Search

Atherosclerotic cardiovascular disease and tooth infection are common in primary care, and both significantly reduce quality of life. Our study aimed to examine signs of vascular inflammation associated with loss of tooth vitality before and after a single tooth extraction. An observational cohort study was performed with adults who had a nonvital tooth and an indicated desire for tooth extraction. Concentrations of total cholesterol, high-density lipoprotein-cholesterol, high-sensitivity C-reactive protein (hs-CRP), myeloperoxidase (MPO), and troponin T were measured in venous blood serum or plasma at baseline and 6-weeks after tooth extraction. Circulating hs-CRP levels were > 3 mg/dL in 15 participants (68.2%) and MPO levels were > 350 pmol/L in 9 (40.9%) of 22 participants at baseline. After tooth extraction (n = 18), MPO levels decreased significantly compared with baseline (P <.00006) and hs-CRP levels moved directionally downward. The response rate for MPO was 88.9% (confidence interval: 65.1%-98.6%) from visit 1 to visit 2. Those with high MPO levels at baseline demonstrated larger reductions in MPO levels by visit 2 than those with lower baseline MPO levels (r =.81; P <.0001). A total of 13 individuals (72.2%) achieved MPO levels < 350 pmol/L and 11 (61.1%) achieved hs-CRP levels < 3 mg/dL at visit 2. Total cholesterol, high-density lipoprotein-cholesterol, and troponin T levels did not significantly change from visit 1 to visit 2. A link between dental infection and circulating levels of inflammation was observed, suggesting that oral infection could be a risk factor for atherosclerotic cardiovascular disease. [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]

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]

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]

The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO. [ABSTRACT FROM AUTHOR]

Risk factors for mild cognitive impairment (MCI) and dementia are often investigated without accounting for the competing risk of mortality, which can bias results and lead to spurious conclusions, particularly regarding protective factors. Here, we apply a semi-Markov modeling approach to 531 participants in the University of Kentucky Biologically Resilient Adults in Neurological Studies (BRAiNS) longitudinal cohort, over one-third of whom died without transitioning to a cognitively impaired clinical state. A semi-Markov approach enables a statistical study of clinical state transitions while accounting for the competing risk of death and facilitates insights into both the odds that a risk factor will affect clinical transitions as well as the age at which the transition to MCI or dementia will occur. Risk factors assessed in the current study were identified by matching those reported in the literature with the data elements collected on participants. The presence of Type II diabetes at baseline shortens the time it takes cognitively intact individuals to transition to MCI by seven years on average while use of estrogen replacement therapy at enrollment (baseline) decreases the time required to convert from MCI to dementia by 1.5 years. Finally, smoking and being overweight do not promote transitions to impaired states but instead hasten death without a dementia. In contrast, conventional statistical analyses based on Cox proportional hazards models fail to recognize diabetes as a risk, show that being overweight increases the risk of clinical MCI, and that high blood pressure at baseline increases the risk of a dementia. [ABSTRACT FROM AUTHOR]

Risk factors for mild cognitive impairment (MCI) and dementia are often investigated without accounting for the competing risk of mortality, which can bias results and lead to spurious conclusions, particularly regarding protective factors. Here, we apply a semi-Markov modeling approach to 531 participants in the University of Kentucky Biologically Resilient Adults in Neurological Studies (BRAiNS) longitudinal cohort, over one-third of whom died without transitioning to a cognitively impaired clinical state. A semi-Markov approach enables a statistical study of clinical state transitions while accounting for the competing risk of death and facilitates insights into both the odds that a risk factor will affect clinical transitions as well as the age at which the transition to MCI or dementia will occur. Risk factors assessed in the current study were identified by matching those reported in the literature with the data elements collected on participants. The presence of Type II diabetes at baseline shortens the time it takes cognitively intact individuals to transition to MCI by seven years on average while use of estrogen replacement therapy at enrollment (baseline) decreases the time required to convert from MCI to dementia by 1.5 years. Finally, smoking and being overweight do not promote transitions to impaired states but instead hasten death without a dementia. In contrast, conventional statistical analyses based on Cox proportional hazards models fail to recognize diabetes as a risk, show that being overweight increases the risk of clinical MCI, and that high blood pressure at baseline increases the risk of a dementia. [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]

Background: We reported a significant 67% reduction in the hazard risk of incident Alzheimer’s disease (AD) with elective statin use in the AD Anti-inflammatory Prevention Trial (ADAPT), without a reduction in risk of incident mild cognitive impairment (MCI). Objective: To assess if cholesterol levels are associated with cognitive performance and determine if statin use alters cognitive performance after onset of MCI. Design: Fractionated cholesterol levels, neurological and cognitive status were evaluated annually. Comparisons of non-LLA (lipid-lowering agent) users or statin-LLA users were performed blind to the ADAPT medication randomization. Pearson’s correlations were validated using a time-dependent linear mixed model. Results: The MMSE performance significantly declined over time in non-LLA users, and, after adjusting for this, a significant positive correlation between MMSE and HDL was identified (p = 0.0002). A negative correlation between total and LDL cholesterol, and immediate and delayed recall of the Rivermead paragraph was significant (total cholesterol, p < 0.003; LDL, p < 0.02). Pilot data suggest a positive signal on delayed recall of both the Hopkins word list and Rivermead paragraph with deterioration in the non-LLA users and improvement in the statin users after conversion to MCI. Conclusion: Cholesterol levels may be associated with differential performance on the MMSE and measures of learning or memory. The trend for improved delayed recall in statin users with MCI compared to non-LLA users with MCI may have contributed to the reduced hazards risk of incident AD without reducing the risk of MCI. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Dementia can be caused by different diseases including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or both (AD + DLB). University of Kentucky AD Center pathologically-diagnosed AD and AD + DLB cases were evaluated who had three or more longitudinal antemortem mental status examinations (n = 156). Patients with important concomitant pathology (n = 5) or patients that were profoundly demented at recruitment (intake MMSE < 20; n = 86) were excluded to strengthen our ability to test the association of specific clinical and pathological indices. Patients with pathologically-diagnosed AD + DLB (n = 25) lost cognitive capacity faster than patients with AD alone (n = 40). In both diseases, treatment with acetylcholinesterase inhibitors was associated with a slower rate of cognitive decline. [ABSTRACT FROM AUTHOR]

Objective: Larger brains may contain more neurons and synaptic connections, providing a greater reserve against cognitive decline in Alzheimer's disease (AD). Larger head circumference (HC) may therefore be associated with later detection and diagnosis of AD. We investigated HC in nondemented individuals and AD patients using cross-sectional and prospective analyses. Methods: The cross sectional analysis compared mean HC between 592 AD patients and 459 nondemented controls. Prospective analysis was based on the same initially normal controls who were followed longitudinally for conversion to dementia. Diagnosis of AD was made by neurologists using NINDS-ADRDA criteria. Results: When compared to AD patients, controls had a significantly larger mean HC by 0.58 cm in men and by 0.31 cm in women, but these differences were no longer significant after adjustment for age and years of education. HC varied inversely with age and directly with years of education but did not vary with presence/absence of dementia in first-degree relatives or with apolipoprotein-E (ApoE) genotype. In the prospective analysis, the hazard ratio for time to conversion to AD was not significant for HC when adjusted for age at entry, ApoE allele status, family history of dementia, gender, and years of education. ApoE allele status, first degree relative with dementia, and baseline age conferred an increased risk for conversion to AD, consistent with other studies. Conclusions: We observed a smaller HC in AD patients compared to nondemented individuals, but AD per se accounted for little of this difference. HC was not a statistically significant predictor for conversion to AD in our longitudinal group. [ABSTRACT FROM AUTHOR]

Background and objectives: The pathologic substrates or neuroanatomic regions responsible for similarities in behavioral features seen in autism spectrum disorder and late-life dementia remain unknown. The present study examined the neuropathologic features of late-life dementia in research volunteers with and without antemortem behaviors characteristic of autism spectrum disorders. Methods: Antemortem cross-sectional assessment of autistic spectrum behaviors proximal to death in persons with diagnosis of mild cognitive impairment or dementia was completed using the Gilliam Autism Rating Scale, 2nd edition (GARS-2), followed by postmortem quantitative and semiquantitative neuropathologic assessment. All individuals who completed the GARS-2 prior to autopsy were included (n = 56) and we note that no participants had known diagnosis of autism spectrum disorder. The GARS-2 was used as an antemortem screening tool to stratify participants into two groups: "Autism Possible/Very Likely" or "Autism Unlikely." Data were analyzed using nonparametric statistics comparing location and scale to evaluate between-group differences in pathologic features. Results: Neurofibrillary tangles (NFT; p = 0.028) density and tau burden (p = 0.032) in the frontal region, the NFT density (p = 0.048) and neuritic plaque burden (p = 0.042), and the tau burden (p = 0.032) of the temporal region, were significantly different in scale between groups. For measures with significant group differences, the medians of the Autism Possible/Very Likely group were roughly equal to the 75th percentile of the Autism Unlikely group (i.e., the distributions were shifted to the right). Discussion: This study links behaviors characteristic of autism to increased pathologic tau burden in the frontal and temporal lobes in persons with late-life dementia. Additional studies are needed to determine causal factors and treatment options for behaviors characteristic of autism behaviors in late-life dementias. [ABSTRACT FROM AUTHOR]

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]

Objectives. This study investigated the efficacy of a social-influences tobacco prevention program conducted with adolescents living in a high tobacco production area. Methods. Students in 10 experimental schools completed the tobacco prevention program and a booster intervention. Control students received health education as usual. Results. After 2 year of treatment, smoking rates in the treatment group (vs the control group) were lower for 30-day, 7-day, and 24-hour smoking. The intervention had more of an impact on those who were involved in raising tobacco than it dif on those not involved in raising tobacco. Conclusions. Although modest, effects were achieved with minimal intervention time in a high-risk group, indicating that social-influences prevention programs may be effective in such groups. [ABSTRACT FROM AUTHOR]

This article is a response to a previous letter from Drs. Timmerman, Van Calster, and Froyman. The authors assert that any estimation of the natural course of simple cyst resolution must exclude surgical cases, as they have done in their previous article. They argue that surgical intervention artificially shortens the time course of cyst existence. The authors also discuss the low risk of malignancy in simple cysts and the shift in clinical management towards surveillance rather than surgery. They present their findings on the time to resolution of cysts and address concerns raised by Timmerman, Van Calster, and Froyman regarding malignancy and menopausal status. [Extracted from the article]

OBJECTIVE: To estimate surveillance intervals of incident ovarian cysts, and describe variables associated with cyst resolution times. METHODS: The UK-OCST (University of Kentucky Ovarian Cancer Screening Trial) was a prospective cohort that enrolled 47,762 individuals over 30 years, including 2,638 individuals with incident cysts. Cyst diameter and structure and patient age, body mass index, use of hormone therapy (HT), family history of ovarian cancer, and menopausal status were examined as variables associated with cyst resolution using t tests, χ² test, Kaplan Meier, and Cox multiple regression. RESULTS: Of 2,638 individuals with incident cysts, 1,667 experienced resolution (63.2%) within 1.2 years, and 971 experienced persistence (36.8%). Within 1 year, unilocular and septated cysts had similar resolution rates (35.4% and 36.7%, respectively, P>.05), but time to resolution was shorter for unilocular cysts compared with septated cysts (mean 1.89 years vs 2.58 years, respectively, P<.001). Both unilocular and septated cysts smaller than 3 cm resolved faster than cysts larger than 6 cm (P<.001). Variables associated with percent resolution included being of younger age, premenopausal status (but not for synchronous bilateral cysts), and those reporting a family history of ovarian cancer (P<.05). Variables associated with a faster cyst resolution rate included being older than age 70 years and not using hormone therapy. Body mass index and family history were not associated with cyst resolution time. CONCLUSION: Different surveillance times may be appropriate depending on cyst structure and size and patient age and HT use. [ABSTRACT FROM AUTHOR]

Cerebrovascular pathologies other than frank infarctions are commonly seen in aged brains. Here, we focus on multi-lumen vascular profiles (MVPs), which are characterized by multiple vessel lumens enclosed in a single vascular channel. Little information exists on the prevalence, risk factors, and co-pathologies of MVPs. Therefore, we used samples and data from the University of Kentucky Alzheimer's Disease Research Center (n = 91), the University of Kentucky Pathology Department (n = 31), and the University of Pittsburgh Pathology Department (n = 4) to study MVPs. Age at death was correlated with MVP density in the frontal neocortex, Brodmann Area 9 (r = 0.51; p < 0.0001). Exploratory analyses were performed to evaluate the association between conventional vascular risk factors (e.g., hypertension, diabetes), cardiovascular diseases (e.g., heart attack, arrhythmia), and cerebrovascular disease (e.g., stroke); the only nominal association with MVP density was a self-reported history of brain trauma (Prevalence Ratio = 2.1; 95 CI 1.1–3.9, before correcting for multiple comparisons). No specific associations were detected between neuropathological (e.g., brain arteriolosclerosis) or genetic (e.g., APOE) variables and MVP density. Using a tissue clearing method called SeeDB, we provide 3-dimensional images of MVPs in brain tissue. We conclude that MVPs are an age-related brain pathology and more work is required to identify their clinical-pathological correlation and associated risk factors. [ABSTRACT FROM AUTHOR]

Finite Markov chains with absorbing states are popular tools for analyzing longitudinal data with categorical responses. The one step transition probabilities can be defined in terms of fixed and random effects but it is difficult to estimate these effects due to many unknown parameters. In this article we propose a three‐step estimation method. In the first step the fixed effects are estimated by using a marginal likelihood function, in the second step the random effects are estimated after substituting the estimated fixed effects into a joint likelihood function defined as a h‐likelihood, and in the third step the covariance matrix for the vector of random effects is estimated using the Hessian matrix for this likelihood function. An application involving an analysis of longitudinal cognitive data is used to illustrate the method. [ABSTRACT FROM AUTHOR]

The Nun Study, a longitudinal study to examine risk factors for the progression of dementia, consists of subjects who were already diagnosed with dementia (ie, prevalent cohort) and those who do not have dementia (ie, incident cohort) at study enrollment. When assessing the risk factors' effects on the survival time from dementia diagnosis until death, utilizing data from both cohorts supports more efficient statistical inference because the two cohorts provide valuable complementary information. A major challenge in analyzing the combined cohort data is that the prevalent cases are not representative of the target population. Moreover, the dates of dementia diagnosis are not ascertained for the prevalent cohort in the Nun Study. Hence, the survival time for the prevalent cohort is only partially observed from study enrollment until death or censoring, with the time from dementia diagnosis to study enrollment missing. In this paper, we propose an efficient estimation method that uses both incident and prevalent cohorts under the proportional mean residual life model. By assuming proportionality of the mean residual life time with covariates in the incident cohort, we can utilize the natural relationship between the mean residual life function and the hazard function of the survival time measured from enrollment until death for the prevalent cohort. We evaluate the efficiency gain from using the combined cohort data through simulations and demonstrate that the proposed method is valid and efficient. [ABSTRACT FROM AUTHOR]

This article is a response to a letter from three doctors regarding the diagnosis and follow-up of ovarian cysts. The authors report that three patients with cysts were ultimately diagnosed with ovarian malignant neoplasms. They argue that their study provides a data-driven approach to determining the resolution of cysts and emphasizes defined intervals for follow-up rather than indefinite surveillance. They also mention guidelines from the American College of Obstetricians and Gynecologists that recommend monitoring simple cysts up to 10 cm in diameter without surgical intervention. The authors clarify that their work does not suggest that every simple cyst should be followed indefinitely and that the risk of unnecessary surgery from follow-up testing has not been demonstrated. [Extracted from the article]

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]

Abstract: Depression is common in Parkinson's disease and is associated with cognitive impairment. Dopaminergic medications are effective in treating the motor symptoms of Parkinson's disease; however, little is known regarding the effects of dopaminergic pharmacotherapy on cognitive function in depressed Parkinson patients. This study examines the neuropsychological effects of dopaminergic pharmacotherapy in Parkinsonian depression. We compared cognitive function in depressed and non-depressed Parkinson patients at two time-points: following overnight withdrawal and after the usual morning regimen of dopaminergic medications. A total of 28 non-demented, right-handed patients with mild to moderate idiopathic Parkinson's disease participated. Ten of these patients were depressed according to DSM IV criteria. Results revealed a statistically significant interaction between depression and medication status on three measures of verbal memory and a facial affect naming task. In all cases, depressed Parkinson's patients performed significantly more poorly while on dopaminergic medication than while off. The opposite pattern emerged for the non-depressed Parkinson's group. The administration of dopaminergic medication to depressed Parkinson patients may carry unintended risks. [Copyright &y& Elsevier]

The Ruff 2&7 Selective Attention Test's (RSAT) current scoring data are relatively limited for older adults because persons over the age of 70 years were not included in the normative sample. Prior evidence suggests that changes in attention skills, such as those evaluated by the RSAT, may distinguish normal cognitive aging from pathologic cognitive decline. Thus normative data for older individuals on this measure increase its utility in diagnosing Mild Cognitive Impairment (MCI) and dementia, and enhance its potential use in clinical and research settings. Data from 415 male volunteers (mean age = 69.5 ± 5.7 years) in the PREADViSE clinical trial were used in the current investigation. Analysis of covariance (ANCOVA) shows statistically significant effects of age, race, and education on RSAT Speed measures. Results indicate that age-expanded norms will provide a more accurate reflection of the typical performance of older individuals on the RSAT. [ABSTRACT FROM PUBLISHER]

Background: Salivary biomarkers of periodontitis were assessed longitudinally to determine response to therapy. Methods: A 6-month case-controlled study of adults with chronic periodontitis was performed, with 33 participants receiving oral hygiene instructions (OHI) alone and 35 with scaling and root planing (SRP) combined with OHI. Saliva samples collected at week 0, 16 and 28 were analysed for interleukin (IL)-1β, IL-8, macrophage inflammatory protein (MIP)-1α, matrix metalloproteinase-8 (MMP-8), osteoprotegerin (OPG), and tumour necrosis factor-α (TNF)-α. Clinical measures of periodontal disease were recorded at each visit. Results: All parameters of periodontal health improved significantly in both groups by week 16 (p<0.0001) with the SRP group demonstrating greater benefit at week 16 and 28. Baseline OPG and TNF-α levels changed significantly at both follow-up visits (p<0.03), regardless of treatment group. IL-1β and MMP-8 levels decreased significantly from baseline (p<0.04) in the SRP group only. OPG, MMP-8, and MIP-1α were significantly reduced in responders compared with non-responders (p = 0.04, 0.01, 0.05, respectively). In receiver-operating characteristic analyses, MMP-8 produced the highest area under the curve (≥0.7; p = 0.01). Conclusion: Salivary levels of IL-1β, MMP-8, OPG, and MIP-1α reflected disease severity and response to therapy suggesting their potential utility for monitoring periodontal disease status. [ABSTRACT FROM AUTHOR]

The success of future neurodegenerative disease (ND) therapies depends partly on accurate antemortem diagnoses. Relatively few prior studies have been performed on large, multicenter-derived datasets to test the accuracy of final clinical ND diagnoses in relation to definitive neuropathological findings. Data were analyzed from the University of Kentucky Alzheimer’s Disease Center autopsy series and from the National Alzheimer’s Coordinating Center (NACC) registry. NACC data are derived from 31 different academic medical centers, each with strong clinical expertise and infrastructure pertaining to NDs. The final clinical diagnoses were compared systematically with subsequent neuropathology diagnoses. Among subjects meeting final inclusion criteria ( N = 2,861 for NACC Registry data), the strength of the associations between clinical diagnoses and subsequent ND diagnoses was only moderate. This was particularly true in the case of dementia with Lewy bodies (DLB): the sensitivity of clinical diagnoses was quite low (32.1% for pure DLB and 12.1% for Alzheimer’s disease (AD + DLB) although specificity was over 95%. AD clinical diagnoses were more accurate (85.0% sensitivity and 51.1% specificity). The accuracy of clinical DLB diagnoses became somewhat lower over the past decade, due apparently to increased “over-calling” the diagnosis in patients with severe cognitive impairment. Furthermore, using visual hallucinations, extrapyramidal signs, and/or fluctuating cognition as part of the clinical criteria for DLB diagnosis was of minimal utility in a group ( N = 237) with high prevalence of severe dementia. Our data suggest that further work is needed to refine our ability to identify specific aging-related brain disease mechanisms, especially in DLB. [ABSTRACT FROM AUTHOR]

Abstract: To reduce the toxicity of traditional conditioning regimens for allogeneic stem cell transplantation (allo-SCT), we used single-agent chemotherapy conditioning with either busulfan (total cumulative dose, 16 mg/kg) or melphalan (200 to 240 mg/m2), followed by the anti-T cell-specific monoclonal antibody T10B9 (MEDI-500) daily for 3 days. T cell-replete SCT was performed from HLA-identical sibling donors. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of 7 additional days of T10B9 and delayed onset of cyclosporine (ie, on day +4 or +5). Twenty-six high-risk hematologic malignancy patients were entered onto this study. All 24 patients who survived longer than 8 days engrafted, although 1 patient experienced late graft failure. Deaths occurred in 21 of 26 patients because of infection (n = 7), progression/recurrence of primary disease (n = 6), aGVHD (n = 4), regimen-related toxicity (n = 1), and other causes (n = 3). Five of these patients are enjoying disease-free survival with a median survival of 1193 days after allo-SCT. The conditioning regimen induced modulation of surface expression of CD3 (but not CD4 or CD8) and was associated with decreasing tumor necrosis factor-α (but not interleukin-6) serum levels. In conclusion, single-agent chemotherapy conditioning with T10B9 produced durable engraftment and long-term survival in some patients who would not have qualified for a traditional allo-SCT. [Copyright &y& Elsevier]

Context: With advances in the treatment of Alzheimer's disease (AD), clinical focus has shifted to early patient identification. Memory recall tests and category fluency distinguish normal individuals from early AD patients.Objective: Develop a brief test for general practitioners to screen for AD. Design. Examination of items from the MMSE and category fluency.Setting and Participants: A Brief Alzheimer Screen (BAS) was developed from cognitive assessments on 406 normal subjects and 342 mild AD patients in the CERAD (Consortium to Establish a Registry for AD) dataset. The derived measure was then applied to a second validation sample.Main Outcome Measure: Logistic regression was used to derive a predictive equation, which was then applied to two validation samples to estimate sensitivity and specificity.Results: The resulting logistic model for discriminating between mild AD and controls included: recall of 3 words, number of animals named in 30 seconds, date, and spelling of WORLD backwards, (p < 0.001 for each) accounting for 77% of the variance. When applied to the validation samples, sensitivity and specificity were over 99% and 87%, respectively.Conclusions: These data support the use of the BAS as a potential screen of patients over 60 years of age. [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]

To better understand clinical and neuropathological features of TDP-43 proteinopathies, data were analyzed from autopsied research volunteers who were followed in the National Alzheimer's Coordinating Center (NACC) data set. All subjects (n = 495) had autopsy-proven TDP-43 proteinopathy as an inclusion criterion. Subjects underwent comprehensive longitudinal clinical evaluations yearly for 6.9 years before death on average. We tested whether an unsupervised clustering algorithm could detect coherent groups of TDP-43 immunopositive cases based on age at death and extensive neuropathologic data. Although many of the brains had mixed pathologies, four discernible clusters were identified. Key differentiating features were age at death and the severity of comorbid Alzheimer's disease neuropathologic changes (ADNC), particularly neuritic amyloid plaque densities. Cluster 1 contained mostly cases with a pathologic diagnosis of frontotemporal lobar degeneration (FTLD-TDP), consistent with enrichment of frontotemporal dementia clinical phenotypes including appetite/eating problems, disinhibition and primary progressive aphasia (PPA). Cluster 2 consisted of elderly limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) subjects without severe neuritic amyloid plaques. Subjects in Cluster 2 had a relatively slow cognitive decline. Subjects in both Clusters 3 and 4 had severe ADNC + LATE-NC; however, Cluster 4 was distinguished by earlier disease onset, swifter disease course, more Lewy body pathology, less neocortical TDP-43 proteinopathy, and a suggestive trend in a subgroup analysis (n = 114) for increased C9orf72 risk SNP rs3849942 T allele (Fisher's exact test p value = 0.095). Overall, clusters enriched with neocortical TDP-43 proteinopathy (Clusters 1 and 2) tended to have lower levels of neuritic amyloid plaques, and those dying older (Clusters 2 and 3) had far less PPA or disinhibition, but more apathy. Indeed, 98% of subjects dying past age 85 years lacked clinical features of the frontotemporal dementia syndrome. Our study revealed discernible subtypes of LATE-NC and underscored the importance of age of death for differentiating FTLD-TDP and LATE-NC. [ABSTRACT FROM AUTHOR]

The article focuses on Revisiting the Food and Drug Administration (FDA) Approval of Aducanumab. Topics discussed include the Food and Drug Administration (FDA) granted accelerated approval to aducanumab (Aduhelm) for treatment of Alzheimer's disease; and the FDA made a late-stage decision to grant approval on the basis of aducanumab's ability to lower levels of beta-amyloid observable on positron-emission tomographic brain imaging.

Structural brain changes in aging are known to occur even in the absence of dementia, but the magnitudes and regions involved vary between studies. To further characterize these changes, we analyzed paired MRI images acquired with identical protocols and scanner over a median 5.8-year interval. The normal study group comprised 78 elders (25M 53F, baseline age range 70–78 years) who underwent an annual standardized expert assessment of cognition and health and who maintained normal cognition for the duration of the study. We found a longitudinal grey matter (GM) loss rate of 2.56 ± 0.07 ml/year (0.20 ± 0.04%/year) and a cerebrospinal fluid (CSF) expansion rate of 2.97 ± 0.07 ml/year (0.22 ± 0.04%/year). Hippocampal volume loss rate was higher than the GM and CSF global rates, 0.0114 ± 0.0004 ml/year (0.49 ± 0.04%/year). Regions of greatest GM loss were posterior inferior frontal lobe, medial parietal lobe and dorsal cerebellum. Rates of GM loss and CSF expansion were on the low end of the range of other published values, perhaps due to the relatively good health of the elder volunteers in this study. An additional smaller group of 6 subjects diagnosed with MCI at baseline were followed as well, and comparisons were made with the normal group in terms of both global and regional GM loss and CSF expansion rates. An increased rate of GM loss was found in the hippocampus bilaterally for the MCI group. [ABSTRACT FROM AUTHOR]

Aim: To investigate the role of Epstein–Barr virus (EBV), cytomegalovirus (CMV), and anaerobic bacteria in the progression of periodontitis. Methods: Eighty‐one adults with generalized moderate to severe periodontitis were randomly assigned to: oral hygiene or scaling and root planning ± placebo or polyunsaturated fatty acids fish oil. Subgingival plaque samples collected from three healthy and three disease sites at weeks 0, 16, and 28 and from sites demonstrating disease progression were analysed for EBV, CMV, P. gingivalis (Pg), T. forsythia (Tf), and T. denticola (Td) DNA using quantitative polymerase chain reaction. Results: Cytomegalovirus was detected in 0.3% (4/1454) sites. EBV was present in 12.2% of healthy sites (89/728) and 27.6% disease sites (201/726; p <.0001), but was in low copy number. Disease progression occurred in 28.4% of participants (23/81) and developed predominantly at sites identified as diseased (75/78; 96.2%). CMV and EBV were not associated with disease progression (p =.13) regardless of treatment. In contrast, disease sites were associated with higher levels of Pg, Td, Tf, and total bacteria, and sites that exhibited disease progression were associated with an abundance of Td and Tf (p <.04). Conclusion: Disease progression was associated with Gram‐negative anaerobic bacteria; not EBV or CMV. [ABSTRACT FROM AUTHOR]

Continuous-time multi-state models are commonly used to study diseases with multiple stages. Potential risk factors associated with the disease are added to the transition intensities of the model as covariates, but missing covariate measurements arise frequently in practice. We propose a likelihood-based method that deals efficiently with a missing covariate in these models. Our simulation study showed that the method performs well for both "missing completely at random" and "missing at random" mechanisms. We also applied our method to a real dataset, the Einstein Aging Study. [ABSTRACT FROM AUTHOR]

The cause of antiseizure drug (ASD) resistance in epilepsy is poorly understood. Here, we focus on the transporter P-glycoprotein (P-gp) that is partly responsible for limited ASD brain uptake, which is thought to contribute to ASD resistance. We previously demonstrated that cyclooxygenase-2 (COX-2) and the prostaglandin E receptor, prostanoid E receptor subtype 1, are involved in seizure-mediated P-gp up-regulation. Thus, we hypothesized that inhibiting microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1), the enzyme generating PGE2, prevents blood-brain barrier P-gp up-regulation after status epilepticus (SE). To test our hypothesis, we exposed isolated brain capillaries to glutamate ex vivo and used a combined in vivo-ex vivo approach by isolating brain capillaries from humanized mPGES-1 mice to study P-gp levels. We demonstrate that glutamate signaling through the NMDA receptor, cytosolic phospholipase A2, COX-2, and mPGES-1 increases P-gp protein expression and transport activity levels. We show that mPGES-1 is expressed in human, rat, and mouse brain capillaries. We show that BI1029539, an mPGES-1 inhibitor, prevented up-regulation of P-gp expression and transport activity in capillaries exposed to glutamate and in capillaries from humanized mPGES-1 mice after SE. Our data provide key signaling steps underlying seizure-induced P-gp up-regulation and suggest that mPGES-1 inhibitors could potentially prevent P-gp up-regulation in epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Mechanical thrombectomy has become standard of care for emergent large vessel occlusive stroke. Estimates of incidence for thrombectomy eligibility vary significantly. National Institutes of Health Stroke Scale (NIHSS) of 10 or greater is highly predictive of large vessel occlusion. Using our Kentucky Appalachian Stroke Registry (KApSR), we evaluated temporal trends in stroke admissions with NIHSS ≥10 to determine patient characteristics among that group along with effects and needs in thrombectomy utilization. Methods: Using the KApSR database that captures patients throughout the Appalachian region in our stroke network, we evaluated patients admitted with ischemic stroke with NIHSS ≥10. We recorded demographics, comorbidities, treatment (thrombectomy, decompressive craniectomy), and county of origin. Change in NIHSS from admission to discharge was used as an indicator of inpatient outcome. Results: Between 2010 and 2016, 1,510 patients were admitted with NIHSS ≥10. 87.2% had high blood pressure, 69.6% had dyslipidemia, and 41.7% used tobacco. There were significant sex differences in the types of patients presenting with NIHSS ≥10 with females being older on average and having more atrial fibrillation and obesity. There was an increase in thrombectomy utilization from 2010 to 2016, but only 7.5% of the potentially eligible patients underwent the procedure. In comparison to the period 2010–2014, the 2015–2016 period had higher rates of obesity and tobacco abuse. Conclusion: Among patients with significant burden of ischemic stroke, the most common coexisting medical condition was high blood pressure. Patients who underwent thrombectomy had significantly better inpatient clinical improvement. These data support the need to maximize utilization of thrombectomy along with need to devote increased resources on modifiable stroke risk factors. [ABSTRACT FROM AUTHOR]

Background: Memory assessment is a key factor for the diagnosis of cognitive impairment. However, memory performance over time may be quite heterogeneous within diagnostic groups. Method: To identify latent trajectories in memory performance and their associated risk factors, we analyzed data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who were classified either as cognitively normal or as Mild Cognitive Impairment (MCI) at baseline and were administered the Rey Auditory Verbal Learning test (RAVLT) for up to 9 years. Group-based trajectory modeling on the 30-minute RAVLT delayed recall score was applied separately to the two baseline diagnostic groups. Results: There were 219 normal subjects with mean age 75.9 (range from 59.9 to 89.6) and 52.5% male participants, and 372 MCI subjects with mean age 74.8 (range from 55.1 to 89.3) and 63.7% male participants included in the analysis. For normal subjects, six trajectories were identified. Trajectories were classified into three types, determined by the shape, each of which may comprise more than one trajectory: stable (~30% of subjects), curvilinear decline (~ 28%), and linear decline (~ 42%). Notably, none of the normal subjects assigned to the stable stratum progressed to dementia during the study period. In contrast, all trajectories identified for the MCI group tended to decline, although some participants were later re-diagnosed with normal cognition. Age, sex, and education were significantly associated with trajectory membership for both diagnostic groups, while APOE ɛ4 was only significantly associated with trajectories among MCI participants. Conclusion: Memory trajectory is a strong indicator of dementia risk. If likely trajectory of memory performance can be identified early, such work may allow clinicians to monitor or predict progression of individual patient cognition. This work also shows the importance of longitudinal cognitive testing and monitoring. [ABSTRACT FROM AUTHOR]

Tobacco smoking was examined as a risk for dementia and neuropathological burden in 531 initially cognitively normal older adults followed longitudinally at the University of Kentucky's Alzheimer's Disease Center. The cohort was followed for an average of 11.5 years; 111 (20.9%) participants were diagnosed with dementia, while 242 (45.6%) died without dementia. At baseline, 49 (9.2%) participants reported current smoking (median pack-years = 47.3) and 231 (43.5%) former smoking (median pack-years = 24.5). The hazard ratio (HR) for dementia for former smokers versus never smokers based on the Cox model was 1.64 (95% CI: 1.09, 2.46), while the HR for current smokers versus never smokers was 1.20 (0.50, 2.87). However, the Fine-Gray model, which accounts for the competing risk of death without dementia, yielded a subdistribution hazard ratio (sHR) = 1.21 (0.81, 1.80) for former and 0.70 (0.30, 1.64) for current smokers. In contrast, current smoking increased incidence of death without dementia (sHR = 2.38; 1.52, 3.72). All analyses were adjusted for baseline age, education, sex, diabetes, head injury, hypertension, overweight, APOEɛ4, family history of dementia, and use of hormone replacement therapy. Once adjusted for the competing risk of death without dementia, smoking was not associated with incident dementia. This finding was supported by neuropathology on 302 of the participants. [ABSTRACT FROM AUTHOR]

Objective: To estimate the effect of ultrasound screening on stage at detection and long-term disease-specific survival of at-risk women with epithelial ovarian cancer.Methods: Eligibility included all asymptomatic women 50 years of age or older and women 25 years of age or older with a documented family history of ovarian cancer. From 1987 to 2017, 46,101 women received annual ultrasound screening in a prospective cohort trial. Women with a persisting abnormal screen underwent tumor morphology indexing, serum biomarker analysis, and surgery.Results: Seventy-one invasive epithelial ovarian cancers and 17 epithelial ovarian tumors of low malignant potential were detected. No women with a low malignant potential tumor experienced recurrent disease. Stage distribution for screen-detected invasive epithelial ovarian cancers was stage I-30 (42%), stage II-15 (21%), stage III-26 (37%), and stage IV-0 (0%). Follow-up varied from 9.2 months to 27 years (mean 7.9 years). Disease-specific survival at 5, 10, and 20 years for women with invasive epithelial ovarian cancer detected by screening was 86±4%, 68±7%, and 65±7%, respectively, vs 45±2%, 31±2%, and 19±3%, respectively, for unscreened women with clinically detected ovarian cancer from the same geographic area who were treated at the same institution by the same treatment protocols (P<.001). Twenty-seven percent of screen-detected malignancies were type I and 73% were type II. The disease-specific survival of women with type I and type II screen-detected tumors was significantly higher than that of women with clinically detected type I and type II tumors and was related directly to earlier stage at detection.Conclusion: Annual ultrasound screening of at-risk asymptomatic women was associated with lower stage at detection and increased 5-, 10-, and 20-year disease-specific survival of women with both type I and type II epithelial ovarian cancer.Clinical Trial Registration: OnCore Clinical Trials Management System, NCI-2013-01954. [ABSTRACT FROM AUTHOR]

Background: We previously reported increased unstimulated blood levels of interferon-gamma in persons with latent tuberculosis infection (LTBI) in the United States, suggesting enhanced immune activation in LTBI. To investigate this further in a TB-endemic setting, we assessed interferon-gamma levels in persons with and without LTBI in Peru. Methods: We analyzed data from patients with and without a recent type 1 (spontaneous) acute myocardial infarction (AMI) who were enrolled from two public hospital networks in Lima, Peru, and underwent LTBI testing using the QuantiFERON® TB Gold In-tube (QFT) assay. Participants with a positive QFT test were defined as having LTBI, whereas participants with a negative QFT test were defined as non-LTBI. Unstimulated interferon-gamma was quantified via enzyme-linked immunosorbent assay in the QFT nil-tube, which does not contain antigens. We compared unstimulated interferon-gamma levels between LTBI and non-LTBI groups using the Wilcoxon rank sum test. We used proportional odds modeling for multivariable analysis. Results: Data from 214 participants were included in this analysis. Of those, 120 (56%) had LTBI. There were no significant differences in age, sex and comorbidities between LTBI and non-LTBI participants, except for recent AMI that was more frequent in LTBI. LTBI participants had higher unstimulated interferon-gamma levels compared to non-LTBI participants (median, interquartile range; 14 pg/mL, 6.5–52.8 vs. 6.5 pg/mL, 4.5–15; P<0.01). LTBI remained associated with higher unstimulated interferon-gamma levels after controlling for age, sex, recent AMI, history of hypertension, diabetes mellitus, dyslipidemia, end stage renal disease, malignancy, obesity, and tobacco use (adjusted odds ratio, 2.93; 95% confidence interval, 1.8–4.9). In a sensitivity analysis that excluded participants with AMI, the association between unstimulated interferon-gamma and LTBI remained present (adjusted odds ratio; 3.93; 95% confidence interval, 1.9–8.2). Conclusions: LTBI was associated with higher unstimulated interferon-gamma levels. These data suggest ongoing immune activation in LTBI. [ABSTRACT FROM AUTHOR]

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage, based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivolex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A2. Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage. [ABSTRACT FROM AUTHOR]

Background. Tuberculosis has been associated with an increased risk of cardiovascular disease (CVD), including acute myocardial infarction (AMI). We investigated whether latent tuberculosis infection (LTBI) is associated with AMI. Methods. We conducted a case-control study in 2 large national public hospital networks in Lima, Peru, between July 2015 and March 2017. Case patients were patients with a first time diagnosis of type 1 (spontaneous) AMI. Controls were patients without a history of AMI. We excluded patients with known human immunodeficiency virus infection, tuberculosis disease, or prior LTBI treatment. We used the QuantiFERON-TB Gold In-Tube assay to identify LTBI. We used logistic regression modeling to estimate the odds ratio (OR) of LTBI in AMI case patients versus non-AMI controls. Results. We enrolled 105 AMI case patients and 110 non-AMI controls during the study period. Overall, the median age was 62 years (interquartile range, 56-70 years); 69% of patients were male; 64% had hypertension, 40% dyslipidemia, and 39% diabetes mellitus; 30% used tobacco; and 24% were obese. AMI case patients were more likely than controls to be male (80% vs 59%; P < .01) and tobacco users (41% vs 20%; P < .01). LTBI was more frequent in AMI case patients than in controls (64% vs 49% [P = .03]; OR, 1.86; 95% confidence interval [CI], 1.08-3.22). After adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, tobacco use, obesity, and family history of coronary artery disease, LTBI remained independently associated with AMI (adjusted OR, 1.90; 95% CI, 1.05-3.45). Conclusions. LTBI was independently associated with AMI. Our results suggest a potentially important role of LTBI in CVD. [ABSTRACT FROM AUTHOR]

To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and >9500 women completed it more than one four times for >43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p < 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p < 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported. [ABSTRACT FROM AUTHOR]

Risk factors and cognitive sequelae of brain arteriolosclerosis pathology are not fully understood. To address this, we used multimodal data from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative data sets. Previous studies showed evidence of distinct neurodegenerative disease outcomes and clinical-pathological correlations in the "oldest-old" compared to younger cohorts. Therefore, using the National Alzheimer's Coordinating Center data set, we analyzed clinical and neuropathological data from two groups according to ages at death: < 80 years (n = 1008) and ≥80 years (n = 1382). In both age groups, severe brain arteriolosclerosis was associated with worse performances on global cognition tests. Hypertension (but not diabetes) was a brain arteriolosclerosis risk factor in the younger group. In the ≥80 years age at death group, an ABCC9 gene variant (rs704180), previously associated with aging-related hippocampal sclerosis, was also associated with brain arteriolosclerosis. A post-hoc arterial spin labeling neuroimaging experiment indicated that ABCC9 genotype is associated with cerebral blood flow impairment; in a convenience sample from Alzheimer's Disease Neuroimaging Initiative (n = 15, homozygous individuals), non-risk genotype carriers showed higher global cerebral blood flow compared to risk genotype carriers. We conclude that brain arteriolosclerosis is associated with altered cognitive status and a novel vascular genetic risk factor. [ABSTRACT FROM AUTHOR]

Background and purpose Vascular dementia ( VAD) is a complex diagnosis at times difficult to distinguish from Alzheimer's disease ( AD). MRI scans often show white matter hyperintensities ( WMH) in both conditions. WMH increase with age, and both VAD and AD are associated with aging, thus presenting an attribution conundrum. In this study, we sought to show whether the amount of WMH in deep white matter ( dWMH), versus periventricular white matter ( PVH), would aid in the distinction between VAD and AD, independent of age. Methods Blinded semiquantitative ratings of WMH validated by objective quantitation of WMH volume from standardized MRI image acquisitions. PVH and dWMH were rated separately and independently by two different examiners using the Scheltens scale. Receiver operator characteristic ( ROC) curves were generated using logistic regression to assess classification of VAD (13 patients) versus AD (129 patients). Clinical diagnoses were made in a specialty memory disorders clinic. Results Using PVH rating alone, overall classification (area under the ROC curve, AUC) was 75%, due only to the difference in age between VAD and AD patients in our study and not PVH. In contrast, dWMH rating produced 86% classification accuracy with no independent contribution from age. A global Longstreth rating that combines dWMH and PVH gave an 88% AUC. Conclusions Increased dWMH indicate a higher likelihood of VAD versus AD. Assessment of dWMH on MRI scans using Scheltens and Longstreth scales may aid the clinician in distinguishing the two conditions. [ABSTRACT FROM AUTHOR]

With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum. [ABSTRACT FROM AUTHOR]