Neuroinflammation is independently associated with brain network dysfunction in Alzheimer's disease.

Brain network dysfunction is increasingly recognised in Alzheimer's disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aß deposition, brain connectivity and cognition. 42 participants (12 Aß-positive MCI, 14 Aß-positive AD and 16 Aß-negative healthy controls) were recruited. Participants had 11C-PBR28 and 18F-flutemetamol PET to quantify Aß deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aß-positive patients. Increased 11C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11C-PBR28 uptake correlated negatively with structural integrity (standardised ß = -0.375, p = 0.037) and network local efficiency (standardised ß = -0.468, p < 0.001), independent of cortical thickness and Aß deposition, while Aß was not. Network structural integrity, small-worldness and local efficiency, and cortical thickness were positively associated with cognition. Our findings suggest cortical neuroinflammation coincide with structural and functional network disruption independent of Aß and cortical atrophy. These findings link the brain connectivity change and pathological process in Alzheimer's disease, and suggest a pathway from neuroinflammation to systemic brain dysfunction.

Differences in treatment for Alzheimer's disease between urban and rural areas in China.

Introduction: In China, the increasing number of people with Alzheimer's disease (AD) poses a great challenge to families and the country. Economic and cultural differences cause a urban-rural gap in medical resources. This multicenter survey aimed to investigate the real-world practice of disease treatment among people with AD. Methods: People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for their treatment experience. Logistic regression was used to explore the factors that influence medication adherence in all areas, urban areas, and rural areas. Results: In this survey, 1,427 participants came from urban areas, and 539 participants came from rural areas. Patients in urban areas were older (mean age 74 vs. 70, p = 0.001), less frequently had mild AD (36.0 vs. 52.1%, p < 0.001), and more often were cared for at professional institutions (8.8 vs. 3.2%, p < 0.001). In terms of pharmacotherapy, 77.8% of people accepted taking lifelong medication, whereas 61.3% of patients insisted on taking medications. Although 72.0% of rural people believed in taking lifelong medication, only 30.0% adhered to drug use. The major factors that influenced medication adherence for all patients with AD were regional distribution (p < 0.001, OR = 6.18, 95% CI: 4.93-7.74) and family earnings (p = 0.003, OR = 1.22, 95% CI: 1.07-1.38). In rural areas, family earnings (p = 0.008, OR = 1.44, 95% CI: 1.10-1.89) and severity of AD (p = 0.033, OR = 1.31, 95% CI: 1.02-1.68) were the main factors. Family earnings (p = 0.038, OR = 1.16, 95% CI: 1.01-1.34) was the only factor among urban areas. Among all non-pharmaceutical activities except for cognitive intervention, the participation rates of rural patients were significantly higher than those of urban patients (p < 0.05). Conclusion: Although national progress has been made in the public awareness of disease treatment, adequate diagnosis and medication adherence need to be prompted, especially in rural areas. Furthermore, lifelong treatment should be improved based on regional characteristics through the joint efforts of the government, health workers, and social volunteers.

Cerebrospinal Fluid sTREM2 Has Paradoxical Association with Brain Structural Damage Rate in Early- and Late-Stage Alzheimer's Disease.

BACKGROUND: Recently it has been proposed that microglial response has a stage-dependent effect on the progression of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) sTREM2 has emerged as a promising microglial activation marker. OBJECTIVE: To test the stage-dependent role of microglia by studying the association between baseline sTREM2 and dynamic brain structural changes in AD and mild cognitive impairment (MCI) patients. METHODS: 22 amyloid-ß-positive (A+) and tau-positive (T+) AD and 24 A+T+MCI patients were identified from the Alzheimer's Disease Neuroimaging Initiative. The patients had baseline CSF amyloid-ß, phosphorylated-tau, and sTREM2, and were followed up for at least one year by T1-weighted and diffusion tensor imaging scans. Gray matter volumes and white matter microstructural integrity were evaluated. Linear mixed models were applied to analyze how baseline sTREM2 may influence the rate of brain structural changes while adjusting for the effects of age, APOE4 status, and the CSF core markers. RESULTS: In A+T+AD patients, baseline CSF sTREM2 was associated with faster mean diffusivity increase in the bilateral posterior corona radiata and right superior longitudinal fasciculus. In A+T+MCI patients, baseline CSF sTREM2 was associated slower gray matter volumetric loss in parahippocampal gyrus, left fusiform cortex, left middle temporal gyrus, and left lateral occipital cortex. Baseline CSF sTREM2 also had a protective effect against mean diffusivity increase in right inferior fronto-occipital fasciculus, left superior longitudinal fasciculus, left forceps minor, and left uncinate fasciculus. CONCLUSION: Microglial activation at early stage might have a protective effect against neurodegeneration, while at late stage it might facilitate AD. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention.

Factors Associated With Alzheimer's Disease Patients' Caregiving Status and Family Caregiving Burden in China.

Background: The increasing prevalence of Alzheimer's disease (AD) has emerged as a major challenge worldwide. China as the most populous country in the globe is amid rapid aging of its population, highlighting the need for appropriate social and medical policies to meet the challenge. The current multicenter cross-sectional observational study aims to provide understanding of the current status of caring given to AD patients in China and investigate the factors that influence the family burden as well as the choice of care given to AD patients. Methods: A total of 1,675 patients with probable AD from 30 provincial regions of mainland China were enrolled in the current study from August 2019 to December 2019. We analyzed the caregiving status and its relationship with family burden and various socio-economical and medical factors. Results: In the current study, 90.87% of the AD patients enrolled adopted family care. The choice of caregiving method was influenced by factors including age (>80 years old, OR 0.648; 95% CI, 0.427-0.983), overall family burden (high, OR 0.574; 95% CI, 0.0.373-0.884), patients' income (OR 0.511; 95% CI, 0.330-0.789) and self-care ability (OR 0.329; 95% CI, 0.183-0.588). Conclusion: Family care is the primary method of care for AD patients in China and the institutional care system for AD patients is still underprepared in China.

Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60-70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-ß (Aß) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD.

Value of top-hat procedure in management of squamous intraepithelial lesion.

AIM: To investigate the features of skip lesions and evaluate value of top-hat procedure in management of squamous intraepithelial lesion. METHODS: We reviewed the records of patients who underwent loop electrosurgical excision procedure (LEEP) in Peking University First Hospital between 2011 and 2016. Patients were confirmed to have CIN1-3. The term 'skip lesion' refers to lesion lying deep in cervical canal discontiguous with other lesions in transformation zone and was confirmed by top-hat. We compared their lesion grade in patients with or without skip lesion using logistic regression. We further reviewed patients who underwent subsequent hysterectomy within 6 months following LEEP and evaluated if top-hat procedure led to less residual lesions or was able to predict residual lesions. RESULTS: A total of 2260 patients were included and 595 underwent top-hat procedure. Thirty-nine out of 595 patients had skip lesions (6.5%), among whom two patients had CIN1 (5.1%), eight had CIN2 (20.5%) and 29 had CIN3 (74.4%). Logistical regression showed CIN3 was associated with higher risk of skip lesions compared to CIN1 (OR = 4.433, 95%CI: 1.036-18.964), while CIN2 was not (OR = 1.762, 95%CI: 0.366-8.471). Sixty-two patients underwent hysterectomy within 6 months following LEEP (CIN1-3), 24 underwent top-hat. Analysis revealed top-hat procedure did not result in less residual lesions. Colposcopy impression or prior HPV test was unable to predict skip lesions. CONCLUSION: About 9.4% patients with CIN3 had skip lesions in the study, which is associated with elevated risk for residual lesion. Top-hat procedure is able to detect skip lesions, but should not be performed on routinely because its prognostic value is not proved.