B. Tavolato

Risk factors for clinically diagnosed Alzheimer's disease A case‐control study of an Italian population

We conducted a case-control study of 116 patients with the clinical diagnosis of Alzheimers disease (AD) in seven Italian centers. One hundred sixteen hospital controls and 97 population controls were matched by age, sex, and region of residence to the cases. A structured questionnaire was administered to the next-of-kin of cases and controls by trained interviewers to identify possible risk factors. Genetic, viral, toxic, immunologic, medical, surgical, and personality factors were investigated. Dementia among first- or second-degree relatives and advanced age of the mother at subjects birth (age over 40) were associated with AD. Head trauma was more frequent in cases than in either hospital or population controls, but the differences were not significant. Our data did not confirm the previously reported association with antecedent thyroid disease or family history of Downs syndrome.

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system; an evaluation of cytokines in cerebrospinal fluid

Cytokines play an important role not only for initiation of immune reactivity but also for development of tissue injury. Of 38 patients infected with human immunodeficiency virus type 1 (HIV-1) interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) were identified in cerebrospinal fluid (CSF) of 22 (58%) and 16 (42%) patients, respectively. Among the IL-1 beta- and IL-6-positive CSF were eight of 15 HIV-1 patients with no clinical signs of central nervous system involvement and four of five patients with acquired immunodeficiency syndrome (AIDS) dementia complex. The presence of IL-6 was often associated with IL-1 beta and soluble interleukin-2 receptor in CSF as well as with intrathecal IgG synthesis. In none of the CSF samples tumor necrosis factor-alpha or interleukin-2 was detected.

Revised diagnostic criteria for neuromyelitis optica (NMO) : Application in a series of suspected patients

We analyzed neuromyelitis optica (NMO) IgG in the serum or CSF samples from 46 patients with suspected NMO (28) and limited forms of NMO (18). One hundred and fifteen samples from multiple sclerosis (MS) patients were included as controls. The final clinical diagnosis after follow-up was 16 NMO, 12 MS, 11 transverse myelitis (TM) and seven recurrent optic neuritis (RON). NMO-IgG was detected in 62.5% of NMO, 50% of the recurrent longitudinally extensive TM, 14.3% of the RON but in none of the MS patients. The authors then compared the newly revised diagnostic criteria for NMO with the criteria published in 1999, in the 28 patients with suspected NMO. The revised criteria had higher specificity, and positive and negative predictive value (83.3% vs. 25%; 87.5% vs. 62.5; 83.3% vs. 75%), but slightly lower sensitivity (87.5% vs. 93.7%). Our study confirms NMO-IgG as a highly specific marker of NMO, and the usefulness of the revised diagnostic criteria in predicting a diagnosis of NMO.

Axonal damage revealed by accumulation of β-APP in HIV-positive individuals without AIDS

The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to β-amyIoid precursor protein (β-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of β-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of β-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.

Immune activation in multiple sclerosis: study of IL-2, sIL-2R, and γ-IFN levels in serum and cerebrospinal fluid

Serum and cerebrospinal fluid (CSF) levels of interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), and gamma-interferon (gamma-IFN) were measured in multiple sclerosis (MS) patients, human immunodeficiency virus type 1 (HIV-1)-infected patients and normal controls (NC). Increased levels of both IL-2 and sIL-2R were found in MS serum. Moreover, 11 of 50 MS patients showed detectable levels of IL-2 in the CSF. HIV-1-infected patients had increased levels of sIL-2R in serum and, less frequently, in the CSF. gamma-IFN was never detected in serum and CSF of all the patients studied. These findings confirm preliminary reports, further stress a systemic T-cell activation in MS, and support the hypothesis that an immunologic disorder exists in such patients.

Tumor necrosis factor alpha (TNFα) and neurological diseases Failure in detecting TNFα in the cerebrospinal fluid from patients with multiple sclerosis, AIDS dementia complex, and brain tumours

Abstract The presence of tumor necrosis factor alpha (TNFα)/cachetin was investigated in 180 paired cerebrospinal fluid (CSF) and serum samples from patients with neurological diseases, and in five paired CSF and serum samples of Macacus cynomolgus monkeys with acute monophasic experimental autoimmune encephalomyelitis (AMEAE). TNFα was never detected in human CSF, even when an extensive demyelination was documented (active multiple sclerosis, acquired immunodeficiency syndrome (AIDS) dementia complex). Only one Macacus with AMEAE had detectable levels of TNFα in CSF but not in serum, suggesting an intrathecal synthesis of this cytokine in AMEAE.

Glutamic acid decarboxylase autoantibodies and neurological disorders

Abstract. Glutamic acid decarboxylase (GAD) is the enzyme that catalyses the production of GABA, a major neurotransmitter of the central nervous system. Antibodies to GAD (GAD-Ab) were first recognised in a patient affected by stiff-person syndrome; subsequently they were reported in a large number of cases with type 1 diabetes. Recently GADAb have been described in a number of patients affected by chronic cerebellar ataxia, drug-resistant epilepsy and myoclonus. These cases usually harbour other autoantibodies or are affected by organ-specific autoimmune diseases. The role of GAD-Ab is still unclear; the lack of experimental models makes it difficult to investigate their potential pathogenetic role. However two mechanisms have been suggested: the reduction by GAD-Ab of GABA synthesis in nerve terminals or the interference with exocytosis of GABA.

Transferrin receptors in rat central nervous system: An immunocytochemical study

Using an immunocytochemical method we demonstrated the presence of TfR on adult rat neurons, particularly in the cerebral cortex and brain stem. The monoclonal antibody (mab) against rat TfR (clone OX 26) stained neurons of all cortical layers and in the brain stem where the reaction was most evident. Purkinje cells in the cerebellum and scattered neurons in the gray matter of the cervical spinal cord were weakly stained. Choroid plexus cells also reacted with the mab against TfR whereas oligodendrocytes in the cerebral white matter were faintly outlined by the mab. The presence of TfR on endothelial cells of brain capillaries was here confirmed.

Immune infiltrates and cytokines in gliomas

SummaryFrozen sections of 21 gliomas were analysed to characterize inflammatory infiltrating cells, HLA-DR antigen expression and cytokine secretion. Mononuclear cells infiltrating the tumours were mostly macrophages, which were detected in 100% of cases, and expressed HLA-DR antigens. Lymphocytes were less frequently seen and expressed the CD8 phenotype.Interleukin-1 beta (IL-1β) and Interleukin-6 (IL-6), two cytokines mainly produced by activated cells of the macrophage lineage, were demonstrated expecially in neoplastic astrocytes. IL-1β immunoreactivity was detected in all tumours, and was prevalent in more anaplastic gliomas; IL-6 was found in anaplastic gliomas and in glioblastomas. IL-1 receptors were expressed by both infiltrating macrophages and neoplastic astrocytes in the gliomas analysed. These findings suggest that cytokine production in gliomas seems not related to immune reactions against the tumour and their synthesis by anaplastic astrocytes could follow an unregulated activation of many metabolic processes after neoplastic transformation.

Programmed cell death in brains of HIV-1-positive AIDS and pre-AIDS patients

Neuropathological studies have revealed that the brains of HIV-1-infected AIDS patients show the typical encephalitis and, in addition, neuronal loss. More recently, this neuronal cell loss has been thought to take place via programmed cell death (apoptosis) which has been demonstrated by an in situ end labelling (ISEL) technique. In this study 54 brains of HIV-1-positive patients were investigated by the ISEL technique to investigate whether apoptosis is also present in the brains of patients at the asymptomatic stage. Of these, 10 patients suffered from HIV encephalitis (HIVE), 8 had AIDS without neuropathological disorders and 36 were HIV-1-positive pre-AIDS patients. Apoptotic cells were detected in 6 of the 10 HIVE, 1 of the 8 AIDS without central nervous system (CNS) disease and 4 of the 36 asymptomatic individuals. A difference seen between the AIDS and pre-AIDS cases was that, in the latter, apoptotic cells were found in the white matter in all 4 cases, while only 2 of these 4 showed apoptotic neurons. The presence of apoptotic cells in a number, albeit small, of brains of HIV-1-positive pre-AIDS individuals, combined with abnormalities described previously in the same group of patients gives further support to the opinion that brain damage already occurs during the early stages of HIV infection.