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Supplementary Figure 4. Activation of HUVECs by serum from patients with neurotoxicity.

Supplementary methods, figure legends, and Supplementary Table 1. Lymphodepletion regimens prior to CAR-T cell infusion; Supplementary Table 2. Neurologic adverse event terms

Purpose:Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short.Experimental Design:Mass spectrometry (MS)–based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables.Results:The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas.Conclusions:RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.

Figure S2, S3, S4, S6, S7, S8, S9 and tables

While a rare ophthalmic pathogen, infections from Exophilia spp. are increasingly identified and have been associated with catastrophic vision loss. In this case report we present a previously undescribed manifestation of the melanin-producing fungus Exophilia Phaeomuriformis to the lower eyelid, establish an effective treatment, and review related cases. Previous cases of ophthalmic E. Phaeomuriformis were confined to the cornea and included iatrogenic tissue trauma. This case shares neither associations however includes a remote SJS history that likely led to changes in conjunctival tissue integrity. Previous cases of Exophilia spp. infecting the eyelid both included surgical source control and adjuvant antibiotic. In this case, topical therapy was deferred due to SJS-related ocular cicatricial disease. Fortunately, a full resolution was achieved with surgical resection and oral antifungal treatment.

This study utilized laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to quantify gadolinium in the hair of autopsy cases that had received gadolinium-based contrast agents (GBCAs) before death. Consecutive autopsy cases were reviewed for GBCA injections and subjects who received a single type of GBCA in the year before death were included. Hair samples were analyzed using LA-ICP-MS as a line scan technique and parameters were optimized to maximize instrument sensitivity, accuracy, and precision. Linear regression analyses between hair measures and gadolinium dose were executed. LA-ICP-MS analysis produced a time-resolved record of GCBA exposure, with the position of the gadolinium peak maxima along the hair shaft providing a good estimate for the day that GBCA injection occurred (R2 = 0.46; p = 0.0022); however, substantial within and between subject variation in the position of the GBCA peak was observed. Average area under the curve for gadolinium peaks in the hair samples was a better predictor of gadolinium dose (R2 = 0.41; p = 0.0046), compared to the average of peak maxima concentration. Correlation between area under the curve and dose suggests that LA-ICP-MS analysis of hair may be an effective method to evaluate gadolinium levels in subjects in vivo after exposure to GBCAs. This study demonstrates that analysis of human hair using techniques with high spatial resolution such as LA-ICP-MS has excellent potential to reveal time-dependent signatures of past exposures.

OBJECTIVES We used laser ablation inductively coupled plasma mass spectrometry to quantify gadolinium in hair samples from autopsy cases with gadolinium-based contrast agent (GBCA) exposure. Hair gadolinium data were correlated with gadolinium concentrations in brain, skin, and bone tissues from the same case to investigate a potential noninvasive method for gadolinium quantification and monitoring. MATERIALS AND METHODS Medical records from autopsy cases at our institution were screened for history of GBCA exposure. Cases with exposure to a single type of GBCA with the most recent injection occurring within 1 year were identified and included in the study. The concentration of gadolinium in hair samples was analyzed by laser ablation inductively coupled plasma mass spectrometry, and brain (globus pallidus, dentate nucleus, white matter), bone, and skin tissues were analyzed by bulk inductively coupled plasma mass spectrometry. The mean of the maximum value in the hair samples was used to generate a representative measurement of the hair gadolinium concentration for each case. A linear regression analysis between each tissue type and hair was conducted to assess for possible correlation. RESULTS Tissue and hair samples from 18 autopsies (16 cases with exposure to GBCA, 2 controls) were included in the study. Comparing the different tissues revealed good correlation between some tissue types. The best model fit occurred between white matter and hair (R = 0.83; P < 0.0001) followed by the comparison between dentate nucleus and hair (R = 0.72; P < 0.0001) and dentate nucleus and skin (R = 0.70; P < 0.0001). CONCLUSIONS A significant correlation in this study between hair gadolinium concentrations and brain and skin gadolinium concentrations suggests that hair may serve as a safe and effective biomonitoring tissue for patients who receive GBCA injections.

Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget’s disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.

Purpose: Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short. Experimental Design: Mass spectrometry (MS)–based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables. Results: The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas. Conclusions: RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.

Objective Autosomal‐dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early‐onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. Results Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild‐type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Aβ 1–40 compared to controls, indicating abnormal γ‐secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age‐matched control brain. Interpretation These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.

Purpose To describe two cases of medium-sized uveal melanoma presenting with hemorrhagic choroidal detachments. Observations The first case is a 39-year-old man who presented with choroidal hemorrhage and angle closure glaucoma. The second case is a 42-year-old man who presented with choroidal hemorrhage and posterior scleritis. Vitrectomy with transvitreous fine needle aspiration biopsy was ultimately required to diagnose malignant uveal melanoma in each case. Conclusions and importance Intraocular hemorrhage is a rare presenting sign of uveal melanoma. When it does occur, it is typically associated with large tumors. Hemorrhagic choroidal detachments are particularly rare in uveal melanoma, and can limit the diagnostic utility of clinical exam, B-scan ultrasonography, and magnetic resonance imaging. Although it is uncommon, it is important to maintain a high index of suspicion for choroidal melanoma in any patient with unexplained choroidal hemorrhage.

Background Linear gadolinium-based contrast agents (GBCAs) are known to be retained at higher levels of gadolinium than macro-cyclic GBCAs. However, very little is known regarding their relative elimination rates and retained fraction of injected gadolinium. Purpose To quantify and compare gadolinium retention and elimination rates in human brain tissue, skin, and bone obtained from cadavers exposed to single-agent administration of either gadoteridol (macrocyclic GBCA) or gadobenate dimeglumine (linear GBCA). Materials and Methods Autopsy cases from August 2014 to July 2019 of patients exposed to a single type of GBCA, either gadoteridol or gadobenate dimeglumine, either single or multiple doses, were included. Gadolinium levels in the brain, skin, and bone were analyzed with inductively coupled plasma mass spectrometry. Linear regression was used to compare gadolinium retention between agents and estimate elimination rates of the retained gadolinium using the time between last injection and death. Results Twenty-eight cadavers with gadoteridol exposure and nine with gadobenate dimeglumine exposure were identified (22 men; age range, 19-83 years). The median gadolinium retention of gadobenate dimeglumine was 3.0-6.5 times higher than that of gadoteridol in the brain (P < .02), 4.4 times higher in bone (P = .002), and 2.9 times higher in skin (P = .05). Gadolinium retention in the globus pallidus (GP), dentate nucleus (DN), white matter (WM), bone, and skin decreased with time elapsed from last administration to death in both the gadobenate dimeglumine (GP: -3% per twofold increase in time, P = .69; DN: -2%, P = .83; WM: -20%, P = .01; bone: -22%, P = .07; skin: -47%, P < .001) and gadoteridol (GP: -17%, P = .11; DN: -16%, P = .15; WM: -30%, P < .001; bone: -11%, P = .16; skin: -24%, P = .01) groups (P values for elimination are compared with a null hypothesis of no elimination). Conclusion The linear agent gadobenate dimeglumine retains several-fold higher levels of gadolinium in the brain and bone compared with the macrocyclic agent gadoteridol. Nonzero elimination of retained gadolinium was detected in the white matter and skin for both agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Background Generally, studies of gadolinium (Gd) deposition in humans measure concentration by analyzing formalin fixed postmortem tissue. However, the effect of formalin fixation on measured Gd concentration has not been well investigated. Purpose To evaluate the effect of fixation by comparing Gd concentration in fresh versus formalin-fixed postmortem human tissues. Material and Methods Fresh samples of bone and skin were collected from autopsy cases with previous exposure to Gd-based contrast agents (GBCAs). The type of GBCA administered, dose, and estimated glomerular filtration rate were recorded. Each tissue sample was cut into three aliquots. Paired samples were stored fresh frozen while the remaining two were stored in 10% neutral buffered formalin for one and three months, respectively. Gd concentration was measured using ICP-MS. Results Of 18 autopsy cases studied, 12 were exposed to only macrocyclic GBCA, one to only linear agents, and five received both macrocyclic and linear agents. On average, Gd concentration for bone decreased 30.7% after one month of fixation ( P = 0.043) compared to non-fixed values. There was minimal, if any, change in concentration between one and three months (average decrease 1.5%; P = 0.89). The findings were numerically similar for skin tissue with an average decrease of 36.9% after one month ( P = 0.11) and 6.0% ( P = 0.73) between one and three months. Conclusion Formalin fixation appears to decrease Gd concentration in bone and skin by approximately 30%–40% on average. The largest decrease occurs within the first 30 days of fixation followed by a considerably smaller decrease at 60 days.

Context.— The coronavirus disease 2019 pandemic, caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2, has resulted in worldwide disruption to the delivery of patient care. The Seattle, Washington metropolitan area was one of the first in the United States affected by the pandemic. As a result, the anatomic pathology services at the University of Washington experienced significant changes in operational volumes early in the pandemic. Objective.— To assess the impact of coronavirus disease 2019 and both state and institutional policies implemented to mitigate viral transmission (including institutional policies on nonurgent procedures) on anatomic pathology volumes. Design.— Accessioned specimens from January to June 2020 were evaluated as coronavirus disease 2019 and institutional policies changed. The data were considered in these contexts: subspecialty, billable Current Procedural Terminology codes, and intraoperative consultation. Comparable data were retrieved from 2019 as a historical control. Results.— There was a significant reduction in overall accessioned volume (up to 79%) from prepandemic levels during bans on nonurgent procedures when compared with 2020 pre–coronavirus disease 2019 volumes and historical controls. The gastrointestinal and dermatopathology services were most impacted, and breast and combined head and neck/pulmonary services were least impacted. Current Procedural Terminology code 88305, for smaller/biopsy specimens, had a 63% reduction during nonurgent procedure bans. After all bans on procedures were lifted, the overall volume plateaued at 89% of prepandemic levels. Conclusions.— A significant decrease in specimen volume was most strongly associated with bans on nonurgent procedures. Although all departmental areas had a decrease in volume, the extent of change varied across subspecialty and specimen types. Even with removal of all bans, service volume did not reach prepandemic levels.

This study utilized laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to quantify gadolinium in the hair of autopsy cases that had received gadolinium-based contrast agents (GBCAs) before death. Consecutive autopsy cases were reviewed for GBCA injections and subjects who received a single type of GBCA in the year before death were included. Hair samples were analyzed using LA-ICP-MS as a line scan technique and parameters were optimized to maximize instrument sensitivity, accuracy, and precision. Linear regression analyses between hair measures and gadolinium dose were executed. LA-ICP-MS analysis produced a time-resolved record of GCBA exposure, with the position of the gadolinium peak maxima along the hair shaft providing a good estimate for the day that GBCA injection occurred (R

Context.—The coronavirus disease 19 (COVID-19) pandemic is placing unparalleled burdens on regional and institutional resources in medical facilities across the globe. This disruption is causing unprecedented downstream effects to traditionally established channels of patient care delivery, including those of essential anatomic pathology services. With Washington state being the initial North American COVID-19 epicenter, the University of Washington in Seattle has been at the forefront of conceptualizing and implementing innovative solutions in order to provide uninterrupted quality patient care amidst this growing crisis.Objective.—To conduct a rapid validation study assessing our ability to reliably provide diagnostic neuropathology services via a whole slide imaging (WSI) platform as part of our departmental COVID-19 planning response.Design.—This retrospective study assessed diagnostic concordance of neuropathologic diagnoses rendered via WSI as compared to those originally established via traditional histopathology in a cohort of 30 cases encompassing a broad range of neurosurgical and neuromuscular entities. This study included the digitalization of 93 slide preparations, which were independently examined by groups of board-certified neuropathologists and neuropathology fellows.Results.—There were no major or minor diagnostic discrepancies identified in either the attending neuropathologist or neuropathology trainee groups for either the neurosurgical or neuromuscular case cohorts.Conclusions.—Our study demonstrates that accuracy of neuropathologic diagnoses and interpretation of ancillary preparations via WSI are not inferior to those generated via traditional microscopy. This study provides a framework for rapid subspecialty validation and deployment of WSI for diagnostic purposes during a pandemic event.

BackgroundSex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences.MethodsCombining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients. Pretreatment MR images of 494 glioblastoma patients (299 males and 195 females) were segmented to quantify tumor volumes. Cox proportional hazard (CPH) models and Student’s t-tests were used to assess which variables were associated with survival outcomes.ResultsAmong males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, pConclusionDespite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes, which emphasizes the importance of considering sex as a biological factor when determining patient prognosis and treatment approach.

A 90-year-old woman presented with 1-year history of right-sided progressive proptosis, neovascular glaucoma, blindness, and worsening ocular pain. No funduscopic examination was possible because of a corneal opacity. Head CT scan without contrast demonstrated a heterogeneous 4.1 cm (anterior-posterior) by 1.7 cm (transverse) cylindrical mass arising in the right optic nerve and extending from the retrobulbar globe to the optic canal. She underwent palliative enucleation with subtotal resection of the orbital optic nerve and tumor. Pathological examination showed effacement of the optic nerve by an infiltrative high-grade glial neoplasm with biphasic sarcomeric differentiation. Invasion into the uvea and retina was present. The neoplasm was negative for melan-A, HMB45, tyrosinase, synaptophysin, smooth muscle actin, and epithelial membrane antigen. The glioma had strongly intense, but patchy immunopositivity for glial fibrillary acidic protein. Multiple foci of neoplastic cells had pericellular reticulin staining. The overall features were diagnostic of a gliosarcoma (World Health Organization grade IV) of the optic nerve. Postoperative MRI demonstrated postsurgical changes and residual gliosarcoma with extension into the optic chiasm. The patient died 2 and a half months after her enucleation surgery at her nursing home. Autopsy was unavailable due to the caregiver wishes, making a definitive cause of death unknown. Gliosarcoma is a rare variant of glioblastoma, and this is the first documented case presenting as a primary neoplasm of the optic nerve.

Head and neck paragangliomas are rare neuroendocrine tumors that arise from paraganglion cells of the parasympathetic nervous system. Paragangliomas arising from the midline skull base have only rarely been reported. Surgery is the mainstay of treatment and adjuvant radiation is often recommended. These tumors can rarely secrete metanephrines and normetanephrines which can complicate operative management. Here we present two cases of clival paragangliomas with unique clinical presentations and review the previous literature on skull base paragangliomas.

Intraoperative consultations, used to guide tumor resection, can present histopathological findings that are challenging to interpret due to artefacts from tissue cryosectioning and conventional staining. Stimulated Raman histology (SRH), a label-free imaging technique for unprocessed biospecimens, has demonstrated promise in a limited subset of tumors. Here, we target unexplored skull base tumors using a fast simultaneous two-channel stimulated Raman scattering (SRS) imaging technique and a new pseudo-hematoxylin and eosin (H&E) recoloring methodology. To quantitatively evaluate the efficacy of our approach, we use modularized assessment of diagnostic accuracy beyond cancer/non-cancer determination and neuropathologist confidence for SRH images contrasted to H&E-stained frozen and formalin-fixed paraffin-embedded (FFPE) tissue sections. Our results reveal that SRH is effective for establishing a diagnosis using fresh tissue in most cases with 87% accuracy relative to H&E-stained FFPE sections. Further analysis of discrepant case interpretation suggests that pseudo-H&E recoloring underutilizes the rich chemical information offered by SRS imaging, and an improved diagnosis can be achieved if full SRS information is used. In summary, our findings show that pseudo-H&E recolored SRS images in combination with lipid and protein chemical information can maximize the use of SRS during intraoperative pathologic consultation with implications for tissue preservation and augmented diagnostic utility.

Although glioblastoma is a fatal primary brain cancer with a short median survival of 15 months, a small number of patients survive more than 5 years after diagnosis; they are known as extreme survivors (ES). Due to their rarity, very little is known about what differentiates these outliers from other glioblastoma patients. For the purpose of identifying unknown drivers of extreme survivorship in glioblastoma, we developed the ENDURES consortium (ENvironmental Dynamics Underlying Responsive Extreme Survivors of glioblastoma). This consortium is a multicenter collaborative network of investigators focused on the integration of multiple types of clinical data and the creation of patient-specific models of tumor growth informed by radiographic and histological parameters. Leveraging our combined resources, the goals of the ENDURES consortium are two-fold: (1) to build a curated, searchable, multilayered repository housing clinical and outcome data on a large cohort of ES patients with glioblastoma and (2) to leverage the ENDURES repository for new insights on tumor behavior and novel targets for prolonging survival for all glioblastoma patients. In this article, we review the available literature and discuss what is already known about ES. We then describe the creation of our consortium and some of our preliminary results.FundingThis review was financially supported by a grant from the James S. McDonnell FoundationConflicts of InterestThe authors have declared that no conflicts of interest exist.AuthorshipConceptualized consortium: LW, RG, KME, PC, and KRS. Built consortium: SKJ, PK, NR, JS, KME, PC, and KRS. Wrote the manuscript: SKJ, PW, SCM, PK, AP, and KME. Reviewed and edited the manuscript: LFGC, MMM, AHD, PRJ, and LSH. Contributed to writing, provided feedback, and approved of final manuscript: All authors.Link to website for ENDUREShttp://mathematicalneurooncology.org/?page_id=2125

Background Adenylate cyclase 5 (ADCY5)-related dyskinesia is a childhood-onset movement disorder. Manifestations vary in frequency and severity and may include chorea, tremor, dystonia, facial twitches, myoclonus, axial hypotonia, and limb hypertonia. Psychosis is likely part of the broader spectrum. ADCY5 is widely expressed in the brain, especially in the striatum. Previous reports of brain autopsies of 2 subjects with likely ADCY5-dyskinesia were limited by the absence of a molecular diagnosis. In 1 case, normal gross pathology was reported. In the other case, ADCY5 expression was not examined and neuropathological findings were confounded by age and comorbidities. Objectives To examine ADCY5 expression and neuropathological changes in ADCY5-dyskinesia. Methods An extensive brain autopsy, including immunohistochemical analyses with antibodies to paired helical filament tau, α-synuclein, amyloid-β, microtubule-associated protein 2, and ADCY5, was performed. Results The patient, with a p.M1029K ADCY5 variant, had severe dyskinesias from early childhood, later recurrent episodes of psychosis, and died at age 46. Gross pathology was unremarkable, but we detected increased immunoreactivity for ADCY5 in neurons in multiple brain regions. Despite no history of brain trauma to suggest chronic traumatic encephalopathy, we found tau deposits in the deep cortical sulci, midbrain, and hippocampus with minimal amyloid pathology and no Lewy bodies. Conclusions We present the first brain autopsy findings in a molecularly proven case of ADCY5-dyskinesia, showing increased ADCY5 immunoreactivity in neurons and evidence of tau deposition. Additional patients will need to be studied to determine whether increased immunoreactivity for ADCY5 is a signature for ADCY5-dyskinesia and whether this disease has a tauopathy component.

Glioblastomas are aggressive primary brain tumors known for their inter- and intratumor heterogeneity. This disease is uniformly fatal, with intratumor heterogeneity the major reason for treatment failure and recurrence. Just like the nature vs nurture debate, heterogeneity can arise from intrinsic or environmental influences. Whilst it is impossible to clinically separate observed behavior of cells from their environmental context, using a mathematical framework combined with multiscale data gives us insight into the relative roles of variation from different sources. To better understand the implications of intratumor heterogeneity on therapeutic outcomes, we created a hybrid agent-based mathematical model that captures both the overall tumor kinetics and the individual cellular behavior. We track single cells as agents, cell density on a coarser scale, and growth factor diffusion and dynamics on a finer scale over time and space. Our model parameters were fit utilizing serial MRI imaging and cell tracking data from ex vivo tissue slices acquired from a growth-factor driven glioblastoma murine model. When fitting our model to serial imaging only, there was a spectrum of equally-good parameter fits corresponding to a wide range of phenotypic behaviors. When fitting our model using imaging and cell scale data, we determined that environmental heterogeneity alone is insufficient to match the single cell data, and intrinsic heterogeneity is required to fully capture the migration behavior. The wide spectrum of in silico tumors also had a wide variety of responses to an application of an anti-proliferative treatment. Recurrent tumors were generally less proliferative than pre-treatment tumors as measured via the model simulations and validated from human GBM patient histology. Further, we found that all tumors continued to grow with an anti-migratory treatment alone, but the anti-proliferative/anti-migratory combination generally showed improvement over an anti-proliferative treatment alone. Together our results emphasize the need to better understand the underlying phenotypes and tumor heterogeneity present in a tumor when designing therapeutic regimens., Author summary Glioblastoma, the most common primary brain tumor, is an aggressive and difficult to treat cancer. A key reason is that the tumors can be very heterogeneous, consisting of many different mutants driving distinct cell behaviors. We believe that treatments for this disease could be significantly improved by understanding and quantifying the functional impact of heterogeneity within the tumor. From a clinical standpoint, the larger tissue-scale dynamics, like growth rate, can be informed from serial MRI imaging, while the cell-scale heterogeneity, can be informed by analysis of biopsies. In this work, we combined information from both scales using a mathematical framework and multiscale data from an animal model of glioblastoma. We found that a wide range of potential tumor compositions matched imaging data alone, as a result the model predicts a wide variety of responses to treatment. Using both imaging and cell-scale data narrowed the range of possible tumor compositions and better predicted responses to treatment. The mathematical model also predicted that while targeting migration alone did not slow tumor growth (in fact it drove a more proliferative tumor), an anti-proliferative/anti-migratory treatment combination improved treatment response.

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher’s exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors.

Until recognition of the association of nephrogenic systemic fibrosis (NSF) and gadolinium based contrast agents (GBCA) in 2006, these agents were considered extremely safe and without major adverse effects. Even after the recognition of NSF, most physicians considered all GBCAs to be safe when used in patients with normal renal function. This belief has been called into question with the discovery by Kanda in 2014 that gadolinium (Gd) is deposited in brain tissue in patients with normal kidney function. Since that initial report, there have been a number of important studies analyzing the effects of various GBCAs in brain using MR T1 signal intensity measurements and postmortem tissue analyses with inductively coupled plasma mass spectrometry. From these our knowledge and understanding of some key issues surrounding these observations has rapidly evolved. This report reviews and summarizes many recent human and animal studies in combination with past studies to better understand Gd tissue deposition not only in brain but also in bone and skin. Brain tissue deposition was initially demonstrated to occur with less stable group 1 linear agents but recent postmortem studies now confirm that Gd deposition also occurs with more stable linear agents as well as with macrocyclic agents although at much lower levels. Although no adverse health effects have been documented to date, even for the group 1 agents that deposit Gd in higher amounts, the implications for possible unrecognized toxicity is discussed. Future studies are being pursued that may provide better understanding of the various chemical forms of Gd that are deposited in tissues. This may help elucidate relative risks of different types of agents, mechanisms involved and even recognition of potential downstream toxic effects.

The purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non-Group 1 agents, either macrocyclic or linear protein interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease.This study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedent's tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non-Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test.Of the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus).Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.

Purpose Despite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype—growth before treatment and during each treatment to recurrence —has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK. Patients and Methods From our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment. Results There was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%). Conclusion Dichotomizing the heterogeneity of GBMs into two populations—one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival—suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.

Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue. Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell–mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell–mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan–T cell encephalitis. Significance: We provide the first immunologically relevant, nonhuman primate model of B cell–directed CAR T-cell therapy–mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750–63. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663

Background Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington's disease (JHD), defined as HD arising before age 20, accounts for 5-10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington's disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline. Objective The neuropathologic changes of AOHD are well characterized, but there are fewer reports that describe the neuropathology of JHD. Here we report a case of a six-year-old boy with paternally-inherited JHD caused by 169 CAG trinucleotide repeats who presented at age four with developmental delay, dysarthria, and seizures before dying at age 6. The boy's clinical presentation and neuropathological findings are directly compared to those of his father, who presented with AOHD and 54 repeats. Methods A full autopsy was performed for the JHD case and a brain-only autopsy was performed for the AOHD case. Histochemically- and immunohistochemically-stained slides were prepared from formalin-fixed, paraffin-embedded tissue sections. Results Both cases had neuropathology corresponding to Vonsattel grade 3. The boy also had cerebellar atrophy with huntingtin-positive inclusions in the cerebellum, findings not present in the father. Conclusions Autopsies of father and son provide a unique opportunity to compare and contrast the neuropathologic findings of juvenile and adult onset HD while also providing the first immunohistochemical evidence of cerebellar involvement in JHD. Additionally this is the first known report to include findings from peripheral tissue in a case of JHD.

Neutral lipid storage disease with myopathy is a rare disorder of lipid metabolism caused by variants in the Patatin-Like Phospholipase Domain Containing 2 (PNPLA2) gene. Diagnosis is often delayed due to variable presentations, which is of concern due to increased risk of cardiomyopathy. Better phenotype–genotype characterization is necessary to improve speed and accuracy of diagnosis. Here, we describe a 32-year-old woman of Hmong descent with progressive muscle pain and weakness who had a muscle biopsy with characteristic features of a lipid storage myopathy. Genetic testing revealed a homozygous splice site variant in PNPLA2, c.757 + 1G > T. This case, in combination with the one previously reported case of this PNPLA2 variant, also in a family of Hmong descent, suggests this particular variant may be unique to the Hmong population, a Southeast Asian minority group living in the United States, who immigrated to the United States as refugees after the Vietnam War.

Aims In response to concerns regarding resource expenditures required to implement fully the 2012 National Institute on Aging and the Alzheimer's Association (NIA-AA) Sponsored Guidelines for the neuropathological assessment of Alzheimer's disease (AD), we previously developed a sensitive and cost-reducing condensed protocol (CP) at the University of Washington (UW) Alzheimer's Disease Research Center (ADRC) that consolidated the recommended NIA-AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA-AA protocols, but instead to make the NIA-AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA-AA guidelines. Methods and results In this regard, we developed practical criteria to instigate CP sampling and immunostaining, and applied these criteria in an academic clinical neuropathological practice. During the course of 1 year, 73 cases were sampled using the CP; of those, 53 (72.6%) contained histological features that prompted CP work-up. We found that the CP resulted in increased identification of AD and Lewy body disease neuropathological changes from what was expected using a clinical history-driven work-up alone, while saving approximately $900 per case. Conclusions This study demonstrates the feasibility and cost-savings of the CP applied to a clinical autopsy practice, and highlights potentially unrecognised neurodegenerative disease processes in the general ageing community.

There is a need to better understand meningioma oncogenesis for biomarker discovery and development of targeted therapies. Histological or genetic criteria do not accurately predict aggressiveness. Post-translational studies in meningioma progression are lacking. In the present work, we introduce a combination of mass spectrometry-based phosphoproteomics and peptide array kinomics to profile atypical and anaplastic (high-grade) meningiomas. In the discovery set of fresh-frozen tissue specimens (14), the A-kinase anchor protein 12 (AKAP12) protein was found downregulated across the grades. AKAP12 knockdown in benign meningioma cells SF4433 increases proliferation, cell cycle, migration, invasion, and confers an anaplastic profile. Differentially regulated pathways were characteristic of high-grade meningiomas. Low AKAP12 expression in a larger cohort of patients (75) characterized tumor invasiveness, recurrence, and progression, indicating its potential as a prognostic biomarker. These results demonstrate AKAP12 as a central regulator of meningioma aggressiveness with a possible role in progression.

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity. Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404–19. ©2017 AACR. See related commentary by Mackall and Miklos, p. 1371. This article is highlighted in the In This Issue feature, p. 1355

Manganese (Mn) is a common neurotoxicant associated with a clinical syndrome that includes signs and symptoms referable to the basal ganglia. Despite many advances in understanding the pathophysiology of Mn neurotoxicity in humans, with molecular and structural imaging techniques, only a few case reports describe the associated pathological findings, and all are in symptomatic subjects exposed to relatively high-level Mn. We performed an exploratory, neurohistopathological study to investigate the changes in the corpus striatum (caudate nucleus, putamen, and globus pallidus) associated with chronic low-level Mn exposure in South African Mn mine workers. Immunohistochemical techniques were used to quantify cell density of neuronal and glial components of the corpus striatum in eight South African Mn mine workers without clinical evidence of a movement disorder and eight age-race-gender matched, non-Mn mine workers. There was higher mean microglia density in Mn mine workers than non-Mn mine workers in the globus pallidus external and internal segments [GPe: 1.33 and 0.87 cells per HPF, respectively (p=0.064); GPi: 1.37 and 0.99 cells per HPF, respectively (p=0.250)]. The number of years worked in the Mn mines was significantly correlated with microglial density in the GPi (Spearman's rho 0.886; p=0.019). The ratio of astrocytes to microglia in each brain region was lower in the Mn mine workers than the non-Mn mine workers in the caudate (7.80 and 14.68; p=0.025), putamen (7.35 and 11.11; p=0.117), GPe (10.60 and 16.10; p=0.091) and GPi (9.56 and 12.42; p=0.376). Future studies incorporating more detailed occupational exposures in a larger sample of Mn mine workers will be needed to demonstrate an etiologic relationship between Mn exposure and these pathological findings.

Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT(hi)). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.We enrolled 7 newly diagnosed glioblastoma patients with MGMT(hi) tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5-57+) months and OS of 20 (range 13-57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG.These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.Clinicaltrials.gov NCT00669669.R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.

BACKGROUNDThe current gold standard for diagnostic classification of many solid-tissue neoplasms is immunohistochemistry (IHC) performed on formalin-fixed, paraffin-embedded (FFPE) tissue. Although IHC is commonly used, there remain important issues related to preanalytic variability, nonstandard methods, and operator bias that may contribute to clinically significant error. To increase the quantitative accuracy and reliability of FFPE tissue–based diagnosis, we sought to develop a clinical proteomic method to characterize protein expression in pathologic tissue samples rapidly and quantitatively.METHODSWe subclassified FFPE tissue from 136 clinical pituitary adenoma samples according to hormone translation with IHC and then extracted tissue proteins and quantified pituitary hormones with multiplex bead-based immunoassays. Hormone concentrations were normalized and compared across diagnostic groups. We developed a quantitative classification scheme for pituitary adenomas on archived samples and validated it on prospectively collected clinical samples.RESULTSThe most abundant relative hormone concentrations differentiated sensitively and specifically between IHC-classified hormone-expressing adenoma types, correctly predicting IHC-positive diagnoses in 85% of cases overall, with discrepancies found only in cases of clinically nonfunctioning adenomas. Several adenomas with clinically relevant hormone-expressing phenotypes were identified with this assay yet called “null” by IHC, suggesting that multiplex immunoassays may be more sensitive than IHC for detecting clinically meaningful protein expression.CONCLUSIONSMultiplex immunoassays performed on FFPE tissue extracts can provide diagnostically relevant information and may exceed the performance of IHC in classifying some pituitary neoplasms. This technique is simple, largely amenable to automation, and likely applicable to other diagnostic problems in molecular pathology.

Phosphorylation of tau protein is a critical event in the pathogenesis of Alzheimer disease (AD). Increased phosphorylated tau and total tau levels, combined with reduced concentrations of amyloid beta 1–42 (Aβ42) in cerebrospinal fluid (CSF), but not in plasma or serum, have been generally accepted as sensitive AD diagnostic markers. However, obtaining CSF is a relatively invasive procedure that requires participation of specially trained medical professionals, i.e., CSF is not an ideal sample source for screening or early diagnosis of AD, which is essential to current and future neuroprotective treatments for the disease. Here, we identified tau, but not Aβ species, with mass spectrometry in human saliva, a body fluid that is much more accessible compared to CSF or even blood. Quantitative assessment of salivary levels of total tau, phosphorylated tau, and Aβ42 using highly sensitive Luminex assays revealed that, while Aβ42 was not detectable, the phosphorylated tau/tau ratio significantly increased in patients with AD compared to healthy controls. These results suggest that salivary tau species could be ideal biomarkers for AD diagnosis, especially at early stages of the disease or even screening asymptomatic subjects, allowing for a much larger therapeutic window for AD patients.

Quantifying antigens in formalin-fixed tissue is challenging and limits investigation in population-based studies of brain aging. To address this major limitation, we have developed a new technique that we call "Histelide": immunohistochemistry (HIST-) and enzyme-linked immunosorbent assay (ELISA) (-EL-) performed on a glass slide (-IDE). We validated Histelide in sections of prefrontal cortex from 20 selected cases: 12 subjects with clinically and neuropathologically diagnosed Alzheimer's disease (AD), either autosomal dominant or late-onset forms, and 8 clinical and neuropathologic controls. AD cases had significantly increased amyloid beta (Aβ) peptide and paired helical filament- (PHF-) tau per area of neocortex that was proteinase K-sensitive, and significantly decreased amount of synaptophysin. We next investigated prefrontal cortex from 81 consecutive cases of high-cognitive performers from the Adult Changes in Thought (ACT) study, a population-based study of brain aging and incident dementia. As expected, latent AD was common in this group; however, our results quantified widely individually varying levels of Aβ peptides and PHF-tau among these high-cognitive performers. This novel approach obtains quantitative data from population-based studies, and our initial studies with high-cognitive performers provide important quantitative insights into latent AD that should help guide expectations from neuroimaging and prevention studies.

Glioblastoma (GBM) is an aggressive primary brain cancer that has a median overall survival (OS) of 15 months from diagnosis. Determining which pretreatment tumor characteristics are predictive of extreme survival (EXS) (OS > 1825 days) and short-term survival (STS) (OS < 210 days) has significant clinical value. Several biological markers have been discovered that are predictive of EXS or STS, but the impact of patient sex on the predictive value of these markers has been minimally explored. In this investigation, machine learning algorithms and statistical tests were used to assess which pretreatment clinical and MR image-based volumetric and kinetic parameters were significant predictors of overall survival duration for male (n=299, including 30 EXS and 46 STS) and female (n=195, including 17 EXS and 42 STS) GBM patients. When compared to the middle survivor group (210 days < OS < 1825 days), female EXS had smaller tumor volumes and both male and female EXS had lower tumor cell proliferation rates at time of diagnosis. Independent predictors of overall survival included tumor cell diffuse invasion rate among females (hazard ratio [HR] =1.011, p < 0.001), tumor size among males (HR=1.027, p=0.044) and age among both males and females (Females: HR=1.021, p=0.006; Males: HR=1.030, p < 0.001). Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes, which emphasizes the importance of considering sex as a biological factor when determining patient prognosis and treatment approach.

Cerebrotendinous xanthomatosis (CTX) also known as van Bogaert–Scherer–Epstein syndrome, Thiebaut’s syndrome and cerebrotendinous cholesterosis, is an autosomal-recessive lipid-storage disease characterized by the triad of juvenile cataracts, tendon xanthomas and progressive neurodegeneration. Excess cholesterol and cholestanol are deposited in multiple organs, including the cerebrum, cerebellum, lens and tendons. Approximately 300 cases are reported worldwide, but it is suspected that the incidence of CTX is underestimated. The disease is attributed to approximately 50 mutations in the CYP27A1 gene coding for the enzyme sterol 27-hydoxylase, which is responsible for initial oxidation of the side chain of the cholesterol molecule in bile acid biosynthesis. CTX has varied clinical presentations, but no genotype–phenotype relationship has been documented. In some intrafamilial cases, clinical presentations may vary considerably. MRI for CTX is sensitive for diagnosis and classically demonstrates cerebral and cerebellar atrophy and xanthomatous lesions preferentially affecting the dentate nuclei. Patients have high serum levels of cholestanol with normal total cholesterol and increased urinary excretion of bile acids. Treatment of patients with chenodeoxycholic acid, particularly when used along with HMG-CoA reductase inhibitors (statins) or low-density lipoprotein apheresis, can normalize cholestanol levels as well as prevent further degeneration. Therefore, the need for early diagnosis is well documented in the literature, as it prevents the significant morbidity and mortality associated with this disease.

Plasmablastic lymphoma of the oral cavity is a form of non-Hodgkin lymphoma (NHL) and was first described in 1997. We describe a case of plasmablastic lymphoma in an HIV-infected patient who presented with an expanding oral lesion and symptoms of a toothache. We review all cases of plasmablastic lymphoma that have been reported in the literature. Plasmablastic lymphoma is strongly associated with immunodeficiency, and most particularly, with HIV infection. The pathophysiological origin of plasmablastic lymphoma has not been fully characterised, but the presence of Epstein-Barr virus (EBV) has often been documented in biopsy specimens, supporting a role for EBV in the pathogenesis of this lymphoma. The differential diagnosis for an expanding oral lesion includes both infectious and malignant processes. Biopsy is essential for making a correct and prompt diagnosis. Treatment usually involves chemotherapy, but antiretroviral therapy may also have an important role. Infectious disease clinicians should be aware of this newly described and increasingly encountered lymphoma, since it is prominently associated with immunosuppression and may be mistaken for other entities.

Background Bilateral internal carotid artery agenesis (ICAA) is a rare developmental anomaly of unknown etiology that is often associated with disruption of adequate perfusion to the central nervous system. Nevertheless, some patients remain asymptomatic due to collateral circulation involving the communicating arteries of the Circle of Willis. Secondary to the hemodynamical stress through the collateral circulation, affected patients are at an increased risk of developing subarachnoid hemorrhage and intracranial aneurysms. Methods and results We report an unusual case of a 62-year-old man with bilateral ICAA who expired following two asystolic events during minor surgery. Conclusion This case emphasizes the plasticity of the cerebral collateral circulation during development, to the point of normal cerebral perfusion throughout life with no ischemic complications.