Robert L. Schelper

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as “definite Alzheimers disease” (AD), “probable AD,” “possible AD,” and “normal brain” to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

Monocytes become macrophages; they do not become microglia: a light and electron microscopic autoradiographic study using 125-iododeoxyuridine

Abstract This light and electron microscopic autoradiographic study of stab injuries in the spinal cord of mice evaluated the ultrastructural characteristics of cells labeled by incorporation of the thymidine analogue 125I-5-iodo-2‘-deoxyuridine (I-UdR), injected one day prior to injury. I-UdR was used instead of tritiated thymidine (H-TdR) because H-TdR can be reutilized and is therefore not a suitable pulse label for long-term studies of cell migration. Using serial thick and thin sections for au-toradiography 614 labeled cells were identified. Labeled cells included 545 monocytes/ macrophages, 50 lymphocytes, 17 pericytes, one endothelial cell, and one arachnoid cell. No labeled cell had the morphology of microglia. We concluded that macrophages in stab injuries of the spinal cord of mice are derived from blood monocytes. Blood-derived lymphocytes are also involved in the reaction to spinal cord stab injury. Microglia are not blood-derived and are not seen as a transitional form in the differentiation of monocytes to macrophages.

The role of radiation therapy in the management of ependymomas of the spinal cord

Twenty patients with biopsy-proven ependymomas of the spinal cord were treated between 1960 and 1984-7 with surgery only, 3 with radiation therapy only, and 10 with surgery and postoperative radiation therapy. Of these, 2 patients developed recurrent tumor at the primary site, 3 developed a recurrent tumor in the thecal sac, and 1 developed distant metastasis. The absolute 5- and 10-year survival rates were 95% (19/20) and 86% (12/14), respectively. None of 13 patients who were treated with radiation therapy only or combined surgery and postoperative radiation therapy developed recurrent tumor at the primary site, and none of 7 patients who received thecal sac irradiation developed thecal sac recurrences. In contrast, 2 of 7 patients (29%) treated with surgery alone developed recurrent tumor at the primary site, and 3 of 13 patients (23%) who received no thecal sac irradiation developed a recurrent tumor in the thecal sac. The failure rates following surgery were greatest in patients who had tumor removed in a piecemeal fashion (43%, 6/14). The results show that radiation therapy is probably not necessary if the tumor has been removed completely in an en bloc fashion. However, radiation therapy is needed if the tumor has been incompletely removed or removed in a piecemeal fashion. If the tumor has been removed in a piecemeal fashion, the radiation portals should be extended to include the thecal sac. Histologic subtypes influenced the pattern of recurrence. Myxopapillary ependymomas and high grade cellular ependymomas appear to be more likely to recur in the thecal sac. However, no big difference could be detected in local recurrence.

Expression of monocyte chemoattractant protein (MCP-1) and nitric oxide synthase-2 following cerebral trauma

Abstract Traumatic injury to the brain initiates multiple interrelated processes that involve parenchymal, vascular, and infiltrating inflammatory cells. Nitric oxide (NO) and chemokines have been implicated as regulators of the central nervous system injury response. Following a cryogenic lesion of the cerebral cortex in mice, mRNA for NO synthase (NOS)-2 was detected by reverse transcriptase polymerase chain reaction ipsilaterally 12 h after injury and persisted for 2 weeks. While mRNA was also detected contralaterally, the time course of expression was shorter (1 week). By immunohistochemistry, NOS-2 protein was initially detected ipsilaterally 12 h after injury in infiltrating inflammatory cells. Astroglial cells expressed NOS-2 from 24 to 72 h after injury. The expression of monocyte chemoattractant protein (MCP-1) mRNA peaked at 6 h on the lesion side, remained for 24 h and then declined by 48 h. On the unlesioned side, MCP-1 mRNA was expressed to a much lesser extent and had declined by 24 h. The up-regulation of MCP-1 was relatively specific as a closely related mRNA encoding IP-10 was not significantly increased. These findings implicate a role for NOS-2 and MCP-1 as potential regulators of cellular events following cryogenic cerebral trauma.

Orbital Malignant Melanoma and Oculodermal Melanocytosis: Report of Two Cases and Review of the Literature

Oculodermal melanocytosis is a congenital melanoblastic hamartoma affecting ocular tissues and facial skin. It is seen more commonly in oriental and black patients. Malignant degeneration, once believed to be rare in this syndrome, occurs in 4.6% of all reported cases, and is more frequent in whites. The actual incidence of malignant melanoma in this syndrome is difficult to determine as many uncomplicated cases go unreported. The most common site of malignant melanoma associated with this entity is in the choroid. Four previously described orbital tumors represent the second most frequent area of presentation. A review of the literature in this disease is discussed as well as a new case of orbital malignant melanoma associated with it. A second case of presumed orbital melanoma associated with oculodermal melanocytosis is also discussed.

Vascular Smooth Muscle Hyperplasia Underlies the Formation of Glomeruloid Vascular Structures of Glioblastoma Multiforme

The origin of the vascular hyperplasia seen in glioblastoma multiforme is a matter of debate. To test the predominant hypothesis that these glomeruloid structures are of endothelial origin the following study was undertaken. Seven glioblastomas containing prominent glomeruloid vascular structures were stained with Ulex europaeus agglutinin I (UEA-1) and with antibodies against factor VIII/related antigen (fVIII/RAg), glial fibrillary acidic protein (GFAP), S-100 protein, muscle specific a-actin (MSA) and smooth muscle specific a-actin (SMSA). The GFAP and S-100 antibodies stained the neoplastic glial component of each tumor but did not bind to vascular cells. Endothelial cells lining the lumina of normal vessels and the lumina of glomeruloid vascular structures stained positively with both UEA-1 and fVIII/RAg antibody. No other cells were found to be stained by UEA-1 or by fVIII/RAg antibody. Smooth muscle cells of the normal vasculature stained positively exclusively with anti-MSA and anti-SMSA antibodies. The same pattern of positive actin antibody staining was seen in the majority of cells forming the glomeruloid structures; however, the cells lining the vascular lumina did not bind the MSA and SMSA antibodies. These data strongly suggest that the vascular proliferation resulting in glomeruloid structures is due in large measure to smooth muscle hyperplasia.

Smooth muscle can comprise the sarcomatous component of gliosarcomas.

The sarcomatous component of gliosarcomas is thought by many to originate from the vascular proliferation seen in glioblastoma multiforme and has, therefore, been assumed to be endothelial. Immunohistochemical staining of four gliosarcomas has led us to an alternate theory. Pathologically all four tumors were composed of at least two cell types; the first had a stellate, glial appearance and the second was either spindled or polygonal in shape. Polygonal cells were associated with glomeruloid vascular structures in some areas. Both components of each neoplasm were cytologically malignant. Glial fibrillary acidic protein and S-100 antibodies stained most of the glial-appearing cells and some of the spindled cells, but not the polygonal cells. Muscle specific a-actin and smooth muscle specific a-actin antibodies stained only the malignant spindled and polygonal cells and normal vascular smooth muscle. Ulex europaeus agglutinin I and anti-factor VIII/related antigen antibody stained only cells lining vascular lumina. The staining results suggest that the malignant mesenchymal component of these tumors is of smooth muscle origin. Having demonstrated elsewhere that glomeruloid vascular structures of glioblastoma multiforme contain smooth muscle cells, we propose here that gliosarcomas can represent one end of the spectrum of glioma-induced vascular smooth muscle proliferation.

Accelerated myelination in early Sturge-Weber syndrome demonstrated by MR imaging.

Magnetic resonance imaging of the brain in two infants with Sturge-Weber syndrome has demonstrated a pattern of accelerated myelination in the abnormal cerebral hemisphere. The extent of myelination was most apparent on the T1-weighted inversion recovery sequence while the T2-weighted images demonstrated concomitant changes in hydration of the brain. We propose an explanation for this finding based on cerebral ischemia underlying the leptomeningeal angioma.

Isolated central nervous system angiitis first presenting as spontaneous intracranial hemorrhage

Two cases of isolated central nervous system angiitis presenting as spontaneous intracranial hemorrhage are reported. The usefulness and limitations of cortical/leptomeningeal biopsy in this condition is described. Emphasis is placed on the clinical awareness of this unusual association to ensure early recognition and prompt management with immunosuppressive therapy.

Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy

Abstract . Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distalmost portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD.