Richard Yanagihara

Advanced Glycation End Products in Alzheimer’s Disease and Other Neurodegenerative Diseases

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimers disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimers disease and other neurodegenerative diseases (progressive supranuclear palsy, Picks disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimers brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimers disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Picks bodies in Picks disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimers disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimers disease.

Low-calcium, high-aluminum diet-induced motor neuron pathology in cynomolgus monkeys

SummaryLong-term epidemiological studies indicate that environmental factors play a causative role in high-incidence amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) in the western Pacific. An increased risk for disease is acquired in youth and remains for life. The low concentrations of calcium and magnesium and high levels of aluminum in the soil and drinking water, along with the relative isolation of these populations, constitute an unusual environmental feature common to all three high-incidence foci. Studies of mineral deposition in brain tissue of Guamanian ALS and PD patients, as well as of neurologically normal Guamanians with neurofibrillary degeneration, demonstrate accumulations of calcium, aluminum and silicon in neurofibrillary tangle-bearing neurons. In an attempt to duplicate the low calcium and high aluminum and manganese in soil and drinking water in these foci, we maintained juvenile cynomolgus monkeys for 41 to 46 months on a low-calcium diet with or without supplemental aluminum and manganese. Experimental animals exhibited mild calcium and aluminum deposition and degenerative changes, compatible with those of early ALS and PD, in motor neurons of the spinal cord, brain stem, substantia nigra and cerebrum. Neuropathological findings included chromatolysis, aberrant perikaryal accumulation of phosphorylated neurofilament, neurofibrillary tangles, axonal spheroids, and basophilic and hyaline-like inclusions consisting of abnormal cytoskeletal elements by electron microscopy. The magnitude and extent of these lesions far exceeded those found in normal aged monkeys.

LTR sequence and phylogenetic analyses of a newly discovered variant of HTLV-I isolated from the Hagahai of Papua New Guinea

A 631-bp region of the long terminal repeat (LTR) of a variant of human T-cell lymphoma/leukemia virus type I (HTLV-I), isolated from a healthy member of a remote, recently contacted group (Hagahai) in Papua New Guinea, was sequenced and compared to LTR sequences of other members of the primate T-cell lymphoma virus group (PTLV), including HTLV-I, simian T-cell lymphoma virus (STLV-I) and HTLV-II. Sequence analysis of the LTR of this New Guinean isolate, designated as HTLV-I(PNG-1), indicated a sequence divergence of 8.4% to 10.4% from prototype Japanese HTLV-I(ATK) and other HTLV-I and STLV-I isolates and 48.6% diversity from HTLV-II. Few mutations were found in the core elements of the transcriptional enhancer regions, the TATA box promoter, and the polyadenylation signal and site. Further, the observed changes did not significantly alter the inferred stability of the Rex response element, a stem loop structure critical for polyadenylation and Rex protein binding. Dendograms based on LTR sequences indicated that the strain of virus that evolved into HTLV-I(PNG-1) diverged from the other PTLV in the distant past, just after the progenitors of STLV-I from Asia, but before the ancestors of STLV-I from Africa. By contrast, other HTLV-I isolates were found to represent strains of virus that have diverged more recently and clustered primarily according to their geographical origin. These data confirm that HTLV-I(PNG-1) is a new and distinct variant of the PTLV group. Also, our analyses suggest that both HTLV-I and STLV-I may have originated in the Indo-Malay region and eventually spread to Africa and then to the New World and Japan with horizontal transmission between man and nonhuman primates possibly occurring over thousands of years.

Immunolocalization of scrapie amyloid (PrP27-30) in chronic wasting disease of Rocky Mountain elk and hybrids of captive mule deer and white-tailed deer.

Scrapie amyloid-immunoreactive plaques are present in brain tissues of captive mule deer with chronic wasting disease (CWD), a progressive neurological disorder characterized neuropathologically by widespread spongiform change of the neuropil, intracytoplasmic vacuolation in neuronal perikarya and astrocytic hypertrophy and hyperplasia. We report here the immunolocalization of scrapie amyloid (PrP27-30) in plaques observed in brain tissues of Rocky Mountain elk (Cervus elaphus nelsoni) and hybrids of mule deer and white-tailed deer (Odocoileus virginianus) naturally affected with CWD. Similar findings have been shown in kuru, Creutzfeldt-Jakob disease, and Gerstmann-Sträussler syndrome in humans. Our data corroborate that CWD in Rocky Mountain elk and hybrids of mule deer and white-tailed deer belongs to the subacute spongiform virus encephalopathies (transmissible cerebral amyloidoses).

Leakey virus: a new hantavirus isolated from Mus musculus in the United States.

A hantavirus, designated Leakey virus, was isolated from a Mus musculus captured in Real County, Texas, U.S.A. in August 1986. Virus-specific fluorescence was first detected 13 days after inoculation of Vero-E6 cells with spleen tissue from the seropositive M. musculus. Ultrastructurally, the new isolate resembled other hantaviruses. Leakey virus induced a fatal meningoencephalitis in infant Fischer rats, with viral antigen detectable in brain, lung, liver, kidney and spleen. Serum dilution, plaque reduction neutralization tests indicated that Leakey virus was antigenically distinct from Hantaan, Seoul, Puumala and Prospect Hill viruses, and therefore constitutes a new serotype.

Isolation and propagation of nephropathia epidemica virus in bank voles.

Three strains of nephropathia epidemica (NE) virus were isolated from lung tissues of bank voles (Clethrionomys glareolus) and a grey-sided vole (C. rufocanus) trapped in Västerbotten county, Sweden. Two of these isolates were serially passaged in seronegative laboratory-bred bank voles. Experimentally infected animals developed a subclinical infection characterized by virus persistence, particularly in lung tissue. Attempts to infect other species of colonized rodents with NE virus and to isolate NE virus from acute phase patient blood were unsuccessful. The serial propagation of NE virus in colonized bank voles provides opportunities to study experimental infection in its reservoir rodent host.

Geographic-Specific Genotypes or Topotypes of Human T-Cell Lymphotropic Virus Type I As Markers for Early and Recent Migrations of Human Populations

Publisher Summary Kuru is one of the better-known paradigms of “place diseases,” or diseases occurring in high incidence in geographically restricted or delimited regions. From the study of kuru among the stone age fore in the Eastern Highlands of Papua, New Guinea, came the discovery of unconventional agents or slow viruses that cause neurodegenerative diseases in humans. In a similar fashion, the study of another place disease, a fulminating hematological malignancy in southwestern Japan, called adult T-cell leukemiailymphoma, led to the discovery of and etiological association with an exogenous replication-competent human retrovirus, human T-cell lymphotropic virus type I (HTLV-I). This initial frontier of HTLV-I research was expanded by the serendipitous discovery that endemic tropical spastic paraparesis, also known as Jamaican neuropathy and paraparesia espastica el Pucifico, another place disease in the Caribbean basin and Colombia, was also caused by HTLV-I. A clinically indistinguishable spastic myelopathy, designated HTLV-I-associated myelopathy, was later recognized among HTLV-I-seropositive individuals in southern Japan, and presently, HTLV-I-associated myelopathy and HTLV-I-positive tropical spastic paraparesis are considered to be the same disease. The study of diseases in populations isolated by the virtue of geography, culture, and/or genetics can also provide insights into the evolution and dissemination of the etiological agent. From the studies of HTLV-I infection in an isolated recently contacted group in the fringe highlands of Papua, New Guinea, and among the lifelong residents of the Solomon Islands has come an augmented perspective on the emergence, evolution, and global dissemination of this lymphotropic retrovirus. In addition, these studies in Melanesia have led to the realization that HTLV-I may, in certain instances, serve as a biological marker for the early and recent migrations of human populations.

Histochemical and X-ray microanalytical localization of aluminum in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam

SummaryHistochemical staining for aluminum, using Solochrome azurine or Morin, provided a rapid, simple and reliable means of identifying areas and structures of the brain of interest for closer scrutiny by X-ray microanalysis in patients with amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Neuronal perikarya, dendritic processes, and the walls of some cerebral vessels were aluminum positive by Solochrome azurine staining. In some cases, the deposition of aluminum was rather diffuse, particularly in the white matter. Fluorescent localization of aluminum using Morin was equally sensitive and specific, but provided less morphological detail than Solochrome azurine. Confirmation of histochemical detection of aluminum was achieved by examining adjacent tissue sections using wavelength-dispersive spectrometry coupled to a computer-controlled electron beam X-ray microprobe. Although the minimum detectable limits for aluminum by these histochemical procedures are unknown, the lower detection limit of our X-ray microanalytical technique is 10–100 ppm dry weight. Solochrome and Morin staining, as verified by X-ray microanalysis, afford a useful and reliable means of surveying multiple anatomical regions for aluminum deposition in naturally occurring and experimentally induced neurodegenerative disorders.

Morphology and Morphogenesis of Viruses of Hemorrhagic Fever with Renal Syndrome

The morphology and morphogenesis of viruses of hemorrhagic fever with renal syndrome (HFRS) were studied by thin-section electron microscopy. Ten strains of HFRS virus isolated in China and one strain isolated in Korea were compared. The virions varied in size as well as in the shape and character of their inner components. Both intracellular and extracellular ribosome-like, electron-dense, virus-associated granules were seen. A viral antigen layer was often visualized on the surface of HFRS virus-infected cells, as confirmed by immune electron microscopy. Aberrant tailed particles and elongated rod-like particles were seen infrequently. The morphogenesis of HFRS viruses appears to be more complex than that of other members of the family Bunyaviridae. The prototype Hantaan virus shares a common morphology and morphogenesis with the other HFRS viruses studied.

Sequence analysis of human T cell lymphotropic virus type I strains from southern India: gene amplification and direct sequencing from whole blood blotted onto filter paper

Human T cell lymphotropic virus type I (HTLV-I) infection in India has been found to be associated with adult T cell leukaemia/lymphoma (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) among life-long residents of southern India. To examine the heterogeneity of HTLV-I strains from southern India and to determine their relationship with the sequence variants of HTLV-I from Melanesia, 1149 nucleotides spanning selected regions of the HTLV-I gag, pol, env and pX genes were amplified and directly sequenced from DNA extracted from whole blood blotted onto filter paper and from peripheral blood mononuclear cells, obtained from one patient with HAM/TSP, two with ATLL and eight asymptomatic carriers from Andhra Pradesh, Kerala and Tamil Nadu. Sequence alignments and comparisons indicated that the 11 HTLV-I strains from southern India were 99.2% to 100% identical among themselves and 98.7% to 100% identical to the Japanese prototype HTLV-I ATK. The majority of base substitutions were transitions and silent. No frameshifts, insertions, deletions or possibly disease-specific base changes were found in the regions sequenced. The observed clustering of the Indian HTLV-I strains with those from Japan, as determined by the maximum parsimony method, suggested a common source of HTLV-I infection with subsequent parallel evolution. Amplification of DNA from blood specimens collected on filter paper may be useful for the study of other blood-borne pathogens.