Search

Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate different aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess GBM invasiveness based on detecting tumor-specific anti-luciferase staining in brain slices, we found that U251-RedFLuc cells are more invasive than U87-luc2 cells. Lastly, we determined expression levels of ABC transporters in both models. Our findings indicate that U87-luc2 and U251-RedFLuc GBM models recapitulate different aspects of GBM heterogeneity that need to be considered in preclinical research. [ABSTRACT FROM AUTHOR]

Cancer and Alzheimer's disease are common diseases in ageing populations. Previous research has reported a lower incidence of Alzheimer's disease-type (amnestic) dementia among individuals with a diagnosis of cancer. Both cancer and amnestic dementia are prevalent and potentially lethal clinical syndromes. The current study was conducted to investigate the association of cancer diagnosis with neuropathological and cognitive features of dementia. Data were analysed from longitudinally evaluated participants in a community-based cohort study of brain ageing who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center. These data were linked to the Kentucky Cancer Registry, a population-based state cancer surveillance system, to obtain cancer-related data. We examined the relationship between cancer diagnosis, clinical dementia diagnosis, Mini-Mental State Examination scores and neuropathological features using inverse probability weighting to address bias due to confounding and missing data. To address bias due to inclusion of participants with dementia at cohort baseline, we repeated all analyses restricted to the participants who were cognitively normal at baseline. Included participants (n = 785) had a mean ± standard deviation age of death of 83.8 ± 8.6 years; 60.1% were female. Cancer diagnosis was determined in 190 (24.2%) participants, and a diagnosis of mild cognitive impairment or dementia was determined in 539 (68.7%). APOE ɛ4 allele dosage was lower among participants with cancer diagnosis compared to cancer-free participants overall (P = 0.0072); however, this association was not observed among those who were cognitively normal at baseline. Participants with cancer diagnosis had lower odds of mild cognitive impairment or dementia, and higher cognitive test scores (e.g. Mini-Mental State Examination scores evaluated 6 and ≤2 years ante-mortem, P < 0.001 for both comparisons). Cancer diagnosis also associated with lower odds of higher Braak neurofibrillary tangle stages (III/IV) or (V/VI), moderate/frequent neuritic plaques, moderate/frequent diffuse plaques and moderate/severe cerebral amyloid angiopathy (all P < 0.05). By contrast, TDP-43, α-synuclein and cerebrovascular pathologies were not associated with cancer diagnosis. Cancer diagnosis was associated with a lower burden of Alzheimer's disease pathology and less cognitive impairment. These findings from a community-based cohort with neuropathological confirmation of substrates support the hypothesis that there is an inverse relationship between cancer and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Late-life cognitive function is heterogeneous, ranging from no decline to severe dementia. Prior studies of cognitive trajectories have tended to focus on a single measure of global cognition or individual tests scores, rather than considering longitudinal performance on multiple tests simultaneously.Objective: The current study aimed to examine cognitive trajectories from two independent datasets to assess whether similar patterns might describe longitudinal cognition in the decade preceding death, as well as what participant characteristics were associated with trajectory membership.Methods: Data were drawn from autopsied longitudinally followed participants of two cohorts (total N = 1,346), community-based cohort at the University of Kentucky Alzheimer's Disease Research Center (n = 365) and National Alzheimer's Coordinating Center (n = 981). We used group-based multi-trajectory models (GBMTM) to identify cognitive trajectories over the decade before death using Mini-Mental State Exam, Logical Memory-Immediate, and Animal Naming performance. Multinomial logistic and Random Forest analyses assessed characteristics associated with trajectory groups.Results: GBMTM identified four similar cognitive trajectories in each dataset. In multinomial models, death age, Braak neurofibrillary tangles (NFT) stage, TDP-43, and α-synuclein were associated with declining trajectories. Random Forest results suggested the most important trajectory predictors were Braak NFT stage, cerebral atrophy, death age, and brain weight. Multiple pathologies were most common in trajectories with moderate or accelerated decline.Conclusion: Cognitive trajectories associated strongly with neuropathology, particularly Braak NFT stage. High frequency of multiple pathologies in trajectories with cognitive decline suggests dementia treatment and prevention efforts must consider multiple diseases simultaneously. [ABSTRACT FROM AUTHOR]

Finite Markov chains are useful tools for studying transitions among health states; these chains can be complex consisting of a mix of transient and absorbing states. The transition probabilities, which are often affected by covariates, can be difficult to estimate due to the presence of many covariates and/or a subset of transitions that are rarely observed. The purpose of this article is to show how to estimate the effect of a subset of covariates of interest after adjusting for the presence of multiple other covariates by applying multidimensional dimension reduction to the latter. The case in which transitions within each row of the one-step transition probability matrix are estimated by multinomial logistic regression is discussed in detail. Dimension reduction for the adjustment covariates involves estimating the effect of the covariates by a product of matrices iteratively; at each iteration one matrix in the product is fixed while the second is estimated using either standard software or nonlinear estimation, depending on which of the matrices in the product is fixed. The algorithm is illustrated by an application where the effect of at least one Apolipoprotein-E (APOE) gene ϵ4 allele on transition probability is estimated in a Markov Chain that includes adjustment for eight covariates and focuses on transitions from normal cognition to several forms of mild cognitive impairment, with possible absorption into dementia. Data were drawn from annual cognitive assessments of 649 participants enrolled in the BRAiNS cohort at the University of Kentucky's Alzheimer's Disease Research Center. [ABSTRACT FROM AUTHOR]

Background: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer's disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals.Objective: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk. We hypothesized that the older individuals diagnosed with incident aMCI already have aMCI-like brain signatures years before diagnosis.Methods: Electroencephalogram (EEG) and memory performance were recorded during a working memory task at baseline. The individualized baseline neuromarkers, annual cognitive status, and longitudinal changes in memory recall scores up to 10 years were analyzed.Results: Seven of the 19 cognitively normal older adults were diagnosed with incident aMCI for a median 5.2 years later. The seven converters' frontal brainwaves were statistically identical to those patients with diagnosed aMCI (n = 14) at baseline. Importantly, the converters' baseline memory-related brainwaves (reduced mean frontal responses to memory targets) were significantly different from those who remained normal. Furthermore, differentiation pattern of left frontal memory-related responses (targets versus nontargets) was associated with an increased risk hazard of aMCI (HR = 1.47, 95% CI 1.03, 2.08).Conclusion: The memory-related neuromarkers detect MCI-like brain signatures about five years before diagnosis. The individualized frontal neuromarkers index increased MCI risk at baseline. These noninvasive neuromarkers during our Bluegrass memory task have great potential to be used repeatedly for individualized prognosis of MCI risk and progression before clinical diagnosis. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to evaluate the number of eyedrops available per bottle of a variety of commonly prescribed glaucoma medications.Methods: Six bottles of each glaucoma medication were tested: three each in the vertical and horizontal orientations. Bottles were housed in a customized force gauge apparatus designed to mimic ballpoint fingertip contact with a bottle. At a standard rate, all drops were expressed from each bottle and counted with an automated drop counter. Simultaneously, bottle volume was measured and drop size and number were also estimated. The main outcome measures were: total number of drops, volume per bottle and drops per milliliter (mL) of glaucoma medication.Results: A total of 192 bottles from 32 bottle designs and manufacturers were tested. Twenty-two of the 32 bottle designs had a significantly different mean number of drops in the vertical and horizontal positions, with 10 designs have more drops dispensed in the horizontal orientation and 12 in the vertical orientation. Six of the 32 bottle designs had a significantly different mean total bottle volume in the vertical and horizontal positions, with all designs having greater volume in the vertical position. An adjusted ratio of mean number of drops/mean bottle volume demonstrated a range from 20.9 drops/mL to 40.8 drops/mL.Conclusions: There is significant variability in drops and volume available per bottle of glaucoma medication depending on both the bottle position and manufacturer. These data point to the need for circumspection in prescribing glaucoma medications and caution in evaluating therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Objective: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI).Methods: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States.Results: Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical diagnosis of MCI. In terms of non-AD pathologies, both primary age-related tauopathy (p < 0.05) and brain arteriolosclerosis pathology (p < 0.001) were more severe in MCI than cognitively intact controls. Among the group that remained MCI until death, mixed AD neuropathologic changes (ADNC; ≥1 comorbid pathology) were more frequent than "pure" ADNC pathology (55% vs 22%); suspected non-Alzheimer pathology comprised the remaining 22% of cases. A majority (74%) of subjects who died with MCI were without "high"-level ADNC, Lewy body disease, or hippocampal sclerosis pathologies; this group was enriched in cerebrovascular pathologies. Subjects who died with dementia and were without severe neurodegenerative pathologies tended to have cerebrovascular pathology and carry the MCI diagnosis for a longer interval.Interpretation: MCI diagnosis usually was associated with comorbid neuropathologies; less than one-quarter of MCI cases showed "pure" AD at autopsy. Ann Neurol 2017;81:549-559. [ABSTRACT FROM AUTHOR]

Continuous-time multi-state stochastic processes are useful for modeling the flow of subjects from intact cognition to dementia with mild cognitive impairment and global impairment as intervening transient cognitive states and death as a competing risk. Each subject's cognition is assessed periodically resulting in interval censoring for the cognitive states while death without dementia is not interval censored. Since back transitions among the transient states are possible, Markov chains are often applied to this type of panel data. In this manuscript, we apply a semi-Markov process in which we assume that the waiting times are Weibull distributed except for transitions from the baseline state, which are exponentially distributed and in which we assume no additional changes in cognition occur between two assessments. We implement a quasi-Monte Carlo (QMC) method to calculate the higher order integration needed for likelihood estimation. We apply our model to a real dataset, the Nun Study, a cohort of 461 participants. [ABSTRACT FROM AUTHOR]

Objectives To investigate the association between baseline sleep apnea and risk of incident dementia in the Prevention of Alzheimer's Disease with Vitamin E and Selenium ( PREADVi SE) study and to explore whether the association depends on apolipoprotein E ( APOE) ɛ4 allele status. Design Secondary analysis based on data collected during PREADVi SE. Setting Participants were assessed at 128 local clinical study sites during the clinical trial phase and later were followed by telephone from a centralized location. Participants Men enrolled in PREADVi SE (without dementia or other active neurological conditions that affect cognition such as major psychiatric disorders, including depression; N = 7,547). Measurements Participants were interviewed at baseline for sleep apnea. The Memory Impairment Screen ( MIS) was administered to each participant annually. Subjects who failed this initial screen were tested with secondary screening tests. Medical history and medication use were determined, and the AD8 dementia screening instrument was used. Results The effect of self-reported sleep apnea on dementia risk depended on APOE ɛ4 status. When the allele was absent, baseline self-reported sleep apnea was associated with a 66% higher risk of developing dementia (95% confidence interval = 2-170%), whereas self-reported sleep apnea conferred no additional risk for participants with an ɛ4 allele. Conclusion Sleep apnea may increase risk of dementia in the absence of APOE ɛ4. This may help inform prevention strategies for dementia or AD in older men with sleep apnea. Registration: PREADVi SE is registered at ClinicalTrials.gov: NCT00040378. [ABSTRACT FROM AUTHOR]

Purpose: This article presents a quantitative method for assessing instantaneous and average lateral vocal-fold motion from high-speed digital imaging, with a focus on developmental changes in vocal-fold kinematics during childhood. Method: Vocal-fold vibrations were analyzed for 28 children (aged 5-11 years) and 28 adults (aged 21-15 years) without voice disorders. The following kinematic features were analyzed from the vocal-fold displacement waveforms: relative velocity-based features (normalized average and peak opening and closing velocities), relative acceleration-based features (normalized peak opening and closing accelerations), speed quotient, and normalized peak displacement. Results: Children exhibited significantly larger normalized peak displacements, normalized average and peak opening velocities, normalized average and peak closing velocities, peak opening and closing accelerations, and speed quotient compared to adult women. Values of normalized average closing velocity and speed quotient were higher in children compared to adult men. Conclusions: When compared to adult men, developing children typically have higher estimates of kinematic features related to normalized displacement and its derivatives. In most cases, the kinematic features of children are closer to those of adult men than adult women. Even though boys experience greater changes in glottal length and pitch as they mature, results indicate that girls experience greater changes in kinematic features compared to boys. [ABSTRACT FROM AUTHOR]

Background: The Boston Naming Test (BNT) is a commonly used neuropsychological test of confrontation naming that aids in determining the presence and severity of dysnomia. Many short versions of the original 60-item test have been developed and are routinely administered in clinical/research settings. Because of the common need to translate similar measures within and across studies, it is important to evaluate the operating characteristics and agreement of different BNT versions. Methods: We analyzed longitudinal data of research volunteers (n = 681) from the University of Kentucky Alzheimer's Disease Center longitudinal cohort. Conclusions: With the notable exception of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) 15-item BNT, short forms were internally consistent and highly correlated with the full version; these measures varied by diagnosis and generally improved from normal to mild cognitive impairment (MCI) to dementia. All short forms retained the ability to discriminate between normal subjects and those with dementia. The ability to discriminate between normal and MCI subjects was less strong for the short forms than the full BNT, but they exhibited similar patterns. These results have important implications for researchers designing longitudinal studies, who must consider that the statistical properties of even closely related test forms may be quite different. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims: To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimer's disease (AD)-type pathological changes. Methods: Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (n = 649) were analyzed to assess the chronic effects of self-reported head injury. Results: The effect of self-reported head injury on the clinical state depended on the age at assessment: for a 1-year increase in age, the OR for the transition to clinical mild cognitive impairment (MCI) at the next visit for participants with a history of head injury was 1.21 and 1.34 for the transition from MCI to dementia. Without respect to age, head injury increased the odds of mortality (OR = 1.54). Moreover, it increased the odds of a pathological diagnosis of AD for men (OR = 1.47) but not women (OR = 1.18). Men with a head injury had higher mean amyloid plaque counts in the neocortex and entorhinal cortex than men without. Conclusions: Self-reported head injury is associated with earlier onset, increased risk of cognitive impairment and dementia, increased risk of mortality, and AD-type pathological changes. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Patients with amyotrophic lateral sclerosis (ALS) experience progressive limb weakness, muscle atrophy, and dysphagia, making them vulnerable to insufficient energy intake. Methods to estimate energy requirements have not been devised for this patient group. Objective: The goal was to develop equations to estimate energy requirements of ALS patients. Design: We enrolled 80 ALS participants at varying stages of their illness and studied them every 16 wk over 48 wk. At each time, we determined total daily energy expenditure (TDEE) in the home setting over a 10-d period by using the doubly labeled water method. We then developed statistical models to estimate TDEE by using factors easily obtained during a routine clinical visit. Results: The most practical TDEE models used the Harris-Benedict, Mifflin-St Jeor, or Owen equations to estimate resting metabolic rate (RMR) and 6 questions from the revised ALS Functional Rating Scale (ALSFRS-R) that relate to physical activity. We developed a Web-based calculator to facilitate its use. In the research setting, measuring body composition with bioelectrical impedance spectroscopy enabled the estimation of RMR with the Rosenbaum equation and the same 6 questions from the ALSFRS-R to estimate TDEE. By using these models, the estimate of TDEE for nutritional maintenance was ±500 kcal/d across the spectrum of ALS progression. Conclusions: Our results emphasize the importance of physical function and body composition in estimating TDEE. Our predictive equations can serve as a basis for recommending placement of a feeding gastrostomy in ALS patients who fail to meet their energy requirements by oral intake. This trial was registered at clinical-trials. gov as NCT00116558. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) refers to the clinical state between normal cognition and probable Alzheimer's disease (AD), but persons diagnosed with MCImay progress to non-AD forms of dementia, remain MCI until death, or recover to normal cognition. Risk factors for these various clinical changes, which we term "transitions," may provide targets for therapeutic interventions. Therefore, it is useful to develop new approaches to assess risk factors for these transitions. Markov models have been used to investigate the transient nature ofMCI represented by amnestic single-domain and mixedMCI states, where mixedMCI comprised all other MCI subtypes based on cognitive assessments. The purpose of this study is to expand this risk model by including a clinically determined MCI state as an outcome. Analyses show that several common risk factors play different roles in affecting transitions to MCI and dementia. Notably, APOE-4 increases the risk of transition to clinical MCI but does not affect the risk for a final transition to dementia, and baseline hypertension decreases the risk of transition to dementia from clinical MCI. [ABSTRACT FROM AUTHOR]

Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical 'dementia' status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. [ABSTRACT FROM AUTHOR]

Preclinical Alzheimer's disease (pAD) reflects neuropathological findings of AD in cognitively normal subjects. The present study represents an effort to determine if differences could be identified in the longitudinal patterns of cognitive performance in persons classified as pAD compared to those who did not meet criteria for AD at autopsy. We included 121 subjects who were cognitively normal from baseline through their last assessment before death and who underwent autopsy. Participants were classified into two groups: pathologically normal (PN; NIA-Reagan low or no-likelihood of AD, n = 89) and preclinical AD (pAD; NIA-Reagan criteria of intermediate or high-likelihood of AD in the absence of clinical dementia symptoms, n = 32) followed for a mean 7.5 years prior to death. Longitudinal rates and patterns of change in scores on a standard cognitive battery were compared between these two groups. While cognitive results at baseline and last evaluations revealed no clear cross sectional group differences after adjustment for age, ApoE status, education, and gender, statistically significant differences between the pAD and PN groups in slope of decline were seen on a composite score of cognitive function. Further analyses showed three components of this score reached significance: constructional praxis, delayed recall of a word list, and category verbal fluency. Despite being clinically viewed as normal at enrollment and at the final exam, there are significant differences in rates of cognitive decline in participants classified as pAD compared to those without this pathology. Longitudinal changes in slope of decline in specific cognitive test measures can serve as non-invasive methods for the detection of pAD. [ABSTRACT FROM AUTHOR]

Background: Salivary biomarkers are potentially important for determining the presence, risk, and progression of periodontal disease. However, clinical translation of biomarker technology from lab to chairside requires studies that identify biomarkers associated with the transitional phase between health and periodontal disease (i.e., gingivitis).Methods: Eighty participants (40 with gingivitis, 40 healthy) provided saliva at baseline and 7 to 30 days later. An additional sample was collected from gingivitis participants 10 to 30 days after dental prophylaxis. Clinical parameters of gingival disease were recorded at baseline and the final visit. Salivary concentrations of interleukin (IL)-1β, IL-6, matrix metalloproteinase (MMP)-8, macrophage inflammatory protein (MIP)-1α, and prostaglandin E2 (PGE2) were measured.Results: Clinical features of health and gingivitis were stable at both baseline visits. Participants with gingivitis demonstrated significantly higher bleeding on probing (BOP), plaque index (PI), and gingival index (GI) (P ≤0.002) and a significant drop in BOP, PI, and GI post-treatment (P ≤0.001). Concentrations of MIP-1α and PGE2 were significantly higher (2.8 times) in the gingivitis group than the healthy group (P ≤0.02). After dental prophylaxis, mean biomarker concentrations did not decrease significantly from baseline in the gingivitis group, although concentrations of IL-1β, IL-6, and MMP-8 approached healthy levels, whereas MIP-1α and PGE2 concentrations remained significantly higher than in the healthy group (P ≤0.04). Odds ratio analyses showed that PGE2 concentrations, alone and in combination with MIP-1α, readily discriminated gingivitis from health.Conclusions: Salivary PGE2 and MIP-1α discriminate gingivitis from health, and patients with gingivitis who return to clinical health continue to produce inflammatory mediators for weeks after dental prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Individuals with opioid use disorder (OUD) exhibit high levels of economic demand for opioids, with high levels of consumption and relative insensitivity to changes in price. Because the medications used to treat OUD in medication-assisted therapy (MAT) act as antagonists or agonists at μ opioid receptors, they may alter the relationship between price and opioid intake.Methods: This study examined demand for a commonly abused synthetic prescription opioid, fentanyl, in male rats following s.c. pre-treatment with naltrexone (0.1-1.0 mg/kg), morphine (0.3-3.0 mg/kg) or buprenorphine (0.3-3.0 mg/kg). We normalized demand curves to intake at the lowest price and estimated effects on elasticity (sensitivity to changes in price). Rats were first trained to earn fentanyl (5 μg/kg/infusion) on a fixed ratio schedule, then they underwent daily training under a threshold procedure designed to produce within-session demand curve estimates. Rats received 14 threshold sessions before undergoing a series of tests encompassing each drug, at each dose.Results: Elasticity was increased by pretreatment with naltrexone, morphine or buprenorphine. Morphine also decreased initial intake, when the price for fentanyl was lowest. In contrast, initial intake was increased by naltrexone (according to an inverted-U shaped curve). The effects of naltrexone did not persist after the test session, but morphine and buprenorphine continued affecting demand elasticity 24 h or 48 h after the test, respectively.Conclusions: These results indicate that fentanyl demand is sensitive to blockade or activation of opioid receptors by the drug classes used for MAT in humans. [ABSTRACT FROM AUTHOR]