Diffuse encephaloventriculitis and substantial leukoencephalopathy after intraventricular administration of recombinant adenovirus.

OBJECTIVES: The use of recombinant adenovirus as a vehicle for gene transfer into ependymal cells is a potential therapeutic tool for the treatment of various neural disorders. However, gene transfer into the ependymal cells of the ventricular wall is associated with high-level expression of the transferred gene, which declines rapidly. The purpose of this study is to understand the cause of this early decline in gene expression. METHODS: Different doses of adenovirus-expressing beta-galactosidase (Ad-beta-gal) were injected into the lateral brain ventricle of C57BL/6 mice, and the brains were observed histologically and with magnetic resonance (MR) imaging for a month. RESULTS: Inoculation of the lateral ventricle with more than 1 x 10(8) viral particles (2.6 x 10(6) pfu) resulted in a rapid decline of beta -gal expression. MR imaging indicated gradual ventriculomegaly and histological analysis showed the loss of the ependymal cells from the ventricular wall, lymphocytes infiltration near the wall, degeneration of myelinated fibers and apoptosis in the external capsule. Reactive astrocytes proliferated in the external capsule 17 days following inoculation. To avoid this irreversible brain atrophy, the inoculated adenovirus should be reduced to less than 1 x 10(7) particles (2.6 x 10(5) pfu) in mice. DISCUSSION: Our results indicate the presence of a unique and diffuse immune response of the brain; therefore, the clinical use of recombinant virus for intraventricular gene transfer must be carefully evaluated.

Cytomegalovirus is present in a very high proportion of brains from vascular dementia patients.

We previously found that herpes simplex type 1 virus (HSV1), when present in brain of carriers of the apolipoprotein E type 4 allele is a strong risk factor for Alzheimer's disease. To find if HSV1 or certain other herpesviruses are involved in vascular dementia (VaD), we searched post mortem brain specimens from patients suffering from VaD for the presence of HSV1, cytomegalovirus (CMV), and human herpesvirus type 6 DNA, using polymerase chain reaction. We have found that a very high proportion of the VaD patients, 93% (14/15), but not of age-matched normals, 34% (10/29), harbor CMV DNA (P = 0.0002); the proportions of the patients harboring the other viruses in brain do not differ significantly from those of the normals. Further studies are needed to reveal whether or not the association of CMV with VaD is causal.

An association of human T-cell lymphotropic virus type I infection with vascular dementia.

Subjects ranging in age from 50 to 89 years old, either with or without dementia were studied by both ELISA for anti-human T-cell lymphotropic virus type I (HTLV-I) gag 100-130 antibody and by cranial CT in order to clarify the relationship between HTLV-I infection and dementia. The frequency of anti-HTLV-I antibody was found to be significantly higher in the patients with dementia (24/130, 18.5%) than in those without dementia (11/139, 7.9%) (P=0.0169). Among the various types of dementia, HTLV-I seropositivity was found to be significantly associated with vascular dementia (11/48, 23%) (P=0.0087), but not with Alzheimer type dementia. In addition, HTLV-I seropositivity was also associated with Babinski sign, and the severity of cerebral infarction, ventricular dilatation and periventricular lucency on CT. The presence of HTLV-I therefore appears to be one of the risk factors for vascular dementia in HTLV-I endemic areas.