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Understanding how diffuse mild traumatic brain injuries can provoke common and persistent post-concussive symptoms (PCS), such as impaired sleep, is crucial to prevent and treat chronic disability and neurodegeneration. We mapped the spatially-resolved single cell landscape of diffuse mTBI pathology in a mouse model of blast exposure; identifying brainstem injuries predictive of later PCS. Repeated mTBI was necessary to establish chronic microglial activation and phagocytosis of myelin in the pontine reticular formation; where IL33 release by oligodendrocytes predicted microgliopathy. In postmortem brainstem tissues from patients with traumatic brain injury, chronic microglial activation and myelin phagocytosis was evident up to 20 years after diffuse mTBI caused by blast. In living patients with chronic blast mTBI, myelin injury in pontine projections mediated sleep disturbance and other PCS, with a dose dependent effect of mTBI number on sleep disturbance severity. These results support a mechanism for diffuse mTBIs to cause delayed persistent PCS.

The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer’s disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease., Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

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.

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome-associated Coronavirus 2 (SARS-CoV-2), has become a global threat to public health. COVID-19 is more pathogenic and infectious than the prior 2002 pandemic caused by SARS-CoV-1. The pathogenesis of certain disease manifestations in COVID-19 such as diffuse alveolar damage (DAD) are thought to be similar to SARS-CoV-1. However, the exact pathogenesis of COVID-19 related deaths remains poorly understood. The aim of this article was to systematically summarize the rapidly emerging literature regarding COVID-19 autopsies. A meta-analysis was also conducted based on data accrued from preprint and published articles on COVID-19 (n=241 patients) and the results compared with postmortem findings associated with SARS-CoV-1 deaths (n=91 patients). Both autopsy groups included mostly adults of median age 70 years with COVID-19 and 50 years with SARS-CoV-1. Overall, prevalence of DAD was more common in SARS-CoV-1 (100.0%) than COVID-19 (80.9%) autopsies (P=0.001). Extrapulmonary findings among both groups were not statistically significant except for hepatic necrosis (P

Context.— This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting. Objective.— To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy. Design.— Comprehensive data from 135 autopsy evaluations of COVID-19–positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses. Results.— Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited. Conclusions.— Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.

Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. Methods In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. Findings The median age of our cohort was 73·5 years (range 42–84; IQR 67·5–77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. Interpretation The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. Funding None.

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.

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.

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.

The broad-range detection and identification of bacterial DNA from clinical specimens are a foundational approach in the practice of molecular microbiology. However, there are circumstances under which conventional testing may yield false-negative or otherwise uninterpretable results, including the presence of multiple bacterial templates or degraded nucleic acids. Here, we describe an alternative, next-generation sequencing approach for the broad range detection of bacterial DNA using broad-range 16S rRNA gene hybrid capture (“16S Capture”). The method is able to deconvolute multiple bacterial species present in a specimen, is compatible with highly fragmented templates, and can be readily implemented when the overwhelming majority of nucleic acids in a specimen derive from the human host. We find that this approach is sensitive to detecting as few as 17 Staphylococcus aureus genomes from a background of 100 ng of human DNA, providing 19- to 189-fold greater sensitivity for identifying bacterial sequences than standard shotgun metagenomic sequencing, and is able to successfully recover organisms from across the eubacterial tree of life. Application of 16S Capture to a proof-of-principle case series demonstrated its ability to identify bacterial species that were consistent with histological evidence of infection, even when diagnosis could not be established using conventional broad range bacterial detection assays. 16S Capture provides a novel means for the efficient and sensitive detection of bacteria embedded in human tissues and for specimens containing highly fragmented template DNA.

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

Case Presentation A 79-year-old man with medical history of atrial fibrillation and esophageal cancer status post trans-hiatal esophageal resection and chemotherapy presented with altered mental status after outpatient esophagogastroduodenoscopy (EGD). One month before presentation, the patient was seen at another hospital with severe anemia and melena requiring transfusion of multiple units of RBCs. No endoscopy was performed during that admission, but his anticoagulation was held. After follow-up with his oncologist, he was referred for outpatient endoscopy. His esophagogastroduodenoscopy demonstrated an intact esophagogastric anastomosis as well as two gastric ulcers with no stigmata of recent bleeding. The patient was discharged to home in good condition with normal mental status. Several hours later, he developed a deteriorating level of consciousness, prompting presentation to the hospital.

BackgroundSARS-CoV-2 is the cause of an ongoing pandemic with a projected 100,000 to 240,000 U.S. deaths. To date, documentation of histopathologic features in fatal cases of COVID-19 has been limited due to small sample size and incomplete organ sampling.MethodsPost-mortem examinations were performed on 12 fatal COVID-19 cases in Washington State during February-March 2020. Clinical and laboratory data were reviewed. Tissue examination of all major organs was performed by light microscopy and electron microscopy. The presence of viral RNA in sampled tissues was tested by RT-PCR.ResultsAll 12 patients were older with significant preexisting comorbidities. The major pulmonary finding was diffuse alveolar damage in the acute and/or organizing phases with virus identified in type I and II pneumocytes by electron microscopy. The kidney demonstrated viral particles in the tubular epithelium, endothelium, and podocytes without significant inflammation. Viral particles were also observed in the trachea and large intestines. SARS-CoV-2 RNA was detected in the cardiac tissue of a patient with lymphocytic myocarditis. RT-PCR also detected viral RNA in the subcarinal lymph nodes, liver, spleen, and large intestines.ConclusionSARS-CoV-2 represents the third novel coronavirus to cause widespread human disease since 2002. Similar to SARS and MERS, the primary pathology was diffuse alveolar damage with virus located in the pneumocytes. However, other major organs including the heart and kidneys may be susceptible to viral replication and damage leading to increased mortality in those with disseminated disease. Understanding the pathology of SARS-CoV-2 will be essential to design effective therapies.

The neocortex is disproportionately expanded in human compared to mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers that selectively make connections within the cortex and other telencephalic structures. Single-cell transcriptomic analyses of human and mouse cortex show an increased diversity of glutamatergic neuron types in supragranular cortex in human and pronounced gradients as a function of cortical depth. To probe the functional and anatomical correlates of this transcriptomic diversity, we describe a robust Patch-seq platform using neurosurgically-resected human tissues. We characterize the morphological and physiological properties of five transcriptomically defined human glutamatergic supragranular neuron types. Three of these types have properties that are specialized compared to the more homogeneous properties of transcriptomically defined homologous mouse neuron types. The two remaining supragranular neuron types, located exclusively in deep layer 3, do not have clear mouse homologues in supragranular cortex but are transcriptionally most similar to deep layer mouse intratelencephalic-projecting neuron types. Furthermore, we reveal the transcriptomic types in deep layer 3 that express high levels of non-phosphorylated heavy chain neurofilament protein that label long-range neurons known to be selectively depleted in Alzheimer’s disease. Together, these results demonstrate the power of transcriptomic cell type classification, provide a mechanistic underpinning for increased complexity of cortical function in human cortical evolution, and implicate discrete transcriptomic cell types as selectively vulnerable in disease.

Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [18F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.

Objective To evaluate the role of paraneoplastic autoantibody testing in the diagnosis of motor neuron disease (MND). Background There have been rare case reports of paraneoplastic MND that have prompted many physicians to test for paraneoplastic autoantibodies in patients with MND. Our study is the first to determine the utility of such testing. Methods Retrospective chart review of patients with MND from a tertiary referral center from 2007 to 2014. Results Of 316 patients with MND reviewed, 44% (n = 138) were evaluated by a Mayo Clinic paraneoplastic autoantibody panel. Of note, 73% of these patients (n = 101) were diagnosed with amyotrophic lateral sclerosis, fulfilling possible, probable, or definite revised El Escorial criteria. Of note, 9% of patients (13/138) of those who had paraneoplastic antibody testing performed were positive for at least 1 paraneoplastic antibody. Three patients had negative testing for malignancy. None had a different disease course than expected. Conclusions Testing for paraneoplastic antibodies does not seem to change the diagnosis, management, or outcome in the setting of MND and is therefore of limited value.

A 42-year-old man with neurofibromatosis type 1 underwent a giant facial neurofibroma resection and enucleation of the right eye. He was found to have a diffusely thickened and cellular choroid containing individual or small clusters of large ganglion and medium-sized neuronal cells. The nomenclature of this lesion is difficult; however, the term choroidal ganglioneuronal hamartoma has been favored due to the lack of proliferative activity and diffuse nature of the lesion arguing against a neoplastic etiology. This case highlights an interesting presentation of neurofibromatosis type I.

As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer’s disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.

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.

Background Tracheal diverticula (TD) are rare anomalies that may harbor infected secretions, posing potential risk to patients with lung disease. In an end-stage cystic fibrosis (CF) cohort, we describe the characteristics and associated post-lung transplant (LTx) outcomes of TD. Methods Pre-transplant computed tomography (CT)'s were reviewed in CF patients undergoing LTx. TD were characterized radiographically and on autopsy when available. Pre-transplant clinical variables and post-transplant outcomes were compared by TD status. Results Of 93 patients, 35 (37.6%) had TD. 58% of TD had fat-stranding, and post-mortem TD examinations revealed histology carrying intense submucosal inflammation, and purulent contents that cultured identical species to sputum. There was no difference in post-LTx survival [HR 1.77 (0.82–3.82), p =0.147], bacterial re-colonization, or rejection in patients with TD compared to those without. Patients with TD were more likely to die from infection, but the result was not statistically significant [HR 2.02 (0.62–6.63), p =0.245]. Conclusions We found a high prevalence of TD in end-stage CF, where diverticula may represent a large-airway bacterial reservoir. TD were not associated with differences in post-LTx outcomes, but given the infectious concerns further investigation is necessary.

Concerns regarding resource expenditures have been expressed about the 2012 NIA-AA Sponsored Guidelines for neuropathologic assessment of Alzheimer disease (AD) and related dementias. Here, we investigated a cost-reducing Condensed Protocol and its effectiveness in maintaining the diagnostic performance of Guidelines in assessing AD, Lewy body disease (LBD), microvascular brain injury, hippocampal sclerosis (HS), and congophilic amyloid angiopathy (CAA). The Condensed Protocol consolidates the same 20 regions into 5 tissue cassettes at ∼75% lower cost. A 28 autopsy brain-retrospective cohort was selected for varying levels of neuropathologic features in the Guidelines (Original Protocol), as well as an 18 consecutive autopsy brain prospective cohort. Three neuropathologists at 2 sites performed blinded evaluations of these cases. Lesion specificity was similar between Original and Condensed Protocols. Sensitivities for AD neuropathologic change, LBD, HS, and CAA were not substantially impacted by the Condensed Protocol, whereas sensitivity for microvascular lesions (MVLs) was decreased. Specificity for CAA was decreased using the Condensed Protocol when compared with the Original Protocol. Our results show that the Condensed Protocol is a viable alternative to the NIA-AA guidelines for AD neuropathologic change, LBD, and HS, but not MVLs or CAA, and may be a practical alternative in some practice settings.

Adult-onset Niemann–Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical (“variant” level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis. Genetic testing revealed two different missense mutations in the NPC1 gene—V950M and N1156S. Symptoms progressed over >20 yr to severe ataxia and spasticity, dementia, and dysphagia with aspiration leading to death. Brain autopsy revealed mild atrophy of the cerebrum and cerebellum. Microscopic examination showed diffuse gray matter deposition of balloon neurons, mild white matter loss, extensive cerebellar Purkinje cell loss with numerous “empty baskets,” and neurofibrillary tangles predominantly in the hippocampal formation and transentorhinal cortex. We performed whole-genome sequencing to examine whether the patient harbored variants outside of the NPC1 locus that could have contributed to his late-onset phenotype. We focused analysis on genetic modifiers in pathways related to lipid metabolism, longevity, and neurodegenerative disease. We identified no rare coding variants in any of the pathways examined nor was the patient enriched for genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) associated with longevity or altered lipid metabolism. In light of these findings, this case provides support for the V950M variant being sufficient for adult-onset NPC disease.

A 26-year-old patient with recurrent choriocarcinoma of the testis presented with headache and progressive left homonymous hemianopsia. On initial MRI a grade 4 arteriovenous malformation (AVM) was identified in the right occipital lobe, which was further characterized by catheter angiography. Continued worsening of the headache in the following days prompted a follow-up MRI, which revealed a new T2 hypointense nodule and adjacent vasogenic edema in the periphery of the AVM. A follow-up MRI showed a marked increase in the size of the nodule with intrinsic enhancement and worsening perilesional edema. Based on the imaging evolution, the nodule was diagnosed as a metastasis and the patient was started on chemotherapy and radiotherapy. One week after the MRI he developed a sudden hemorrhage within the mass requiring decompression craniectomy and resection of both AVM and tumor. The histopathology of the resected mass confirmed the diagnosis of choriocarcinoma metastasis to the AVM.