Structural, static, and dynamic functional MRI predictors for conversion from mild cognitive impairment to Alzheimer's disease: Inter-cohort validation of Shanghai Memory Study and ADNI.

Mild cognitive impairment (MCI) is a critical prodromal stage of Alzheimer's disease (AD), and the mechanism underlying the conversion is not fully explored. Construction and inter-cohort validation of imaging biomarkers for predicting MCI conversion is of great challenge at present, due to lack of longitudinal cohorts and poor reproducibility of various study-specific imaging indices. We proposed a novel framework for inter-cohort MCI conversion prediction, involving comparison of structural, static, and dynamic functional brain features from structural magnetic resonance imaging (sMRI) and resting-state functional MRI (fMRI) between MCI converters (MCI_C) and non-converters (MCI_NC), and support vector machine for construction of prediction models. A total of 218 MCI patients with 3-year follow-up outcome were selected from two independent cohorts: Shanghai Memory Study cohort for internal cross-validation, and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort for external validation. In comparison with MCI_NC, MCI_C were mainly characterized by atrophy, regional hyperactivity and inter-network hypo-connectivity, and dynamic alterations characterized by regional and connectional instability, involving medial temporal lobe (MTL), posterior parietal cortex (PPC), and occipital cortex. All imaging-based prediction models achieved an area under the curve (AUC) > 0.7 in both cohorts, with the multi-modality MRI models as the best with excellent performances of AUC > 0.85. Notably, the combination of static and dynamic fMRI resulted in overall better performance as relative to static or dynamic fMRI solely, supporting the contribution of dynamic features. This inter-cohort validation study provides a new insight into the mechanisms of MCI conversion involving brain dynamics, and paves a way for clinical use of structural and functional MRI biomarkers in future.

Education, neighborhood environment, and cognitive decline: Findings from two prospective cohort studies of older adults in China.

INTRODUCTION: The impacts of education on cognitive decline across different neighborhood environments (NEs) have rarely been studied. METHODS: We investigated and compared the associations between educational attainment and cognitive decline using data of 1286 participants from the Taizhou Imaging Study (TIS) and the Shanghai Aging Study (SAS). RESULTS: Compared with low-educated participants, in TIS with disadvantaged NE, high-educated participants manifested a significantly slower decline in global cognition (.062 Z score per year, P < .001), memory (.054 Z score per year, P < .05), and attention (.065 Z score per year, P < .01), whereas in SAS with advanced NE, highly educated individuals exhibited a slower decline only in attention (.028 Z score per year, P < .05). DISCUSSION: We observed the additive effect of educational attainment and NE on cognitive decline in older adults. Education is especially important for maintaining cognitive health in a disadvantaged environment.

Plasma Aß42/Aß40 and p-tau181 Predict Long-Term Clinical Progression in a Cohort with Amnestic Mild Cognitive Impairment.

BACKGROUND: Previous studies reported the value of blood-based biomarkers in predicting Alzheimer disease (AD) progression among individuals with different disease stages. However, evidence regarding the value of these markers in those with amnestic mild cognitive impairment (aMCI) is insufficient. METHODS: A cohort with 251 aMCI individuals were followed for up to 8 years. Baseline blood biomarkers were measured on a single-molecule array platform. Multipoint clinical diagnosis and domain-specific cognitive functions were assessed to investigate the longitudinal relationship between blood biomarkers and clinical AD progression. RESULTS: Individuals with low Aß42/Aß40 and high p-tau181 at baseline demonstrated the highest AD risk (hazard ratio = 4.83, 95% CI 2.37-9.86), and the most dramatic decline across cognitive domains. Aß42/Aß40 and p-tau181, combined with basic characteristics performed the best in predicting AD conversion (AUC = 0.825, 95% CI 0.771-0.878). CONCLUSIONS: Combining Aß42/Aß40 and p-tau181 may be a feasible indicator for AD progression in clinical practice, and a potential composite marker in clinical trials.

Development of a Plasma Biomarker Diagnostic Model Incorporating Ultrasensitive Digital Immunoassay as a Screening Strategy for Alzheimer Disease in a Chinese Population.

BACKGROUND: The ultrasensitive detection of blood-based biomarkers such as amyloid ß (Aß), tau, and neurofilament light (NFL) has drawn much attention in Alzheimer disease (AD) diagnosis. However, few studies have been conducted in the Chinese population. This study aimed to evaluate the ability of plasma biomarker diagnostic models for AD in the Chinese population based on a novel digital immunoassay technology. METHODS: 159 patients with AD, 148 patients with amnestic mild cognitive impairment (aMCI), and 121 cognitively normal control participants were recruited from 2 cohorts. The concentrations of plasma Aß42, Aß40, Aß42/Aß40, total tau (t-tau), phosphorylated tau 181 (p-tau 181), and NFL were quantified using an ultrasensitive single molecule array (Simoa) platform. Comprehensive and simplified diagnostic models were established based on the plasma biomarker profile and clinical characteristics. RESULTS: Among all blood biomarkers, p-tau181 had the greatest potential for identifying patients with cognitive impairment. The simplified diagnostic model, which combined plasma p-tau181, Aß42, and clinical features, achieved 93.3% area under the curve (AUC), 78.6% sensitivity, and 94.2% specificity for distinguishing AD from control participants, indicating a diagnostic ability approaching that of the comprehensive diagnostic model including 5 plasma biomarkers and clinical characteristics (95.1% AUC, 85.5% sensitivity, 94.2% specificity). Moreover, the simplified model reached 95.9% AUC and 94.0% AUC for early- and late-onset AD/control participants, respectively. CONCLUSIONS: We established AD diagnostic models using plasma biomarkers for Chinese participants. These findings suggest the simplified diagnostic model provides an accessible and practical way for large-scale screening in the clinic and community, especially in developing countries.

Comprehensive analysis reveals that LTBR is a immune-related biomarker for glioma.

Glioma is a common malignant brain tumor with great heterogeneity and huge difference in clinical outcomes. Although lymphotoxin (LT) beta receptor (LTBR) has been linked to immune system and response development for decades, the expression and function in glioma have not been investigated. To confirm the expression profile of LTBR, integrated RNA-seq data from glioma and normal brain tissues were analyzed. Functional enrichment analysis, TMEscore analysis, immune infiltration, the correlation of LTBR with immune checkpoints and ferroptosis, and scRNAseq data analysis in gliomas were in turn performed, which pointed out that LTBR was pertinent to immune functions of macrophages in gliomas. In addition, after being trained and validated in the tissue samples of the integrated dataset, an LTBR DNA methylation-based prediction model succeeded to distinguish gliomas from non-gliomas, as well as the grades of glioma. Moreover, by virtue of the candidate LTBR CpG sites, a prognostic risk-score model was finally constructed to guide the chemotherapy, radiotherapy, and immunotherapy for glioma patients. Taken together, LTBR is closely correlated with immune functions in gliomas, and LTBR DNA methylation could serve as a biomarker for diagnosis and prognosis of gliomas.

The impact of kidney function on plasma neurofilament light and phospho-tau 181 in a community-based cohort: the Shanghai Aging Study.

BACKGROUND: The blood-based biomarkers are approaching the clinical practice of Alzheimer's disease (AD). Chronic kidney disease (CKD) has a potential confounding effect on peripheral protein levels. It is essential to characterize the impact of renal function on AD markers. METHODS: Plasma phospho-tau181 (P-tau181), and neurofilament light (NfL) were assayed via the Simoa HD-X platform in 1189 dementia-free participants from the Shanghai Aging Study (SAS). The estimated glomerular filter rate (eGFR) was calculated. The association between renal function and blood NfL, P-tau181 was analyzed. An analysis of interactions between various demographic and comorbid factors and eGFR was conducted. RESULTS: The eGFR levels were negatively associated with plasma concentrations of NfL and P-tau181 (B = - 0.19, 95% CI - 0.224 to - 0.156, P < 0.001; B = - 0.009, 95% CI - 0.013 to -0.005, P < 0.001, respectively). After adjusting for demographic characteristics and comorbid diseases, eGFR remained significantly correlated with plasma NfL (B = - 0.010, 95% CI - 0.133 to - 0.068, P < 0.001), but not with P-tau181 (B = - 0.003, 95% CI - 0.007 to 0.001, P = 0.194). A significant interaction between age and eGFR was found for plasma NfL (Pinteraction < 0.001). In participants ≥ 70 years and with eGFR < 60 ml/min/1.73 m2, the correlation between eGFR and plasma NfL was significantly remarkable (B = - 0.790, 95% CI - 1.026 to - 0,554, P < 0.001). CONCLUSIONS: Considering renal function and age is crucial when interpreting AD biomarkers in the general aging population.

Oral microbiome in older adults with mild cognitive impairment.

The association between the oral microbiome and mild cognitive impairment (MCI) remains unclear. This study aimed to investigate such an association among Chinese older adults. Participants without dementia were recruited from the community. A battery of neuropsychological tests was administered to evaluate the cognitive function. The diagnosis of MCI was based on Peterson's criteria. The non-stimulated saliva was collected to extract sequences of the oral microbiome. Forty-seven MCI and 47 cognitively normal participants were included. There was significant difference in alpha diversity and insignificant difference in beta diversity between the two groups of participants. Compared with the cognitively normal group, Gemella haemolysans and Streptococcus gordonii were two significantly decreased species while Veillonella unclassified_Veillonella and Fusobacterium sp._HMT_203 were two significantly increased species in the MCI group. The richness of Gemella haemolysans presented the best discriminate value for MCI with the AUC (Area Under Curve) of 0.707, a cut-off value of 0.008 for relative abundance, the sensitivity of 63.8% and specificity of 70.2%. The dysbiosis of oral microbiome and relative abundance of Gemella haemolysans was significantly associated with MCI. Further studies were needed to develop new treatment strategies targeting the oral microbiome for cognitive impairment.

The heterogeneity of asymmetric tau distribution is associated with an early age at onset and poor prognosis in Alzheimer's disease.

PURPOSE: Left-right asymmetry, an important feature of brain development, has been implicated in neurodegenerative diseases, although it's less discussed in typical Alzheimer's disease (AD). We sought to investigate whether asymmetric tau deposition plays a potential role in AD heterogeneity. METHODS: Two independent cohorts consisting of patients with mild cognitive impairment due to AD and AD dementia with tau PET imaging were enrolled [the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with 18F-Flortaucipir, the Shanghai Memory Study (SMS) cohort with 18F-Florzolotau]. Based on the absolute global tau interhemispheric differences, each cohort was divided into two groups (asymmetric versus symmetric tau distribution). The two groups were cross-sectionally compared in terms of demographic, cognitive characteristics, and pathological burden. The cognitive decline trajectories were analyzed longitudinally. RESULTS: Fourteen (23.3%) and 42 (48.3%) patients in the ADNI and SMS cohorts showed an asymmetric tau distribution, respectively. An asymmetric tau distribution was associated with an earlier age at disease onset (proportion of early-onset AD: ADNI/SMS/combined cohorts, p = 0.093/0.026/0.001) and more severe pathological burden (i.e., global tau burden: ADNI/SMS cohorts, p < 0.001/= 0.007). And patients with an asymmetric tau distribution were characterized by a steeper cognitive decline longitudinally (i.e., the annual decline of Mini-Mental Status Examination score: ADNI/SMS/combined cohorts, p = 0.053 / 0.035 / < 0.001). CONCLUSIONS: Asymmetry in tau deposition, which may be associated with an earlier age at onset, more severe pathological burden, and a steeper cognitive decline, is potentially an important characteristic of AD heterogeneity.

Changes in lifestyle, mood, and disease management among community-dwelling older adults during the COVID-19 pandemic in China.

Background: Lives of older adults have been greatly affected by the COVID-19 pandemic. Methods: A telephone survey was conducted among the older adults aged 60 and above who lived in downtown Shanghai. We compared the lifestyle, mood, and disease management of older adults before and during the COVID-19 pandemic. Results: One hundred and fifty-six older adults in Shanghai completed the survey. The proportions of older adults with adequate consumption of meat (49.4% vs. 53.1%, P = 0.0339) and eggs (73.7% vs. 77.6%, P = 0.0143) were significantly higher than before. Participants spent significantly more time on housework (median: 2.0, IQR:1.0-3.0 vs. median: 2.0, IQR:1.0-2.0 h/day; P = 0.0361) and leisure activities (median: 7.0, IQR: 5.0-8.6 vs. median: 6.0, IQR: 4.0-8.5 h/day; P<0.0001) during the pandemic than before. More participants developed new hobbies (27.6% vs. 36.5%, P = 0.0470) and learned new skills (5.1% vs. 19.9%, P<0.0001). However, the number of participants routinely self-testing blood glucose and/or blood pressure decreased from 77.6% before to 64.1% during the pandemic (P = 0.0002). Conclusions: The COVID-19 pandemic affected the lifestyle, mood, and chronic diseases management among community-dwelling older adults. Supportive measures and interventions need to be tailored to older adults living in the community.

Altered Gut Microbiota and Its Clinical Relevance in Mild Cognitive Impairment and Alzheimer's Disease: Shanghai Aging Study and Shanghai Memory Study.

Altered gut microbiota has been reported in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Previous research has suggested that specific bacterial species might be associated with the decline of cognitive function. However, the evidence was insufficient, and the results were inconsistent. To determine whether there is an alteration of gut microbiota in patients with MCI and AD and to investigate its correlation with clinical characteristics, the fecal samples from 94 cognitively normal controls (NC), 125 participants with MCI, and 83 patients with AD were collected and analyzed by 16S ribosomal RNA sequencing. The overall microbial compositions and specific taxa were compared. The clinical relevance was analyzed. There was no significant overall difference in the alpha and beta diversity among the three groups. Patients with AD or MCI had increased bacterial taxa including Erysipelatoclostridiaceae, Erysipelotrichales, Patescibacteria, Saccharimonadales, and Saccharimonadia, compared with NC group (p < 0.05), which were positively correlated with APOE 4 carrier status and Clinical Dementia Rating (correlation coefficient: 0.11~0.31, p < 0.05), and negatively associated with memory (correlation coefficient: −0.19~−0.16, p < 0.01). Our results supported the hypothesis that intestinal microorganisms change in MCI and AD. The alteration in specific taxa correlated closely with clinical manifestations, indicating the potential role in AD pathogenesis.

Low dietary vitamin E intake is associated with high risk of incident dementia among older adults: The Shanghai Aging Study.

Background: Growing evidence has shown the association between vitamin E intake and the risk of cognitive decline, but the conclusions were inconsistent. This study aimed to verify the hypothesis that vitamin E intake is associated with incident dementia and deterioration of global cognition. Materials and methods: We followed 1,550 non-demented community residents aged ≥60 years for an average of 5.2 years in the Shanghai Aging Study. Baseline vitamin E intake were measured by the Food Frequency Questionnaire. Cognitive function was evaluated by a battery of neuropsychological tests. Consensus diagnosis of incident dementia was made based on the DSM-IV criteria. Results: During the follow-up, 135 cases (8.7%) of incident dementia were identified. The incidence rates of dementia in low, low-medium, medium-high, and high vitamin E intake groups were 2.8, 1.5, 1.6, and 0.7 per 100 person-years, respectively (P < 0.001). Participants with low vitamin E intake had a significantly higher risk of incident dementia than those with higher intake [compared with the highest intake group: hazard ratio (HR) 2.34, 95% confidence interval (CI) 1.20-4.57] after adjusting for confounders. Vitamin E intake was negatively correlated to the rate of annual decline of Mini-Mental State Examination score with the adjustment of confounders (ß = 0.019, p = 0.001). Conclusion: Vitamin E intake is negatively correlated with the risk of dementia in older adults. An appropriate high amount of vitamin E intake from the diet might be helpful to prevent future cognitive decline.

Plasma biomarker profiles and the correlation with cognitive function across the clinical spectrum of Alzheimer's disease.

BACKGROUND: Plasma biomarkers showed a promising value in the disease diagnosis and management of Alzheimer's disease (AD). However, profiles of the biomarkers and the associations with cognition across a spectrum of cognitive stages have seldom been reported. METHODS: We recruited 320 individuals with cognitive impairment and 131 cognitively normal participants from a memory clinic and a community cohort. Participants were classified into 6 groups based on their Clinical Dementia Rating (CDR) scores and clinical diagnosis, including AD, amnestic mild cognitive impairment (aMCI), and normal cognition (NC). A battery of neuropsychological tests was used to assess the global and domain-specific cognition. Plasma Aß1-40, Aß1-42, Aß1-42/Aß1-40, total tau (t-tau), neurofilament protein light chain (NfL), and phosphorylated tau at threonine 181 (p-tau181) were quantified using the single-molecule array (Simoa) platform. RESULTS: All the plasma markers (Aß1-40, Aß1-42, Aß1-42/Aß1-40, t-tau, NfL, p-tau181) showed certain discrepancies among NC, aMCI, and AD groups. The p-tau181 level showed a continuous escalating trend as the CDR scores increased from 0 (NC group) to 3 (severe AD). Compared with other biomarkers, p-tau181 had correlations with broader cognitive domains, covering global cognition (r = -0.536, P < 0.0001), memory (r = -0.481, P < 0.0001), attention (r = -0.437, P < 0.0001), visuospatial function (r = -0.385, P < 0.0001), and language (r = -0.177, P = 0.0003). Among participants with CDR ≥ 1, higher p-tau181 was correlated with worse global cognition (r = -0.301, P < 0.001). CONCLUSIONS: Plasma p-tau181 had correlations with broader cognitive domains, suggesting its potential as a promising clinical-relevant blood-based biomarker.

Decreased Retinal Vascular Density in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI): An Optical Coherence Tomography Angiography (OCTA) Study.

BACKGROUND: To explore the retinal vascular density changes in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients using optical coherence tomography angiography (OCTA). METHODS: We recruit 62 AD patients, 47 MCI patients, and 49 cognitively healthy controls (HC) in this study. All participants in the study received a comprehensive ophthalmological and neurological evaluation, including global cognitive screening, as well as the Mini-Mental State Examination (MMSE), and completed the following eye examinations: visual acuity (VA), intraocular pressure (IOP), examination with slit-lamp, fundus photography (Version 1.5.0.0, NIDEK CO, LTD) and Optical coherence tomography imaging (software ReVue version 2017.1.0.155, Optovue Inc., Fremont, CA, United States). The visual rating scales for atrophy and white matter lesion in MRI was evaluated for all the patients with AD and MCI. RESULTS: In the AD patient group, the superficial vascular density in the superior, inferior and whole retina was 44.64 ± 3.34, 44.65 ± 3.55, and 44.66 ± 3.36, respectively. These values were 44.24 ± 3.15, 43.72 ± 3.16, and 44 ± 3.07, respectively, in the MCI patient group. After multivariate analysis of the generalized linear model, adjustments for the confounding factors of sex, age, hypertension, diabetes and the quality index of OCTA image, the superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group (P < 0.05): 46.94 ± 2.04, 46.67 ± 2.26, and 46.82 ± 2.08, respectively. No difference in the area of the FAZ among the three groups was observed (AD group: 0.34 ± 0.11 mm2; MCI group: 0.36 ± 0.12 mm2; control group: 0.33 ± 0.12 mm2, p > 0.05). The ganglion cell complex (GCC) thickness, inner parafovea thickness, and peripapillary retinal nerve fiber layer (p-RNFL) thickness were associated with the superficial vascular density. We found no significant correlation between the global cognition (MMSE scores) or between the Fazekas score and retinal OCT angiogram flow density. CONCLUSION: The superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group. Our findings suggest the retinal microvascular dysfunction occurred in MCI and AD.