Initial Management of Meningiomas: Analysis of the National Cancer Database

BACKGROUND: Meningiomas are the most common central nervous system tumor. We describe current trends in treatment and survival using the largest cancer dataset in the United States. METHODS: We analyzed the National Cancer Database from 2004 to 2014, for all patients with diagnosis of meningioma. RESULTS: 201,765 cases were analyzed. Patients were most commonly White (81.9%) females (73.2%) with a median age of 64 years. Fifty percent of patients were diagnosed by imaging. Patients were reported as grade I (24.9%), grade II (5.0%), grade III (0.7%), or unknown WHO grade (69.4%). Patients diagnosed by imaging were older, received treatment in community facilities, had higher Charlson-Deyo score, and a lower rate of private insurance. Watchful waiting was the most common treatment modality (46.7%), followed by surgery only (40%). Grade II and III patients were more likely to receive therapy. Watchful waiting increased from 35.2% in 2004 to 51.4% in 2014. Younger age, male gender, private insurance, and treatment in academic facilities were determinants for receipt of surgery and/or radiation. Median survival was 12.6 years, higher in histologically confirmed cases (13.1 years). Older patients, Blacks, males, those that received radiation plus surgery, and were treated in community facilities had an increased risk of mortality. CONCLUSIONS: Over half of patients were diagnosed by imaging, suggesting a higher role of clinical determinants over histological confirmation in treatment decisions. Watchful waiting as initial management is increasing. Our survival analysis favored histological confirmation. Patients receiving radiation and surgery had an increased risk of mortality

Dynamically-Coupled Oscillators -- Cooperative Behavior via Dynamical Interaction --

We propose a theoretical framework to study the cooperative behavior of dynamically coupled oscillators (DCOs) that possess dynamical interactions. Then, to understand synchronization phenomena in networks of interneurons which possess inhibitory interactions, we propose a DCO model with dynamics of interactions that tend to cause 180-degree phase lags. Employing an approach developed here, we demonstrate that although our model displays synchronization at high frequencies, it does not exhibit synchronization at low frequencies because this dynamical interaction does not cause a phase lag sufficiently large to cancel the effect of the inhibition. We interpret the disappearance of synchronization in our model with decreasing frequency as describing the breakdown of synchronization in the interneuron network of the CA1 area below the critical frequency of 20 Hz.Comment: 10 pages, 3 figure

Ipsilateral and Contralateral Torque Responses to Bilateral and Unilateral Maximal, Fatiguing, Isokinetic Leg Extensions

Background: Few studies have compared performance fatigability (PF) for bilateral versus unilateral isokinetic tasks. Objectives: The purpose of this study was to examine: Mode- specific testing responses to isokinetic fatigue, differences in PF between bilateral and unilateral leg extensions, and the effects of fatiguing, unilateral, dynamic leg extensions on contralateral isokinetic peak torque (PT) and maximal voluntary isometric contraction (MVIC). Methods: Eight men (mean ± SD: age= 22.5 ± 2.5 yr.) completed pre- and post-testing for PT and MVIC following 50 bilateral, unilateral right or left leg maximal, isokinetic leg extensions at 180°·s-1, on three separate days. Fatigue-induced decreases in PT and MVIC were used to quantify PF. The data were analyzed with a 4-way repeated measures ANOVA, follow up, and post-hoc analyses. Results: The results indicated that there were no differences (p \u3e 0.05) in PF for the bilateral versus unilateral fatiguing tasks, decreases in PT (p \u3c 0.001 - 0.016; d = 0.54 - 2.58) and MVIC (p \u3c 0.001 - 0.006; η2p = 0.682 - 0.962) for the exercised legs during unilateral fatigue, and a contralateral increase (p = 0.007) in PT following the right leg fatiguing task. Conclusion: The results indicated that PT was more sensitive to fatiguing isokinetic tasks than was MVIC. In addition, there was a facilitation of PT in the contralateral leg following unilateral right leg fatigue. The differences in PT and MVIC testing may be attributable to the timing and/ or relative contributions of peripheral and central fatigue

Rod-Shaped Microglia Morphology Is Associated with Aging in 2 Human Autopsy Series

A subtype of microglia is defined by the morphological appearance of the cells as rod-shaped. Little is known about this intriguing cell type, as there are only a few case reports describing rod-shaped microglia in the neuropathological literature. Rod-shaped microglia were shown recently to account for a substantial proportion of the microglia cells in the hippocampus of both demented and cognitively intact aged individuals. We hypothesized that aging could be a defining feature in the occurrence of rod-shaped microglia. To test this hypothesis, two independent series of autopsy cases (total n=168 cases), which covered the adult lifespan from 20 – 100+ years old, were included in the study. The presence or absence of rod-shaped microglia was scored on IBA1 immunohistochemically stained slides for the hippocampus and cortex. We found that age was one of the strongest determinants for the presence of rod-shaped microglia in the hippocampus and the cortex. We found no association with the presence of rod-shaped microglia and a self-reported history of a TBI. Alzheimer’s disease related pathology was found to influence the presence of rod-shaped microglia, but only in the parietal cortex and not in the hippocampus or temporal cortex. Future studies are warranted to determine the functional relevance of rod-shaped microglia in supporting the health of neurons in the aged brain, and the signaling processes that regulate the formation of rod-shaped microglia

Perceptual Fatigability and Neuromuscular Responses During a Sustained, Isometric Forearm Flexion Muscle Action Anchored to a Constant Level of Perceived Exertion

Objective: The purpose of the present study was to examine the fatigue-induced changes in torque, and the electromyographic (EMG) and mechanomyographic (MMG) responses during a sustained submaximal, isometric forearm flexion muscle action anchored to a constant rating of perceived exertion (RPE). Methods: Eleven women (mean ± SD: age = 20.5 ± 1.9 yrs.; height = 169.9 ± 6.6 cm; body mass = 73.2 ± 15.9 kg) performed 2, 3s forearm flexion maximal voluntary isometric contractions (MVIC) before a sustained isometric muscle action anchored to RPE = 7 until task failure (defined as torque that would require RPE \u3e 7, or the torque was reduced to zero). The EMG amplitude (AMP), EMG mean power frequency (MPF), MMG AMP, and MMG MPF signals from the biceps brachii (BB) were recorded. Regression analyses were conducted to examine the torque and neuromuscular responses vs. time relationships. Results: The percent decline in torque during the sustained isometric muscle action was 95.69 ± 6.54 %. There was a significant (p \u3c 0.001; R = -0.998), negative quadratic EMG AMP relationship and a significant (p \u3c 0.046; R = 0.952), positive quadratic MMG AMP relationship vs. Time, but no significant (p \u3e 0.05) relationships for EMG MPF or MMG MPF vs. Time. Conclusion: The findings suggested that torque was initially regulated by an anticipatory feedforward mechanism and continually adjusted due to afferent feedback. In addition, substantial inter-individual, as well as differences between the individual and composite responses, were observed for the neuromuscular response patterns

Disease-Related Microglia Heterogeneity in the Hippocampus of Alzheimer\u27s Disease, Dementia with Lewy Bodies, and Hippocampal Sclerosis of Aging

Introduction: Neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer\u27s disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions. Results: Here we studied cases with pathologically-confirmed AD (n = 7), HS-Aging (n = 7), AD + HS-aging (n = 4), DLB (n = 12), and normal (cognitively intact) controls (NC) (n = 9) from the University of Kentucky Alzheimer\u27s Disease Center autopsy cohort. We defined five microglia morphological phenotypes in the autopsy samples: ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. The Aperio ScanScope digital neuropathological tool was used along with two well-known microglial markers: IBA1 (a marker for both resting and activated microglia) and CD68 (a lysosomal marker in macrophages/microglia associated with phagocytic cells). Hippocampal staining analyses included studies of subregions within the hippocampal formation and nearby white matter. Using these tools and methods, we describe variation in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in HS-aging and AD + HS-aging; (2) low microglia density in DLB; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in DLB. Conclusions: We conclude that variations in morphologies among microglial cells, and cells of macrophage lineage, can help guide future work connecting neuroinflammatory mechanisms with specific neurodegenerative disease subtypes

Hippocampal Sclerosis of Aging, a Prevalent and High-Morbidity Brain Disease

Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5-30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available

Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing

Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer's Disease Centre, Nun Study, and National Alzheimer's Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case-control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P 5 0.001). This enables informative evaluation of anatomical regions outside of the hippocampus. To assess the morphology of brain microvasculature far more rigorously than what is possible using semi-quantitative pathological scoring, we applied digital pathological (Aperio ScanScope) methods on a subsample of frontal cortex sections from hippocampal sclerosis of ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P 5 0.05), larger perimeters (P 5 0.03), and larger vessel areas (P 5 0.03) than controls. Unlike the arterioles, CD34-immunoreactive capillaries had dimensions that were unchanged in cases with hippocampal sclerosis of ageing versus controls. Arteriolosclerosis appears specific to hippocampal sclerosis of ageing brains, because brains with Alzheimer's disease pathology did not show the same morphological alterations. We conclude that there may be a pathogenetic change in aged human brain arterioles that impacts multiple brain areas and contributes to hippocampal sclerosis of ageing

\u3cem\u3eABCC9\u3c/em\u3e Gene Polymorphism Is Associated with Hippocampal Sclerosis of Aging Pathology

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer\u27s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer\u27s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer\u27s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor