Postmortem Evidence Research Articles

Elevated Pontine and Putamenal GABA Levels in Mild-Moderate Parkinson Disease Detected by 7 Tesla Proton MRS

BackgroundParkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown.Methodology/Principal FindingTo map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. γ-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p<0.001 for pons and p<0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls.Conclusion/SignificanceThe GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of the lower brainstem. This study provides in vivo evidence for an alteration in the GABAergic tone in the lower brainstem and striatum in early-moderate PD, which may underlie disease pathogenesis and may provide a biomarker for disease staging.

Fatalities Temporally Associated with the Ingestion of Ibogaine

Ibogaine is a naturally occurring psychoactive plant alkaloid that is used globally in medical and nonmedical settings for opioid detoxification and other substance use indications. All available autopsy, toxicological, and investigative reports were systematically reviewed for the consecutive series of all known fatalities outside of West Central Africa temporally related to the use of ibogaine from 1990 through 2008. Nineteen individuals (15 men, four women between 24 and 54 years old) are known to have died within 1.5-76 h of taking ibogaine. The clinical and postmortem evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical comorbidities, which were mainly cardiovascular, and/or one or more commonly abused substances explained or contributed to the death in 12 of the 14 cases for which adequate postmortem data were available. Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and the uninformed use of ethnopharmacological forms of ibogaine.

Ethyl sulphate and ethyl glucuronide in vitreous humor as postmortem evidence marker for ethanol consumption prior to death

To clarify the circumstances of death, the degree of inebriation is of importance in many cases, but for several reasons the determination of the ethanol concentration in post-mortem samples can be challenging and the synopsis of ethanol and the direct consumption markers ethyl glucuronide (EtG) and ethyl sulphate (EtS) has proved to be useful. The use of a rather stable matrix like vitreous humor offers further advantages. The aim of this study was to determine the concentrations of ethanol and the biomarkers in the robust matrix of vitreous humor and to compare them with the respective levels in peripheral venous blood and urine.

Orbitofrontal Connectivity with Resting-State Networks Is Associated with Midbrain Dopamine D3 Receptor Availability

Animal research and human postmortem evidence highlight the importance of brain dopamine D3 receptor (D3R) function in multiple neuropsychiatric disorders, including addiction. Separate anatomical and functional neuroimaging findings implicate disrupted frontal cortical connectivity with distributed brain networks in processes relevant for these diseases. This potential conjunction between molecular and functional markers has not, however, been tested directly. Here, we used a novel combination of [(11)C]-(+)-PHNO positron emission tomography and resting-state functional magnetic resonance imaging in the same healthy individuals to investigate whether differences in midbrain D3R availability are associated with functional interactions between large-scale networks and regions involved in reward processing and cognition. High midbrain D3R availability was associated with reduced functional connectivity between orbitofrontal cortex (OFC) and networks implicated in cognitive control and salience processing. The opposite pattern was observed in subcortical reward circuitry and the "default mode" network, which showed greater connectivity with OFC in individuals with high D3R availability. These findings demonstrate that differential interactions between OFC and networks implicated in cognitive control and reward are associated with midbrain D3R availability, consistent with the hypothesis that dopamine D3R signaling is an important molecular pathway underlying goal-directed behavior.

Evidence of Renal Infection in Fatal Cases of 2009 Pandemic Influenza A (H1N1)

The 2009 pandemic influenza A (H1N1) caused significant morbidity and mortality. Acute lung injury is the hallmark of the disease, but multiple organ system dysfunction can develop and lead to death. Therefore, we sought to investigate whether there was postmortem evidence of H1N1 presence and virus-induced organ injury in autopsy specimens. Five cases in which patients died of influenza A (H1N1) virus infection were studied. The lungs of all patients showed macroscopic and microscopic findings already described for H1N1 (consolidation, edema, hemorrhage, alveolar damage, hyaline membrane, and inflammation), and H1N1 viruses were present in alveolar cells in immunochemical studies. Acute tubular necrosis was present in all cases, but there was no evidence of direct virus-induced kidney injury. Nevertheless, H1N1 viruses were found in the cytoplasm of glomerular macrophages in the kidneys of 4 patients. Therefore, our data provide strong evidence that H1N1 presence is not restricted to the lungs.

S14 * IDENTIFICATION OF NEUROINFLAMMATION IN THE BRAIN IN VIVO AND IN VITRO AND THERAPEUTIC STRATEGIES TO COMBAT ITS PROGRESSION * S14.1 * INFLAMMATORY PROCESSES IN NEURODEGENERATIVE DISEASES

S14 * IDENTIFICATION OF NEUROINFLAMMATION IN THE BRAIN IN VIVO AND IN VITRO AND THERAPEUTIC STRATEGIES TO COMBAT ITS PROGRESSION * S14.1 * INFLAMMATORY PROCESSES IN NEURODEGENERATIVE DISEASES

Surgical Anatomy of the Vertebrobasilar Territory and Posterior Circle of Willis

In the present era of microscopic and neuroendoscopic procedures, the surgical anatomy of the skull base vessels has gained increased significance. The pattern of the vertebrobasilar arterial complex and the posterior circle of Willis (COW) in Nigerians has not been previously reported despite various variants of these complexes existing in different populations. To review and document the size, distribution and anomalies of the vertebrobasilar territory and posterior COW pattern in a Nigerian set of brains. The target population for this study was a group of Nigerian adults 18 years and above. Specimens from patients with an ante-mortem or post-mortem evidence of meningitis or atherosclerosis were excluded. The size, distribution and anomalies of the vertebrobasilar artery, its branches, and the posterior COW were defined in 50 brains. The male: female ratio was 1.9:1 and a mean age of 44 years. Statistical analysis showed significant differences between the sizes of posterior inferior cerebellar arteries and anterior inferior cerebellar arteries (Student's t=-30.189; p-value= 0.000). Fifty-six percent of the brains had no anomalies. Thirty anomalies were noted in posterior COW compared with six in the vertebrobasilar territory. There were no aneurysms in all the specimens studied. Anomalies in the region of the posterior COW are commoner than the vertebrobasilar territory and the region of the posterior communicating artery is the most common site of anomalies in the posterior COW territory. These variations should be taken into account during skull base and carotid surgeries, and cerebral angiography.

Ethyl sulphate and ethyl glucuronide in vitreous humor as postmortem evidence marker for ethanol consumption prior to death

To clarify the circumstances of death, the degree of inebriation is of importance in many cases, but for several reasons the determination of the ethanol concentration in post-mortem samples can be challenging and the synopsis of ethanol and the direct consumption markers ethyl glucuronide (EtG) and ethyl sulphate (EtS) has proved to be useful. The use of a rather stable matrix like vitreous humor offers further advantages. The aim of this study was to determine the concentrations of ethanol and the biomarkers in the robust matrix of vitreous humor and to compare them with the respective levels in peripheral venous blood and urine. Samples of urine, blood from the femoral vein and vitreous humor were taken from 26 deceased with suspected ethanol consumption prior to death and analyzed for ethanol, EtS and EtG. In the urine samples creatinine was also determined. The personal data, the circumstances of death, the post-mortem interval and the information about ethanol consumption prior to death were recorded. EtG and EtS analysis in urine was performed by LC-ESI-MS/MS, creatinine concentration was determined using the Jaffé reaction and ethanol was detected by HS-GC-FID and by an ADH-based method. In general, the highest concentrations of the analytes were found in urine and showed statistical significance. The mean concentrations of EtG were 62.8mg/L (EtG100 206.5mg/L) in urine, 4.3mg/L in blood and 2.1mg/L in vitreous humor. EtS was found in the following mean concentrations: 54.6mg/L in urine (EtS100 123.1mg/L), 1.8mg/L in blood and 0.9mg/L in vitreous humor. Ethanol was detected in more vitreous humor samples (mean concentration 2.0g/kg) than in blood and urine (mean concentration 1.6g/kg and 2.1g/kg respectively). There was no correlation between the ethanol and the marker concentrations and no statistical conclusions could be drawn between the markers and matrices.

A novel in vivo ovine model of transfusion‐related acute lung injury (TRALI)

Even with the introduction of specific risk-reduction strategies, transfusion-related acute lung injury (TRALI) continues to be a leading cause of transfusion-related morbidity and mortality. Existing small animal models have not yet investigated TRALI resulting from the infusion of heat-treated supernatant from whole blood platelet concentrates. In this study, our objective was the development of a novel in vivo two-event model of TRALI in sheep. Lipopolysaccharide (LPS; 15 μg/kg) as a first event, modelled clinical infection. Transfusion (estimated at 10% of total blood volume) of heat-treated pooled supernatant from date-of-expire human whole blood platelet concentrates (d5-PLT-S/N) was used as a second event. TRALI was defined by both hypoxaemia that developed either during the transfusion or within two hours of its completion and post-mortem histological evidence of pulmonary oedema. LPS infusion did not cause lung injury itself, but did result in decreased circulating levels of lymphocytes and neutrophils with evidence of the latter becoming sequestered in the lungs. Sheep that received LPS (first event) followed by d5-PLT-S/N (second event) displayed decreased pulmonary compliance, decreased end tidal CO(2) and increased arterial partial pressure of CO(2) relative to control sheep, and 80% of these sheep developed TRALI. This novel ovine two-event TRALI model presents a new tool for the investigation of TRALI pathogenesis. It represents the first description of an in vivo large animal model of TRALI and the first description of TRALI caused by transfusion with heat-treated pooled supernatant from human whole blood platelet concentrates.

Oligodendrocytes in Schizophrenia

Oligodendrocytes in Schizophrenia

A Case of In-Stent Neointimal Plaque Rupture 10 Years After Bare Metal Stent Implantation: Intravascular Ultrasound and Optical Coherence Tomographic Findings

Neointimal hyperplasia mainly develops within several months of coronary stent deployment, after which it stabilizes. Although it was widely accepted, particularly during the bare-metal stent (BMS) era, that in-stent restenosis (ISR) generally does not present as an acute coronary syndrome (ACS), but rather as a gradual recurrence of angina symptoms, recent data have shown that a substantial number of patients with ISR present as ACS. There has also been consistent postmortem evidence of plaque rupture secondary to atherosclerotic change within the neointima of a BMS. We report here a case of ACS in which intravascular ultrasound and optical coherent tomographic assessments revealed neointimal atherosclerotic change and ruptured plaque 10 years after BMS deployment.

Preservation of dental evidence following exposure to high temperatures

The success of the Disaster Victim Identification (DVI) process relies upon sufficient post-mortem data being recovered to allow for a meaningful comparison with ante-mortem records of the missing person. Human bodies subjected to prolonged high temperatures, as experienced during the Black Saturday bushfires in Victoria, are often reduced to fragile skeletal elements. The dental structures, however, are the most durable tissues of the body and often survive these prolonged high temperatures. Without protecting the fragile remains at the scene and during transportation to the mortuary, disruption of the skeletal and dental elements may occur. This disruption will result in difficulties in obtaining post-mortem evidence and lead to problems during the reconciliation (formal identification) phase of the investigation. In the two case reports presented to illustrate these problems, there was significant loss and degradation of dental structures at the scene and during transportation to the mortuary. In the first case described, where no protection was afforded to the remains, total loss of all anatomical dental structures occurred. In the second case, where protection of the structures was undertaken, vital dental evidence was preserved. As a result of the experience in this particular DVI incident, where remains were exposed to prolonged high temperature and physical damage, new protocols have been formulated. Adherence to these protocols will maximise the recovery and preservation of dental evidence at the scene and during transportation to the mortuary.

Ventral Hippocampus, Interneurons, and Schizophrenia

Dysfunction within the dopamine system has been the predominant hypothesized cause of schizophrenia for some time; however, there is little anatomical or postmortem evidence showing that the roots of this disorder are to be found within the dopaminergic neurons. Instead, the dopamine system appears to be dysregulated due to pathological influences from other structures. Recent postmortem and imaging studies have looked to the hippocampus as a potential site of this pathology. Our studies using a developmental animal model of schizophrenia found hyperactivity in the hippocampus likely drives the disruption in dopamine system function. This overactivity appears to be due to the functional loss of short axon interneurons that control the activity of the primary output neurons of the hippocampus. These data suggest that a more effective treatment of schizophrenia may be to normalize hippocampal function rather than block dopamine receptors. Moreover, given the high sensitivity of the hippocampus to stress-induced damage and the fact that stress is a risk factor for schizophrenia, controlling stress in the premorbid state may be an effective preventative measure to circumvent the transition to psychosis.

Does cognitive reserve apply to multiple sclerosis?

Cognitive reserve (CR) is the degree of spare cognitive capacity available to protect against the effects of disease or trauma to the brain.1 Individuals with more CR are theorized to be less likely to show cognitive changes associated with neurologic change. CR has mostly been studied in Alzheimer disease (AD); there is significant support for CR buffering the effects of AD. A seminal study found significant postmortem evidence for AD pathology in the brains of 10 elderly individuals whose brains were larger than average and who had not shown any clinical signs of AD while living.2 In this issue of Neurology ®, Sumowski and colleagues3 studied CR in patients with multiple sclerosis (MS), making a central contribution. The authors tested 44 patients with MS using a task of memory and learning known as the Selective Reminding Test. The authors chose to examine memory, because memory deficits are often the most commonly reported cognitive problems in MS.4 Importantly, although neuroimaging indices (e.g., brain atrophy) can partially explain lower performance on such tasks, such indices can only account for about 10%–15% of variance. The authors reason that …

Development and field evaluation of a new serological test for Taenia saginata cysticercosis

Cattle infected with the tapeworm cyst, Taenia saginata metacestode (synonym: Cysticercus bovis) are a source of human infection if affected beef is eaten raw or undercooked. Control measures targeted at individual cattle rather than all animals in a T. saginata-exposed herd should help reduce costs and alleviate current constraints associated with managing an outbreak. To that end, we have developed a reliable diagnostic test for use in live animals that would enable veterinary regulators to focus disease control strategies. The test detects bovine anti- T. saginata immunoglobulin G1 antibodies using an enzyme-linked immunosorbent assay (ELISA) which relies on the excretory-secretory antigens of T. saginata. Animals were inoculated with 10, 100 or 1000 viable T. saginata eggs in order to simulate the parasite burden of field-infected animals (parasite load = 1–86; n = 28). By testing sera obtained from the inoculated animals 84 days post-inoculation, test sensitivity was estimated to be 92.9% (95% confidence interval or CI = 83.4–100.0%). Another 17 animals inoculated with 5000 or 10,000 viable eggs of T. saginata and shown to harbour metacestodes at post-mortem, all tested positive in the ELISA. Test specificity estimated from a herd of field animals with no historical, epidemiological, or post-mortem evidence of infection was 90.6% (95% CI = 87.0–94.2%; n = 256 field cattle). Using the test on samples ( n = 347) from a T. saginata-infected feedlot, the Bayesian approach estimate of seroprevalence was 4.6% (95% probability intervals = 0.5–10.3%). The test performance characteristics of the ELISA suggest that it will be adequate for field application in bovine cysticercosis outbreaks.

Postmortem evidence of interactions of bottlenose dolphins (Tursiops truncatus) with other dolphin species in south-west England

Reports of violent interactions between bottlenose dolphins (Tursiops truncatus) and harbour porpoises (Phocoena phocoena) in the coastal waters of the UK are well documented. Examination of stranded cetaceans by the...

Neuronal and glial cerebrospinal fluid protein biomarkers are elevated after West Nile Virus infection

Neurotrophic West Nile virus (WNV) disease is a severe arbovirus infection in which neuronal loss is the likely anatomical substrate for the high morbidity and mortality. We investigated whether cerebrospinal fluid (CSF) protein biomarkers were elevated in vivo and related to disease severity in patients with WNV infection. This exploratory study included 114 patients (24 acute WNV, 77 noninflammatory controls, six peripheral neuropathies, seven aseptic meningoencephalitis). CSF levels of neuronal (neurofilaments, NfH-SMI35) and glial (glial fibrillary acidic protein, GFAP, S100B) biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Immunocytochemistry was performed in two fatal WNV cases. A significant proportion of patients with WNV had pathological CSF levels for NfH-SMI35 (58%, median concentration 1.01 ng/mL), GFAP (58%, 10 pg/mL), and S100B (90%, 1.29 ng/mL). The results were consistent with postmortem evidence for neuronal death and astrogliosis. Surprisingly, CSF protein biomarker levels were also found to be pathological in a considerable proportion of patients who presented with WNV fever only (100% for GFAP and S100B and 43% for NfH-SMI35). Elevated CSF protein biomarker levels are suggestive of neuronal death and glial pathology in human WNV infection. The results indicate the presence of neuroinvasive disease across the spectrum of WNV disease, including WNV fever.

A rodent model of schizophrenia derived from postmortem studies

There is compelling postmortem evidence that GABA cell dysfunction plays a role in the pathophysiology of schizophrenia (SZ). Based on a unique distribution of postmortem abnormalities in layer II of the anterior cingulate cortex and sectors CA3/2 of the hippocampus, we postulated that afferent fibers from the basolateral amygdala to these sites may contribute to diminished GABAergic modulation in these disorders. To test this hypothesis, picrotoxin (PICRO), a non-competitive antagonist of the GABA-A receptor, is stereotaxically infused the basolateral complex of the amygdala (BLA) to increase the flow of excitatory activity into stratum oriens (SO) of sectors CA3/2 of the hippocampus. This pharmacological manipulation results in a selective reduction of GABAergic interneurons containing parvalbumin, calbindin and calretinin in CA3/2. Using single cell recordings in a hippocampal slide preparation, these changes in PICRO-treated rats seem to be associated with a reduction in evoked and spontaneous inhibitory post-synaptic potentials (sIPSCs) recorded from pyramidal neurons in sector CA3/2, but not CA1. A lower resting membrane potential and an increased action potential firing rate have been recorded in interneurons in the SO of CA2/3, but not CA1. Additionally, currents associated with hyperpolarization-activated cationic channels (Ih), which help to control neuronal firing rates of GABA cells in the hippocampus, were also increased. Overall, these studies support the view that postmortem studies contribute information for the development of empiric models of SZ, ones that can be used as translational tools for elucidating the functional changes that may be present in GABA cell subtypes their molecular regulatory mechanisms in this disorder.

A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder

Autism Spectrum Disorder (ASD) is associated with both (i) post-mortem and neuroimaging evidence of abnormal cortical development, and (ii) altered signalling in Brain Derived Neurotrophic Factor (BDNF) pathways - which regulate neuroproliferative and neuroplastic processes. In healthy controls genotype at a single nucleotide polymorphism that alters BDNF signalling (Val66met) has been related to regional cortical volume. It is not known however if this influence on brain development is intact in ASD. Therefore we compared the relationship between genotype and cortical anatomy (as measured using in vivo Magnetic Resonance Imaging) in 41 people with ASD and 30 healthy controls. We measured cortical volume, and its two sole determinants - cortical thickness and surface area - which reflect differing neurodevelopmental processes. We found “Group-by-Genotype” interactions for cortical volume in medial (caudal anterior cingulate, posterior cingulate) and lateral (rostral middle, lateral orbitofrontal, pars orbitalis and pars triangularis) frontal cortices. Furthermore, within (only) these regions “Group-by-Genotype” interactions were also found for surface area. No effects were found for cortical thickness in any region. Our preliminary findings suggest that people with ASD have differences from controls in the relationship between BDNF val66met genotype and regional (especially frontal) cortical volume and surface area, but not cortical thickness. Therefore alterations in the relationship between BDNF val66met genotype and surface area in ASD may drive the findings for volume. If correct, this suggests ASD is associated with a distorted relationship between BDNF val66met genotype and the determinants of regional cortical surface area – gyrification and/or sulcal positioning.

Antidepressant Use in Elderly Suicide Victims in New York City

We examined postmortem evidence of antidepressant, analgesic, and anxiolytic-hypnotic drugs in suicide victims aged 65 years and older. We assessed data on Medical Examiner-certified suicide victims aged 65 years or older from 2001 through 2004 who had resided and died in New York City and who underwent toxicologic investigation for antidepressant, analgesic, and anxiolytic-hypnotic drugs. We calculated annual population-based suicide rates and rates of positive toxicologic findings for each of the 3 classes of medications across 3 age strata: 65 to 74, 75 to 84, and 85 years and older. There were 255 certified suicide victims among New York City residents aged 65 years or older from 2001 through 2004. Results of toxicologic testing were available for 63.5% (162) of suicide victims. Antidepressants were detected in 22.0% of suicide victims aged 65 to 74 years, 26.8% of those aged 75 to 84 years, and 16.7% of those aged 85 years and older. The oldest age stratum had both the highest suicide rates in the over-65-years population at 10.7 per 100,000 and the lowest percentage of antidepressant use among all geriatric suicide victims. Rates of detection of antidepressant medication were low for all geriatric suicide victims, especially the oldest. Analgesics and anxiolytic-hypnotics may have been taken in lieu of antidepressants by suicide victims aged 85 years and older. Assuming that many of the suicide victims had clinically treatable depression, these findings implicate problems in the delivery of specific antidepressant pharmacologic treatment to the "old-old."