Autopsy Cardiac Troponin I Plasma Levels Can Be Elevated in Myocardial Infarction Type 3: A Proposal to Modify the Definition of Myocardial Infarction Type 3.

AIMS: The definition of myocardial infarction (MI) type 3 does not include the possible elevation of postmortem biomarkers if measured at autopsy. We determined postmortem cardiac troponin I (cTnI) levels in plasma samples obtained at autopsy in patients who died from MI type 3 to determine whether cTnI plasma levels may be elevated. METHODS AND RESULTS: Using a chemiluminescent microparticle immunoassay system, we determined postmortem cTnI plasma levels at autopsy performed within 24 hours of death in every decedent who died from MI type 3, confirmed by an autopsy. Over 2 years, autopsy confirmed 52 decedents who died from MI type 3 due to coronary atherosclerotic disease. The age range and mean age were 40 to 78 and 60.6 years, respectively, 38 (73%) men and 14 (27%) women. Ten percent of the decedents exhibited postmortem cTnI plasma levels that were within the normal reference levels (0.01-0.30 ng/mL). Ninety percent of the decedents exhibited elevated cTnI plasma levels at autopsy, which ranged from 0.31 to greater than 4400 ng/mL. Sixty-nine percent of our decedents showed severe/significant (75%-100%) luminal occlusion in 2 or 3 major coronary arteries. CONCLUSIONS: If cTnI plasma levels are measured in autopsy blood samples after sudden and unexpected death due to MI type 3, highly elevated cTnI plasma levels may be detected. We propose that the current MI type 3 definition be slightly modified to include the possible elevation of cTnI plasma levels if measured at autopsy in the immediate postmortem period.

Forensic Neuropathologic Phenotypes of Fungal Central Nervous System Infections: A Case Series.

ABSTRACT: Fungal infections of the central nervous system (FI-CNS) are life-threatening infections that most commonly affect immunocompromised individuals, but immunocompetent individuals may also be infected. Although FI-CNS are relatively rare, the prevalence of FI-CNS is on the rise because of the increasing number of transplant recipients, human immunodeficiency virus-infected individuals, and use of immunosuppressive therapies. Most cases of FI-CNS originate from outside the central nervous system. The etiologic fungi can be classified into 3 fungal groups: molds, dimorphic fungi, and yeasts. The clinical presentation of FI-CNS is highly variable and may be difficult to diagnose premortem. We present a case series of 3 patients, each infected by 1 representative species from each of the 3 fungal groups (Aspergillus species, Blastomyces species, Candida species) to illustrate different neuropathologic phenotypes of FI-CNS. All 3 patients had no history of immunodeficiency and were not suspected to have FI-CNS until they were diagnosed at autopsy. Fungal infections of the central nervous system are often fatal due to delayed diagnosis and diagnostic testing. Awareness of such poly-phenotypic manifestations of FI-CNS will be helpful in reducing delayed diagnosis. It is important for clinicians to include FI-CNS on the differential diagnosis when radiographic findings are nonspecific.

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

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-ß] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

Progressive Focal Gray Matter Volume Loss in a Former High School Football Player: A Possible Magnetic Resonance Imaging Volumetric Signature for Chronic Traumatic Encephalopathy.

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.

PET scanning of brain tau in retired national football league players: preliminary findings.

OBJECTIVE: Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP). METHODS: Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index. RESULTS: FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma. CONCLUSIONS: The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.

Accuracy and validity of determined cause of death and manner of death following forensic autopsy prosection.

AIMS: The purpose of this study is to evaluate the accuracy and validity of the determination of cause of death (COD) and manner of death (MOD) at the completion of the forensic autopsy prosection. METHODS: We analysed 952 autopsy cases conducted from 2019 to 2020 and compared every patient's COD, other significant contributing factors to death (OSC), and MOD after prosection to their COD, OSC and MOD after completion of the final autopsy report. RESULTS: We found that 83% of cases (790 patients) did not have an unexpected change and 17% of cases (162 patients) exhibited a true change in their final diagnosis; the relationship between age and changes in COD and MOD was significant. CONCLUSIONS: Our findings indicate that in the majority of forensic autopsy cases, medical professionals can reasonably complete death certification after the autopsy prosection. In addition to improving the accuracy of COD and MOD, advances in this field will enhance timely decedent affairs management, timely investigations of crimes and timely closure to families who have lost loved ones. We recommend implementing combined interventional education and consultation with expert pathologists, and a well-followed structured method of death classification as the best course of practice.

Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide.

Following his discovery of chronic traumatic encephalopathy (CTE) in football players in 2002, Dr. Bennet Omalu hypothesized that posttraumatic stress disorder (PTSD) in military veterans may belong to the CTE spectrum of diseases. The CTE surveillance at the Brain Injury Research Institute was therefore expanded to include deceased military veterans diagnosed with PTSD. The authors report the case of a 27-year-old United States Marine Corps (USMC) Iraqi war veteran, an amphibious assault vehicle crewman, who committed suicide by hanging after two deployments to Fallujah and Ramadi. He experienced combat and was exposed to mortar blasts and improvised explosive device blasts less than 50 m away. Following his second deployment he developed a progressive history of cognitive impairment, impaired memory, behavioral and mood disorders, and alcohol abuse. Neuropsychiatric assessment revealed a diagnosis of PTSD with hyperarousal (irritability and insomnia) and numbing. He committed suicide approximately 8 months after his honorable discharge from the USMC. His brain at autopsy appeared grossly unremarkable except for congestive brain swelling. There was no atrophy or remote focal traumatic brain injury such as contusional necrosis or hemorrhage. Histochemical and immunohistochemical brain tissue analysis revealed CTE changes comprising multifocal, neocortical, and subcortical neurofibrillary tangles and neuritic threads (ranging from none, to sparse, to frequent) with the skip phenomenon, accentuated in the depths of sulci and in the frontal cortex. The subcortical white matter showed mild rarefaction, sparse perivascular and neuropil infiltration by histiocytes, and mild fibrillary astrogliosis. Apolipoprotein E genotype was 3/4. The authors report this case as a sentinel case of CTE in an Iraqi war veteran diagnosed with PTSD to possibly stimulate new lines of thought and research in the possible pathoetiology and pathogenesis of PTSD in military veterans as part of the CTE spectrum of diseases, and as chronic sequelae and outcomes of repetitive traumatic brain injuries.

Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: the role of the forensic pathologist.

We present 5 cases of professional American contact sport athletes who committed parasuicides and suicides aged 50, 45, 44, 36, and 40 years old. Full forensic autopsies and immunohistochemical analyses of the brains revealed chronic traumatic encephalopathy (CTE). The brains appeared grossly normal at autopsy without gross evidence of remote traumatic injuries or neurodegenerative disease. Brain immunohistochemical analyses revealed widespread cerebral taupathy in the form of neurofibrillary tangles and neuritic threads without neuritic amyloid plaques. CTE refers to chronic cognitive and neuropsychiatric symptoms of chronic neurodegeneration following a single episode of severe traumatic brain injury or repeated episodes of mild traumatic brain injury. CTE can only be definitively diagnosed by direct tissue examination. Without full autopsies and immunohistochemical brain analyses these cases would never have been identified. Forensic pathologists will play a vital and central role in the emerging disease surveillance of CTE in professional American athletes, in the identification of CTE cases, and in the establishment of the epidemiology of CTE, with the goal of eventually developing preventive and interventional therapeutic protocols for CTE outcomes.

FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy1.

BACKGROUND: Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls. OBJECTIVE: To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI). METHODS: FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups. RESULTS: FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02). CONCLUSION: This first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy.

Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.

Systemic distribution of West Nile virus infection: postmortem immunohistochemical study of six cases.

Rare cases of West Nile virus (WNV)-associated inflammation outside the central nervous system (CNS) have been reported. We evaluated the systemic distribution of WNV in postmortem tissues during encephalitis in six patients using immunohistochemistry. WNV antigens were detected in neurons of CNS (all 6 cases), kidney (4 cases), lungs (2 cases), pancreas (2 cases), thyroid (2 cases), intestine (2 cases), stomach (1 case), esophagus (1 case), bile duct (1 case), skin (1 case), prostate (1 case) and testis (1 case). In systemic organs epithelial cells were infected. In none of the six cases were viral antigens identified in hepatocytes, heart, adrenal gland, nerves, skeletal muscles, bone, vessels and fat. All cases in which viral antigens were identified in systemic organs in addition to CNS were severely immunocompromised transplant recipients. With the exception of testis and brain, most foci of infection were not associated with inflammation. While the absence of inflammation may in part be due to patient immunosuppression or to possible transient nature of any host response, compartmentalization of viral antigen to the luminal region of epithelial cells may sequester WNV from immune recognition. Comparison of our findings with previous reports suggests that patients with WNV encephalitis can have widespread systemic infection.

Death rates and causes of death after bariatric surgery for Pennsylvania residents, 1995 to 2004.

BACKGROUND: Bariatric surgery has emerged as the most effective treatment for class III obesity (body mass index, >or=40). The number of operations continues to increase. We measured case fatality and death rates by time since operation, sex, age, specific causes of death, and mortality rates. DESIGN AND SETTING: Data on all bariatric operations performed on Pennsylvania residents between January 1, 1995, and December 31, 2004, were obtained from the Pennsylvania Health Care Cost and Containment Council. Matching mortality data were obtained from the Division of Vital Records, Pennsylvania State Department of Health. OUTCOME MEASURES: Age- and sex-specific death rates after bariatric surgery. RESULTS: There were 440 deaths after 16 683 operations (2.6%). Age-specific death rates were much higher in men than in women and increased with age. Age- and sex-specific death rates after bariatric surgery were substantially higher than comparable rates for the age- and sex-matched Pennsylvania population. The 1-year case fatality rate was approximately 1% and nearly 6% at 5 years. Less than 1% of deaths occurred within the first 30 days. Fatality increased substantially with age (especially among those > 65 years), with little evidence of change over time. Coronary heart disease was the leading cause of death overall, being cited as the cause of death in 76 patients (19.2%). Therapeutic complications accounted for 38 of 150 natural deaths within the first 30 days, including pulmonary embolism in 31 (20.7%), coronary heart disease in 26 (17.3%), and sepsis in 17 (11.3%). CONCLUSIONS: There was a substantial excess of deaths owing to suicide and coronary heart disease. Careful monitoring of bariatric surgical procedures and more intense follow-up could likely reduce the long-term case fatality rate in this patient population.

Nursing home deaths which fall under the jurisdiction of the coroner: an 11-year retrospective study.

Twenty percent of deaths in the United States occur in nursing homes, yet less than 1% come to autopsy. The current study analyzed causes and manners of death in all nursing homes between 1993 and 2003, investigated by the coroner of Allegheny County, PA, which has the second highest elderly population in the United States. Two hundred eight decedents were identified, aged 19 to 91 years, 58% women and 42% men, 88% Caucasian and 22% African-American. Fifty-eight percent were accidental and 38.5% were natural manners of death, with 2 homicides, 2 suicides, and 3 undetermined cases. The manner of death was significantly different between Caucasians and African-Americans, with 92.6% of accidental deaths occurring in Caucasians and 6.6% in African-Americans (P < 0.1). Most common natural deaths were arteriosclerotic cardiovascular disease, nonarteriosclerotic cardiovascular disease, pneumonia, pulmonary thromboembolism, chronic obstructive pulmonary disease (COPD), seizure disorder, and atraumatic intracranial hemorrhage. Blunt force trauma was the single most commonly identified traumatic accidental death. Accidental deaths were more common in Caucasians than African-Americans. Homicides and suicides were rare events (<2%). Blunt force trauma is a major autopsy finding in accidental nursing home deaths, and a root-cause analysis may be helpful in developing policies and procedures to decrease the incidence of blunt force trauma.

The role of environmental factors in the causation of sudden death in infants: two cases of sudden unexpected death in two unrelated infants who were cared for by the same babysitter.

We report two cases of sudden unexpected death in two unrelated African American female infants, 2 months and 4 months old. Both infants were attended to by the same babysitter in the same apartment and died 39 days apart in the same bed and in the same bedroom. The autopsy of the first infant revealed sudden unexplained death in an infant. Toxicologic analysis for carbon monoxide (CO) was not performed because it was not suspected. When the second infant died, investigation into the ambient air quality within the apartment revealed high levels of CO emanating from a poorly ventilated and defective hot water heater, which was located across a hallway from the bedroom where the two babies died. CO saturation levels in the postmortem blood samples of the two babies were elevated and were similar (13% and 14%). Nicotine and cotinine were not detected in the blood sample of the two infants. Cherry-red livor mortis was absent. Acute CO intoxication was determined to be the underlying cause of these two unexpected deaths. These two cases underscore the need to integrate ambient air analysis and postmortem CO analysis as routine components of the comprehensive death investigation of infants who die suddenly and unexpectedly.

Autopsy-proven Mirtazapine Withdrawal-induced Mania/Hypomania Associated with Sudden Death.

Manic episodes induced by antidepressant withdrawal are rarely reported. Mirtazapine is a tetracyclic, piperazinoazepine compound and is a noradrenergic, adrenergic, serotonergic, histaminergic, and muscarinic-antagonist antidepressant that is used for the treatment of major depression and other psychiatric illnesses. There are several reported cases of manic/hypomanic episodes induced by mirtazapine withdrawal based on suspected clinical symptoms that were not confirmed by autopsy and toxicology. We present the first reported case of mirtazapine withdrawal-induced mania/hypomania associated with sudden death and confirmed by autopsy and toxicology. Our patient was a 26-year-old male who had been diagnosed with schizophreniform disorder, borderline intellectual functioning, polysubstance abuse, mild mental retardation, and attention deficit hyperactive disorder. He took only mirtazapine in the final and terminal weeks of his life and stopped taking mirtazapine 4 days before his death. He exhibited a sudden manic/hypomanic episode and died during a physical altercation during this episode. A full autopsy with comprehensive toxicologic analysis of his body fluids and tissues was performed. Autopsy revealed that he died from blunt force trauma of the head, neck, and trunk with extremely low and markedly subtherapeutic levels of mirtazapine and desmethylmirtazapine in the blood (mirtazapine: 0.005 mg/L; desmethylmirtazapine 0.011 mg/L). Advanced selective radioligand and neurochemical assays for density and affinity-binding parameters of dopamine transporter and heat shock protein 70 did not reveal any evidence of excited delirium or autonomic hyperactivity state. We recommend that toxicologic analysis of blood for antidepressants should become routine parts of autopsy protocols for the investigation of sudden death following terminal manic/hypomanic episodes for further elucidation of mania/hypomania induced by antidepressant withdrawal.

Role of Tau Acetylation in Alzheimer's Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment.

Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.