•MK6240 meningeal off-target signal (OTS) is adjacent to target and reference regions.•Across individuals OTS is continuously distributed and related to sex (F>M).•Erosion of the reference region ...results in greater OTS influence in target regions.•Approaches to optimize MK6240 processing perform similarly to standard processing.
Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET (18FMK6240), beta-amyloid (Aβ)-PET (18Fflorbetaben FBB) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aβ and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aβ+> Aβ- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.
We define `ousiometrics' to be the study of essential meaning in whatever context that meaningful signals are communicated, and `telegnomics' as the study of remotely sensed knowledge. From work ...emerging through the middle of the 20th century, the essence of meaning has become generally accepted as being well captured by the three orthogonal dimensions of evaluation, potency, and activation (EPA). By re-examining first types and then tokens for the English language, and through the use of automatically annotated histograms -- `ousiograms' -- we find here that: 1. The essence of meaning conveyed by words is instead best described by a compass-like power-danger (PD) framework, and 2. Analysis of a disparate collection of large-scale English language corpora -- literature, news, Wikipedia, talk radio, and social media -- shows that natural language exhibits a systematic bias toward safe, low danger words -- a reinterpretation of the Pollyanna principle's positivity bias for written expression. To help justify our choice of dimension names and to help address the problems with representing observed ousiometric dimensions by bipolar adjective pairs, we introduce and explore `synousionyms' and `antousionyms' -- ousiometric counterparts of synonyms and antonyms. We further show that the PD framework revises the circumplex model of affect as a more general model of state of mind. Finally, we use our findings to construct and test a prototype `ousiometer', a telegnomic instrument that measures ousiometric time series for temporal corpora. We contend that our power-danger ousiometric framework provides a complement for entropy-based measurements, and may be of value for the study of a wide variety of communication across biological and artificial life.
To examine the prevalence of circadian misalignment in clinically diagnosed delayed sleep phase disorder (DSPD) and to compare mood and daytime functioning in those with and without a circadian basis ...for the disorder.
One hundred and eighty-two DSPD patients aged 16-64 years, engaged in regular employment or school, underwent sleep-wake monitoring in the home, followed by a sleep laboratory visit for assessment of salivary dim light melatonin onset (DLMO). Based on the DLMO assessments, patients were classified into two groups: circadian DSPD, defined as DLMO occurring at or after desired bedtime (DBT), or non-circadian DSPD, defined as DLMO occurring before DBT.
One hundred and three patients (57%) were classified as circadian DSPD and 79 (43%) as non-circadian DSPD. DLMO occurred 1.66 hours later in circadian DSPD compared to non-circadian DSPD (p < .001). Moderate-severe depressive symptoms (Beck Depression Inventory-II) were more prevalent in circadian DSPD (14.0%) than in non-circadian DSPD (3.8%; p < .05). Relative to non-circadian DSPD patients, circadian DSPD patients had 4.31 times increased odds of at least mild depressive symptoms (95% CI 1.75 to 10.64; p < .01). No group differences were found for daytime sleepiness or function, but DSPD symptoms were rated by clinicians to be more severe in those with circadian DSPD.
Almost half of patients clinically diagnosed with DSPD did not show misalignment between the circadian pacemaker and the DBT, suggesting that the reported difficulties initiating sleep at the DBT are unlikely to be explained by the (mis)timing of the circadian rhythm of sleep propensity. Circadian misalignment in DSPD is associated with increased depressive symptoms and DSPD symptom severity.
Methods for predicting circadian phase have been developed for healthy individuals. It is unknown whether these methods generalize to clinical populations, such as delayed sleep-wake phase disorder ...(DSWPD), where circadian timing is associated with functional outcomes. This study evaluated two methods for predicting dim light melatonin onset (DLMO) in 154 DSWPD patients using ~ 7 days of sleep-wake and light data: a dynamic model and a statistical model. The dynamic model has been validated in healthy individuals under both laboratory and field conditions. The statistical model was developed for this dataset and used a multiple linear regression of light exposure during phase delay/advance portions of the phase response curve, as well as sleep timing and demographic variables. Both models performed comparably well in predicting DLMO. The dynamic model predicted DLMO with root mean square error of 68 min, with predictions accurate to within ± 1 h in 58% of participants and ± 2 h in 95%. The statistical model predicted DLMO with root mean square error of 57 min, with predictions accurate to within ± 1 h in 75% of participants and ± 2 h in 96%. We conclude that circadian phase prediction from light data is a viable technique for improving screening, diagnosis, and treatment of DSWPD.
Recruitment of older adults into long-term clinical trials involving behavioral interventions is a significant challenge. The Lifestyle Interventions and Independence for Elders (LIFE) Study is a ...Phase 3 multicenter randomized controlled multisite trial, designed to compare the effects of a moderate-intensity physical activity program with a successful aging health education program on the incidence of major mobility disability (the inability to walk 400 m) in sedentary adults aged 70-89 years, who were at high risk for mobility disability (scoring ≤ 9 on the Short Physical Performance Battery) at baseline.
Recruitment methods, yields, efficiency, and costs are described together with a summary of participant baseline characteristics. Yields were examined across levels of sex, race and ethnicity, and Short Physical Performance Battery, as well as by site.
The 21-month recruiting period resulted in 14,812 telephone screens; 1,635 participants were randomized (67.2% women, 21.0% minorities, 44.7% with Short Physical Performance Battery scores ≤ 7). Of the telephone-screened participants, 37.6% were excluded primarily because of regular participation in physical activity, health exclusions, or self-reported mobility disability. Direct mailing was the most productive recruitment strategy (59.5% of randomized participants). Recruitment costs were $840 per randomized participant. Yields differed by sex and Short Physical Performance Battery. We accrued 11% more participant follow-up time than expected during the recruitment period as a result of the accelerated recruitment rate.
The LIFE Study achieved all recruitment benchmarks. Bulk mailing is an efficient method for recruiting high-risk community-dwelling older persons (including minorities), from diverse geographic areas for this long-term behavioral trial.
In the SPRINT (Systolic Blood Pressure Intervention Trial), intensive BP treatment reduced acute decompensated heart failure (ADHF) events. Here, we report the effect on HF with preserved ejection ...fraction (HFpEF) and HF with reduced EF (HFrEF) and their subsequent outcomes.
Incident ADHF was defined as hospitalization or emergency department visit, confirmed, and formally adjudicated by a blinded events committee using standardized protocols. HFpEF was defined as EF ≥45%, and HFrEF was EF <45%.
Among the 133 participants with incident ADHF who had EF assessment, 69 (52%) had HFpEF and 64 (48%) had HFrEF (
value: 0.73). During average 3.3 years follow-up in those who developed incident ADHF, rates of subsequent all-cause and HF hospital readmission and mortality were high, but there were no significant differences between those who developed HFpEF versus HFrEF. Randomization to the intensive arm had no effect on subsequent mortality or readmissions after the initial ADHF event, irrespective of EF subtype. During follow-up among participants who developed HFpEF, although relatively modest number of events limited statistical power, age was an independent predictor of all-cause mortality, and Black race independently predicted all-cause and HF hospital readmission.
In SPRINT, intensive BP reduction decreased both acute decompensated HFpEF and HFrEF events. After initial incident ADHF, rates of subsequent hospital admission and mortality were high and were similar for those who developed HFpEF or HFrEF. Randomization to the intensive arm did not alter the risks for subsequent all-cause, or HF events in either HFpEF or HFrEF. Among those who developed HFpEF, age and Black race were independent predictors of clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.
Abstract
BACKGROUND:
We review our experience with lung cancer patients with newly diagnosed brain metastases treated with Gamma Knife radiosurgery (GKRS).
OBJECTIVE:
To determine whether tumor ...histology predicts patient outcomes.
METHODS:
Between July 1, 2000, and December 31, 2010, 271 patients with brain metastases from primary lung cancer were treated with GKRS at our institution. Included in our study were 44 squamous cell carcinoma (SCC), 31 small cell carcinoma (SCLC), and 138 adenocarcinoma (ACA) patients; 47 patients with insufficient pathology to determine subtype were excluded. No non-small cell lung cancer (NSCLC) patients received whole-brain radiation therapy (WBRT) before their GKRS, and SCLC patients were allowed to have prophylactic cranial irradiation, but no previously known brain metastases. A median of 2 lesions were treated per patient with median marginal dose of 20 Gy.
RESULTS:
Median survival was 10.2 months for ACA, 5.9 months for SCLC, and 5.3 months for SCC patients (P = .008). The 1-year local control rates were 86%, 86%, and 54% for ACA, SCC, and SCLC, respectively (P = .027). The 1-year distant failure rates were 35%, 63%, and 65% for ACA, SCC, and SCLC, respectively (P = .057). The likelihood of dying of neurological death was 29%, 36%, and 55% for ACA, SCC, and SCLC, respectively (P = .027). The median time to WBRT was 11 months for SCC and 24 months for ACA patients (P = .04). Multivariate analysis confirmed SCLC histology as a significant predictor of worsened local control (hazard ratio HR: 6.46, P = .025) and distant failure (HR: 3.32, P = .0027). For NSCLC histologies, SCC predicted for earlier time to salvage WBRT (HR: 2.552, P = .01) and worsened overall survival (HR: 1.77, P < .0121).
CONCLUSION:
Histological subtype of lung cancer appears to predict outcomes. Future trials and prognostic indices should take these histology-specific patterns into account.
Relationships between early kidney disease, neurocognitive function, and brain anatomy are poorly defined in African Americans with type 2 diabetes mellitus (T2DM).
Cross-sectional associations were ...assessed between cerebral anatomy and cognitive performance with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in African Americans with T2DM.
African Americans with cognitive testing and cerebral magnetic resonance imaging (MRI) in the African American−Diabetes Heart Study Memory in Diabetes (AA-DHS MIND; n=512; 480 with MRI) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) MIND (n=484; 104 with MRI) studies.
eGFR (CKD-EPI creatinine equation), spot UACR.
MRI-based cerebral white matter volume (WMV), gray matter volume (GMV), and white matter lesion volume; cognitive performance (Mini-Mental State Examination, Digit Symbol Coding, Stroop Test, and Rey Auditory Verbal Learning Test). Multivariable models adjusted for age, sex, body mass index, scanner, intracranial volume, education, diabetes duration, hemoglobin A1c concentration, low-density lipoprotein cholesterol concentration, smoking, hypertension, and cardiovascular disease were used to test for associations between kidney phenotypes and the brain in each study; a meta-analysis was performed.
Mean participant age was 60.1±7.9 (SD) years; diabetes duration, 12.1±7.7 years; hemoglobin A1c concentration, 8.3%±1.7%; eGFR, 88.7±21.6mL/min/1.73m2; and UACR, 119.2±336.4mg/g. In the fully adjusted meta-analysis, higher GMV associated with lower UACR (P<0.05), with a trend toward association with higher eGFR. Higher white matter lesion volume was associated with higher UACR (P<0.05) and lower eGFR (P<0.001). WMV was not associated with either kidney parameter. Higher UACR was associated with lower Digit Symbol Coding performance (P<0.001) and a trend toward association with higher Stroop interference; eGFR was not associated with cognitive tests.
Cross-sectional; single UACR measurement.
In African Americans with T2DM, mildly high UACR and mildly low eGFR were associated with smaller GMV and increased white matter lesion volume. UACR was associated with poorer processing speed and working memory.
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Background
The prevalence and significance of low normal and abnormal ankle brachial index (ABI) values in a community‐dwelling population of sedentary, older individuals is unknown. We describe the ...prevalence of categories of definite peripheral artery disease (PAD), borderline ABI, low normal ABI, and no PAD and their association with lower‐extremity functional performance in the LIFE Study population.
Methods and Results
Participants age 70 to 89 in the LIFE Study underwent baseline measurement of the ABI, 400‐m walk, and 4‐m walking velocity. Participants were classified as follows: definite PAD (ABI <0.90), borderline PAD (ABI 0.90 to 0.99), low normal ABI (ABI 1.00 to 1.09), and no PAD (ABI 1.10 to 1.40). Of 1566 participants, 220 (14%) had definite PAD, 250 (16%) had borderline PAD, 509 (33%) had low normal ABI, and 587 (37%) had no PAD. Among those with definite PAD, 65% were asymptomatic. Adjusting for age, sex, race, body mass index, smoking, and comorbidities, lower ABI was associated with longer mean 400‐m walk time: (definite PAD=533 seconds; borderline PAD=514 seconds; low normal ABI=503 seconds; and no PAD=498 seconds P<0.001). Among asymptomatic participants with and without PAD, lower ABI values were also associated with longer 400‐m walk time (P<0.001) and slower walking velocity (P=0.042).
Conclusion
Among older community‐dwelling men and women, 14% had PAD and 49% had borderline or low normal ABI values. Lower ABI values were associated with greater functional impairment, suggesting that lower extremity atherosclerosis may be a common preventable cause of functional limitations in older people.
Clinical Trial Registration
URL: http://clinicaltrials.gov/ Unique identifier: NCT01072500.
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