Cytomegalovirus (CMV) disease of the brain in AIDS and connatal infection: a comparative study by histology,immunocytochemistry and in situ DNA hybridization

Summary Brain tissues from 45 patients with AIDS and two brains with connatal cytomegalic inclusion body disease were investigated for a cytomegalovirus (CMV) etiology of encephalitic lesions. Nineteen brains showed evidence of CMV infection by histology, immunocytochemistry (ICC) using two different antibodies (mono- and polyclonal), and in situ hybridization (ISH). Fourteen cases with typical cytomegalic cells in conventional histology [eight with focally necrotizing encephalitis/ventriculitis including the two connatal infections and six with nodular encephalitis (NE)] revealed CMV with any method. In 5 of 15 AIDS cases of NE without cytomegalic cells, CMV infection was established by ISH, whereas ICC remained negative in these cases. Typical lesions of human immunodeficiency virus (HIV)-induced multifocal giant cell encephalitis (HIV encephalitis) in 13 brains were never labeled for CMV. In necrotizing encephalitis/ventriculitis, cell types which labeled for CMV, with and without cytomegalic change, comprised neurons, astrocytes, oligodendrocytes, ependyma, choroid plexus, endothelia, and cells in periand endoneurium, and in leptomeninges. Both ISH and ICC were able to detect widespread non-cytomegalic CMV-infected cells in normal parenchyma, well beyound the necrotizing lesions, in two AIDS cases. Labeling patterns of nuclei versus cytoplasms varied between the three methods for CMV detection. We conclude that in CNS tissues with cytomegalic cells, ICC and ISH are of comparable sensitivity; however, a diagnosis of CMV disease is possible in such cases by conventional histology. For an in situ diagnosis of CMV infection in NE without cytomegalic cells in AIDS, ISH is the method of choice. A selective vulnerability to CMV infection of any specific cell type of the human CNS is absent. With our detection methods, typical lesions of HIV encephalitis do not show local co-infection by CMV.Supported by The Lord Mayor's Medico-Scientific Fund Vienna, Austria     

Dementia lacking distinctive histopathology: clinicopathological evaluation of 32 cases

We report the neuropathological findings in 32 patients, aged 46–86 years, with demential lacking distinctive histopathology. All of the patients were classified clinically as having Pick's or atypical Pick's disease, but the routine neuropathological evaluation showed no specific histopathological changes such as Pick bodies, senile plaques, neurofibrillary tangles or Lewy bodies. In 50% of the cases the first symptoms appeared before 65 years of age. However, there were 9 patients with onset in the eighth decade. Positive family history was found only in 6 presenile cases. The retrospective evaluation of the clinical records revealed the consistent presence of frontal symptomatology, including loss of personal awareness, inappropriate euphoria and stereotyped behavior. Speech disorders were observed in 80% of the cases, whereas temporospatial disorientation and memory impairment were less frequent. Praxis and gnosis were strikingly preserved in most of the cases. The macroscopic neuropathological examination revealed frontal or temporopolar atrophy in 97% of the cases, while the hippocampus and subcortical structures were relatively spared in the majority of the cases. Histologically, four groups were recognized. Group A showed moderate to severe neuron loss and gliosis in the frontal and/or temporopolar cortex without subcortical involvement. In group B, the neocortical cell loss was widespread, and the striatum and substantia nigra displayed differential degrees of gliosis but no neuron loss. Group C patients showed a lesion distribution comparable to that observed in group B but with severe neuron loss in at least one subcortical region. Four cases formed group D, which was characterized by the preservation of the pyramidal neurons in the neocortex and variable subcortical changes. Despite these differences in the topography of pathological changes, all of the cases shared a similar clinical profile. These findings further demonstrate the epidemiological and neuropathological heterogeneity of dementia lacking distinctive histopathology. Furthermore, they suggest that the same clinical manifestations may correspond to several distinct pathological processes in this condition.     

Cytomegalovirus infection of the developing brain alters catecholamine and indoleamine metabolism

Tissue concentrations of noradrenaline (NA), serotonin (5-HT), dopamine (DA) and selected metabolites were measured in the spinal cord, cerebellum, cerebral cortex and caudate-putamen of developing mice following intraventricular inoculation with murine cytomegalovirus (MCMV) on postnatal day 10. MCMV-infected animals exhibited transient signs of neurological impairment, including apparent hypertonicity of hindlimb extensors and abnormal gait, beginning on days 14-16 and continuing for 3-5 days. At the onset of neurological impairment, tissue concentrations of NA were significantly reduced in the spinal cord (20%), cerebellum (32%) and cerebral cortex (40%) of infected animals. Levels of 5-HT were significantly increased in the caudate-putamen (50%), while 5-hydroxyindoleacetic acid (5-HIAA) was increased in both the spinal cord (94%) and caudate-putamen (65%). The ratio of 5-HIAA/5-HT, which is frequently used as an estimate of turnover of 5-HT, was significantly increased in the spinal cord (90%) at the onset of neurological impairment. In the caudate-putamen of MCMV-infected animals, there were significant increases in the tissue levels of DA (37%), homovanillic acid (HVA, 41%) and 3,4-dihydroxyphenylacetic acid (DOPAC, 34%). All neurochemical parameters were normal in the MCMV-infected animals by postnatal day 70, approximately 50 days after the resolution of neurological signs. These results indicate transient alterations in monoamine metabolism in the developing nervous system during the pathogenesis of cytomegalovirus-induced movement and postural disorders.     

老年脑梗塞与巨细胞病毒感染的关系

了解巨细胞病毒感染与老年动脉粥样硬经性血栓性脑梗塞的关系。方法；采用间接免疫荧光法和单盲法测定老年动脉粥样硬化性脑醒塞。老年健康体检者血清巨细胞病毒抗原的ＩｇＧ抗体，用Ｘ＾２检验对两组抗体阳性率作比较。     

Rabies encephalitis in a patient with AIDS: a clinicopathological study

A 46-year-old man was bitten by a dog in Mali; anti-rabies vaccination was incomplete. Three months later he was admitted to hospital with fever and diarrhea. Human immunodeficiency virus (HIV) serology was positive and CD4 count was 70/mm³. His status worsened rapidly with confusion hydrophobia and hypersialorrhea. Despite anti-rabies serotherapy and vaccination, he died suddenly 12 days after admission. Immunofluorescence on cerebral tissue samples established rabies encephalitis. Neuropathology showed mild encephalitis with occasional Babès nodules and rare perivascular mononuclear cuffs. Intraneuronal Negri inclusion bodies were remarkably diffuse and abundant. They were clearly demonstrated by immunocytochemistry and electron microscopy. Apoptotic neurons were identified in the brain stem and hippocampus in the vicinity of inflammatory foci. In contrast, apoptosis could not be demonstrated in non-inflammatory areas, even where Negri bodies were numerous. There was no associated HIV encephalitis or opportunistic infection. The occurrence of rabies encephalitis in AIDS represents a random association, but is probably not exceptional as rabies is endemic in many countries and the AIDS epidemic is spreading worldwide. In this case, although the incubation duration and clinical presentation were comparable to those in classical rabies, the T-cell-mediated immunosuppression may account for the weak inflammatory reaction and unusually abundant viral multiplication. This observation confirms that all those at risk for rabies, particularly immunocompromised patients, should receive complete anti-rabies treatment including vaccines and specific immunoglobulins, as soon as possible after infection. Received: 1 February 1996 / Revised, accepted: 24 April 1996     

Neuropathological changes in the cerebral cortex of 1258 cases from a geriatric hospital: retrospective clinicopathological evaluation of a 10-year autopsy population

To examine the neuropathological and clinical characteristics of cerebral aging, we evaluated retrospectively a non-selected autopsy population of 1258 patients from the Geriatric Hospital of the University of Geneva School of Medecine. The prevalence of Alzheimer's disease increased with age below 90 years of age. In the nonagenarians and centenarians, there was a decline in the number of affected cases. The distribution with age of neurofibrillary tangles and senile plaques varied among the cortical areas studied. The CA1 field of the hippocampus and the inferior temporal cortex displayed increasing densities of neurofibrillary tangles with age, whereas the superior frontal and the occipital cortex were relatively spared, especially in patients in their tenth and eleventh decade. The percentage of cases presenting with senile plaques in the neocortex and hippocampal structure increased with age with a marked predominance of cases with moderate to high senile plaque densities. Neurofibrillary tangles were often observed in the CA1 field and the inferior temporal cortex of non-demented individuals and were present in most cases with Alzheimer's disease. Conversely, the involvement of the superior frontal and occipital cortex was moderate even in demented patients. The distribution of senile plaques was homogeneous in all of the neocortical areas independently of the clinical diagnosis. Moreover, there was no correlation between the presence of heurofibrillary tangles and senile plaques in the cerebral regions studied. These results indicate a differential topography of neurofibrillary tangles and senile plaques, and suggest that overt clinical signs of Alzheimer's disease are linked to the progression of the neurodegenerative process in neocortical areas.Supported in part by grants from the NIH (AG05138) and the Brookdale Foundation (to P.R.H.)     

Progressive cytomegalovirus encephalopathy following congenital infection in an infant with acquired immunodeficiency syndrome

Congenital central nervous system infection with cytomegalovirus (CMV) usually results in a nonprogressive encephalopathy. Ninety percent of patients with clinically apparent infections at birth have a permanent neurological disability. It has been suggested that some infants may have persistent infection manifested by progressive encephalopathy during infancy. In the present case, clinical and pathological findings suggest the reactivation of a prior intrauterine CMV infection in a child with human T-lymphotrophic virus type III (HTLV-III) infection. The presence of HTLV-III may have reduced the immune surveillance of this infant, allowing the CMV to reactivate.     

Cytomegalovirus infection inhibits the expression of N-methyl-d-aspartate receptors in the developing mouse hippocampus and primary neuronal cultures

Cytomegalovirus (CMV) is the most significant infectious cause of developmental brain disorders in humans. The infection occasionally persists and causes neurological disorders. The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors is essential for the development and plasticity of synapses, but also is involved in neuronal excitotoxicity during viral infection. Here we investigated the effects of murine CMV (MCMV) infection on the expression of NMDA receptors in the hippocampal neurons of neonatal mice and primary neuronal cultures. Viral antigen was mostly found in hippocampal pyramidal neurons from the CA1 to CA3. Image analysis of immunohistochemistry demonstrated that the expression of NMDA receptor subunit 1 (NMDA-R1) protein in CA1 neurons of MCMV-infected brain was reduced to 40% of that in uninfected brain. The signal of in situ hybridization for NMDA-R1 mRNA was also decreased in CA1 neurons of MCMV-infected brain. In primary neuronal cultures, reduction of NMDA-R1 expression in MCMV-infected neurons was also detected by immunocytochemistry and Western blotting. These results suggest that reduction of NMDA receptor expression by MCMV infection may cause a decrease in the susceptibility of the neurons to excitotoxic cell death, and may be related to the establishment of viral persistence and functional disturbances in MCMV-infected neurons.     

Cerebral atrophy in AIDS: a stereological study

Summary Stereological estimates of mean volumes, surface areas, and cortical thicknesses were obtained on formalin-fixed brains from 19 men with AIDS and 19 controls. Volumes of neocortex, white matter, central brain nuclei, ventricles and archicortex were estimated using point counting and Cavalieri's unbiased principle for volume estimation. In AIDS, the mean volume of neocortex was reduced by 11%, and that of the central brain nuclei by 18%. Mean ventricular volume was increased by 55%. Mean neocortical thickness was reduced by 12%. The mean volume of white matter was reduced by 13%. The findings in 6 clinically demented AIDS patients were not statistically different from the rest of the group.Supported by the Direktør Emil Hertz and wife Inger Hertz'Foundation, the Ferd. and Ellen Hindsgauls Foundation and Fonden for Neurologisk Forskning     

Concurrent herpes simplex type 1 necrotizing encephalitis,cytomegalovirus ventriculoencephalitis and cerebral lymphoma in an AIDS patient

Unlike cytomegalovirus (CMV) ventriculoencephalitis, herpes simplex virus type 1 necrotizing encephalitis has only rarely been observed in AIDS patients. A 40-year-old bisexual man was followed for an HIV1 infection from 1987 onwards. In June 1993 he was referred for sudden confusion, left hemiparesia and fever. The blood contained less than 10 CD4 lymphocytes/mm³. The patient remained comatose and febrile, and died 4 weeks later. In coronal sections of the brain there was necrosis of the internal parts of the left temporal lobe, necrosis of certain areas of the ventricular walls and a small tumor at the top of the right frontal lobe, which proved to be a polymorphic high-grade lymphoma. CMV ventriculoencephalitis lesions were prominent in the ventricular walls of the oecipital lobes and there was a strong nuclear signal for CMV using in situ hybridization. Herpes simplex virus type 1 was shown in the nuclei and cytoplasm of certain neurons and astrocytes in the borders of the necrotized temporal lobe areas by immunohistochemistry, in situ hybridization and electron microscopy, whereas in situ hybridization and immunohistochemistry for CMV were negative in such areas. Necrotizing type 1 encephalitis must not be overlooked in immunodeficient patients.     

Assessing the cognitive impact of Alzheimer disease pathology and vascular burden in the aging brain: the Geneva experience

The progressive development of Alzheimer disease (AD)-related lesions, such as neurofibrillary tangles (NFT), amyloid deposits and synaptic loss, and the occurrence of microvascular and small macrovascular pathology within the cerebral cortex are conspicuous neuropathologic features of brain aging. Recent neuropathologic studies strongly suggested that the clinical diagnosis of dementia depends more on the severity and topography of pathological changes than on the presence of a qualitative marker. However, several methodological problems, such as selection biases, case–control design, density-based measures and masking effects, of concomitant pathologies persisted. In recent years, we performed several clinicopathologic studies using stereological counting of AD lesions. In order to define the cognitive impact of lacunes and microvascular lesions, we also analyzed pure vascular cases without substantial AD pathology. Our data revealed that total NFT numbers in the CA1 field, cortical microinfarcts and subcortical gray matter lacunes were the stronger determinants of dementia. In contrast, the contribution of periventricular and subcortical white matter demyelinations had a modest cognitive effect even in rare cases with isolated microvascular pathology. Importantly, in cases with pure AD pathology, more than 50% of Clinical Dementia Rating scale variability was not explained by NFT, amyloid deposits and neuronal loss in the hippocampal formation. In cases with microvascular pathology or lacunes, this percentage was even lower. The present review summarizes our data in this field and discusses their relevance within the theoretical framework of the functional neuropathology of brain aging and with particular reference to the current efforts to develop standardized neuropathological criteria for mixed dementia.     

Dendritic changes in the hippocampal formation of AIDS patients: a quantitative Golgi study

We have previously shown that in the hippocampal formation of patients with acquired immunodeficiency syndrome (AIDS) there is neuronal atrophy, without cell loss. Because reductions in neuronal size are suggestive of associated neuritic alterations, we decided to study the dendritic trees of the main neuronal populations in the hippocampal formation. Material was obtained in five male AIDS patients and five male controls. After Golgi impregnation, the dendritic arborizations of dentate granule and hilar basket cells, and of CA3 and CA1 pyramidal cells, were hand traced, and their segments classified, counted and measured. We found an impoverishment of the dendritic trees in all neuronal populations in the AIDS group, which was more striking in the hilus and CA3 field. Specifically, hilar neurons had fewer dendritic segments, and reduced branching density and dendritic extent; in CA3 pyramids there was a decrease in the number of terminal segments in the basal trees, and a reduction in the total number of segments, number of medium order terminals, dendritic branching density and dendritic extent in the apical trees. In CA1 pyramids, the terminals were shorter in the apical trees and the dendritic spine density decreased in the basal trees, whereas in granule cells only the dendritic spine density was reduced in AIDS patients. Subtle signs suggestive of dendritic reorganization were observed. These results point to a regional vulnerability of the hippocampal formation to HIV infection, and might contribute to explaining the occurrence of dementia, as a consequence of overall reduction in the hippocampal neuronal receptive surface.     

巨细胞病毒致神经系统感染的证据

本研究检测了193例病人的439份CSF和血清标本,CMV特异性抗体阳性者40例(20.7％)。CSF中特异性抗体检出率高于血清标本,提示阳性病例为中枢神经系统CMV感染。CMV特异性抗体阳性的病种有脑炎、脑膜炎,格林一巴利综合征,多发性硬化、脑脊髓炎和脊髓小脑变性。     

Migration of virus-infected neuronal cells in cerebral slice cultures of developing mouse brains after in vitro infection with murine cytomegalovirus

To investigate the effect of murine cytomegalovirus (MCMV) infection on the developing mouse brain in vitro, we developed an infection system using cerebral slice cultures. Using a micromanipulator, the cerebral slices from mouse embryos on day 18.5 of gestation were injected in the subventricular zone with recombinant MCMV in which the lacZ gene was inserted into a late gene, and were cultured for 7 days. Viral infection, detected by β-galactosidase reaction, was developed at the injection sites of the slices. The virus-infected spots in the slices were enhanced by adding tumor necrosis factor-α to the medium and inhibited by adding phosphonoacetic acid or ganciclovir. Sections from paraffin-embedded slices were subjected to immunohistochemical analyses. Neuronal cells, labeled with 5-bromo-2-deoxyuridine 24 h before cutting the slices, migrated to the cerebral cortex in the slices. Virus-infected neuronal cells expressing only the early viral antigen migrated to the cortex, whereas glial cells expressing the immediate early and late antigens tended to remain at the injected sites. The neuronal migration of infected cells was not observed in the cerebral slices from 7-day-old mice and viral infection was not detected after injection in the cerebral slices from 14- and 21-day-old mice. These results from these cerebral slices may reflect the infectious dynamics in vivo, and this system may provide a useful model for analysis of disorders of brain development caused by CMV. Received: 9 February 1999 / Revised, accepted: 31 March 1999     

Distribution of cerebral cortical lesions in corticobasal degeneration: a clinicopathological study of five autopsy cases in Japan

We investigated five Japanese patients with autopsy-proven corticobasal degeneration (CBD) both clinically and pathologically, and examined the distribution of their cerebral cortical lesions in hemisphere specimens. The lesions were classified into three categories (slight, moderate and severe). Only two of our patients had clinical features considered to be typical of CBD. Severe lesions were present in the posterior portions of the frontal lobe, anterior to the precentral gyrus in two patients with the clinical diagnosis of CBD. By comparison, in two patients with clinically diagnosed frontal Pick’s disease, and one with the clinical diagnosis of progressive supranuclear palsy (PSP), severe lesions were seen in the anterior portions of the frontal lobe. The primary motor area of all five had mostly slight to moderate lesions. We postulate that the clinical features of CBD have a much wider spectrum than previously believed. Our data also indicate that the lesion responsible for limb-kinetic apraxia in CBD is in the premotor cortex. We suggest that when the anterior portions of the frontal lobe are damaged, the clinical picture mimics those of Pick’s disease and PSP. In addition, we consider that focal cerebral atrophy of CBD is multicentric. Received: 3 February 1997 / Revised: 14 April 1997 / Accepted: 2 May 1997     

Cerebral toxoplasmosis in AIDS. Case report

In a patient with AIDS presenting partial epilepsy cerebral toxoplasmosis was diagnosed on the serological and CT evidence. The diagnosis was confirmed by the immediate response to sulfonamide therapy.

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Sommario In un paziente sofferente di AIDS che presentò una crisi epilettica venne diagnosticata una toxoplamosi cerebrale per i dati TAC e neurologici. La diagnosi è stata confermata dall'immediato successo della terapia con sulfamidici.

     

AIDS does not alter the total number of neurons in the hippocampal formation but induces cell atrophy: a stereological study

Although cognitive dysfunction is a common finding in patients with acquired immunodeficiency syndrome (AIDS) its pathogenesis remains controversial. Given the involvement of the hippocampal formation in the processing of cognitive information and the scarcity of quantitative studies in this brain region, we have examined, using stereological methods, the hippocampal formations of AIDS patients. The study was performed in ten AIDS patients and ten age-matched controls. All cases were male. The Principle of Cavalieri was applied to estimate the volume of the layers of the dentate gyrus and of the CA3 and CA1 hippocampal fields. The fractionator and the nucleator were used as estimators of the total number, and mean somatic and nuclear volumes of the neurons in the cell-containing layers of all hippocampal subdivisions. No cell death was detected in AIDS patients but the global volume of their hippocampal formations was significantly decreased due to the reduced volume of its layers, mainly the cell-containing layers. Furthermore, the somatic and nuclear volumes of the neurons in the hippocampal formation were significantly decreased in AIDS patients. No correlation was found between the estimates obtained and the presence or absence of neurological involvement. Our results show that neurons in the hippocampal formation of AIDS patients display marked morphological changes, despite the maintenance of their total number. These alterations are likely to lead to dysfunction of the hippocampal circuitries and, thus, might contribute to explaining the demential features which occur in this condition. Received: 13 July 1999 / Revised, accepted: 4 October 1999     

A comparision of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients

Twenty patients with AIDS who had intracranial lesions underwent both brain biopsy and cerebro-spinal fluid (CSF) examination to compare histological diagnosis with the polymerase chain reaction (CSF-PCR) for the identification of infectious agents. CSF-PCR was performed for herpes simplex virus, varicella zoster virus, cytomegalovirus (CMV), JC virus (JCV), Epstein-Barr virus (EBV), Toxoplasma gondii and Mycobacterium tuberculosis. A definitive diagnosis was obtained by brain biopsy in 14 patients (2 with astrocytoma, 12 with brain infection). CSF-PCR was positive for EBV DNA in 3 of 3 cases of primary cerebral lymphoma, positive for JCV DNA in 6 of 7 biopsy-proven (and one autopsy-proven) cases of progressive multifocal leukoencephalopathy (PML). CSF-PCR was positive for CMV DNA in one biopsy-proven and one autopsy-proven case of CMV encephalitis (the former also had PML) and positive for M. tuberculosis DNA in one case of tuberculous encephalitis. None of the five toxoplasmic encephalitis cases (one definite, four presumptive) were T. gondii DNA positive. There was close correlation between histology and CSF-PCR for CMV encephalitis, PML and PCL. Antitoxoplasma therapy affected the sensitivity of both histological and CSF-PCR methods. Received: 8 November 1995 Received in revised form: 9 July 1996 Accepted: 19 July 1996     

Parkinsonism in a patient with AIDS and cerebral opportunistic granulomatous lesions

The localization of opportunistic infections in the basal ganglia in patients with acquired immunodeficiency syndrome (AIDS) can cause movement disorders, such as choreoathetosis, dystonia, hemiballism and, more rarely, parkinsonism. We describe the case of an AIDS patient who developed cerebral opportunistic granulomatous lesions and, subsequently, a parkinsonian akinetic-rigid syndrome. In agreement with cases reported in the literature, the parkinsonian syndrome developed only when the lesions bilaterally involved basal ganglia. The critical localization of the opportunistic lesions in the direct and indirect strio-pallidal pathways possibly associated with the HIV-related neurotoxicity might have contributed to determine this clinical picture. Received: 4 February 2000 / Accepted in revised form: 3 May 2000     

Coinfection of the central nervous system by cytomegalovirus and herpes simplex virus type 1 or 2 in AIDS patients: autopsy study on 82 cases by immunohistochemistry and polymerase chain reaction

We evaluated the frequency and histopathological features of concomitant infections of the central nervous system (CNS) with cytomegalovirus (CMV) and herpes simplex viruses type 1 or 2 (HSV1/2) in a large series of patients who had died from AIDS. Eighty-two autopsy cases with a histological diagnosis of CMV necrotizing encephalitis were examined retrospectively. CMV and HSV1/2 were detected by immunohistochemistry (IHC) with poly- and monoclonal antibodies and by nested polymerase chain reaction (PCR) for HSV 1 and 2 on DNA extracted from paraffin blocks. PCR for a β-globin genomic sequence was performed in all IHC-positive cases to verify the integrity of extracted DNA. Concomitant CMV/HSV infections were demonstrated by IHC in 13 cases (16%); using monoclonal antibodies, HSV1 was found in 9 cases and HSV2 in 4 cases. In half of the cases, HSV1- or HSV2-positive cells represented more than 25% of immunopositive CMV cells. In all 13 cases, double immunochemical staining showed cells containing both CMV and HSV antigens. PCR for HSV1 and 2 was positive in only 7 of 13 cases (5 HSV1 and 2 HSV2). In the remaining 6 negative cases PCR for β-globin was also repeatedly negative. HSV1 or 2 infection can be demonstrated by IHC in a significant proportion of AIDS cases with necrotizing CMV encephalitis. Nested PCR for HSV1 and 2 on DNA extracted from formalin-fixed and paraffin-embedded autopsy tissues was positive in only slighty above 50% of IHC-positive cases. Received: 28 November 1995 / Revised, accepted: 26 February 1996