We evaluated the relationship between baseline CSF p-tau181 and the rate of tau PET change in the temporal meta-ROI and entorhinal cortex (ERC) and how it varied by amyloid level (CSF Aβ42 or amyloid ...PET) among 143 individuals from the Mayo Clinic Study of Aging and Mayo Alzheimer Disease Research Center. Higher CSF p-tau181, lower CSF Aβ42, and higher amyloid PET levels were associated with faster rates of tau PET change in both the temporal meta-ROI and ERC. In the temporal meta-ROI, longitudinal tau PET accumulation occurred primarily in participants with abnormal biomarker levels and a diagnosis of dementia, which supports the hypothesis that tau aggregation begins later in the disease process. Compared to the temporal meta-ROI, the ERC showed greater change in tau PET in non-demented participants but less change in later disease stages, supporting ERC as a more sensitive marker of early tau PET changes but with less dynamic range over the disease spectrum. We found both amyloid and CSF p-tau181 were associated with rates of tau PET change but there were some differences in associations by region, amyloid biomarker, and disease stage.
INTRODUCTION
The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co‐evolution of plasma and positron emission tomography (PET) ...Alzheimer's disease (AD) biomarkers.
METHODS
We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p‐tau217, p‐tau181, and glial fibrillary acidic protein (GFAP) as endpoints.
RESULTS
Individual timing of plasma p‐tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p‐tau, and tau PET temporal meta‐regions of interest when applying cut points based on young, cognitively unimpaired participants.
DISCUSSION
Plasma p‐tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p‐tau and Aβ PET was the strongest.
Highlights
Plasma p‐tau progression was more strongly associated with Aβ than tau PET.
Progression on plasma p‐tau was associated with Aβ PET and GFAP progression.
P‐tau181 and p‐tau217 become abnormal after Aβ PET and before tau PET.
GFAP became abnormal first, before plasma p‐tau and Aβ PET.
Background
Localized regions of left–right image intensity asymmetry (LRIA) were incidentally observed on T2‐weighted (T2‐w) and T1‐weighted (T1‐w) diagnostic magnetic resonance imaging (MRI) images. ...Suspicion of herpes encephalitis resulted in unnecessary follow‐up imaging. A nonbiological imaging artifact that can lead to diagnostic uncertainty was identified.
Purpose
To investigate whether systematic LRIA exist for a range of scanner models and to determine if LRIA can introduce diagnostic uncertainty.
Study Type
A retrospective study using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data base.
Subjects
One thousand seven hundred fifty‐three (median age: 72, males/females: 878/875) unique participants with longitudinal data were included.
Field Strength
3T.
Sequences
T1‐w three‐dimensional inversion‐recovery spoiled gradient‐echo (IR‐SPGR) or magnetization‐prepared rapid gradient‐echo (MP‐RAGE) and T2‐w fluid‐attenuated inversion recovery (FLAIR) long tau fast spin echo inversion recovery (LT‐FSE‐IR). Only General Electric, Philips, and Siemens' product sequences were used.
Assessment
LRIA was calculated as the left–right percent difference with respect to the mean intensity from automated anatomical atlas segmented regions. Three neuroradiologists with 37 (**), 32 (**), and 3 (**) years of experience rated the clinical impact of 30 T2‐w three‐dimensional FLAIR exams with LRIA to determine the diagnostic uncertainty. Statistical comparisons between retrospective intensity normalized T1m and original T1‐w images were made.
Statistical Tests
For each image type, a linear mixed effects model was fit using LRIA scores from all scanners, regions, and participants as the outcome and age and sex as predictors. Statistical significance was defined as having a P‐value <0.05.
Results
LRIA scores were significantly different from zero on most scanners. All clinicians were uncertain or recommended definite diagnostic follow‐up in 62.5% of cases with LRIA >10%. Individuals with acute brain pathology or focal neurologic deficits are not enrolled in ADNI; therefore, focal signal abnormalities were considered false positives.
Data Conclusion
LRIA is system specific, systematic, creates diagnostic uncertainty, and impacts IR‐SPGR, MP‐RAGE, and LT‐FSE‐IR product sequences.
Level of Evidence: 2
Technical Efficacy Stage: 3
BACKGROUND
We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals.
METHODS
...We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aβ)42/40, phosphorylated tau (p‐tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p‐tau217. The outcome was a change in a memory composite measure.
RESULTS
All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p‐tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person‐level prediction intervals were wide.
DISCUSSION
Plasma p‐tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.
Cardiac resynchronization therapy (CRT) improves outcomes in patients with left bundle branch block (LBBB), but the benefits of CRT in patients with other QRS morphologies or previous pacing are ...uncertain.
The purpose of this study was to describe outcomes in patients with prior right ventricular pacing and non-LBBB morphologies.
We studied 505 patients who underwent de novo CRT (n = 338) or CRT upgrade (n = 167). De novo patients were categorized by underlying QRS morphology: LBBB (67%), right bundle branch block (RBBB; 11%), intraventricular conduction delay (IVCD; 13%), and QRS <120 ms (9%). Upgrade patients were categorized by the percentage of previous ventricular pacing.
Patients were followed for death over a median of 2.6 years (interquartile range 1.6-4.0). New York Heart Association (NYHA) functional class and echocardiographic improvements were similar in de novo and upgrade patients. However, within the de novo group, NYHA improvements were less in patients with RBBB (0.3 +/- 0.8; P = .014) or IVCD (0.2 +/- 0.7; P = .001) than in those with LBBB (0.7 +/- 0.8). These patients had less left ventricular functional improvement as well. Survival was comparable after de novo versus upgrade CRT (61% vs 63% at 4 years; P = .906). No clinical or survival differences were noted in upgrade patients based on the percentage of previous pacing. However, survival in de novo CRT recipients with RBBB (32%) was lower than in those with LBBB (66%; P <.001), and RBBB independently predicted death (hazard ratio 3.5, confidence interval 1.9-6.5; P <.001).
RBBB and IVCD result in less clinical improvement or worsened survival after CRT. Additional selection criteria may be beneficial in identifying potential responders with RBBB, IVCD, or narrow QRS.
The purpose of this study was to characterize the prognosis of minimally symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM).
Recent data have suggested that obstruction may be ...present in the majority of HCM patients, irrespective of cardiac symptoms. The prognosis of minimally symptomatic obstructive HCM remains poorly defined.
We examined 544 consecutive adult patients (age 59 +/- 16 years; 55% men) with obstructive HCM documented by Doppler echocardiography who were free of severe cardiac symptoms, and we performed clinical follow-up (median 9.3 years).
There was only a slight excess mortality of the cohort in comparison to the expected survival of a similar U.S. general population (10-year observed vs. expected survival, 69.3% vs. 71.9%; p = 0.04) and 46% of the deaths were attributable to noncardiac causes. However, there was a clear relation between increasing severity of the left ventricular outflow tract (LVOT) gradient and outcome. For patients with high resting gradients (Doppler peak velocity >4 m/s), survival was significantly impaired (53% at 10 years; p = 0.001 vs. expected), and death or severe symptoms occurred in 68% of these patients within 10 years after the initial evaluation. Conversely, there was no impairment of long-term survival for patients with less-severe resting obstruction. Independent predictors of mortality in the entire cohort were age, prior stroke, and LVOT gradient severity.
Patients with obstructive HCM and mild or no symptoms have only slight excess mortality. However, patients with markedly elevated resting LVOT gradients are at a high risk of heart failure and death. These findings may have important implications for therapy, including the timing of septal reduction therapy.
The Surgical Treatment for Ischemic Heart Failure (STICH) randomized trial was designed to identify an optimal management strategy for patients with ischemic cardiomyopathy. Baseline ...echocardiographic examinations were required for all patients. The primary aim of this report is to describe the baseline STICH Echocardiography Core Laboratory data. The secondary aim is to provide recommendations regarding how echocardiography should be used in clinical practice and research on the basis of the experience gained from echocardiography in STICH.
Between September 2002 and January 2006, 2,136 patients with ejection fractions (EFs) ≤ 35% and coronary artery disease amenable to coronary artery bypass grafting were enrolled. Echocardiography was acquired by 122 clinical enrolling sites, and measurements were performed by the Echocardiography Core Laboratory after a certification process for all clinical sites.
Echocardiography was available for analysis in 2,006 patients (93.9%); 1,734 (86.4%) were men, and the mean age was 60.9 ± 9.5 years. The mean left ventricular end-systolic volume index, measureable in 72.8%, was 84.0 ± 30.9 mL/m(2), and the mean EF was 28.9 ± 8.3%, with 18.5% of patients having EFs > 35%. Single-plane measurements of left ventricular and left atrial volumes were similar to their volumes by biplane measurement (r = 0.97 and r = 0.92, respectively). Mitral regurgitation severity by visual assessment was associated with a wide range of effective regurgitant orifice area, while effective regurgitant orifice area ≥ 0.2 cm(2) indicated at least moderate mitral regurgitation by visual assessment. Deceleration time of mitral inflow velocity had a weak correlation with EF (r = 0.25) but was inversely related to estimated pulmonary artery systolic pressure (r = -0.49).
In STICH patients with ischemic cardiomyopathy, Echocardiography Core Laboratory analysis of baseline echocardiographic findings demonstrated a wide spectrum of left ventricular shape, function, and hemodynamics, as well as the feasibility and limitations of obtaining essential echocardiographic measurements. It is critical that the use of echocardiographic parameters in clinical practice and research balance the strengths and weaknesses of the technique.
To describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research.
Eight ...participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status.
All participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR <1.33).
The participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD.
We present the case of a cognitively unimpaired 77-year-old man with elevated, asymmetric, and longitudinally increasing Flortaucipir tau PET despite normal (visually negative) amyloid PET. His ...atypical tau PET signal persisted and globally increased in a follow-up scan five years later. Across eight years of observations, temporoparietal atrophy was observed consistent with tau PET patterns, but he retained the cognitively unimpaired classification. Altogether, his atypical tau PET signal is not explained by any known risk factors or alternative pathologies, and other imaging findings were not remarkable. He remains enrolled for further observation.
The appearance of β-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer disease ...(AD), but their interaction is poorly understood.
To test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration. DESIGN Longitudinal cohort study.
Population-based Mayo Clinic Study of Aging.
One hundred ninety-one CN persons (median age, 77 years; range, 71-93 years) in the Mayo Clinic Study of Aging who underwent magnetic resonance, fludeoxyglucose F 18 (FDG) positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET imaging at least twice 15 months apart. Participants were grouped according to the recommendations of the National Institute on Aging-Alzheimer Association preclinical AD criteria based on the presence of β-amyloidosis, defined as a PiB PET standardized uptake value ratio (SUVr) greater than 1.5, alone (stage 1) or with brain injury (stage 2 + 3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of patients with mild cognitive impairment (n = 17) or dementia (n = 9) from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had undergone comparable imaging and had a PiB PET SUVr greater than 1.5.
Rate of change of cortical volume on volumetric magnetic resonance images and rate of change of glucose metabolism on FDG PET scan results.
There were 25 CN participants with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (preclinical AD stages 2 + 3). On follow-up scans, the preclinical AD stage 2 + 3 participants had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared with the other CN groups. The changes were similar to those in the cognitively impaired participants. Extratemporal regions did not show similar changes.
Higher rates of medial temporal neurodegeneration occur in CN individuals who, on their initial scans, had abnormal levels of both β-amyloid and brain injury biomarkers. Although preclinical AD is currently only a research topic, the description of its brain structural changes will be critical for trials designed to prevent or forestall dementia due to AD.
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