Fan Zeng

Myelin loss has been implicated in the development of Alzheimer’s disease (AD). We investigated the changes in myelin basic protein (MBP) levels in cerebrospinal fluid (CSF) in an ageing cohort comprising 116 cognitively normal and Aβ-negative controls aged 26 to 82 years, as well as in a clinical cohort. We found that CSF MBP levels was positively correlated with age in a nonlinear pattern over the lifetime of the ageing cohort and that CSF MBP continually increased until it began to decline around age of 51 years and rose again around age 62. CSF MBP levels were correlated with the Mini-Mental State Examination (MMSE) score and CSF phosphorylated tau-181 (p-tau181) and total tau (t-tau) levels but not the Aβ42/Aβ40 ratio. CSF MBP levels moderated age-related changes in cognitive function. In the clinical cohort, CSF MBP levels were higher in the CSF Aβ+ patients than in the CSF Aβ- participants, and CSF MBP levels were higher in the Aβ–PET+ patients than in the Aβ–PET- participants. CSF MBP levels were higher in apolipoprotein E ε4 allele (APOE-ε4) carriers than in APOE-ε4 noncarriers in the clinical cohort. Our study reveals the possible changes in CSF MBP levels during ageing and in AD patients, providing evidence that demyelination is involved in brain ageing and AD pathogenesis in humans.

This study reports an uncommon case of autosomal dominant Alzheimer disease (AD) with negative PiB-PET findings. A 55-year-old woman was admitted to the hospital due to a progressive cognitive decline for over 9 years, along with a possible dementia family history. The patient underwent routine laboratory tests, neuropsychological assessments, and neuroimaging examinations. Additionally, the cerebrospinal fluid sample was analyzed for AD biomarkers using the Single Molecular Array (Simoa) technique. A targeted Next-Generation-Sequencing (NGS) panel screening was also conducted. Routine blood and CSF laboratory tests, as well as CSF tap test, yielded negative results. Cranial MRI showed atrophy of the whole brain. PiB-PET scanning indicated that PiB was merely retained in her brain with an overall standard uptake value ratio (SUVR) <1.0. Simoa analysis showed an increase in the level of CSF t-tau and a decrease in that of CSF Aβ42. NGS panel screening detected a c.G2032A (p.D678N) heterozygous mutation in APP. Consequently, the patient was diagnosed with autosomal dominant AD. We have reported an uncommon case of autosomal dominant AD carrying p.D678N variant in APP with negative PiB-PET results. The diagnosis of AD should not be directly excluded solely based on the negative PiB-PET results.

Background: This study aims to investigate the clinical characteristics and the length of hospital stay (LOS), as well as risk factors for prolonged LOS in a cohort of asymptomatic and mild COVID-19 patients infected with the Omicron variant. Methods: A total of 1166 COVID-19 patients discharged from the inpatient ward of the largest makeshift hospital (May 8–10, 2022) in Shanghai, China, were included. The demographics, medical history, and the lowest and admission cycle threshold (Ct) values of the RT-PCR tests for SARS-CoV-2 genes of the open reading frame 1ab (Ct-ORF) and the nucleocapsid protein (Ct-N) during hospitalization were recorded. Patients with LOS > 7 days, or LOS ≤ 7 days were included in the Prolonged group or the Control group, separately. The clinical characteristics and LOS of the participants in the two groups were described and compared. Multivariate Logistic and linear regression analyses were applied to explore the risk factors for prolonged LOS. The diagnostic efficacy of the lowest and admission Ct values for the Prolonged group was tested via the receiver operating characteristic (ROC) curve analysis. Results: The median LOS was 6 days in the total study population. The age was older (45.52 ± 14.78 vs. 42.54 ± 15.30, P = 0.001), while both the lowest and admission Ct-ORF (27.68 ± 3.88 vs. 37.00 ± 4.62, P < 0.001; 30.48 ± 5.03 vs. 37.79 ± 3.81, P < 0.001) and Ct-N (25.79 ± 3.60 vs. 36.06 ± 5.39, P < 0.001; 28.71 ± 4.95 vs. 36.95 ± 4.59, P < 0.001) values were significantly lower in the Prolonged group. There were more mild cases in the Prolonged group (23.8% vs. 11.5%, P < 0.001). The symptom spectrum differed between the two groups. In multivariate analyses, age, disease category, and the lowest Ct-N values were shown to be associated with prolonged LOS. Besides, both the lowest and admission Ct-ORF (AUC = 0.911 and 0.873) and Ct-N (AUC = 0.912 and 0.874) showed robust diagnostic efficacy for prolonged LOS. Conclusions: Our study firstly reports the clinical characteristics and risk factors for prolonged LOS during the wave of the Omicron epidemic in Shanghai, China. These findings provide evidence for the early identification of asymptomatic and mild COVID-19 patients at a high risk of prolonged hospitalization who may require early intervention, and long-term monitoring and management.

Introduction and Aims: Alzheimer's disease (AD) is the most common form of dementia with a complex genetic background. The cause of sporadic AD (sAD) remains largely unknown. Increasing evidence shows that genetic variations play a crucial role in sAD. P75 neurotrophin receptor (p75NTR, encoded by NGFR) plays a critical role in the pathogenesis of AD. Yet, the relationship between NGFR gene polymorphisms and AD was less studied. This study aims to analyze the relationship of NGFR gene polymorphism with the risk of AD in the Chinese Han population and amyloid-beta deposition in the ADNI cohort. Methods: This case-control association study was conducted in a Chinese Han cohort consisting of 366 sporadic AD (sAD) patients and 390 age- and sex-matched controls. Twelve tag-SNPs were selected and genotyped with a multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The associations between tag-SNPs and the risk of AD were analyzed by logistic regression. Moreover, another cohort from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database was included to examine the association of one tag-SNP (rs2072446) with indicators of amyloid deposition. Kaplan-Meier survival analysis and Cox proportional hazards models were used to test the predictive abilities of rs2072446 genotypes for AD progression. The mediation effects of A beta deposition on this association were subsequently tested by mediation analyses. Results: After multiple testing corrections, one tag-SNP, rs2072446, was associated with an increased risk of sAD (additive model, OR = 1.79, P-adjustment = 0.0144). Analyses of the ADNI cohort showed that the minor allele (T) of rs2072446 was significantly associated with the heavier A beta burden, which further contributed to an increased risk of AD progression in APOE epsilon 4 non-carrier. Conclusion: Our study found that rs2072446 in NGFR is associated with both the risk of sAD in the Chinese Han population and the amyloid burden in the ADNI cohort, which reveals the role of p75NTR in AD from a genetic perspective.

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer’s disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

Cerebrospinal fluid (CSF) biomarkers are essential for the accurate diagnosis of Alzheimer’s disease (AD), yet their measurement levels vary widely across centers and regions, leaving no uniform cutoff values to date. Diagnostic cutoff values of CSF biomarkers for AD are lacking for the Chinese population. As a member of the Alzheimer’s Association Quality Control program for CSF biomarkers, we aimed to establish diagnostic models based on CSF biomarkers and risk factors for AD in a Chinese cohort. A total of 64 AD dementia patients and 105 age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study cohort were included. CSF Aβ42, P-tau181, and T-tau levels were measured by ELISA. Combined biomarker models and integrative models with demographic characteristics were established by logistic regression. The cutoff values to distinguish AD from CN were 933 pg/mL for Aβ42, 48.7 pg/mL for P-tau181 and 313 pg/mL for T-tau. The AN model, including Aβ42 and T-tau, had a higher diagnostic accuracy of 89.9%. Integrating age and APOE ε4 status to AN model (the ANA’E model) increased the diagnostic accuracy to 90.5% and improved the model performance. This study established cutoff values of CSF biomarkers and optimal combined models for AD diagnosis in a Chinese cohort.

Background: Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease (AD). However, there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology. We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans. Methods: We enrolled a group of cognitively normal patients (median age: 64 years) with unilateral chronic cerebral hypoperfusion. Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion. ¹¹C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient. Results: The median age of the 10 participants, consisting of 4 males and 6 females, was 64 years (47–76 years). We found that there were no differences in standard uptake ratios of the cortex (volume of interest [VOI]: P = 0.721, region of interest [ROI]: P = 0.241) and grey/white ratio (VOI: P = 0.333, ROI: P = 0.445) and brain atrophy indices (Bicaudate, Bifrontal, Evans, Cella, Cella media, and Ventricular index, P > 0.05) between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion. Conclusion: Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebral β-amyloid deposition and neurodegeneration in humans.

Background: The pandemic of COVID‐19 has a persistent impact on global health, yet its sequelae need to be addressed at a wide scale around the globe. This study aims to investigate the characteristics, prevalence, and risk factors for mid‐term (>6 months) clinical sequelae in a cohort of COVID‐19 survivors.Methods: Totally 715 COVID‐19 survivors discharged before April 1, 2020, from three medical centers in Wuhan, China, were included. The longitudinal study was conducted by telephone interviews based on a questionnaire including the clinical sequelae of general, respiratory, and cardiovascular systems. Demographics and some characteristics of clinical sequelae of the survivors were recorded and analyzed. Multivariate logistic regression analysis was applied to explore the risk factors for the sequelae.Results: The median time interval from discharge to telephone interview was 225.0 days. The COVID‐19 survivors' median ages were 69 years, and 51.3% were male. Among them, 29.9% had at least one clinical sequela. There were 19.2%, 22.7%, and 5.0% of the survivors reporting fatigue, respiratory symptoms, and cardiovascular symptoms, respectively. Comorbidities, disease severity, the application of mechanical ventilation and high‐flow oxygen therapy, and the history of re‐admission were associated with the presence of clinical sequelae.Conclusions: Our study provides further evidence for the prevalence and characteristics of clinical sequelae of COVID‐19 survivors, suggesting long‐term monitoring and management is needed for their full recovery.

NAbs to different epitopes of Aβ are differentially associated with the severity and progression of Alzheimer’s disease.