Xie, Weiwei, Xianli Wu, Yiding Li, Qing Xiang, Na Wu, Haolun Sun, Bianba Duojie, Hongda Zhao, Jun Liang, and Ye Fan. Erythrocytapheresis Improves Health-Related Quality of Life in High-Altitude Migrans with Chronic Mountain Sickness: A Single-Arm Before-After Trial at 4,000-4,500 m. High Alt Med Biol. 00:00-00, 2026.Chronic mountain sickness (CMS) arises from maladaptive responses to prolonged residence at altitudes exceeding 2,500 m. Despite the known efficacy of erythrocytapheresis on CMS, the impact of this intervention on health-related quality of life for individuals diagnosed with CMS remains poorly understood. We conducted a single-arm before-after trial using erythrocytapheresis on a total of 22 male migrants with CMS who had resided at high altitudes (4,000-4,500 m) for 6.5 (3.8, 9.3) years. Participants underwent between 1 and 4 erythrocytapheresis sessions, with 1-2 days between each one. The participants exhibited significant improvements following the intervention: health-related quality of life score increased from 85.0 (80.0, 85.3) to 90.0 (90.0, 94.3) (p < 0.001, d = 0.57); CMS score decreased from 7.0 (6.0, 8.0) to 3.0 (2.8, 4.0) (p < 0.0001, d = 0.62); the distance in the 6-Minute Walk Test improved from 612.5 (598.8, 623.0) meters to 654.0 (636.3, 676.3) meters (p < 0.0001, d = 0.62); and SpO2 levels rose from 87.5 (85.8, 90.0) to 90.0 (87.0, 92.5) (p = 0.012, d = 0.38). Erythrocytapheresis proves to be an effective intervention for enhancing health-related quality of life and reducing the severity of CMS in migrant populations.

BackgroundChronic hypoxia has been acknowledged as a significant risk factor for Alzheimer's disease (AD), yet the impact of high-altitude hypoxia on AD pathogenesis remains poorly understood.ObjectiveThis study aims to investigate the effects of chronic high-altitude hypoxia on cognitive function and AD-related pathology.MethodsA cross-sectional cohort comprising 186 high-altitude migrants (HAM) and 378 high-altitude natives (HAN) was recruited for a preliminary assessment. We further conducted 101 HAM, 135 HAN, and 66 low-altitude controls (LA) for plasma biomarkers research. Plasma Aβ40, Aβ42, and T-tau levels were quantified by SIMOA. In parallel, APP/PS1 mice were exposed to hypobaric hypoxia (simulated at 5,500 m) or normoxia for 30 days, followed by behavioral tests, brain immunohistochemistry, and transcriptomic/proteomic analyses.ResultsHAM subjects exhibited significant deficits in Montreal Cognitive Assessment scores and delayed recall subscores compared to LA controls, with both measures showing a positive correlation with peripheral oxygen saturation (SpO₂). Notably, HAN showed preserved memory despite lower overall cognitive scores. Plasma levels of amyloid-β (Aβ)40, Aβ42, and Aβ42/Aβ40 ratio were significantly lower in both HAM and HAN groups compared to the LA group. In mice, chronic hypoxia exacerbated hippocampal Aβ deposition and induced spatial memory decline. Multi-omics analyses revealed the upregulation of oxidative stress and neuroinflammatory pathways and identified S100A8/A9 as a potential key mediator in hypoxia-accelerated AD pathology.ConclusionsOur findings demonstrate that chronic high-altitude hypoxia contributes to cognitive decline and AD-related pathological changes, likely mediated by Aβ burden and oxidative stress. High-altitude hypoxia might be an important environmental risk factor for AD.

The optimal timing and duration of neuroprotective therapy for acute ischemic stroke (AIS) remain unclear. Previous studies showed benefits of edaravone treatment when started within 48 h of AIS onset for 14 d, but it remains unknown whether earlier initiation (within 24 h of onset) and longer treatment (28 d) can yield better outcomes. In ERASE-STROKE, oral edaravone (TTYP01) was demonstrated to improve functional outcomes in patients with AIS. Here, to evaluate the neuroprotective effects of TTYP01, a phase 3, multicenter, double-blind trial was conducted among patients with disabling anterior circulation stroke who did not undergo reperfusion therapy. Within 24 h of symptom onset, 614 eligible patients were randomly assigned to receive TTYP01 60 mg or placebo twice daily for 28 d plus standard care. The primary endpoint was excellent functional outcome (mRS score 0-1) at 90 d. Among 614 patients in the intention-to-treat population, excellent outcome was achieved in 65.4% with TTYP01 vs. 47.1% with placebo (odds ratio 2.12; 95% CI 1.53-2.94; P < 0.001). Rates of symptomatic intracranial hemorrhage, mortality, and serious adverse events did not differ significantly. In patients with disabling anterior circulation stroke not receiving reperfusion, 28-d TTYP01 is safe and improves functional recovery. ClinicalTrials.gov: NCT06648304; Chinese Drug Clinical Trial Registry: CTR20230707.

Outer nuclear layer (ONL) thinning has been identified in frontotemporal lobar degeneration (FTLD); however, its utility for distinguishing the subtypes of FTLD-tauopathy (FTLD-tau) and TDP-43 proteinopathy (FTLD-TDP) remains unknown. We investigated whether ONL thickness provides a subtype-informative retinal signal for differentiating PET-supported probable FTLD-tau (pFTLD-tau) from probable FTLD-TDP (pFTLD-TDP) in vivo. Patients clinically diagnosed with FTLD were subtyped into pFTLD-tau and pFTLD-TDP groups based on multimodal PET and clinical criteria. Normal controls (NCs) were cognitively unimpaired on standardized testing and clinical evaluation. Macular images were acquired using swept-source OCT. A custom deep learning algorithm segmented the retina into eight sublayers. The thickness of each retinal sublayer was assessed across the eight sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Retinal thickness differences were analyzed using generalized estimating equations, and exploratory discrimination models were evaluated using age- and sex-adjusted stepwise logistic regression with apparent and bootstrap optimism-corrected AUCs reported. Exploratory partial correlation analysis was conducted to examine the associations between ONL thickness and cognitive scores. A total of 86 participants were included (21 pFTLD-tau, 27 pFTLD-TDP and 38 NCs). Widespread ONL thinning was observed in pFTLD-tau (Cohen’s d= -0.753 to -1.268 vs. controls; -0.666 to -1.069 vs. pFTLD-TDP; all FDR-adjusted P < 0.05), while ONL in pFTLD-TDP remained preserved. A model combining retinal nerve fiber layer (RNFL), ONL, and myoid–ellipsoid zone (MEZ) thickness showed exploratory discrimination for differentiating pFTLD-tau from pFTLD-TDP (apparent AUC, 0.922; optimism-corrected AUC, 0.866). The outer thickness model yielded higher AUC estimates than the inner thickness model (0.884/0.835 vs. 0.713/0.630), and the individual ONL model showed moderate exploratory discrimination (0.808/0.765). ONL thickness was correlated with cognitive scores in pFTLD-tau (partial r = 0.433–0.483; all P < 0.05), whereas corresponding associations in pFTLD-TDP did not reach statistical significance. ONL thinning was preferentially observed in pFTLD-tau and contributed to exploratory discrimination between PET-supported probable FTLD subtypes. These findings suggest that ONL thickness may provide complementary, noninvasive information for probable FTLD subtype stratification, with potential to facilitate therapeutic trial enrollment and personalized management. Future studies incorporating neuropathological confirmation and fluid biomarkers are warranted to validate these findings.

Ischemic stroke is the leading cause of death in the Chinese population.The incidence of cerebral infarction is higher in high-altitude regions,particularly those above 3,500 m,than in populations residing at lower altitudes[1].There are various speculations regarding the mechanisms behind this phenomenon,one of which is that the low oxygen content and cold climate at high altitudes may increase the occurrence of vascular diseases[2].The multifactorial effect of high-altitude environments on residential populations makes it challenging for researchers to determine the specific pathways through which these diseases occur.Given that vascular blockage is the direct cause of cerebral infarction,alterations in the vascular structure and blood flow components may be the most direct factors influencing the human body at high altitudes.

Introduction RESLES (Reversible splenial lesion syndrome) can be observed secondary to various diseases, and intramyelinic edema may play a crucial role in the pathogenesis of SCC (Splenium of the corpus callosum). Some studies have suggested that hypoxic-ischaemic encephalopathy may constitute a risk factor for SCC lesions. However, the potential impact of high-altitude environments on SCC, especially during chronic exposure, remain obscure.Methods Our study included 19 patients who satisfied the diagnostic criteria of RESLES at high altitudes. Ten low-altitude patients with RESLES were included as controls. All participants received MRI (Magnetic resonance imaging) scans twice. Routine blood tests, liver, kidney and thyroid function, coagulation function, electrolytes and vitamins were detected during hospitalization and before discharge. In addition, the patients were followed up in May 2023.Results Hypoxic environments at high altitudes may increase the risk of RESLES. The two groups showed different clinical symptoms. High-altitude patients had significantly higher CRP levels than low-altitude patients. The lesion size in high-altitude patients showed a positive correlation with SaO2 levels. However, the patients at low altitudes had positive correlation trends between lesion size and several inflammatory markers (WBC, NEU and CRP). All patients had a benign prognosis that may not be affected by the use of prednisone acetate.Conclusions Hypoxic environments at high altitudes may play a role in the aetiology of RESLES. Additionally, RESLES is a reversible disease and the administration of glucocorticoids may be dispensable for its treatment.

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 Aβ plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Cerebral amyloid-β (Aβ) accumulation due to impaired Aβ clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aβ is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aβ and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aβ42 and 8.9% of Aβ40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aβ receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aβ levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aβ clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aβ burden and cognitive deficits, while enhancing hepatic Aβ clearance via LRP-1 overexpression attenuated cerebral Aβ deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aβ and regulates brain Aβ levels, suggesting that a decline of hepatic Aβ clearance during aging could be involved in AD development, and hepatic Aβ clearance is a novel therapeutic approach for AD.

Amyloid β (Aβ) and tau play pivotal roles in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that brain-derived Aβ and tau can be cleared through transport into the periphery, and the kidneys may be vital organs involved in the clearance of Aβ and tau. However, the effects of deficiency in the clearance of Aβ and tau by the kidneys on brain AD-type pathologies in humans remain largely unknown. In this study, we first recruited 41 patients with chronic kidney disease (CKD) and 40 age- and sex-matched controls with normal renal function to analyze the associations of the estimated glomerular filtration rate (eGFR) with plasma Aβ and tau levels. To analyze the associations of eGFR with cerebrospinal fluid (CSF) AD biomarkers, we recruited 42 cognitively normal CKD patients and 150 cognitively normal controls with CSF samples. Compared with controls with normal renal function, CKD patients had higher plasma levels of Aβ40, Aβ42 and total tau (T-tau), lower CSF levels of Aβ40 and Aβ42 and higher levels of CSF T-tau/Aβ42 and phosphorylated tau (P-tau)/Aβ42. Plasma Aβ40, Aβ42, and T-tau levels were negatively correlated with eGFR. In addition, eGFR was negatively correlated with CSF levels of T-tau, T-tau/Aβ42, and P-tau/Aβ42 but positively correlated with Mini-Mental State Examination (MMSE) scores. Thus, this study showed that the decline in renal function was correlated with abnormal AD biomarkers and cognitive decline, which provides human evidence that renal function may be involved in the pathogenesis of AD.

CD22 has been suggested to contribute to Alzheimer's disease (AD) pathogenesis by inhibiting microglial amyloid β (Aβ) phagocytosis. Soluble CD22 (sCD22) generated by cleavage from cell membranes may be a marker of inflammation and microglial dysfunction; but alterations of sCD22 levels in AD and their correlation with AD biomarkers remain unclear. Plasma sCD22 levels were measured in cognitively normal non-AD participants and patients with preclinical AD and AD dementia from a Chinese cohort and the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Plasma sCD22 levels were elevated in patients with preclinical and dementia AD. Plasma sCD22 levels were negatively correlated with cerebrospinal fluid (CSF) Aβ42 levels and Aβ42/Aβ40, and positively correlated with CSF phosphorylated tau levels and brain Aβ burden, but negatively correlated with cognitive function. Moreover, higher plasma sCD22 levels were associated with faster cognitive decline during follow-up. These findings suggest that CD22 plays important roles in AD development, and that sCD22 is a potential biomarker for AD.

Background: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer’s disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. Objective: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. Methods: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. Results: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. Conclusion: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.

Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age- and gender-matched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of AT8-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy.

Amyloid-β (Aβ) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer’s disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aβ produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aβ clearance remain largely unknown. The kidney is thought to be responsible for Aβ clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aβ in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aβ clearance via the kidney were assessed. We detected Aβ in the kidneys and urine of both humans and animals and found that the Aβ level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aβ deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aβ levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aβ from the blood, suggesting that facilitation of Aβ clearance via the kidney represents a novel potential therapeutic approach for AD.

Recent studies show that fibrinogen plays a role in the pathogenesis of Alzheimer’s disease (AD), which may be crucial to neurovascular damage and cognitive impairment. However, there are few clinical studies on the relationship between fibrinogen and AD. 59 11 C-PiB-PET diagnosed AD patients and 76 age- and gender-matched cognitively normal controls were included to analyze the correlation between plasma β-amyloid (Aβ) and tau levels with fibrinogen levels. 35 AD patients and 76 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation between CSF Aβ and tau levels with fibrinogen levels. In AD patients, plasma fibrinogen levels were positively correlated with plasma Aβ40 and Aβ42 levels, and negatively correlated with CSF Aβ42 levels. Besides, fibrinogen levels were positively correlated with CSF total tau (t-tau), and phosphorylated tau-181 (p-tau) levels and positively correlated with the indicators of Aβ deposition in the brain, such as t-tau/Aβ42, p-tau/Aβ42 levels. In normal people, fibrinogen levels lack correlation with Aβ and tau levels in plasma and CSF. This study suggests that plasma fibrinogen levels are positively correlated with Aβ levels in the plasma and brain in AD patients. Fibrinogen may be involved in the pathogenesis of AD.

Deficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22–89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aβ 1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aβ 1-42 uptake by monocytes was associated with Aβ 1-42 levels in the blood. Among the Aβ uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ uptake function by blood monocytes represents a potential therapeutic strategy for AD.

It is traditionally believed that cerebral amyloid-beta (Aβ) deposits are derived from the brain itself in Alzheimer’s disease (AD). Peripheral cells such as blood cells also produce Aβ. The role of peripherally produced Aβ in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aβ to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aβ in the blood, and caused AD phenotypes including Aβ plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aβ levels, and alleviated brain Aβ burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aβ plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aβ can decrease brain Aβ deposition and represents a novel therapeutic approach for AD.

OBJECTIVE:Obstructive sleep apnea syndrome (OSAS) is characterized by nocturnal intermittent hypoxemia and can increase the risk of Parkinson's disease. This study aimed to investigate the association between plasma α-synuclein levels and hypoxia in the patients with OSAS.METHODS:We recruited 42 OSAS patients and 46 controls with simple snoring matched for age and gender. OSAS was diagnosed on the basis of the clinical symptoms as well as the nighttime polysomnography. Plasma total α-synuclein and phosphorylated α-synuclein levels were measured by ELISA kits.RESULTS:The OSAS patients had significant higher levels of plasma total α-synuclein and phosphorylated α-synuclein levels. Both of the above indexes were positively correlated with the apnea-hypopnea index and the oxygen desaturation index, while they were negatively correlated with the mean and lowest oxyhemoglobin saturations.INTERPRETATION:This study suggests that chronic intermittent hypoxia can increase the α-synuclein levels, which may contribute to the pathogenesis of Parkinson's disease.

Purpose Recent study shows that blood-derived amyloid-beta (Aβ) can induce cerebral amyloidosis and is involved in the pathogenesis of Alzheimer's disease (AD). The vast majority of blood Aβ is generated from platelet. Whether blood Aβ levels are associated with the count of platelets remains unknown. Methods 58 clinically diagnosed AD patients, 18 11C-PIB-PET diagnosed AD patients, and 61 age- and gender-matched cognitively normal controls were included to analyze the correlation of plasma Aβ levels with platelet count. 13 AD patients and 40 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation of CSF Aβ levels with platelet count. Aβ40 and Aβ42 levels in plasma and CSF were measured by ELISA kits. Results The plasma Aβ42 level was positively correlated with platelet count in both AD patients and control group, especially in AD patients with positive PIB-PET, while there was no correlation as to Aβ40. The CSF Aβ levels also had no significant correlation with platelet count. Conclusion It suggests that platelets may be involved in the pathogenesis of AD and become a potential peripheral biomarker for AD.