Space-Occupying Brain Lesions, Trauma-Related Tau Astrogliopathy, and ARTAG: A Report of Two Cases and a Literature Review

Astrocytes with intracellular accumulations of misfolded phosphorylated tau protein have been observed in advanced-stage chronic traumatic encephalopathy (CTE) and in other neurodegenerative conditions. There is a growing awareness that astrocytic tau inclusions are also relatively common in the brains of persons over 70 years of age-affecting approximately one-third of autopsied individuals. The pathologic hallmarks of aging-related tau astrogliopathy (ARTAG) include phosphorylated tau protein within thorn-shaped astrocytes (TSA) in subpial, subependymal, perivascular, and white matter regions, whereas granular-fuzzy astrocytes are often seen in gray matter. CTE and ARTAG share molecular and histopathologic characteristics, suggesting that trauma-related mechanism(s) may predispose to the development of tau astrogliopathy. There are presently few experimental systems to study the pathobiology of astrocytic-tau aggregation, but human studies have made recent progress. For example, leucotomy (also referred to as lobotomy) is associated with a localized ARTAG-like neuropathology decades after the surgical brain injury, suggesting that chronic brain injury of any type may predispose to later life ARTAG. To examine this idea in a different context, we report clinical and pathologic features of two middle-aged men who came to autopsy with large (\u3e 6 cm in greatest dimension) arachnoid cysts that had physically displaced and injured the subjects\u27 left temporal lobes through chronic mechanical stress. Despite the similarity of the size and location of the arachnoid cysts, these individuals had dissimilar neurologic outcomes and neuropathologic findings. We review the evidence for ARTAG in response to brain injury, and discuss how the location and molecular properties of astroglial tau inclusions might alter the physiology of resident astrocytes. These cases and literature review point toward possible mechanism(s) of tau aggregation in astrocytes in response to chronic brain trauma

ABCC9/SUR2 in the Brain: Implications for Hippocampal Sclerosis of Aging and a Potential Therapeutic Target

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“K ATP ”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K ATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9 /SUR2 may provide a “druggable target”, relevant perhaps to both HS-Aging and Alzheimer\u27s disease. We conclude that more work is required to better understand the roles of ABCC9 /SUR2 in the human brain during health and disease conditions

Sensory Processing Abnormalities in Community-Dwelling Older Adults with Cognitive Impairment: A Mixed Methods Study

Mild cognitive impairment (MCI) or dementia often leads to behavioral and psychiatric symptoms of dementia (BPSD). Sensory processing abnormalities may be associated with BPSD. The purpose of this study was to explore relationships among sensory processing, behavior, and environmental features within the homes of people with MCI or dementia. This project used mixed methods to assess participants’ sensory processing, care partner perspectives on behaviors, and in situ observations of the home environment. Nine participants with cognitive impairment (MCI n = 8, early dementia = 1) and their care partners were included. Seven participants with cognitive impairment were reported to have abnormal sensory processing. Findings suggest that unique environmental adaptations, tailored to personal and sensory preferences for each participant, were associated with a decreased level of behavioral disruption during the observation periods. Implementing sensory-based approaches to maximize environment adaptation may be beneficial in reducing disruptive behaviors for adults with cognitive impairment

Geochronology, geochemistry and geodynamics of the Cabo de Gata volcanic zone, Southeastern Spain

© 2014 Societa Geologica Italiana, Roma. New 40Ar/39Ar ages and major and trace element geochemistry of the middle-late Miocene Cabo de Gata volcanic complex, southeast Spain, indicate that the volcanic activity of the Cabo de Gata volcanic zone developed over a short period through several pulses of geochemically and isotopically different parental magmas. The oldest volcanic rocks exposed in the Cabo de Gata volcanic zone are the shoshonite and high-K calc-Alkaline rocks of Bujo group, which cry - stallised from a parental magma transitional from calc-Alkaline to alkaline potassic generated through large degrees of partial melting, and then affected by a minor contribution from metasomatised veins and a larger one from the surrounding mantle wedge, in comparison to ultrapotassic melts. Subsequent partial melting of the mantle source produced typical calc-Alkaline parental magmas belonging to the Rodalquilar and Agua Amarga groups. Sr-Nd-Pb isotope and incompatible trace element distributions of Cabo de Gata rocks are in agreement with a mantle-wedge source affected by a two-fold metasomatism. The data suggested that mild potassic to sub-Alkaline subduction-related parental magmas (i.e., high-K calc-Alkaline and calc-Alkaline) were generated in the Cabo de Gata sector within a mantle wedge metasomatised by a fluid-dominated agent. In contrast, the enrichment in K2O of shoshonitic to ultrapotassic magmas was achieved through recycling of subducted sediments through melts that enriched the mantle wedge in K and related elements. Such a scenario can be easily reconciled with a geodynamic setting at the edge of a destructive plate margin with the subducted slab responsible for the recycling of sediments within the mantle wedge.Geochemical, petrographic and analytical work were supported by the Italian MIUR through Cofin_2004 (grants #2004040502_001 and 2004040502_002), Cofin_2008 (grants #2008HMHYFP_002 and 2008HMHYFP_004) and Cofin_2010-2011 (grants #2010TT22SC_001, 2010TT22SC_005 and 2010TT22SC_006; 2010TT22SC_003) projects, to Sandro Conticelli and Massimo Mattei, respectively. Further financial support for geochronological analyses was provided by Spanish projects CGL2009-06968-E, CGL2005-03511/BTE and HI2006-0073 to Carles C. Soriano.Peer Reviewe

The Volsci Volcanic Field (central Italy). Eruptive history, magma system and implications on continental subduction processes.

Here, we report on the Quaternary Volsci Volcanic Field (VVF, central Italy). In light of new 40Ar/39Ar geochronological data and compositional characterization of juvenile eruptive products, we refine the history of VVF activity, and outline the implications on the pre-eruptive magma system and the continental subduction processes involved. Different from the nearby volcanic districts of the Roman and Campanian Provinces, the VVF was characterized by small-volume (0.01–0.1 km3) eruptions from a network of monogenetic centers (mostly tuff rings and scoria cones, with subordinate lava occurrences), clustered along high-angle faults of lithospheric depth. Leucite-bearing, high-K (HKS) magmas (for which we report for the first time the phlogopite phenocryst compositions) mostly fed the early phase of activity (∼761–539 ka), then primitive, plagioclase-bearing (KS) magmas appeared during the climactic phase (∼424–349 ka), partially overlapping with HKS ones, and then prevailed during the late phase of activity (∼300–231 ka). The fast ascent of primitive magma batches is typical of a tectonically controlled volcanic field, where the very low magma flux is a passive byproduct of regional tectonic strain. We suggest that the dominant compressive stress field acting at depth was accompanied by an extensional regime in the upper crust, associated with the gravity spreading of the Apennine chain, allowing the fast ascent of magma from the mantle source with limited stationing in shallow reservoirs

Ferritin Levels in the Cerebrospinal Fluid Predict Alzheimer\u27s Disease Outcomes and Are Regulated by APOE

Brain iron elevation is implicated in Alzheimer\u27s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer\u27s risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD

Human Cerebral Neuropathology of Type 2 Diabetes Mellitus

The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the ‘Pubmed Era’. Recent neuroimaging studies have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer\u27s disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer\u27s Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (N = 234), 139 met inclusion criteria. These patients provided the basis for comparing the prevalence of pathological and clinical indices between well-characterized cases with (N = 50) or without (N = 89) the premortem diagnosis of diabetes. In diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non-diabetics. Finally, a series of photomicrographs demonstrates histopathological features (including clinical–radiographical correlation) observed in brains of persons that died after a history of diabetes. These preliminary, correlative, and descriptive studies may help develop new hypotheses about CNDM2. We conclude that more work should be performed on human material in the context of CNDM2

Multi-Vendor and Multisite Evaluation of Cerebrovascular Reactivity Mapping Using Hypercapnia Challenge

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain\u27s vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials

Limbic-Predominant Age-Related TDP-43 Encephalopathy Differs from Frontotemporal Lobar Degeneration

TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer’s disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists’ diagnoses from two research centres—University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is ‘Alpha’ versus ‘Beta’ in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively ‘pure’ severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at \u3e 98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P \u3c 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria