Neurofibrillary tangles, one of the neuropathologic hallmarks of Alzheimer's disease, have a dynamic lifespan of maturity that associates with progressive neuronal dysfunction and cognitive deficits. ...As neurofibrillary tangles mature, the biology of the neuron undergoes extensive changes that may impact biomarker recognition and therapeutic targeting. Neurofibrillary tangle maturity encompasses three levels: pretangles, mature tangles, and ghost tangles. In this review, we detail distinct and overlapping characteristics observed in the human brain regarding morphologic changes the neuron undergoes, conversion from intracellular to extracellular space, tau immunostaining patterns, and tau isoform expression changes across the lifespan of the neurofibrillary tangle. Post‐translational modifications of tau such as phosphorylation, ubiquitination, conformational events, and truncations are discussed to contextualize tau immunostaining patterns. We summarize accumulated and emerging knowledge of neurofibrillary tangle maturity, discuss the current tools used to interpret the dynamic nature in the postmortem brain, and consider implications for cognitive dysfunction and tau biomarkers.
Abstract Introduction Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness. Methods We examined five ...methods for determining cut points. Results The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal. Discussion In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method.
Background
Cdc20 is a crucial activator of the anaphase-promoting complex (APC/C) and is known to be essential in mitosis regulation. Abnormally high expression of Cdc20 has been reported in several ...malignancies. We aimed to study the Cdc20 expression in human breast cancer tissues, focusing specifically on Cdc20 in Triple-Negative Breast Cancer (TNBC).
Methods
The expression of mitotic regulators mRNA in three TNBC cell lines or three other breast cancer cell lines was determined by the RNA-sequencing database. 14,713 human breast cancer patient samples included in Breast Cancer-GenExminer v4.5 were used to analyze whether cell division cycle 20 (
Cdc20
) expression was related to TNBC. To find whether Cdc20 expression impacted prognosis in TNBC, we used 2,249 TNBC patients database. The loss of
Cdc20
by RNA interference (shRNA) and several mitotic inhibitors including Apcin, ZM447439, BI 2536, and VX-680 on the capacities of proliferation, migration, invasion were evaluated by colony-forming, wound-healing, transwell assay, and western blot, respectively.
Results
We studied the mitosis-related genes and proteins that are closely related to TNBC through the National Center for Biotechnology Information (NCBI) database. We found that
Cdc20
, one of the central mitotic regulators, is significantly upregulated in human TNBC, and its expression level is positively correlated with metastasis-free and relapse-free patient survival. We also found Cdc20 is highly conserved in TNBC in comparison to other breast cancer subtype cell lines. Cdc20 deficiency results in a decrease in cell growth and migration in four TNBC cell lines. Also, several mitotic inhibitors, such as Apcin, VX-680, ZM447439, and BI 2536, blocked cancer cell growth and invasion.
Conclusions
These results suggest an essential role of Cdc20 in tumor formation and metastasis of TNBC, which might be a potential target therapy for TNBC treatment.
Summary Background As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with ...Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of β-amyloidosis and neurodegeneration. Methods We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50–89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET,18 F-fluorodeoxyglucose (18 F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive A+ or negative A– ) was determined by amyloid PET with11 C Pittsburgh compound B. Neurodegeneration status (positive N+ or negative N– ) was determined by an Alzheimer's disease signature18 F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative A– N– , amyloid positive and neurodegeneration negative A+ N– , amyloid negative and neurodegeneration positive A– N+ , or amyloid positive and neurodegeneration positive A+ N+ ) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models. Findings The study population consisted of 985 eligible participants. The population frequency of A– N– was 100% (n=985) at age 50 years and fell to 17% (95% CI 11–24) by age 89 years. The frequency of A+ N– increased to 28% (24–32) at age 74 years, then decreased to 17% (11–25) by age 89 years. The frequency of A– N+ increased from age 60 years, reaching 24% (16–34) by age 89 years. The frequency of A+ N+ increased from age 65 years, reaching 42% (31–52) by age 89 years. The results from our multinomial models suggest that A+ N– and A+ N+ were more frequent in APOE ɛ4 carriers than in non-carriers and that A+ N+ was more, and A+ N– less frequent in men than in women. Interpretation Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals. Funding US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research.
Objective
To investigate the associations between age, vascular health, and Alzheimer disease (AD) imaging biomarkers in an elderly sample.
Methods
We identified 430 individuals along the cognitive ...continuum aged >60 years with amyloid positron emission tomography (PET), tau PET, and magnetic resonance imaging (MRI) scans from the population‐based Mayo Clinic Study of Aging. A subset of 329 individuals had fluorodeoxyglucose (FDG) PET. We ascertained presently existing cardiovascular and metabolic conditions (CMC) from health care records and used the summation of presence/absence of hypertension, hyperlipidemia, cardiac arrhythmias, coronary artery disease, congestive heart failure, diabetes mellitus, and stroke as a surrogate for vascular health. We used global amyloid from Pittsburgh compound B PET, entorhinal cortex tau uptake (ERC‐tau) from tau‐PET, and neurodegeneration in AD signature regions from MRI and FDG‐PET as surrogates for AD pathophysiology. We dichotomized participants into CMC = 0 (CMC−) versus CMC > 0 (CMC+) and tested for age‐adjusted group differences in AD biomarkers. Using structural equation models (SEMs), we assessed the impact of vascular health on AD biomarker cascade (amyloid leads to tau leads to neurodegeneration) after considering the direct and indirect age, sex, and apolipoprotein E effects.
Results
CMC+ participants had significantly greater neurodegeneration than CMC− participants but did not differ by amyloid or ERC‐tau. The SEMs showed that (1) vascular health had a significant direct and indirect impact on neurodegeneration but not on amyloid; and (2) vascular health, specifically the presence of hyperlipidemia, had a significant direct impact on ERC‐tau.
Interpretation
Vascular health had quantifiably greater impact on neurodegeneration in AD regions than on amyloid deposition. Longitudinal studies are warranted to clarify the relationship between tau deposition and vascular health. Ann Neurol 2017;82:706–718
Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of ...tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer's clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer's disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.
Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations ...is unclear. We examined P-tau181 and P-tau217 (n = 1,329, aged 30-98 years), in the population-based Mayo Clinic Study of Aging. Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81-0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid. The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis or prognosis at the population level.
Summary Background In a 2014 cross-sectional analysis, we showed that amyloid and neurodegeneration biomarker states in participants with no clinical impairment varied greatly with age, suggesting ...dynamic within-person processes. In this longitudinal study, we aimed to estimate rates of transition from a less to a more abnormal biomarker state by age in individuals without dementia, as well as to assess rates of transition to dementia from an abnormal state. Methods Participants from the Mayo Clinic Study of Aging (Olmsted County, MN, USA) without dementia at baseline were included in this study, a subset of whom agreed to multimodality imaging. Amyloid PET (with11 C-Pittsburgh compound B) was used to classify individuals as amyloid positive (A+ ) or negative (A− ).18 F-fluorodeoxyglucose (18 F-FDG)-PET and MRI were used to classify individuals as neurodegeneration positive (N+ ) or negative (N− ). We used all observations, including those from participants who did not have imaging results, to construct a multistate Markov model to estimate four different age-specific biomarker state transition rates: A− N− to A+ N− ; A− N− to A− N+ (suspected non-Alzheimer's pathology); A+ N− to A+ N+ ; and A− N+ to A+ N+ . We also estimated two age-specific rates to dementia: A+ N+ to dementia and A− N+ to dementia. Using these state-to-state transition rates, we estimated biomarker state frequencies by age. Findings At baseline (between Nov 29, 2004, to March 7, 2015), 4049 participants did not have dementia (3512 87% were clinically normal and 537 13% had mild cognitive impairment). 1541 individuals underwent imaging between March 28, 2006, to April 30, 2015. Transition rates were low at age 50 years and, with one exception, exponentially increased with age. At age 85 years compared with age 65 years, the rate was nearly 11-times higher (17·2 vs 1·6 per 100 person-years) for the transition from A− N− to A− N+ , three-times higher (20·8 vs 6·1) for A+ N− to A+ N+ , and five-times higher (13·2 vs 2·6) for A− N+ to A+ N+ . The rate of transition was also increased at age 85 years compared with age 65 years for A+ N+ to dementia (7·0 vs 0·8) and for A− N+ to dementia (1·7 vs 0·6). The one exception to an exponential increase with age was the transition rate from A− N− to A+ N− , which increased from 4·0 transitions per 100 person-years at age 65 years to 6·9 transitions per 100 person-years at age 75 and then plateaued beyond that age. Estimated biomarker frequencies by age from the multistate model were similar to cross-sectional biomarker frequencies. Interpretation Our transition rates suggest that brain ageing is a nearly inevitable acceleration toward worse biomarker and clinical states. The one exception is the transition to amyloidosis without neurodegeneration, which is most dynamic from age 60 years to 70 years and then plateaus beyond that age. We found that simple transition rates can explain complex, highly interdependent biomarker state frequencies in our population. Funding National Institute on Aging, Alexander Family Professorship of Alzheimer's Disease Research, the GHR Foundation.
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