Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

Alzheimer\u27s disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer\u27s disease continuum. Data were acquired from the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer\u27s Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age \u3e65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer\u27s disease

The association of long-term exposure to criteria air pollutants, fine particulate matter components, and airborne trace metals with late-life brain amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study

BACKGROUND: Studies suggest associations between long-term ambient air pollution exposure and outcomes related to Alzheimer\u27s disease (AD). Whether a link exists between pollutants and brain amyloid accumulation, a biomarker of AD, is unclear. We assessed whether long-term air pollutant exposures are associated with late-life brain amyloid deposition in Atherosclerosis Risk in Communities (ARIC) study participants. METHODS: We used a chemical transport model with data fusion to estimate ambient concentrations of PM RESULTS: At PET imaging, eligible participants (N = 318) had a mean age of 78 years, 56% were female, 43% were Black, and 27% had mild cognitive impairment. We did not find evidence of associations between long-term exposure to any pollutant and brain amyloid positivity in adjusted models. Findings were materially unchanged in sensitivity analyses using alternate air pollution estimation approaches for PM CONCLUSIONS: Air pollution may impact cognition and dementia independent of amyloid accumulation, though whether air pollution influences AD pathogenesis later in the disease course or at higher exposure levels deserves further consideration

Sleep-wake patterns are altered with age, Prdm13 signaling in the DMH, and diet restriction in mice

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specifi

Rapid aneuploidy testing (knowing less) versus traditional karyotyping (knowing more) for advanced maternal age: What would be missed, who should decide?

Objectives The application of rapid aneuploidy testing as a stand-alone approach in prenatal diagnosis is much debated. The major criticism of this targeted approach is that it will not detect other chromosomal abnormalities that will be picked up by traditional karyotyping. This study aimed to study the nature of such chromosomal abnormalities and whether parents would choose to terminate affected pregnancies. Design Retrospective study on a cytogenetic database. Setting Eight public hospitals in Hong Kong. Participants The karyotype results of 19 517 amniotic fluid cultures performed for advanced maternal age (≥35 years) from 1997 to 2002 were classified according to whether they were detectable by rapid aneuploidy testing. The outcomes of pregnancies with abnormal karyotypes were reviewed from patient records. Results In all, 333 (1.7%) amniotic fluid cultures yielded abnormal karyotypes; 175 (52.6%) of these were detected by rapid aneuploidy testing, and included trisomy 21 (n=94, 28.2%), trisomy 18 or 13 (n=21, 6.3%), and sex chromosome abnormalities (n=60, 18.0%). The other 158 (47.4%) chromosomal abnormalities were not detectable by rapid aneuploidy testing, of which 63 (18.9%) were regarded to be of potential clinical significance and 95 (28.5%) of no clinical significance. Pregnancy outcomes in 327/333 (98.2%) of these patients were retrieved. In total, 143 (42.9%) of these pregnancies were terminated: 93/94 (98.9%) for trisomy 21, 20/21 (95.2%) for trisomy 18 or 13, 19/60 (31.7%) for sex chromosome abnormalities, and 11/63 (17.5%) for other chromosomal abnormalities with potential clinical significance. There were no terminations in the 95 pregnancies in which karyotyping results were regarded to be of no clinical significance. Conclusions 'Knowing less' by the rapid aneuploidy stand-alone testing could miss about half of all chromosomal abnormalities detectable by amniocentesis performed for advanced maternal age. Findings from two fifths of the latter were of potential clinical significance, and the parents chose to terminate one out of six of the corresponding pregnancies. If both techniques are available, parents could have enhanced autonomy to choose.published_or_final_versio

Capacity for the management of kidney failure in the International Society of Nephrology Oceania and South East Asia (OSEA) region:Report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)

The International Society of Nephrology (ISN) region of Oceania and South East Asia (OSEA) is a mix of high and low-income countries, with diversity in population demographics and densities. There have been three iterations of the ISN-Global Kidney Health Atlas (GKHA) which have aimed to deliver in-depth assessments of global kidney care across the spectrum from early detection of CKD to treatment of kidney failure. This paper reports the findings of the latest ISN-GKHA in relation to kidney care capacity in OSEA. Among the 30 countries/territories in OSEA, 19 (63%) participated in the ISN-GKHA, representing over 97% of the region’s population. The overall prevalence of treated kidney failure in OSEA was 1,203 per million population (pmp), 45% higher than the global median of 823 pmp. In contrast, kidney replacement therapy (KRT) in OSEA was less available than the global median (chronic hemodialysis 89% OSEA vs 98% globally, peritoneal dialysis 72% vs 79%, kidney transplantation 61% vs 70%). Only 56% of countries could provide access to dialysis to at least half of people with incident kidney failure, lower than the global median of 74% of countries with available dialysis services. There were inequalities in access to KRT across OSEA, with widespread availability and low out-of-pocket costs in high-income countries and limited availability, often coupled with large out-of-pocket costs, in middle-and low-income countries. Workforce limitations were observed across OSEA, especially in lower middle-income countries. Extensive collaborative work within OSEA and globally will help close the noted gaps in kidney care provision