Catherine Keohane

Neuronal apoptosis in HIV infection in adults

Productive infection of the central nervous system by HIV predominantly involves the white matter and basal ganglia. Involvement of the cerebral cortex with neuronal loss is also described in AIDS patients but not in asymptomatic HIV‐positive patients. The mechanism of neuronal damage is unknown. To enquire whether neuronal loss in AIDS may be due to an apoptotic process, we examined the cerebral cortex from 12 patients who died from AIDS using two different methods: in situ end labelling and gel electrophoresis of DNA to demonstrate DNA fragmentation. None of the patients had cerebral opportunistic infection or tumour. Four patients had no significant neuropathological changes, eight patients had variable cerebral atrophy and four of them also had productive HIV infection of the brain. These patients were compared with four HIV‐positive asymptomatic patients, five seronegative asymptomatic controls, and two seronegative patients with Alzheimers disease. We demonstrated neuronal apoptosis in the cortex in all AIDS patients, as well as in the Alzheimers patients. Apoptosis was not observed in the asymptomatic cases whether seropositive or seronegative. Neuronal apoptosis was more severe in atrophic brains, and did not directly correlate with productive HIV infection, suggesting an indirect mechanism of neuronal damage is most likely.

Early Brain Changes in HIV Infection: Neuropathological Study of 11 HIV Seropositive, Non-AIDS Cases

Abstract. We examined 11 brains of human immunodeficiency virus (HIV) seropositive cases who died from unnatural causes (10 intravenous drug abusers who died from heroin overdose and 1 homosexual dead from a gunshot injury); 10 brains of HIV seronegative heroin addicts who died from overdose and 1 seronegative drug abuser who died from gunshot injury served as controls. Complete postmortem examination did not show evidence of acquired immune deficiency syndrome (AIDS) or AIDS related complex. Terminal changes including nerve cell ischemia, edema and diffuse vascular congestion were observed in all cases. Perivascular pigment deposition with macrophages was a constant finding in drug addicts and was probably related to chronic intravenous injection. In contrast, cerebral vasculitis was significantly more frequent and marked in HIV seropositive cases and was often associated with lymphocytic meningitis. Granular ependymitis, myelin pallor with reactive astrocytosis and microglial proliferation were also more frequent and more severe in HIV seropositive cases. Immunocytochemistry was negative for HIV antigens. Our study further supports the view that early central nervous system changes occur in HIV infection.

PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM IN 40 CASES OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)

Pathology of the central nervous system in 40 cases of acquired immune deficiency syndrome (AIDS)

Zidovudine therapy and Hiv encephalitis: a 10-year neuropathological survey

Objective:To assess the effect of zidovudine on productive HIV infection of the brain. Design:To correlate the incidence of HIV-specific neuropathology with zidovudine therapy. Patients:We examined 192 AIDS cases neuropathologically; 97 had never been treated with zidovudine, 72 had received zidovudine for over 3 months and until death, 23 had their treatment terminated more than 1 month before death. Results:The incidence of HIV encephalitis/HIV leukoencephalopathy (HIVE/HIVL) and of multinucleated giant cells (MGC) was significantly lower in patients who had received zidovudine than in those who had never received zidovudine. The yearly incidence of HIVE/HIVL increased between 1982 and 1987 probably because of improved survival, and decreased between 1987 and 1990 although the percentage of patients treated with zidovudine increased. Since 1991 the incidence of HIVE/HIVL and of MCC increased slightly. The percentage of patients treated with zidovudine until death decreased and that of patients whose treatment was terminated increased concomitantly. In 1989 and 1990, most patients whose treatment was terminated had MGC and HIVE/HIVL. In 1991 and 1992 this incidence decreased markedly, coinciding with the introduction of dideoxyinosine therapy. Conclusion:Zidovudine treatment significantly reduces the occurence of productive HIV infection of the brain in AIDS. Discontinuing zidovudine therapy may favour the occurrence of HIV encephalitis. Substitution therapy with dideoxyinosine also appears to protect against HIV-specific brain pathology.

Fatal vertebral giant cell arteritis.

Death due to giant cell arteritis (GCA) is rare, and is usually caused by coronary or vertebral arteritis in the acute phase of the disease. A case of fatal GCA is reported in a woman with a normal erythrocyte sedimentation rate, who had been treated for temporal arteritis for eight months. Post mortem examination showed a dissection and thrombosis of the intracranial portion of the left vertebral artery caused by giant cell arteritis. Focal coronary artery GCA was also found. As far as is known, this is the only case in which dissection of the vertebral artery attributable to GCA has been reported.

Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®).

Summary.  Previous studies have suggested that development of inhibitors in previously treated patients (PTPs) may be attributable to a switch in factor VIII (FVIII) therapeutic product. Consequently, it is widely recognized that inhibitor development must be assessed in PTPs following the introduction of any new FVIII product. Following a national tender process in 2006, all patients with haemophilia A in Ireland changed their FVIII treatment product en masse to a plasma and albumin‐free recombinant full‐length FVIII product (ADVATE®). In this study, we retrospectively reviewed the case records of Irish PTPs to evaluate risk of inhibitor formation following this treatment switch. One hundred and thirteen patients participated in the study. Most patients (89%) had severe haemophilia. Only one of 96 patients with no inhibitor history developed an inhibitor. Prior to the switch in his recombinant FVIII (rFVIII) treatment of choice, this child had only experienced three exposure days (EDs). Consequently, in total he had only received 6 EDs when his inhibitor was first diagnosed. In keeping with this lack of de novo inhibitor development, we observed no evidence of any recurrent inhibitor formation in any of 16 patients with previously documented inhibitors. Similarly, following a previous en masse switch, we have previously reported that changing from a Chinese hamster ovary cell‐produced to a baby hamster kidney cell‐produced rFVIII was also associated with a low risk of inhibitor formation in PTPs. Our cumulative findings from these two studies clearly emphasizes that the risk of inhibitor development for PTPs following changes in commercial rFVIII product is low, at least in the Irish population.

Atypical presentation of macrophagic myofasciitis 10 years post vaccination.

Macrophagic myofasciitis (MMF) is an uncommon inflammatory disorder of muscle believed to be due to persistence of vaccine-derived aluminium hydroxide at the site of injection. The condition is characterised by diffuse myalgias, arthralgia and fatigue. We describe a patient with histologically confirmed MMF whose presentation was atypical with left chest and upper limb pain beginning more than 10 years post vaccination. Treatment with steroids led to symptomatic improvement. Although rare, clinicians should consider MMF in cases of atypical myalgia.

Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.

The mechanisms of neuronal apoptosis in Creutzfeldt-Jakob disease (CJD) and their relationship to accumulated prion protein (PrP) are unclear. A recent cell culture study showed that intracytoplasmic PrP may induce phosphorylated RNA-dependent protein kinase (PKRp)-mediated cell stress. The double-stranded RNA protein kinase PKR is a proapoptotic and stress kinase that accumulates in degenerating neurons in Alzheimer disease. To determine whether neuronal apoptosis in human CJD is associated with activation of the PKRp signaling pathway, we assessed in situ end labeling and immunocytochemistry for PrP, glial fibrillary acidic protein, CD68, activated caspase 3, and phosphorylated PKR (Thr451) in samples of frontal, occipital, and temporal cortex, striatum, and cerebellum from 6 patients with sporadic CJD and 5 controls. Neuronal immunostaining for activated PKR was found in all CJD cases. The most staining was in nuclei and, in contrast to findings in Alzheimer disease, cytoplasmic labeling was not detected. Both the number and distribution of PKRp-positive neurons correlated closely with the extent of neuronal apoptosis, spongiosis, astrocytosis, and microglial activation and with the phenotype and disease severity. There was no correlation with the type, topography, or amount of extracellular PrP deposits. These findings suggest that neuronal apoptosis in human CJD may result from PKRp-mediated cell stress and are consistent with recent studies supporting a pathogenic role for intracellular or transmembrane PrP.

The neuropathology of hiv infection in the era of highly active antiretroviral therapy (HAART)

Introduction Approximately 20 years ago, the first autopsy series of AIDS patients were published and the virus responsible for the acquired immune deficiency syndrome (AIDS) was identified. Originally known as “lymphadenopathy associated virus” (LAV) (5) or “human T cell lymphotropic virus type III ‘’(HTLV-III) (32), the causative retrovirus was finally named “human immunodeficiency virus” (HIV). Involvement of the nervous system was quickly recognized as a major cause of disability and death in AIDS patients. The third issue of Brain Pathology, 12 years ago, reviewed the major problems raised by HIV infection and the nervous system. A neuropathology-based classification and consensus nomenclature of the neurological complications of AIDS proposed then (7) is still valid today. Three key issues were highlighted, namely HIV neurotropism (10), immunopathogenesis of HIV encephalitis (1), and HIV-related neurotoxicity (26). Because the disease was invariably fatal, the spectrum of HIV neuropathology was established by many concordant autopsy series; these showed 3 major ways in which the nervous system could be affected: i) opportunistic infections and tumours related to immunodeficiency, ii) less specific changes secondary to general or systemic complications of AIDS, and iii) new specific HIV-induced neuropathology, never seen prior to the AIDS epidemic and found only in HIV-infected individuals, without evidence of another cause (17). Productive infection of the central nervous system (CNS) by HIV was shown by a number of virological and morphological techniques, and demonstrated that the main cells in which HIV replicates were of monocyte/macrophage lineage, including microglial cells. At the same time, clinicians were describing HIV-related neurological syndromes, particularly a specific progressive cognitive/motor disorder “HIV dementia” which occurred in about 20% of AIDS patients (33). The pathological basis of HIV dementia is still a matter of debate, since none of the different HIV-specific CNS changes, HIV encephalitis, HIV leukoencephalopathy or diffuse poliodystrophy exactly correlates with the cognitive disorder (18). It is frustrating for neuropathologists not to be able to make a precise clinico-pathologic correaltion; however, it seems likely that HIV dementia reflects a specific neuronal dysfunction resulting from the combined effects of several mechanisms, some of which may be reversible. There is no evidence for a direct infection of neurones, supporting the view that neuronal damage is indirect, from the deleterious effects of HIV proteins and products of activated macrophages/ microglial cells. Despite enormous research on this topic, the precise mechanism of neuronal damage is still not established; however, there is general acceptance that it involves apoptosis, oxidative stress and glutamate toxicity (23).

The novel Tau mutation G335S: clinical, neuropathological and molecular characterization

Mutations in Tau cause the inherited neurodegenerative disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known coding region mutations cluster in the microtubule-binding region, where they alter the ability of tau to promote microtubule assembly. Depending on the tau isoforms, this region consists of three or four imperfect repeats of 31 or 32 amino acids, each of which contains a characteristic and invariant PGGG motif. Here, we report the novel G335S mutation, which changes the PGGG motif of the third tau repeat to PGGS, in an individual who developed social withdrawal, emotional bluntness and stereotypic behavior at age 22, followed by disinhibition, hyperorality and ideomotor apraxia. Abundant tau-positive inclusions were present in neurons and glia in the frontotemporal cortex, hippocampus and brainstem. Sarkosyl-insoluble tau showed paired helical and straight filaments, as well as more irregular rope-like filaments. The pattern of pathological tau bands was like that of Alzheimer disease. Experimentally, the G335S mutation resulted in a greatly reduced ability of tau to promote microtubule assembly, while having no significant effect on heparin-induced assembly of recombinant tau into filaments.