Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer's Disease: A Longitudinal Study.

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Clinical laboratory tests and dementia incidence: A prospective cohort study.

BACKGROUND: Dementia is a major public health issue and a heavy economic burden. It is urgently necessary to understand the underlying biological processes and to identify biomarkers predicting risk of dementia in the preclinical stage for prevention and treatment. METHODS: By using the data of the 367,093 white British individuals from UK Biobank, we investigated the relationship between 56 laboratory measures and 5-year dementia incidence using logistic regression. Adjusted odds ratios for dementia incidence with values below or above the 95 % confidence interval (<2.5th or > 97.5th percentile) on each of clinical laboratory tests were computed. RESULTS: We observed that markers of endocrine dysregulation: elevated hemoglobin A1C (AOR = 2.01 [1.35, 2.88]) was associated with increased dementia incidence. Indicators of liver dysfunction: elevated gamma glutamyltransferase (AOR = 2.28 [1.49, 3.32]), and albumin (AOR = 2.01 [1.15, 3.25]), indicators of renal impairment: high urea (AOR = 1.69 [1.15, 2.40]), and cystatin C (AOR = 1.89 [1.30, 2.67]), and some immune markers, like elevated neutrophill count, low lymphocyte count, and indicators of anemia were also observed to be associated with increased dementia incidence. Both low and high concentrations of insulin-like growth factor 1 were found to be risk factors for dementia. LIMITATIONS: This is an observational study. CONCLUSION: Several systemic biomarkers were associated with dementia incidence. These results implicate a contributory role of diverse biological processes to dementia onset, and enrich our understanding of potential dementia prevention strategy.

Association between cerebrospinal fluid clusterin and biomarkers of Alzheimer's disease pathology in mild cognitive impairment: a longitudinal cohort study.

Background: Clusterin, a glycoprotein implicated in Alzheimer's disease (AD), remains unclear. The objective of this study was to analyze the effect of cerebrospinal fluid (CSF) clusterin in relation to AD biomarkers using a longitudinal cohort of non-demented individuals. Methods: We gathered a sample comprising 86 individuals under cognition normal (CN) and 134 patients diagnosed with MCI via the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. To investigate the correlation of CSF clusterin with cognitive function and markers of key physiological changes, we employed multiple linear regression and mixed-effect models. We undertook a causal mediation analysis to inspect the mediating influence of CSF clusterin on cognitive abilities. Results: Pathological characteristics associated with baseline Aß42, Tau, brain volume, exhibited a correlation with initial CSF clusterin in the general population, Specifically, these correlations were especially prominent in the MCI population; CSF Aß42 (PCN = 0.001; PMCI = 0.007), T-tau (PCN < 0.001; PMCI < 0.001), and Mid temporal (PCN = 0.033; PMCI = 0.005). Baseline CSF clusterin level was predictive of measurable cognitive shifts in the MCI population, as indicated by MMSE (ß = 0.202, p = 0.029), MEM (ß = 0.186, p = 0.036), RAVLT immediate recall (ß = 0.182, p = 0.038), and EF scores (ß = 0.221, p = 0.013). In MCI population, the alterations in brain regions (17.87% of the total effect) mediated the effect of clusterin on cognition. It was found that variables such as age, gender, and presence of APOE ε4 carrier status, influenced some of these connections. Conclusion: Our investigation underscored a correlation between CSF clusterin concentrations and pivotal AD indicators, while also highlighting clusterin's potential role as a protective factor for cognitive abilities in MCI patients.

Association of biological age with health outcomes and its modifiable factors.

Identifying the clinical implications and modifiable and unmodifiable factors of aging requires the measurement of biological age (BA) and age gap. Leveraging the biomedical traits involved with physical measures, biochemical assays, genomic data, and cognitive functions from the healthy participants in the UK Biobank, we establish an integrative BA model consisting of multi-dimensional indicators. Accelerated aging (age gap >3.2 years) at baseline is associated incident circulatory diseases, related chronic disorders, all-cause, and cause-specific mortality. We identify 35 modifiable factors for age gap (p < 4.81 × 10-4 ), where pulmonary functions, body mass, hand grip strength, basal metabolic rate, estimated glomerular filtration rate, and C-reactive protein show the most significant associations. Genetic analyses replicate the possible associations between age gap and health-related outcomes and further identify CST3 as an essential gene for biological aging, which is highly expressed in the brain and is associated with immune and metabolic traits. Our study profiles the landscape of biological aging and provides insights into the preventive strategies and therapeutic targets for aging.

Age-Related Association Between APOE ɛ4 and Cognitive Progression in de novo Parkinson's Disease.

BACKGROUND: APOE ɛ4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson's disease (PD). Meanwhile, the differential influence of APOE ɛ4 on cognition in young and old individuals interpreted as antagonistic pleiotropy. OBJECTIVE: To examine whether the effect of APOE ɛ4 on cognitive progression in de novo PD is age dependent. METHODS: In this study, 613 de novo PD patients were recruited from Parkinson's Progression Markers Initiative (PPMI). To examine the age-dependent relationship between APOE ɛ4 and cognitive changes, we added 3-way interaction of APOE ɛ4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE ɛ4 in the middle age group and elderly group separately. Cox regression was utilized to examine the progression of cognition in age-stratified PD participants. RESULTS: Age significantly modified relationship between APOE ɛ4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE ɛ4 carriers showed steeper decline in global cognition (p = 0.001) as well as in most cognitive domains, and they had a greater risk of cognitive progression (adjusted HR 1.625, 95% CI 1.143-2.310, p = 0.007), compared with non-carriers. However, in the middle age group, no significant relationships between APOE ɛ4 and cognitive decline can be detected. CONCLUSION: Our results indicated that the APOE ɛ4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future.

Cataract, Cataract Surgery, and Risk of Incident Dementia: A Prospective Cohort Study of 300,823 Participants.

BACKGROUND: Visual impairment and interventions to preserve vision may impact dementia risk. Thus, we aimed to explore the associations of cataract and cataract surgery with the risk of dementia. METHODS: Prospective data from 300,823 individuals in the UK Biobank were used. We used multivariate Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals for associations, with healthy control subjects as a reference. The same method was used to explore the effects of surgery on dementia outcomes of patients with cataract. One-way analysis of variance was performed to examine the associations between cataract and brain morphometric measures. RESULTS: After a mean follow-up of 8.4 years, 3226 individuals were diagnosed with dementia. The nonsurgical cataract group had increased risk of all-cause dementia (HR, 1.214; 95% CI, 1.012-1.456; p = .037) and Alzheimer's disease (HR, 1.479; 95% CI, 1.105-1.981; p = .009). However, there was no difference in dementia risk between the cataract surgery group and the healthy control group. Cataract surgery was associated with decreased risk of all-cause dementia (HR, 0.632; 95% CI, 0.421-0.947; p = .026) and Alzheimer's disease (HR, 0.399; 95% CI, 0.196-0.812; p = .011) compared with the nonsurgical group. Additionally, cataract was negatively associated with cortical volumes, aging-related subcortical volumes, and fractional anisotropy of white matter fibers. CONCLUSIONS: Cataract patients who did not receive surgical treatment had an increased risk of dementia. However, cataract surgery could reverse the risk of dementia. Our findings on brain structures and pathways in patients with cataract also provided evidence for the mechanism. Reversible visual impairment, such as cataract, is a promising modifiable risk factor for dementia.

Dynamic changes of CSF clusterin levels across the Alzheimer's disease continuum.

BACKGROUND: Clusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD. METHODS: Following the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aß42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aß42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aß42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aß42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aß42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups. RESULTS: Compared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P <  0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aß42 (ß = 0.040, P <  0. 001), CSF p-tau (ß = 0.325, P <  0.001) and CSF t-tau (ß = 0.346, P <  0.001). CONCLUSIONS: Our results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aß pathology; and the increased levels are associated with tau pathology and neurodegeneration.

Application of the Amyloid/Tau/Neurodegeneration Framework in Cognitively Intact Adults: The CABLE Study.

OBJECTIVES: The amyloid/tau/neurodegeneration (AT[N]) framework has conceptualized the Alzheimer's disease (AD) continuum as a continuum of disease with evidence of amyloid-related pathologies independent of clinical manifestation. Based on this framework, it is necessary to reveal the distribution and risk factors of AD continuum in the cognitively intact population among different cohorts and races, including the northern Chinese Han population. METHODS: This study classified cognitively intact Chinese Alzheimer's Biomarker and LifestylE (CABLE) participants through the AT(N) scheme. Gaussian mixture models were used to identify the cutoff values of cerebrospinal fluid biomarkers, which distinguished AD continuum ( A + T-N-, A + T + N-, A + T-N + and A + T + N +) from 1,005 participants (mean age 61 years; 40% female). Multivariable logistic regressions and Cochran-Armitage trend tests were used to test neuropsychological performance and risk factors for AD continuum. RESULTS: Approximately one-third of individuals (33.7%) belonged to the AD continuum. Four potential modifiable risk factors, including hypertension, thyroid diseases, social isolation, and minimal depression symptoms, were identified for the AD continuum (OR ranging 1.68-6.90). A trend toward higher prevalence of the AD continuum was associated with a larger number of risk factors (p for trend <0.0001). The risk of AD continuum increased by approximately twofold for each additional modifiable risk factor (OR 1.9, 95% CI 1.65-2.24, p < 0.0001). INTERPRETATION: This study revealed the distribution and potential risk factors of the AD continuum in a cognitively intact Han population in northern China, which filled the gap in the area about the performance of the AT(N) framework in the Asian population. ANN NEUROL 2022;92:439-450.

The variation in crown-root morphology of anterior teeth assessed with cone-beam computed tomography.

OBJECTIVE: To determine the discrepancy of crown-root morphology of anterior teeth, using cone-beam computed tomography (CBCT), and to provide a guidance for proper torque expression. METHODS: A total of eligible 200 CBCT were imported into Invivo v. 5.4 software, to obtain the middle labio-lingual sections of anterior teeth. AutoCAD 2007 software was applied to measure the crown-root angulation (Collum angle) and the angle formed by a tangent to the center of the labial surface and the long axis of the crown (labial surface angle). SPSS 18.0 was used for statistical comparisons of the two measurements, at the level of p< 0.05, and the Pearson correlation analysis was applied to investigate the association between the two measurements. RESULTS: The value of Collum angle in maxillary central incisor was close to 0°. Significantly negative Collum angle in lateral incisors and maxillary canine, and positive value in mandibular canine were detected (p < 0.001). The labial surface angle in canine was significantly greater than the intra-arch incisors (p< 0.001), and no significant difference was detected between the central and lateral incisors (p > 0.05). Notably, there was also a significant positive correlation between the two measurements. CONCLUSIONS: The crown-root angulations were greatly different among anterior teeth. Accompanying the obvious crown-root angulations, the canines both in maxillary and mandibular arches presented considerable labial surface curvatures. Hence, equivalent deviation during bracket bonding might cause greater torque expression error and increase the risk of alveolar fenestration and dehiscence.

Time spent in outdoor light is associated with the risk of dementia: a prospective cohort study of 362094 participants.

BACKGROUND: Data on the association between free-living daytime sunlight exposure and incident dementia are scarce. The objective is to evaluate whether the time spent in outdoor light is related to the dementia risk and to investigate whether the optimal duration varies with clinical parameters. METHODS: Data were from a prospective cohort of 362,094 UK Biobank participants. A questionnaire survey was conducted to investigate how many hours the participants spent outdoors on typical summer and winter days. A restricted cubic spline (RCS) was performed to explore the potential nonlinear relationship between sunlight exposure and the risk of dementia. We used multivariate Cox proportional hazard regression models to estimate the hazard ratios (HRs) for the associations between sunlight exposure and dementia outcomes, with the change points as a reference. RESULTS: After a median follow-up of 9.0 years, 4149 (1.15%) individuals were diagnosed with dementia. RCS showed a J-shaped relationship between time spent in outdoor light and the dementia risk, with the lowest risk at three change points (1.5 h/day on average, 2 h/day in summer, and 1 h/day in winter). Cox hazard regression models showed a marked increase in risk at low exposure (HR=1.287, 95%CI 1.094-1.515) but a relatively slow increase at higher exposure (HR=1.070, 95%CI 1.031-1.10). Results are more pronounced among participants over 60 years old, females, and those with exactly 7 h of sleep every night. CONCLUSIONS: Sunlight exposure had a J-shaped association with dementia risk. Giving detailed guidance on sunlight exposure can effectively prevent dementia.

sTREM2 mediates the associations of minimal depressive symptoms with amyloid pathology in prodromal Alzheimer's disease: The CABLE study.

The effects of microglial activation on the associations between depression and Alzheimer's disease (AD) are still unclear. TREM2 gene plays a pivotal role in microglial activation, has been identified as a risk factor for AD. In this work, we aimed to assess the interrelationships of soluble TREM2 (sTREM2) level in cerebrospinal fluid (CSF), minimal depressive symptoms (MDSs), and CSF amyloid markers. The linear regression analyses were conducted on 796 cognitively unimpaired participants from the CABLE (Chinese Alzheimer's Biomarker and LifestylE) study. Causal mediation analyses with 10,000 bootstrapped iterations were used to test the mediation effects. In addition, similar statistical analyses were performed in subgroups stratified by sex, age, and APOE ε4 carrier status. In total subjects, MDSs were associated with lower CSF sTREM2 levels (p < 0.0001), lower CSF amyloid markers (p < 0.0001), and poorer cognitive performance (MMSE, p = 0.0014). The influence of MDSs on CSF amyloid markers was partially mediated by CSF sTREM2 (proportion from 2.91 to 32.58%, p < 0.0001). And we found that the sTREM2-amyloid pathway partially mediated the effects of MDSs on cognition. Of note, exploratory subgroup analyses showed that the above influences of CSF sTREM2 were pronounced in the APOE ε4 (-) group. These results suggest that early depression is associated with amyloid pathology, which might be partly mediated by microglial activation, especially in the absence of APOE ε4.

Cerebrospinal fluid neurofilament dynamic profiles predict cognitive progression in individuals with de novo Parkinson's disease.

Background: Neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) reflects the severity of neurodegeneration, with its altered concentrations discovered in Parkinson's disease (PD) and Parkinson's disease dementia (PD-D). Objective: To determine whether CSF NfL, a promising biomarker of neuronal/axonal damage, can be used to monitor cognitive progression in de novo Parkinson's disease and predict future cognitive decline. Methods: A total of 259 people were recruited in this study, including 85 healthy controls (HC) and 174 neonatal PD patients from the Parkinson's Progression Markers Initiative (PPMI). Multiple linear regression and linear mixed effects models were used to examine the associations of baseline/longitudinal CSF NfL with cognitive decline and other CSF biomarkers. Kaplan-Meier analysis and log-rank test were used to compare the cumulative probability risk of cognition progression during the follow-up. Multivariate cox regression was used to detect cognitive progression in de novo PD. Results: We found PD patients with mild cognitive impairment (PD-MCI) was higher than with normal cognition (PD-NC) in terms of CSF NfL baseline levels (p = 0.003) and longitudinal increase rate (p = 0.034). Both baseline CSF NfL and its rate of change predicted measurable cognitive decline in de novo PD (MoCA, ß = -0.010, p = 0.011; ß = -0.0002, p < 0.001, respectively). The predictive effects in de novo PD patients aged >65, male, ill-educated (<13 years) and without carrying Apolipoprotein E ε4 (APOE ε4) seemed to be more obvious and reflected in more domains investigated. We also observed that CSF NfL levels predicted progression in de novo PD patients with different cognitive diagnosis and amyloid status. After an average follow-up of 6.66 ± 2.54 years, higher concentration above the median of baseline CSF NfL was associated with a future high risk of PD with dementia (adjusted HR 2.82, 95% CI: 1.11-7.20, p = 0.030). Conclusion: Our results indicated that CSF NfL is a promising prognostic predictor of PD, and its concentration and dynamics can monitor the severity and progression of cognitive decline in de novo PD patients.

Late-Life Obesity Associated with Tau Pathology in Cognitively Normal Individuals: The CABLE Study.

BACKGROUND: Existed evidence suggests that midlife obesity increases the risk of Alzheimer's disease (AD), while there is an inverse association between AD and obesity in late life. However, the underlying metabolic changes of AD pathological proteins attributed to obesity in two life stages were not clear. OBJECTIVE: To investigate the associations of obesity types and obesity indices with AD biomarkers in cerebrospinal fluid (CSF) in different life stages. METHODS: We recruited 1,051 cognitively normal individuals (61.94±10.29 years, 59.66%male) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF detections for amyloid-ß 42 (Aß42), total-tau (T-tau), and phosphorylated tau (P-tau). We utilized body mass index, waist circumference, waist-to-height ratio, and metabolic risk factors to determine human obesity types. Multiple linear models and interaction analyses were run to assess the impacts of obesity on AD biomarkers. RESULTS: The metabolically unhealthy obesity or healthy obesity might exert a reduced tau pathology burden (p < 0.05). Individuals with overweight, general obesity, and central obesity presented lower levels of tau-related proteins in CSF than normal controls (p < 0.05). Specially, for late-life individuals, higher levels of obesity indices were associated with a lower load of tau pathology as measured by CSF T-tau and T-tau/Aß42 (p < 0.05). No similar significant associations were observed in midlife. CONCLUSION: Collectively, late-life general and central obesity seems to be associated with the reduced load of tau pathology, which further consolidates the favorable influence of obesity in specific life courses for AD prevention.

The variation in crown-root morphology of anterior teeth assessed with cone-beam computed tomography

ABSTRACT Objective: To determine the discrepancy of crown-root morphology of anterior teeth, using cone-beam computed tomography (CBCT), and to provide a guidance for proper torque expression. Methods: A total of eligible 200 CBCT were imported into Invivo v. 5.4 software, to obtain the middle labio-lingual sections of anterior teeth. AutoCAD 2007 software was applied to measure the crown-root angulation (Collum angle) and the angle formed by a tangent to the center of the labial surface and the long axis of the crown (labial surface angle). SPSS 18.0 was used for statistical comparisons of the two measurements, at the level of p< 0.05, and the Pearson correlation analysis was applied to investigate the association between the two measurements. Results: The value of Collum angle in maxillary central incisor was close to 0°. Significantly negative Collum angle in lateral incisors and maxillary canine, and positive value in mandibular canine were detected (p < 0.001). The labial surface angle in canine was significantly greater than the intra-arch incisors (p< 0.001), and no significant difference was detected between the central and lateral incisors (p > 0.05). Notably, there was also a significant positive correlation between the two measurements. Conclusions: The crown-root angulations were greatly different among anterior teeth. Accompanying the obvious crown-root angulations, the canines both in maxillary and mandibular arches presented considerable labial surface curvatures. Hence, equivalent deviation during bracket bonding might cause greater torque expression error and increase the risk of alveolar fenestration and dehiscence.

RESUMO Objetivo: Determinar a discrepância na morfologia coroa-raiz de dentes anteriores, utilizando tomografia computadorizada de feixe cônico (TCFC), e fornecer parâmetros para a expressão apropriada do torque. Método: No total, 200 tomografias elegíveis foram importadas para o software Invivo 5.4 para obtenção das secções médias vestibulolinguais dos dentes anteriores. Osoftware AutoCAD 2007 foi usado para medir a angulação coroa-raiz (ângulo Collum) e o ângulo formado por uma tangente ao centro da superfície vestibular da coroa e o longo eixo da coroa (ângulo da superfície vestibular). O software SPSS 18.0 foi utilizado para as comparações estatísticas das duas medições, com nível de significância de p< 0,05, e a análise de correlação de Pearson foi aplicada para investigar a associação entre as duas medições. Resultados: O valor do ângulo Collum do incisivo central superior foi próximo a 0°. Foram detectados valores significativamente negativos para o ângulo Collum nos incisivos laterais e caninos superiores, mas valores positivos nos caninos inferiores (p< 0,001). O ângulo da superfície vestibular no canino foi significativamente maior do que nos incisivos intra-arcada (p< 0,001), e nenhuma diferença significativa foi detectada entre incisivos centrais e laterais (p> 0,05). Também foi observada uma correlação positiva significativa entre as duas medições. Conclusões: As angulações coroa-raiz foram muito diferentes entre os dentes anteriores. Os caninos superiores e inferiores apresentaram considerável curvatura na superfície vestibular, associada a uma evidente angulação coroa-raiz. Consequentemente, desvios durante a colagem de braquetes podem desencadear maior erro na expressão de torque e aumentar o risco de fenestração alveolar e deiscência, sendo necessária uma avaliação antes da colagem.

P-tau and neurodegeneration mediate the effect of ß-amyloid on cognition in non-demented elders.

BACKGROUND: There are many pathological changes in the brains of Alzheimer's disease (AD) patients. For many years, the mainstream view on the pathogenesis of AD believes that ß-amyloid (Aß) usually acts independently in addition to triggering functions. However, the evidence now accumulating indicates another case that these pathological types have synergies. The objective of this study was to investigate whether effects of Aß pathology on cognition were mediated by AD pathologies, including tau-related pathology (p-tau), neurodegeneration (t-tau, MRI measurements), axonal injury (NFL), synaptic dysfunction (neurogranin), and neuroinflammation (sTREM2, YKL-40). METHODS: Three hundred seventy normal controls (CN) and 623 MCI patients from the ADNI (Alzheimer's Disease Neuroimaging Initiative) database were recruited in this research. Linear mixed-effects models were used to evaluate the associations of baseline Aß with cognitive decline and biomarkers of several pathophysiological pathways. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of AD pathologies on cognition. RESULTS: Tau-related pathology, neurodegeneration, neuroinflammation are correlated with the concentration of Aß, even in CN participants. The results show that age, gender, and APOE ε4 carrier status have a moderating influence on some of these relationships. There is a stronger association of Aß with biomarkers and cognitive changes in the elderly and females. In CN group, Aß pathology is directly related to poor cognition and has no mediating effect (p < 0.05). In mild cognitive impairment, tau-related pathology (26.15% of total effect) and neurodegeneration (14.8% to 47.0% of total effect) mediate the impact of Aß on cognition. CONCLUSIONS: In conclusion, early Aß accumulation has an independent effect on cognitive decline in CN and a tau, neurodegeneration-dependent effect in the subsequent cognitive decline in MCI patients.

Associations of Sleep Characteristics with Cerebrospinal Fluid sTREM2 in Cognitively Normal Older Adults: the CABLE Study.

As brain insults, sleep disorders could enhance microglial activation and aggravate neuroinflammation. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) serves as a readout for TREM2-associated microglial responses. We aimed to study the association of sleep characteristics with CSF sTREM2 in cognitively normal (CN) older adults. Linear and non-linear regression analyses were conducted in 830 participants with measurements of sleep characteristics and CSF sTREM2, after adjusting for age, sex, education, the Chinese-Modified Mini-Mental State Examination (CM-MMSE) scores, and APOE4 status. These analyses were also performed in amyloid-negative (A -) and amyloid-positive (A +) individuals. Linear relationships between sleep characteristics and CSF sTREM2 were found. In all the participants, sleep efficiency score in Pittsburgh Sleep Quality Index (PSQI) (p = 0.037) showed a positive linear association with CSF sTREM2. In A + individuals, the grade of PSQI total score (p = 0.011) as well as subjective sleep quality score (p = 0.048) and sleep efficiency score (p < 0.001) in PSQI were positively associated with CSF sTREM2. Besides, several U-shaped relationships were revealed of sleep-time measures, such as insufficient or excessive nocturnal sleep duration, with CSF sTREM2 in A + individuals (the optimal model: bedtime 22:21 p.m., time to fall asleep 22:52 p.m., nocturnal sleep duration 7.36 h). In A - individuals, the above relationships were not found. Poor self-reported sleep characteristics and sleep indicators were associated with higher CSF sTREM2, suggesting that sleep might play an important role in the regulation of TREM2-associated microglial activity.

Serum Neurofilament Dynamics Predicts Cognitive Progression in de novo Parkinson's Disease.

BACKGROUND: Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. OBJECTIVE: Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson's disease (PD) remains unclear. METHODS: In this research, 144 healthy controls and 301 de novo PD patients from Parkinson's Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression in PD participants. RESULTS: We found PD patients had higher serum NfL than controls at baseline (p = 0.031), and NfL increase was faster in PD group (p < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, ß= -0.014, p < 0.001; ß= -0.002, p < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62-15.29, p < 0.001). CONCLUSION: In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD.

Metabolically healthy obesity and risk of stroke: a meta-analysis of prospective cohort studies.

BACKGROUND: Metabolic healthy obesity (MHO) is a unique subgroup of overweight and obese individuals with normal metabolic characteristics. Its association with the risk of stroke remains unclear. We aimed to examine the risk of stroke in MHO individuals and the further associations between stroke and metabolic abnormalities under different bodyweight conditions. METHODS: We systematically searched PubMed, Embase and Cochrane Library from December 1946 to January 2019, and only included prospective cohort studies. Random effects models were used to evaluate the pooled risk ratios (RR) and 95% confidence intervals (95% CI) of incident stroke. RESULTS: A total of eight studies comprising 4,256,888 participants were included in the meta-analysis. MHO individuals had an increased risk of stroke compared with metabolically healthy normal weight (MH-NW) individuals (RR =1.17, 95% CI: 1.11-1.23). However, the stroke risk of metabolically healthy overweight individuals was the same (RR =1.02, 95% CI: 0.84-1.23). All groups with unhealthy metabolism had a similarly elevated risk: normal weight (RR =1.83, 95% CI: 1.57-2.14), overweight (RR =1.93, 95% CI: 1.44-2.58), and obesity (RR =2.00, 95% CI: 1.40-2.87). CONCLUSIONS: The meta-analysis confirms a positive association between MHO phenotype and the risk of stroke. Individuals with metabolic abnormalities under different bodyweight conditions are at elevated risk.

Reference Values of Carotid Ultrafast Pulse-Wave Velocity: A Prospective, Multicenter, Population-Based Study.

BACKGROUND: Ultrafast ultrasound imaging has been demonstrated to be an effective method to evaluate carotid stiffness through carotid pulse-wave velocity (PWV) with high reproducibility, but a lack of reference values has precluded its widespread use in clinical practice. The aims of this study were to establish reference values of PWV for ultrafast ultrasound imaging in a prospective, multicenter, population-based cohort study and to investigate the main determinants of carotid PWV. METHODS: A total of 1,544 healthy Han Chinese volunteers (581 men [38%]; age range, 18-95 years) were enrolled from 32 collaborating laboratories in China. The participants were categorized by age, blood pressure (BP), and body mass index (BMI). Basic clinical parameters and carotid PWV at the beginning of systole (BS) and at end-systole (ES) were measured using ultrafast ultrasound imaging techniques. RESULTS: PWV at both BS and ES was significantly higher in the left carotid artery than in the right carotid artery. PWV at BS was significantly higher in men than in women; however, no significant difference was noted in PWV at ES between men and women. Multiple linear regression analyses revealed that age, BP, and BMI were independently correlated with PWV at both BS and ES. PWV at BS and ES progressively increased with increases in age, BP, and BMI. Furthermore, age- and sex-specific reference values of carotid PWV for ultrafast ultrasound imaging were established. CONCLUSIONS: Reference values of carotid PWV for ultrafast ultrasound imaging, stratified by sex and age, were determined for the first time. Age, BP, and BMI were the dominant determinants of carotid PWV for ultrafast ultrasound imaging, which should be considered in clinical practice for assessing arterial stiffness.

Serum Calcium Predicts Cognitive Decline and Clinical Progression of Alzheimer's Disease.

Relationship between serum calcium and Alzheimer's disease (AD) remains unclear. The aim of this study is to test whether serum calcium is associated with other AD-associated biomarkers and could predict clinical progression in nondemented elders. This was a longitudinal population-based study. The sample was derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, which included 1224 nondemented elders: 413 cognitively normal (CN) and 811 mild cognition impairment (MCI). Associations were investigated between serum calcium and longitudinal changes in Aß/tau pathologic features, brain structure, cognitive function, and disease progression. Serum calcium concentrations increased with disease severity. Serum calcium predicted longitudinal cognitive decline and conversion from nondemented status to AD dementia (adjusted HR = 1.41, 95% CI 1.13-1.76). Furthermore, serum calcium levels were negatively correlated with CSF-Aß42 (ß = - 0.558, P = 0.008), FDG-PET (ß = - 0.292, P < 0.001), whole brain volume (ß = - 0.148, P = 0.001), and middle temporal volume (ß = - 0.216, P = 0.042). Similar results were obtained in CN and MCI groups. Higher serum calcium status (even if not hypercalcemia) may increase the risk of AD in elders. Serum calcium is a useful biomarker in predicting clinical progression in nondemented elders. More researches are needed in the future to explore the underlying mechanism.