ImportanceAlzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.ObjectiveTo evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.Design, Setting, and ParticipantsThis prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.ExposuresBaseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.Main Outcomes and MeasuresThe primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.ResultsAmong 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.Conclusions and RelevanceIn this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.
The purpose of this study was to characterize the nutritional status of infants diagnosed with cystic fibrosis (CF) through neonatal screening and to determine if they would achieve normal nutrition when managed with early intervention. In addition, nutrient intake was assessed to determine energy and macronutrient-consumption patterns. Evaluation of growth revealed that normal patterns could be achieved with mean energy intake values at ages 6 and 12 mo of 481 and 426 kJ/kg body wt (115 and 102 kcal/kg body wt), respectively. Biochemical assessment demonstrated low alpha-tocopherol and linoleic acid values at diagnosis in the majority of infants whereas one-third had abnormal indices of protein nutriture. Essential fatty acid deficiency was also demonstrated at diagnosis by abnormal triene-tetraene ratio values in 27% of screened infants. With predigested formula and dietary supplementation, there was improvement in all indices of nutritional status and only a low percentage of patients showed mild biochemical abnormalities at age 12 mo.
Stretched diameter of the atrial septal defect (ASD), determined by balloon sizing at cardiac catheterization, is commonly used to select the sizes of the devices used for transcatheter closure of the secundum ASD. We have previously evaluated the utility of pulmonary/systemic flow ratio and angiographic and echocardiographic (echo) sizes of the ASD in estimating stretched ASD diameter in a group of 16 patients and determined that echo diameter had the best correlation with stretched diameter (r = 0.82; p less than 0.001). The stretched diameter can be estimated: 1.05 x echo diameter in millimeters + 5.49. In this study we have prospectively evaluated this formula in estimating the stretched ASD diameter by two-dimensional echo measurements obtained in two (long and short-axis) subcostal views in another group of 21 patients aged 2.5 to 29 years (median 4.5 years). The echo size of the ASD was 9.7 +/- 3.0 mm, whereas the measured stretched diameter was 15.3 +/- 4.0 mm. The predicted stretched ASD diameter was calculated according to the above formula and was 15.7 +/- 3.1 mm, not significantly different (p greater than 0.1) from the measured stretched diameter. The correlation between predicted and measured stretched ASD sizes was excellent (r = 0.9; p less than 0.001). The mean squared error was 2.4. The differences between measured and predicted values were within 2 mm in all but three patients. It is concluded that stretched ASD diameter can be estimated accurately by two-dimensional subcostal echo measurements, which in turn could be used for selection of device size for occlusion of the ASD.
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