Borna disease virus-specific circulating immune complexes, antigenemia, and free antibodies--the key marker triplet determining infection and prevailing in severe mood disorders.

Borna disease virus (BDV), a unique genetically highly conserved RNA virus (Bornaviridae; Mononegavirales), preferentially targets neurons of limbic structures causing behavioral abnormalities in animals. Markers and virus in patients with affective disorders and schizophrenia have raised worldwide interest. A persistent infection was suggestive from follow-up studies, but inconstant detectability weakened a possible linkage.This study for the first time discloses that detection gaps are caused by BDV-specific circulating immune complexes (CIC), and their interplay with free antibodies and plasma antigens (p40/p24). Screening 3000 sera each from human and equine patients over the past 4 years by new enzyme immunoassays (EIAs) revealed that BDV-CICs indicate 10 times higher infection rates (up to 30% in controls, up to 100% in patients) than did previous serology. Persistence of high amounts of CICs and plasma antigens correlates with severity of depression. Even BDV RNA could be detected in plasma samples with strong antigenemia. Our discovery not only explains the course of persistent infection, but offers novel easy-to-use diagnostic tools by which new insights into BDV-related etiopathogenesis of disease and epidemiology are possible.

Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection.

Amantadinesulfate is a well known substance which has proven useful in the treatment and prophylaxis of viral infections, in treating symptoms of Parkinson's disease, cocaine dependence, and apathy in multiple sclerosis. It has also been reported as having mild antidepressive effects not sufficient to warrant its use as an antidepressant. Striking antidepressive effects in some patients have been attributed to its antiviral activity against human Borna disease virus (BDV) infection which is frequently seen in patients with depressive episodes. In this 8 to 12 week open study of oral amantadine in 30 depressed patients with various states of BDV infection we found a significant antidepressive response in 19 of 30. Peripheral BDV antigen indicating acute infection was cleared in both responders and non-responders, but only in responders peripheral infection was significantly reduced.

Activated Borna disease virus in affective disorders.

BACKGROUND: Borna disease virus (BDV) is an animal pathogen that causes behavioral changes in animals. Previous studies have found a high prevalence of serum antibodies as well as Borna disease viral antigens (BDVAGs) and RNA in the white blood cells of psychiatric patients, especially those with affective disorders. The present study attempts to offer a better description of the BDVAG cohort using clinical parameters. METHODS: The prevalence of BDVAG was examined in the peripheral mononuclear leukocytes of patients with a major depressive episode. A subgroup of patients underwent further clinical analysis. RESULTS: In this pilot study, at least, there was a significant difference in the prevalence of BDVAG between psychiatric inpatients with a major depressive episode and control individuals. It also appeared that BDVAG is more frequent in patients with recurrent major depression or bipolar disorder than in those with any other psychiatric disorder studied. The number of previous depressive episodes, as well as symptoms involving fatigue and concentration difficulties were positively related to BDVAG. CONCLUSIONS: The high rate of BDVAG, especially in fatigued patients with recurrent major depression or bipolar disorder, may be a nonspecific aspect of immunosuppression. The question remains whether this neurotropic virus may contribute to the pathogenesis of some types of affective disorder.

Neural correlates of recognition memory with and without recollection in patients with Alzheimer's disease and healthy controls.

To dissociate recognition memory with and without recollection, event-related potentials (ERPs) of patients with Alzheimer's disease (AD) and matched controls were recorded in a test of verbal recognition memory accompanied by a source judgement. AD patients who had smaller hippocampi showed a disability to recollect the study context (source). Their ERPs elicited by correctly recognized old words compared to new items were more positive only between 300 and 500 ms with a maximum over the frontal scalp. Controls exhibited a sustained old/new effect over left temporoparietal and frontal sites. The present findings suggest that preserved recognition memory in patients with mild AD is independent of hippocampally mediated processes recollecting episodic memories.

First isolates of infectious human Borna disease virus from patients with mood disorders.

Borna disease virus (BDV), an unique type of non-segmented negative-stranded enveloped RNA virus, is known as an animal pathogen that causes behavioral diseases in higher vertebrates. Past studies have found antibodies to BDV as well as BDV proteins and genomic transcripts in peripheral blood mononuclear cells (PBMCs) of infected animals and human psychiatric patients. Here, we present the first isolation of infectious BDV from such patients' PBMCs. Isolation attempts were conducted with randomly collected PBMC samples from 33 psychiatric inpatients, by co-cultivation and long-term passaging with a human cell line. BDV isolates were identified by infectivity, analysis of viral antigens, sequencing of one viral gene, and successful infection of animals. Three individual isolates could be recovered. They originated from two bipolar patients with acute depression, and one patient with a chronic obsessive-compulsive disorder. Rescue of human BDV required PBMC samples with strong viral antigen expression, and at least 11 subcultures per sample. Genetic and biological properties point to a close relationship of human and animal strains, but also to the uniqueness of each human isolate. Isolation of BDV from patients with major mood disorders at a time of acute depression strengthens the possibility that BDV infection is one of the environmental factors that contributes to recurrent depressive illnesses in man. These isolates represent the first three defined strains of the infectious human BDV.

Borna disease virus genome transcribed and expressed in psychiatric patients.

Borna disease virus (BDV) is a neurotropic, negative and single-stranded enveloped RNA virus that persistently infects various domestic animal species. Infection causes disturbances in behaviour and cognitive functions, but can also lead to a fatal neurologic disease. Human infections seemed likely, since serum antibodies were detected in neuropsychiatric patients. Further proof came from our discovery that peripheral blood monocytes carry viral antigens. Here, we present the first data on different viral genomic transcripts in such patients' cells as well as sequence data of transcripts. Both viral markers seem to coincide with acute episodes of mood disorders, thus pointing to a new human virus infection possibly threatening mental health.

Borna disease virus infection and affective disorders in man.

Borna Disease virus (BDV) can persistently infect the central nervous system of a broad spectrum of animal species. The clinical course varies from slight behavioral disturbances to a fatal neurological syndrome. In-vivo diagnosis is based on the strong humoral immune response to BDV antigens. Since also human infections could be confirmed by specific antibodies and increased seroprevalence was found in patients with chronic neurologic or immunologic disorders, the contribution of BDV or a BDV-like human variant to syndromes with yet unknown etiology became of great interest. We presented the first data of a current follow-up study on 70 psychiatric patients who were tested three times each after hospitalization. In contrast to previously found low prevalence of antibody carriers by screening (2-4%), we now found 20% positives by follow-up testing. Furthermore, of the randomly selected patients with different psychiatric diagnosis, the highest proportion of antibody carriers was detected among patients with major depression (more than 30%), compared to only 8% among patients with dysthymia (neurotic depression). This led us to hypothesize that Bornavirus infection might contribute somehow to the syndrome of major depressive illness by altering neuronal cells in the limbic system.

Brain lesions following combined treatment with methotrexate and craniospinal irradiation.

Eight patients with meningeal seeding by carcinoma or lymphomas were treated with intravenous (i.v.) and/or intrathecal (i.th.) Methotrexate (MTX). Seven patients received additional craniospinal irradiation and in all seven a fatal encephalopathy developed. On the bases of clinical and morphological findings we identified an acute and a delayed form of encephalopathy and concluded that the concurrent administration of Methotrexate and of craniospinal irradiation increases considerably the risk of brain damage.

The basal nucleus of Meynert revised: the nerve cell number decreases with age.

There is an age-dependent nerve cell loss in some areas of the brain, while other brain regions are stable with aging. The nucleus basalis of Meynert (NbM) is believed to be the source of cholinergic innervation of the cerebral cortex, and loss of its neurons seems to be followed by cognitive deficits. The normal age kinetics of the NbM are, therefore, of considerable importance. Sixteen autoptic human brains were examined, ages ranging from 35th week of gestation to 90 years of age. Blocks containing the NbM in its entirety were cut into 20-mu thick serial sections; every 25th section was cresyl-violet stained and underwent morphometric analysis. Nerve cell counts were slightly but significantly higher in the right hemisphere. The total number of neurons in the 9th decade was 23% below that in newborns. This decrease was statistically significant. We hypothesize that there is a threshold number of nerve cells below which cognitive failure is highly probable.

The relevance of pathological diagnosis for therapy and outcome of brain stem gliomas.

41 patients with brain stem gliomas are presented and analyzed. Optimal therapy as well as outcome depend on the histological identity of the tumours. Histological examination cannot be replaced by CT, angiography and NMR. Therefore stereotactic biopsies are recommended in all cases with brain stem gliomas.

Intracerebral neurinomas in a case of von Recklinghausen's disease (neurofibromatosis).

We report the third case of intracerebral neurinoma in a patient with von Recklinghausen's disease, who died of recurrent subdural hematomas after head injury. A total of ten tumors were found in the brain. Both by histological and ultrastructural standards the multiple tumors resembled neurinomas. The pattern of positivity for S-100 and myelin basic protein indicated the Schwann cell origin of the tumors. The ultrastructural findings indicated Schwann cells and numerous areas showing a well defined basement membrane surrounding spindle-shaped neoplastic cells and other areas lacking basement membrane with Schwann cells embedded in collagen. The present case may be categorized as a mixed form of peripheral and central neurofibromatosis. It seems safe to assume that perivascular nerves are the site of origin of the tumors.

[Neuropathologic findings in 13 deceased patients with acquired immunologic deficiency syndrome]. / Neuropathologische Befunde bei 13 Verstorbenen mit erworbenem Immundefektsyndrom.

The neuropathological findings in 13 patients with the acquired immune deficiency syndrome (AIDS) and with AIDS related complex (ARC) are reported. Six patients presented with neurological symptoms, whereas autopsy revealed CNS involvement in nine cases. Four patients showed neither neurological nor neuropathological abnormalities. The most frequent neuropathological diagnoses were toxoplasma encephalitis (4 cases) and multiple or solitary cerebral necroses (3 cases). Long tract degeneration of the spinal cord was found in 2 cases. Cytomegalovirus infection, progressive multifocal leukoencephalopathy, primary lymphoma of the CNS, infiltration of the leptomeninges by plasmocytoma cells and a solitary metastasis of a bronchial carcinoma were diagnosed in one case each. Subacute leukoencephalitis, mentioned frequently in the literature, was not present in this material. In one case, however, status spongiosus and gliosis was found in the cortex and basal ganglia. As similar spongy changes can be seen in mice infected experimentally with retroviruses, a pathogenetic role of the human T-cell lymphotropic/leukaemia virus type III (HTLV-III) cannot be ruled out. Astrogliosis and hypertrophy of astrocytes were found in nine cases. Morphometrically, the number of astrocytes was significantly higher in AIDS patients than in control cases which were selected randomly on grounds of comparable age. Whether this finding bears some relationship with HTLV-III encephalopathy remains open to further investigation. Glial nodules were found in four cases; according to silver impregnation they were composed of microglial elements.

Low doses of L-monosodium glutamate promote neuronal growth and differentiation in vitro.

Monosodium glutamate given at a concentration of 5 X 10(-6) M to whole-brain dissociated cultures of 18-day-old rats promotes neuronal growth. Neurons are larger due to an increased size of both cytoplasm and nucleus. Rough endoplasmic reticulum is more developed and mitochondria are more abundant. Synaptic vesicles are significantly increased in number with respect to control cultures. Synapses are more abundant and show a more differentiated morphology. These findings are interpreted as evidence for accelerated development secondary to the stimulatory effects of glutamate.

Intranuclear vacuoles in Creutzfeldt-Jakob disease.

In an electron microscopic study of brain biopsy material from a case with Creutzfeldt-Jakob disease intranuclear vacuoles containing membrano-vesicular structures were found. To our knowledge this finding has not been previously reported in human spongiform encephalopathies. It may represent a specific alteration associated with Creutzfeldt-Jakob disease, and suggests the possibility of nuclear infection.

Lesions of high signal intensity at magnetic resonance imaging in vascular dementia.

Twenty-five patients with vascular dementia, 18 patients with senile dementia of Alzheimer type (SDAT) and 17 normal persons were examined by magnetic resonance imaging. Lesions of high signal intensity were always recognizable and were frequently very marked in patients with vascular dementia, while they were absent or mild in patients with pure SDAT and in non-demented patients without vascular disease. The possible nature of this disease as well as the role played in determining the type of dementia are discussed.

Peritumoral edema in meningiomas. A radiological and histological study.

Peritumoral edema associated with 76 supratentorial meningiomas was studied. The results of radiological investigation (CT, NMR, Angiography) and histological studies are described and correlated to each other. Mechanical factors alone are not sufficient to explain edema in the majority of the cases. It may be assumed that a secretory activity of the tumor itself also plays a role. The mechanism of this is described and discussed.

[Cerebrovascular malformations occult in angiography (author's transl)]. / Angiographisch stumme zerebrovaskuläre Malformationen.

Cerebral angiography still remains the method of choice for the evaluation of cerebral vascular malformations--even in this day and age of CT. In rare cases, however, these conditions can be missed by angiography, whereas CT can provide important though not pathognomonic clues, with a definite diagnosis possible only by surgical exploration.