Data System. The Pregnancy Risk Assessment Monitoring System (PRAMS) is an ongoing state-based surveillance system of maternal behaviors, attitudes, and experiences before, during, and shortly after ...pregnancy. PRAMS is conducted by the Centers for Disease Control and Prevention's Division of Reproductive Health in collaboration with state health departments. Data Collection/Processing. Birth certificate records are used in each participating jurisdiction to select a sample representative of all women who delivered a live-born infant. PRAMS is a mixed-mode mail and telephone survey. Annual state sample sizes range from approximately 1000 to 3000 women. States stratify their sample by characteristics of public health interest such as maternal age, race/ethnicity, geographic area of residence, and infant birth weight. Data Analysis/Dissemination. States meeting established response rate thresholds are included in multistate analytic data sets available to researchers through a proposal submission process. In addition, estimates from selected indicators are available online. Public Health Implications. PRAMS provides state-based data for key maternal and child health indicators that can be tracked over time. Stratification by maternal characteristics allows for examinations of disparities over a wide range of health indicators.
Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three ...cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials.
There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).
To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD.
Three ...cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017).
Plasma P-tau217.
Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography PET).
Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve AUC, 0.89 95% CI, 0.81-0.97) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 95% CI, 0.93-0.98) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 95% CI, 0.91-0.96) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22).
Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.
The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known.
To examine the novel tau PET tracer RO948 F 18 (18FRO948) performance in ...discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders.
In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer 18FRO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between 18FRO948 and flortaucipir F 18 (18Fflortaucipir) in patients with semantic variant primary progressive aphasia (svPPA).
18FRO948 (all patients) and 18Fflortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aβ42 and Aβ40 ratioAβ42/Aβ40, and Aβ42/p-tau181 ratio).
Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between 18FRO948 and 18Fflortaucipir.
Diagnostic groups among the 613 participants included cognitively unimpaired (mean SD age, 65.8 12.1 years; 117 men 46%), mild cognitive impairment (age, 70.8 8.3 years; 82 men 53%), AD dementia (age, 73.5 6.7 years; 57 men 57%), and non-AD disorders (age, 70.5 8.6 years; 41 men 40%). Retention of 18FRO948 was higher in AD dementia compared with all other diagnostic groups. 18FRO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aβ42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aβ42/Aβ40). Generally, tau PET positivity using 18FRO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of 18FRO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with 18Fflortaucipir.
In this study, elevated 18FRO948 SUVRs were most often seen among Aβ-positive cases, which suggests that 18FRO948 has high specificity for AD-type tau and highlights its potential as a diagnostic marker in the differential diagnosis of AD.
Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe ...neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.
Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate ...the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer
Fflortaucipir, and more accurately identifies individuals with abnormally increased
Fflortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with
Fflortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and
Fflortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.
Purpose: The hippocampus is affected by tau pathology early in Alzheimer's disease (AD) development. Accurate quantification of hippocampal tau signal using the tau-PET tracer 18F-flortaucipir is ...complicated, however, by off-target binding in the adjacent choroid plexus. We here present a new method for compensating for this off-target choroid plexus signal.
Methods: As off-target binding in the choroid plexus is known to be higher using 18F-flortaucipir compared to 18F-RO948, we created a binary hippocampal mask in template space where 18F-flortaucipir signal was higher than 18F-RO948, using data from 30 patients that underwent both 18F-flortaucipir and 18F-RO948 PET. This mask, presumably representing hippocampal voxels affected by off-target binding from the choroid plexus, was then converted to native space and applied as an exclusion mask to 145 patients across the AD-spectrum scanned with 18F-flortaucipir. As an alternative approach exclusion masks were generated by expanding the choroid plexus ROI in native space. Results were analysed both without and with partial volume error correction (non-PVEc/PVEc).
Results: Unmasked hippocampal standardized uptake value ratios (SUVR) were significantly correlated to choroid plexus SUVRs using both non-PVEc (p < 0.001, r = 0.28) and PVEc data (p < 0.05, r = 0.18). After applying the mask, however, these correlations disappeared. The diagnostic accuracy in separating cognitively impaired (CI) from cognitively unimpaired (CU) subjects improved after masking, from an AUC of 0.792 (95% C.I.,0.715–0.869) to 0.837 (95% C.I.,0.768–0.906) for non-PVEc data (p < 0.001), and from 0.798 (95% C.I.,0.722–0.873) to 0.834 (95% C.I.,0.766–0.903) for PVEc data (p < 0.001). The correlations to memory improved significantly for MMSE for unmasked vs. masked data both without (r = −0.440 vs. r = −0.499, p < 0.001) and with (r = −0.454 vs. r = −0.503, p < 0.001) PVEc. Similar results were found using the ADAS-Cog Delayed Word Recall test.
Conclusion: Choroid plexus off-target binding interferes with the estimation of true hippocampal retention using 18F-flortaucipir PET. Using a mask to correct for this off-target signal, we improved the diagnostic accuracy of 18F-flortaucipir in the hippocampus and the correlation between 18F-flortaucipir hippocampal SUVR and cognitive measures.
A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau ...neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A
) and tau PET-positive (T
) in the medial temporal lobe (A
T
) and/or in the temporal neocortex (A
T
) and compared them with A
T
and A
T
groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A
T
(hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A
T
(HR = 14.6, 95% CI = 8.1-26.4) and A
T
(HR = 2.4, 95% CI = 1.4-4.3) groups versus the A
T
(reference) group. Both A
T
(HR = 6.0, 95% CI = 3.4-10.6) and A
T
(HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A
T
group. Linear mixed-effect models indicated that the A
T
(β = -0.056 ± 0.005, T = -11.55, P < 0.001), A
T
(β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A
T
(β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A
T
(reference) group (all P < 0.001). Both A
T
(P < 0.001) and A
T
(P = 0.002) groups also progressed faster than the A
T
group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.
There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD).
To describe longitudinal 18FRO948 tau ...positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment.
This longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies.
Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET (18Fflutemetamol), and tau PET (18FRO948 in the BioFINDER-2 study; 18Fflortaucipir in the BioFINDER-1 study).
Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial.
Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% 95% CI, 2.67%-5.32%). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% 95% CI, 3.41%-5.49%) and IV (certain frontal regions; 5.22% 95% CI, 3.95%-6.49%), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% 95% CI, 0.78%-1.99% and 1.80% 95% CI, 0.76%-2.84%, respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2 = 0.27, P < .005), tau PET (stage I baseline SUVR; R2 = 0.13, P < .05) and amyloid PET (R2 = 0.10, P < .05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R2 = 0.24, P < .005) and tau PET (stage II baseline SUVR; R2 = 0.44, P < .001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal 18Fflortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P < .005) in Aβ-positive CU individuals and of 68% (95% CI, 61%-73%; P < .001) in Aβ-positive individuals with MCI.
In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD.
PDF
