanced disease stages and the duration needed for the progression. The analysis showed: (1) CIS is a solid disease identity: more than 85% of the subjects with a diagnosis of CIS progress to RRMS or more advanced stages within 20 years; (2) the reduction of life expectancy in subjects with CIS is marginal.