We determined whether head trauma was associated with amyloid deposition and neurodegeneration among individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI).
Participants ...included 448 CN individuals and 141 individuals with MCI from the Mayo Clinic Study of Aging who underwent Pittsburgh compound B (PiB)-PET, fluorodeoxyglucose-PET, and MRI. Head trauma was defined as a self-reported brain injury with at least momentary loss of consciousness or memory. Regression models examined whether head trauma was associated with each neuroimaging variable (assessed as continuous and dichotomous measures) in both CN and MCI participants, controlling for age and sex.
Among 448 CN individuals, 74 (17%) self-reported a head trauma. There was no difference in any neuroimaging measure between CN subjects with and without head trauma. Of 141 participants with MCI, 25 (18%) self-reported a head trauma. MCI participants with a head trauma had higher amyloid levels (by an average 0.36 standardized uptake value ratio units, p = 0.002).
Among individuals with MCI, but not CN individuals, self-reported head trauma with at least momentary loss of consciousness or memory was associated with greater amyloid deposition, suggesting that head trauma may be associated with Alzheimer disease-related neuropathology. Differences between CN individuals and individuals with MCI raise questions about the relevance of head injury-PET abnormality findings in those with MCI.
Introduction
We aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers.
Methods
Cut points for Elecsys amyloid beta 42 (Aβ42), total tau ...(t‐tau), hyperphosphorylated tau (p‐tau), and t‐tau/Aβ42 and p‐tau/Aβ42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants.
Results
The t‐tau/Aβ42 and p‐tau/Aβ42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers. Reciever Operating Characteristic (ROC)‐based cut points were 0.26 (0.24–0.27) for t‐tau/Aβ42 and 0.023 (0.020–0.025) for p‐tau/Aβ42. Ratio cut points derived from other cohorts performed as well in our cohort as our own did. Individual biomarkers had worse diagnostic properties and more variable results in terms of positive and negative percent agreement (PPA and NPA).
Conclusion
CSF t‐tau/Aβ42 and p‐tau/Aβ42 ratios are very robust indicators of AD. For individual biomarkers, the intended use should determine which cut point is chosen.
Abstract Background Cardiac resynchronization therapy (CRT) has been shown to improve heart failure (HF) symptoms and survival. We hypothesized that a greater improvement in left-ventricular ejection ...fraction (LVEF) after CRT is associated with greater survival benefit. Methods and Results In 693 patients across 2 international centers, the improvement in LVEF after CRT was determined. Patients were grouped as non-/modest-, moderate-, or super-responders to CRT, defined as an absolute change in LVEF of ≤5%, 6–15%, and >15%, respectively. Changes in New York Heart Association (NYHA) functional class and left ventricular end-diastolic dimension (LVEDD) were assessed for each group. There were 395 non-/modest-, 186 moderate-, and 112 super-responders. Super-responders were more likely to be female and to have nonischemic cardiomyopathy, lower creatinine, and lower pulmonary artery systolic pressure than non-/modest- and moderate-responders. Super-responders were also more likely to have lower LVEF than non-/modest-responders. There was no difference in NYHA functional class, mitral regurgitation grade, or tricuspid regurgitation grade between groups. Improvement in NYHA functional class (−0.9 ± 0.9 vs −0.4 ± 0.8 P < .001 and −0.6 ± 0.8 P = .02) and LVEDD (−8.7 ± 9.9 mm vs −0.5 ± 5.0 and −2.4 ± 5.8 mm P < .001 for both) was greatest in super-responders. Kaplan-Meier survival analysis revealed that super-responders achieved better survival compared with non-/modest- ( P < .001) and moderate-responders ( P = .049). Conclusions Improvement in HF symptoms and survival after CRT is proportionate to the degree of improvement in LV systolic function. Super-response is more likely in women, those with nonischemic substrate, and those with lower pulmonary artery systolic pressure.
Do MRI-based metrics of a CSF-dynamics disorder, disproportionately enlarged subarachnoid-space hydrocephalus (DESH), correlate with discordant amyloid biomarkers (low CSF β-amyloid 1–42, normal ...Aβ-PET scan)? Individuals ≥50 years from the Mayo Clinic Study of Aging, with MRI, 11C-Pittsburgh compound B (Aβ) PET scans, and CSF phosphorylated-tau protein and Aβ42, were categorized into 4 groups: normal and/or abnormal by CSF β-amyloid 1–42 and Aβ amyloid PET. Within groups, we noted MRI patterns of CSF-dynamics disorders and Aβ-PET accumulation-change rate. One-hundred participants (21%) in the abnormal-CSF and/or normal-PET group had highest DESH-pattern scores and lowest CSF-phosphorylated-tau levels. Among normal amyloid-PET individuals, a 1-unit DESH-pattern score increase correlated with 30%-greater odds of abnormal amyloid CSF after age, and sex adjustment. Mean rate over time of amyloid-PET accumulation in abnormal-CSF and/or normal-PET individuals approximated individuals with normal amyloid values. Adjusting for phosphorylated-tau, abnormal CSF-amyloid and/or normal amyloid-PET individuals had higher mean amyloid-PET accumulation rates than normal individuals. CSF dynamics disorders confound β-amyloid and phosphorylated-tau CSF-biomarker interpretation.
Cardiac resynchronization therapy (CRT) is a therapy of proven benefit in patients with advanced heart failure. Identifying potential responders remains challenging, and whether the etiology of the ...heart failure is related to the potential hemodynamic benefit and long-term outcome of CRT is unclear.
The purpose of this study was to evaluate whether heart failure etiology (ischemic cardiomyopathy ICM vs nonischemic dilated cardiomyopathy DCM) was associated with CRT outcome and implantable cardioverter-defibrillator (ICD) shocks.
The study included 503 CRT recipients (CRT-D 90%) in a longitudinal CRT database: ICM (n = 312) and DCM (n = 191). Clinical variables and echocardiographic measures preimplant and postimplant were collected. Actuarial survival and ICD therapy data were assessed with Kaplan-Meier curve and log rank tests.
Pre-CRT, ICM patients were older and had higher creatinine levels (P <.001). At median follow-up of 7.1 months, the DCM group experienced greater improvement in left ventricular ejection fraction (8.3% ± 10% vs 6.2% ± 10%, P = .05) and left ventricular end-diastolic volumes than did those with ICM (-28%.4 ± 53 mL vs -15.3 ± 46 mL, P = .024). Survival estimates at 4 years were 55% for ICM and 77% for DCM groups (P <.001), respectively, whereas no significant difference in the incidence of appropriate/inappropriate ICD shocks was observed. The ICM group remained at higher risk for death compared to the DCM group after controlling for preimplant variables (hazard ratio 1.6, 95% confidence interval 1.1-2.3, P = .008).
In response to CRT and in contrast to ICM, DCM patients experienced greater improvement in left ventricular systolic function and reverse remodeling while also sustaining a greater survival benefit.
INTRODUCTION
This study evaluated the performance of the Lumipulse plasma beta‐amyloid (Aβ) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid‐positron emission tomography ...(PET).
METHODS
Plasma samples from cognitively unimpaired (N = 179) and MCI/AD dementia (N = 36) individuals were retrospectively evaluated. Plasma Aβ42/40 and pTau181 were measured using the Lumipulse and Simoa immunoassays. An immunoprecipitation mass spectrometry (IP‐MS) assay for plasma Aβ42/40 was also evaluated. Amyloid‐PET status was the outcome measure.
RESULTS
Lumipulse and IP‐MS Aβ42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid‐PET (areas under the curve AUCs of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aβ42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aβ42/40 and pTau181 did not significantly improve performance over Aβ42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71)
DISCUSSION
The Lumipulse Aβ42/40 assay showed similar performance to the IP‐MS Aβ42/40 assay for detection of an abnormal amyloid‐PET; and both assays performed better than the two p‐tau181 immunoassays. The Simoa Aβ42/Aβ40 assay was the least accurate at predicting an abnormal amyloid‐PET status.
Highlights
Lumipulse plasma Aβ42/Aβ40 AUC for abnormal amyloid‐PET detection was 0.81.
This performance was comparable to previously reported IP‐MS and higher than Simoa.
Performance of Alzheimer's disease blood biomarkers varies between assays.
We studied interrelationships between CSF biomarkers and associations with
ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota.
We included 774 ...Mayo Clinic Study of Aging participants (693 cognitively unimpaired CU; 71 with mild cognitive impairment MCI). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of
ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population.
Interrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 71%), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 29%). Group 2 was associated with older age,
ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall,
ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk.
We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins.
Localized regions of left-right image intensity asymmetry (LRIA) were incidentally observed on T
-weighted (T
-w) and T
-weighted (T
-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.
To investigate whether systematic LRIA exist for a range of scanner models and to determine if LRIA can introduce diagnostic uncertainty.
A retrospective study using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data base.
One thousand seven hundred fifty-three (median age: 72, males/females: 878/875) unique participants with longitudinal data were included.
3T.
T
-w three-dimensional inversion-recovery spoiled gradient-echo (IR-SPGR) or magnetization-prepared rapid gradient-echo (MP-RAGE) and T
-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.
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 T
-w three-dimensional FLAIR exams with LRIA to determine the diagnostic uncertainty. Statistical comparisons between retrospective intensity normalized T
m and original T
-w images were made.
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.
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.
LRIA is system specific, systematic, creates diagnostic uncertainty, and impacts IR-SPGR, MP-RAGE, and LT-FSE-IR product sequences.
2 Technical Efficacy Stage: 3.
The association between hypertension in pregnancy and future cardiovascular disease (CVD) increasingly is recognized. We aimed to assess the role of hypertension in pregnancy as an independent risk ...factor for hypertension, coronary heart disease (CHD), and stroke later in life.
Women who participated in the Phase 2 (2000-2004) Family Blood Pressure Program study (n = 4782) were categorized into women with no history of pregnancy lasting more than 6 months (n = 718), women with no history of hypertension in pregnancy (n = 3421), and women with a history of hypertension in at least one pregnancy (n = 643). We used Kaplan-Meier and Cox proportional hazard models to estimate and contrast the risks of subsequent diagnoses of hypertension, CHD, and stroke among the groups.
Women with a history of hypertension in pregnancy, compared with those without such a history, were at increased risks for the subsequent diagnoses of hypertension (50% hypertensive at the age 53 vs. 60, P < 0.001), CHD (14% estimated event rate vs. 11%, P = 0.009), and stroke (12% estimated event rate vs. 5%, P < 0.001). The increased risk for subsequent hypertension remained significant after controlling for race, family history of CVD, smoking, dyslipidemia, and diabetes mellitus, with an adjusted hazard ratio of 1.88 95% confidence interval (CI) 1.49-2.39, P < 0.001. After controlling for traditional risk factors, including subsequent hypertension, the increased risk for stroke remained statistically significant (hazard ratio 2.10, 95% CI 1.19-3.71, P = 0.01), but not for CHD.
Hypertension in pregnancy may be an independent risk factor for subsequent diagnoses of hypertension and stroke.
Concern regarding risk of late thrombosis after "off-label" treatment with drug-eluting stents has prompted increased use of bare-metal stents (BMS) in current practice. The sequelae of late BMS ...failures, however, have been poorly characterized.
We performed a retrospective study of 4503 consecutive patients treated with at least 1 BMS and dual antiplatelet therapy between 1994 and 2000. The cumulative incidence of stent thrombosis was 0.5% at 30 days (95% CI, 0.3% to 0.7%), 0.8% at 1 year (95% CI, 0.6% to 1.1%), and 2.0% at 10 years (95% CI, 1.5% to 2.5%). Risk of late (30 days to 1 year) and very late (>1 year) BMS thrombosis was increased among patients considered off label for drug-eluting stent use (P=0.024). When saphenous vein graft interventions were excluded, however, risk after off-label use was not significantly increased (P=0.23). Other correlates included vein graft intervention, prior myocardial infarction (MI), peripheral vascular disease, and ulcerated lesion (P<0.001). Mortality was markedly increased after late and very late BMS thrombosis, particularly during the first 30 days (hazard ratios, 22 95% CI, 3.1 to 159 and 40 95% CI, 15 to 107, respectively). The 10-year incidence of clinical restenosis was 18.1% (95% CI, 16.5% to 19.7%), presenting with MI in 2.1% (95% CI, 1.6% to 2.6%). Restenosis presenting with MI was associated with increased mortality compared with no restenosis (hazard ratio, 2.37; P<0.001) and with restenosis with a non-MI presentation (hazard ratio, 2.42; P<0.001).
The incidence of BMS thrombosis and of MI caused by restenosis during extended follow-up is significant. Both complications are associated with mortality.
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