Tau accumulation in autosomal dominant Alzheimer\u27s disease: A longitudinal [18F]flortaucipir study

Cortical tau accumulation is a key pathological event that partly defines Alzheimer\u27s disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p \u3c 0.001). There were no significant regional differences between presymptomatic carriers and non-carriers in FTP SUVRs, or their rates of change (p \u3e 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging

The Roles of Vertical Advection and Eddy Diffusion in the Equatorial Mesospheric Semi-Annual Oscillation (MSAO)

Observations of the mesospheric semi-annual oscillation (MSAO) in the equatorial region have been reported dating back several decades. Seasonal variations in both species densities and airglow emissions are well documented. The extensive observations available offer an excellent case study for comparison with model simulations. A broad range of MSAO measurements is summarised with emphasis on the 80-100 km region. The objective here is not to address directly the complicated driving forces of the MSAO, but rather to employ a combination of observations and model simulations to estimate the limits of some of the underlying dynamical processes. Photochemical model simulations are included for near-equinox and near-solstice conditions, the two times with notable differences in the observed MSAO parameters. Diurnal tides are incorporated in the model to facilitate comparisons of observations made at different local times. The roles of water vapour as the driver species and ozone as the response species are examined to test for consistency between the model results and observations. The simulations suggest the interactions between vertical eddy diffusion and background vertical advection play a significant role in the MSAO phenomenon. Further, the simulations imply there are rigid limits on vertical advection rates and eddy diffusion rates. For August at the Equator, 90 km altitude, the derived eddy diffusion rate is approximately 1 x 106 cm2 s-1 and the vertical advection is upwards at 0.8 cm s-1. For April the corresponding values are 4 x 105 cm2 s-1 and 0.1 cm s-1. These results from the current 1-D model simulations will need to be verified by a full 3-D simulation. Exactly how vertical advection and eddy diffusion are related to gravity wave momentum as discussed by Dunkerton (1982) three decades ago remains to be addressed

Centerscope

Centerscope, formerly Scope, was published by the Boston University Medical Center "to communicate the concern of the Medical Center for the development and maintenance of improved health care in contemporary society.

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer\u27s disease: A longitudinal observational study

BACKGROUND: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer\u27s disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer\u27s pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer\u27s disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer\u27s disease. METHODS: We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer\u27s disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR\u3e0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. FINDINGS: In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10 INTERPRETATION: Our findings in autosomal dominant Alzheimer\u27s disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. FUNDING: German Research Foundation, US National Institutes of Health

A randomized controlled trial of amyloid positron emission tomography results disclosure in mild cognitive impairment

IntroductionRecent studies suggest that Alzheimer’s disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers.MethodsRandomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow‐up.ResultsGains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow‐up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms.DiscussionThese findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163444/2/alz12129_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163444/1/alz12129.pd

Evolutionary life history theory as an organising framework for cohort studies : insights from the Cebu Longitudinal Health and Nutrition Survey

By tracking a group of individuals through time, cohort studies provide fundamental insights into the developmental time course and causes of health and disease. Evolutionary life history theory seeks to explain patterns of growth, development, reproduction and senescence, and inspires a range of hypotheses that are testable using the longitudinal data from cohort studies. Here we review two decades of life history theory-motivated work conducted in collaboration with the Cebu Longitudinal Health and Nutrition Survey (CLHNS), a birth cohort study that enrolled more than 3000 pregnant women in the Philippines in 1983 and has since followed these women, their offspring and grandoffspring. This work has provided evidence that reproduction carries “costs” to cellular maintenance functions, potentially speeding senescence, and revealed an unusual form of genetic plasticity in which the length of telomeres inherited across generations is influenced by reproductive timing in paternal ancestors. Men in Cebu experience hormonal and behavioural changes in conjunction with changes in relationship and fatherhood status that are consistent with predictions based upon other species that practice bi-parental care. The theoretical expectation that early life cues of mortality or environmental unpredictability will motivate a “fast” life history strategy are confirmed for behavioural components of reproductive decision making, but not for maturational tempo, while our work points to a broader capacity for early life developmental calibration of systems like immunity, reproductive biology and metabolism. Our CLHNS findings illustrate the power of life history theory as an integrative, lifecourse framework to guide longitudinal studies of human populations

Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage

OSIRIS: A Decade of Scattered Light

Into year 11 of a 2-yr mission, OSIRIS is redefining how limb-scattered sunlight can be used to probe the atmosphere, even into the upper troposphere

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer\u27s disease

Alzheimer\u27s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau

Re-Analysis of Modeling a Switch from a 13-Valent to 10-Valent Pneumococcal Conjugate Vaccine in Canada:Leveraging Real-World Experience from Belgium

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