Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock

BACKGROUND: The role of inflammation in patients with coronary artery disease is emerging. We sought to assess the profile and outcomes of patients with a clinical syndrome of severe systemic inflammation that led to a diagnosis of suspected sepsis in the setting of acute myocardial infarction complicated by cardiogenic shock (CS). METHODS: Patients enrolled in the randomized SHOCK (SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK) trial (n = 302) were divided into those with clinical signs of severe systemic inflammation (eg, fever [94%] or leukocytosis [72%]) that led to a diagnosis of suspected sepsis (n = 54 [18%]) and those without suspected sepsis (controls; n = 243 [80%]). The patients with suspected sepsis were then further subdivided into those who were considered to be potentially infectious (positive culture result ["culture-positive"]; n = 40) and those who were not (negative culture result ["culture-negative"]; n = 14). RESULTS: Severe systemic inflammation was diagnosed 4 and 2 days after the onset of CS in culture-positive and culture-negative patients, respectively. Patients who developed systemic inflammation tended to be younger (P = .05) and to have lower systemic vascular resistance (SVR) near the onset of CS (P = .006). Many culture-positive patients (40%) had undergone coronary artery bypass graft surgery. However, the lower the initial SVR, the higher the risk of developing culture-positive systemic inflammation (P = .01), even after controlling for age and coronary artery bypass graft surgery. A time-dependent model, adjusted for age, showed that culture-positive patients were at significantly higher risk for death than were controls (hazard ratio, 2.22; 95% confidence interval, 1.32-3.76; P = .008). CONCLUSIONS: Almost one fifth of patients with acute myocardial infarction complicated by CS showed clinical signs of severe systemic inflammation, and those who were culture-positive for sepsis had twice the risk of death. The observation of lower SVR at the onset of shock in patients who subsequently had culture-positive systemic inflammation suggests that inappropriate vasodilation may play an important role in the pathogenesis and persistence of shock and in the risk of infection.     

Patient preference and willingness to pay for transient elastography versus liver biopsy: A perspective from British Columbia

BACKGROUND:

The cost of liver biopsy (LB) is publicly funded in British Columbia, while the cost of transient elastography (FibroScan [FS], Echosens, France) is not. Consequently, there is regional variation regarding FS access and monitoring of liver disease progression.

OBJECTIVE:

To evaluate patient preference for FS versus LB and to assess the willingness to self-pay for FS.

METHODS:

Questionnaires were distributed in clinic and via mail to LB-experienced and LB-naive patients who underwent FS at Vancouver General Hospital, Vancouver, British Columbia.

RESULTS:

The overall response rate was 76%. Of the 422 respondents, 205 were LB-experienced. The mean age was 53.5 years, 50.2% were male, 54.7% were Caucasian, 38.2% had hepatitis C and 26.3% had an annual household income >$75,000. Overall, 95.4% of patients preferred FS to LB. FS was associated with greater comfort than LB, with the majority reporting no discomfort during FS (84.1% versus 7.8% for LB), no discomfort after (96.2% versus 14.6% LB) and no feelings of anxiety after FS explanation (78.2% versus 12.7% LB). FS was also associated with greater speed, with the majority reporting short test duration (97.2% versus 48.3% LB) and short wait for the test result (95.5% versus 30.2% LB). Most (75.3%) respondents were willing to self-pay for FS, with 26.3% willing to pay $25 to $49. Patients with unknown liver disease preferred LB (OR [FS preference] 0.20 [95% CI 0.07 to 0.53]).

CONCLUSIONS:

FS was the preferred method of assessing liver fibrosis among patients, with the majority willing to self-pay. To ensure consistency in access, provincial funding for FS is needed. However, LB remains the procedure of choice for individuals with an unknown diagnosis.     

Metformin increases peroxisome proliferator–activated receptor γ Co‐activator‐1α and utrophin a expression in dystrophic skeletal muscle

Introduction: Metformin (MET) stimulates skeletal muscle AMP‐activated protein kinase (AMPK), a key phenotype remodeling protein with emerging therapeutic relevance for Duchenne muscular dystrophy (DMD). Our aim was to identify the mechanism of impact of MET on dystrophic muscle. Methods: We investigated the effects of MET in cultured C₂C₁₂ muscle cells and mdx mouse skeletal muscle. Expression of potent phenotypic modifiers was assessed, including peroxisome proliferator–activated receptor (PPAR)γ coactivator‐1α (PGC‐1α), PPARδ, and receptor‐interacting protein 140 (RIP140), as well as that of the dystrophin‐homolog, utrophin A. Results: In C₂C₁₂ cells, MET augmented expression of PGC‐1α, PPARδ, and utrophin A, whereas RIP140 content was reciprocally downregulated. MET treatment of mdx mice increased PGC‐1α and utrophin A and normalized RIP140 levels. Conclusions: In this study we identify the impact of MET on skeletal muscle and underscore the timeliness and importance of investigating MET and other AMPK activators as relevant therapeutics for DMD. Muscle Nerve 52 : 139–142, 2015     

Vesicular stomatitis virus enables gene transfer and transsynaptic tracing in a wide range of organisms

Current limitations in technology have prevented an extensive analysis of the connections among neurons, particularly within nonmammalian organisms. We developed a transsynaptic viral tracer originally for use in mice, and then tested its utility in a broader range of organisms. By engineering the vesicular stomatitis virus (VSV) to encode a fluorophore and either the rabies virus glycoprotein (RABV‐G) or its own glycoprotein (VSV‐G), we created viruses that can transsynaptically label neuronal circuits in either the retrograde or anterograde direction, respectively. The vectors were investigated for their utility as polysynaptic tracers of chicken and zebrafish visual pathways. They showed patterns of connectivity consistent with previously characterized visual system connections, and revealed several potentially novel connections. Further, these vectors were shown to infect neurons in several other vertebrates, including Old and New World monkeys, seahorses, axolotls, and Xenopus. They were also shown to infect two invertebrates, Drosophila melanogaster, and the box jellyfish, Tripedalia cystophora, a species previously intractable for gene transfer, although no clear evidence of transsynaptic spread was observed in these species. These vectors provide a starting point for transsynaptic tracing in most vertebrates, and are also excellent candidates for gene transfer in organisms that have been refractory to other methods. J. Comp. Neurol. 523:1639–1663, 2015. © 2015 Wiley Periodicals, Inc.     

Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours

Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high‐grade brain tumours in the context of bMMRD. We performed exome sequencing of two second‐cousin patients from a large consanguineous family of Indian origin with early onset of high‐grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo^–, i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two‐fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo^– disorders. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Tamoxifen stimulates calcitonin-producing thyroid C-cells and prevents trabecular bone loss in a rat model of androgen deficiency

Thyroid C-cells produce calcitonin (CT), a hypocalcemic hormone, that acts as an inhibitor of bone resorption. In this study, we investigated the effects of tamoxifen (TAM) as a selective estrogen receptor modulator on thyroid C-cells, trabecular bone and biochemical markers of bone metabolism in an animal model of androgen deficiency, represented by middle-aged orchidectomized (Orx) rats. Fifteen-month-old male Wistar rats were divided into: Orx and sham-operated (SO) groups. Rats from one Orx group were injected subcutaneously with TAM citrate (Orx + TAM; 0.3 mg kg⁻¹ b.w.), while the rats from SO and a second Orx group received vehicle alone, once a day for 3 weeks. The peroxidase–antiperoxidase method was applied for localization of CT in C-cells. Thyroid C-cells were morphometrically and ultrastructurally analyzed. An ImageJ image-processing program was used to measure bone histomorphometric parameters. Blood serum samples were analyzed for CT, osteocalcin (OC), calcium (Ca²⁺) and phosphorus (P). Urinary Ca²⁺ concentrations were measured. TAM treatment significantly increased thyroid C-cell volume (V_c) and serum CT when compared with vehicle-treated Orx rats. Analysis of trabecular microarchitecture of the tibia showed that administration of TAM significantly increased cancellous bone area, trabecular thickness and trabecular number, whereas trabecular separation was significantly decreased compared with vehicle-treated Orx rats. Serum OC and urinary Ca²⁺ concentrations were significantly lower in comparison with the control Orx group. These results indicate that in our rat model of androgen deficiency, TAM stimulated calcitonin-producing thyroid C-cells and increased trabecular bone mass.     

Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells

In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here, we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from macular dystrophy patients with pathologic BEST1 mutations. Disruption of the orthologous mouse gene (Best1^−/−) does not result in obvious retinal pathology but leads to a severe subfertility phenotype in agreement with minor endogenous expression of Best1 in murine RPE but highly abundant expression in mouse testis. Sperm from Best1^−/− mice showed reduced motility and abnormal sperm morphology, indicating an inability in RVD. Together, our data suggest that the molecular identity of VRACs is more complex—that is, instead of a single ubiquitous channel, VRACs could be formed by cell type- or tissue-specific subunit composition. Our findings provide the basis to further examine VRAC diversity in normal and diseased cell physiology, which is key to exploring novel therapeutic approaches in VRAC-associated pathologies.Tight regulation of cell volume is fundamental to proper cell function and survival. In general, rapid water influx across cell membranes leads to cell swelling, which in turn activates net efflux of K⁺ and Cl⁻, thereby triggering the release of osmotically obligated water from the cell. Essential to this process is the activation of a current primarily carried by chloride ions (I_swell). This current is gated by volume-regulated anion channels (VRACs) returning the cell to a controlled state of homeostatic integrity, a complex mechanism commonly referred to as regulatory volume decrease (RVD) (1, 2). Although VRACs share common features in almost all cell types, it is unclear whether there is one ubiquitous channel or a diversity of chloride channels with slightly differing functional properties. In this context, three families of proteins—the Ca²⁺- and/or volume-sensitive anoctamins, bestrophins, and the recently discovered LRRC8s—are presently at the center of interest (3–7).Bestrophin 1 (BEST1), a member of the human bestrophin family of four paralogous genes, encodes an integral membrane protein strongly expressed in the human retinal pigment epithelium (RPE) (8). Mutations in BEST1 have been associated with various macular dystrophies most prominently represented by Best disease (BD), a central retinopathy with autosomal dominant inheritance but variable penetrance and expressivity (9, 10). Key features of BD pathology include a striking lipofuscin accumulation in the macular RPE (11) and an abnormal light peak (LP)/dark trough ratio in the electro-oculogram (EOG) reflective of an impaired RPE (12). The abnormalities in the LP were suggested to be compatible with a function of BEST1 as a Ca²⁺-activated Cl⁻ channel (CaCC) (13, 14).Addressing BEST1 function, several studies have suggested a role of the protein in distinct basic cellular processes such as Ca²⁺ homeostasis, neurotransmitter release, and cell volume regulation. These studies mostly relied on BEST1 overexpression in HEK293 cells or conducted in vitro experiments with isolated cells from existing Best1-deficient mouse lines. In summarizing these data, BEST1 was shown to be (i) a calcium sensor localized to the endoplasmic reticulum (ER) of mouse RPE (15), (ii) an intracellular Cl⁻ channel activating anoctamin 1 (ANO1) located at the plasma membrane of mouse trachea (5), (iii) a modulator of voltage-gated Ca²⁺ channels in murine RPE (16), and (iv) a channel for tonic GABA or slow glutamate release in mouse glia cells and astrocytes (17, 18). To date, the functional role of Best1 has not been determined in the mouse testis, the site of highest endogenous Best1 expression in the mouse (19). In addition, using patient-derived hiRPE cells, the role of BEST1 in mediating ER calcium release and/or uptake was shown (20). In contrast, two independent studies in S2R+ cells from Drosophila melanogaster strongly suggested the invertebrate Drosophila Best1 (dBest1) to act as a volume-regulated chloride channel but with biophysical characteristics clearly distinct from a vertebrate VRAC (3, 21). By small interfering RNA (siRNA)-mediated knockdown of BEST1 in HEK293 cells (6) and mouse Best1 (mBest1) gene disruption in murine peritoneal macrophages (22), two studies could not show a functional effect of BEST1 on I_swell, thus questioning this protein as a candidate for mammalian VRAC in these cell types. Instead, two studies identified the LRRC8A gene as an essential component of a VRAC in various cultured cell lines (6, 7). In these latter studies, the authors propose a scenario where LRRC8A and the isoforms LRRC8B to LRRC8E form variable cell type-specific hexamers, explaining the variability of VRAC properties in different cell types.Together, the rather disparate reports on BEST 1 function underscore the need to further clarify its role in mammalian VRACs. To this end, we focused on two tissues with strong endogenous BEST1 protein expression—namely, human RPE (8) and mouse sperm (19). Major insight into BEST1 function was gained from (i) RPE cell culture models established via hiPSC technology from a healthy donor and two macular dystrophy patients with established pathologic mutations in BEST1 and (ii) a mouse strain deficient for Best1, the murine ortholog of the human BEST1 gene. When exposed to hypo-osmotic challenge, both the mutant hiPSC-RPE cells and Best1-deficient mouse spermatozoa exhibited severe phenotypes, suggesting BEST1 as a crucial component of VRAC function in these cell types. In addition, membrane rupture experiments and voltage-clamp recordings in oocytes from Xenopus laevis, coexpressing aquaporin-1 (AQP1) and BEST1 from mouse and human, respectively, demonstrated identical functional properties of the mammalian BEST1 orthologs.     

Clique topology reveals intrinsic geometric structure in neural correlations

Detecting meaningful structure in neural activity and connectivity data is challenging in the presence of hidden nonlinearities, where traditional eigenvalue-based methods may be misleading. We introduce a novel approach to matrix analysis, called clique topology, that extracts features of the data invariant under nonlinear monotone transformations. These features can be used to detect both random and geometric structure, and depend only on the relative ordering of matrix entries. We then analyzed the activity of pyramidal neurons in rat hippocampus, recorded while the animal was exploring a 2D environment, and confirmed that our method is able to detect geometric organization using only the intrinsic pattern of neural correlations. Remarkably, we found similar results during nonspatial behaviors such as wheel running and rapid eye movement (REM) sleep. This suggests that the geometric structure of correlations is shaped by the underlying hippocampal circuits and is not merely a consequence of position coding. We propose that clique topology is a powerful new tool for matrix analysis in biological settings, where the relationship of observed quantities to more meaningful variables is often nonlinear and unknown.Neural activity and connectivity data are often presented in the form of a matrix whose entries, C_ij,  indicate the strength of correlation or connectivity between pairs of neurons, cell types, or imaging voxels. Detecting structure in such a matrix is a critical step toward understanding the organization and function of the underlying neural circuits. In this work, we focus on neural activity, whose structure may reflect the coding properties of neurons, rather than their physical locations within the brain. For example, place cells in rodent hippocampus act as position sensors, exhibiting a high firing rate when the animal’s position lies inside the neuron’s “place field,” its preferred region of the spatial environment (1). Without knowledge of the coding properties, however, it is unclear whether such a geometric organization could be detected purely from the pattern of neural correlations. Alternatively, a correlation or connectivity matrix could be truly unstructured, such as the connectivity pattern observed in the fly olfactory system (2), indicating random network organization.Can we distinguish these possibilities, using only the intrinsic features of the matrix C_ij? The most common approach is to use standard tools from matrix analysis that rely on quantities, such as eigenvalues, that are invariant under linear change of basis. This strategy is natural in physics, where meaningful quantities should be preserved by linear coordinate transformations. In contrast, measurements in biological settings are often obtained as nonlinear transformations of the underlying “real” variables, whereas the choice of basis is meaningful and fixed. For example, basis elements might represent particular neurons or genes, and measurements (matrix elements) could consist of pairwise correlations in neural activity, or the coexpression of pairs of genes. Instead of change of basis, the relevant structure in these data should be invariant under matrix transformations of the following form:C_ij = f(A_ij), [1]where f is a nonlinear monotonic function (Fig. 1A). In the case of hippocampal place cells, f captures the manner in which pairwise correlations C_ij decrease with distance between place field centers (3). In less studied contexts, the represented stimuli—and the function f—may be completely unknown.Open in a separate windowFig. 1.Order-based analysis of symmetric matrices. (A) A symmetric matrix A is related to another matrix C via a nonlinear monotonically increasing function f(x), applied entrywise. (B, Left) Distribution of eigenvalues for a random symmetric N × N matrix A,  whose entries were drawn independently from the normal distribution with zero mean and variance 1/N (N = 500). (Right) Distribution of eigenvalues for the transformed matrix with entries C_ij = f(A_ij), for f(x) = 1 ? e^?30x. Red curves show Wigner’s semicircle distribution with matching mean and variance. (C, Top) The order complex of A is represented as a sequence of binary adjacency matrices, indexed by the density ρ of nonzero entries. (Bottom) Graphs corresponding to the adjacency matrices. Minimal examples of a 1-cycle (yellow square), a 2-cycle (red octahedron), and a 3-cycle (blue orthoplex) appear at ρ = 0.1, 0.25,  and 0.45, respectively. (D) At edge density ρ₀, there are no cycles. Cliques of size 3 and 4 are depicted with light and dark gray shading. As the edge density increases, a new 1-cycle (yellow) is created, persists, and is eventually destroyed at densities ρ₁, ρ₂,  and ρ₃, respectively. (E) For a distribution of 1,000 random N × N symmetric matrices (N = 88), average Betti curves β₁(ρ), β₂(ρ),  and β₃(ρ) are shown (yellow, red, and blue dashed curves), together with 95% confidence intervals (shaded areas).Unfortunately, eigenvalues are not invariant under transformations of the form (Eq. 1) (Fig. 1B and SI Appendix, Fig. S1). Although large random matrices have a reliable eigenvalue spectrum [e.g., Wigner’s semicircle law (4)], it is possible that a random matrix with independent and identically distributed (i.i.d.) entries could be mistaken as structured, purely as an artifact of a monotonic nonlinearity (Fig. 1B).^* The results of eigenvalue-based analyses can thus be difficult to interpret, and potentially misleading.Here, we introduce a new tool to reliably detect signatures of structure and randomness that are invariant under nonlinear monotone transformations of the form (Eq. 1). Using pairwise correlations of hippocampal place cells recorded during both spatial and nonspatial behaviors, we demonstrate that our method is capable of detecting geometric structure from neural activity alone. To our knowledge, this is the first example of a method that detects geometric organization intrinsically from neural activity, without appealing to external stimuli or receptive fields.     

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer’s dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.The consensus statement on concussions from the Fourth International Conference on Concussion in Sports (Zurich 2012) (1) defines acute mild traumatic brain injury (mTBI) or cerebral concussion as a brain injury with a complex pathophysiological process induced by biomechanical forces. Cerebral concussion causes white matter axonal injury due to axonal shearing and stretching (2), typically resulting in the rapid onset of short-lived impairment of neurological function that resolves spontaneously and largely reflects a functional disturbance rather than a structural injury. As such, no abnormality is seen on standard structural neuroimaging determinations (1).A number of early literature reports described a neurodegenerative disease associated with a history of repetitive TBI in retired professional boxers (3, 4), with a prevalence rate of up to 47% among retired professional boxers aged 50 y and older who boxed for more than 10 y (5). Initially named “punch drunk syndrome” (3) and dementia pugilistica (4), this syndrome is now known as chronic traumatic encephalopathy (CTE) in the current literature (6, 7).Compelling autopsy evidence (6–8) and neurobehavioral determinations (9) of retired professional American football athletes indicate that a subgroup develops neurodegenerative and clinical changes typical of CTE, a progressive syndrome distinctively different from Alzheimer’s disease (AD), which is the most common form of dementia in the elderly (10). The connection between multiple concussions and subconcussive head impacts (2) and CTE is compelling, because history of repetitive concussions is the strongest risk factor for development of CTE in numerous contact sports (e.g., American football, rugby, boxing, ice hockey, soccer, and professional wrestling), in war veterans with a history of blast or blunt force TBI, and in conditions where trauma to the head occurs for various reasons (e.g., falls during seizures, head-banging in autistic children, motor vehicle and domestic accidents, domestic violence and abuse) (6, 8, 11–14). As with most neurodegenerative diseases, clinical diagnosis remains elusive due to the lack of specificity of CTE clinical symptomatology criteria, and histopathological examination of brain at autopsy is the most definitive diagnostic modality (6, 8, 11).The novel imaging approaches leading to the in vivo characterization of CTE brain neuropathology premortem (e.g., PET) are complementary to structural imaging modalities [e.g., diffusion tensor imaging MRI (DTI MRI)] and offer a specific and sensitive strategy to facilitate diagnosis of CTE. Neuronal and glial fibrillar hyperphosphorylated microtubule-associated protein tau deposits composed of paired helical filament (PHF)-tau are the primary brain proteinopathy of CTE based on autopsy determinations, and their 3R/4R tau isoform ratio is similar to that of AD (11). Their topographically predictable pattern of distribution was used as a basis for a severity staging system of CTE neuropathology (7), ranging from mild (neuropathology stages I and II) to advanced (neuropathology stages III and IV) (7) (Tables S1 and S2). In addition, more than 80% of analyzed pathologically confirmed CTE cases also show transactive response (TAR) DNA-binding protein of ∼43 kDa (TDP-43) either as inclusions in sparse neurites in cortex, medial temporal lobe structures, and brainstem in CTE neuropathology stages I–III, as widespread neuronal and glial inclusions in severe CTE cases (neuropathology stage IV), or in CTE cases with motor neuron disease (7, 15) (Tables S1 and S2). CTE cases also can exhibit the presence of other fibrillar protein aggregates. McKee et al. (7) and Omalu et al. (8) reported that in autopsy determinations, less than half of all CTE cases and less than one third of “pure” CTE cases show amyloid-β (Aβ) deposits, predominantly as scattered cortical diffuse plaques in low density (Tables S1 and S2). Of note is that subjects with Aβ deposits were significantly older than those without. Moreover, their neuropathology was more severe than that in cases without Aβ deposits and was often combined with α-synuclein deposits (7). As an example, as reported by McKee et al. (7), of 30 CTE cases with at least some cortical Aβ deposits (of 68 confirmed CTE cases), 29 brains were from subjects who died in their seventh decade of life and one from a subject who died in his sixth decade.Subsequent to our preliminary report (16), in this work we use [F-18]FDDNP, an imaging agent for fibrillar insoluble protein aggregates (16–20), and PET imaging with the aim of establishing (i) topographic brain localization of [F-18]FDDNP PET signals indicative of fibrillar neuroaggregates in retired professional American football players with suspected CTE (mTBI group) vs. controls (CTRL); (ii) determination of [F-18]FDDNP PET signal patterns in the mTBI group; (iii) presence of [F-18]FDDNP PET signal as a measure of neuropathology in the brain areas involved in mood disorders related neurocircuits; (iv) correlation of [F-18]FDDNP PET results with neuropathology distributions in confirmed CTE cases; (v) differential patterns of [F-18]FDDNP PET signals, and thus deposition of fibrillar neuroaggregates, in the mTBI group with respect to the AD group; and (vi) preliminary demonstration of differences in [F-18]FDDNP PET signal patterns in mTBI cases with different etiology, i.e., contact-sport–related mTBI in retired professional American football players vs. blast-induced mTBI in war veterans. We further intended to demonstrate that tau (vs. Aβ) specificity of high affinity PET molecular imaging probes may not be a necessary requirement when used in CTE subjects with primary proteinopathy in the form of PHF-tau (8): PET imaging probes potentially sensitive to TDP-43 aggregates and Aβ deposits, which are present in higher densities almost exclusively in older CTE cases with more advanced neuropathology (e.g., stage IV), could better define disease progression based on quantification of differences in regional loads of combined neuropathologies because additional neuropathologies appear in predictable topographical and temporal patterns.