Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.

The presence of maternal antibodies protected suckling C57BL/6 mice from the clinical manifestations of the acute encephalomyelitis caused by mouse hepatitis virus, strain JHM (MHV-JHM), a coronavirus, even though histological evidence of encephalomyelitis was found at early times after inoculation. 100% of infected suckling mice developed a fatal disease in the absence of maternal antibody. By 14 days after inoculation, the brains of all antibody-protected mice examined were nearly normal on histological examination. At 3-8 weeks post-inoculation, approximately 40% of the antibody-protected mice developed a neurological disease characterized by hindlimb paralysis and wasting. Evidence of inflammation and demyelination was apparent in the spinal cord and brainstem. The mice that remained asymptomatic at this time showed few signs of inflammation and none developed clinical disease over the following 9 months. Viral antigen could be detected in most of the mice examined at all times after inoculation, whether symptomatic or not, and was particularly evident in the animals with hindlimb paralysis. MHV-JHM could be consistently cultured from the mice with hindlimb paralysis. These results show that maternal immune factors can completely protect susceptible mice from the acute, fatal, clinical encephalomyelitis caused by MHV-JHM, but cannot prevent the establishment of a latent state and subsequent development of virus-induced, clinically evident, demyelinating disease. This model will be useful for studying the virus and host factors important for the development of MHV-JHM latency and subsequent virus-induced demyelination.

We describe a family with nearly 300 members over 8 generations with 32 affected individuals who have an autosomal dominant neurodegenerative disease characterized by progressive parkinsonism with dystonia unrelated to medications, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, perseverative vocalizations, and urinary incontinence. The course is exceptionally aggressive; symptom onset and death consistently occur in the fifth decade. Positron emission tomographic studies with [18F]6-fluoro-L-dopa (6FD) were performed in 4 patients and 7 individuals at risk for development of the disease. All affected subjects had markedly reduced striatal uptake of 6FD (p less than 0.001). All individuals at risk had normal striatal uptake, but high 6FD uptake rate constants were noted in 3 of the 7 studied. Autopsy findings revealed severe neuronal loss with gliosis in substantia nigra, pontine tegmentum, and globus pallidus, with less involvement of the caudate and the putamen. There were no plaques, tangles, Lewy bodies, or amyloid bodies. This kindred appears to represent a neurodegenerative disease not heretofore described. We propose the following name for this new genetic disease: autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration.

A group of similar autosomal dominant hereditary neurodegenerative disorders have been linked to chromosome 17 in thirteen kindreds. One of these disorders, known as pallido-ponto-nigral degeneration (PPND), is characterized by extensive degeneration of the globus pallidus and substantia nigra as well as accumulation of abnormally phosphorylated tau proteins. The authors now present comprehensive data on the cellular and molecular pathology of PPND, allowing its classification among chromosome 17-linked neurodegenerative disorders as well as its classification among sporadic and other familial tauopathies. First, we showed that PPND is characterized by abundant ballooned neurons in neocortical and subcortical regions as well as by tau-rich inclusions in the cytoplasm of neurons and oligodendroglia morphologically similar to those seen in corticobasal degeneration (CBD), but in a distribution pattern resembling progressive supranuclear palsy (PSP). Second, we demonstrated that antibodies to phosphorylation-independent (Alz50, 133, 304, Tau-2, T-46) as well as phosphorylation-dependent (AT8, PHF-6, 12E8, PHF-1, T3P, pS422) epitopes in human tau proteins stain these glial and neuronal inclusions as intensely as they stain CBD or PSP inclusions. Third, we probed PPND brain by Western blots using some of the same anti-tau antibodies to reveal 2 tau immunobands with molecular weights of 69 kD and 64 kD in gray and white matter extracts, as reported for both PSP and CBD. Finally, electron microscopy showed that these abnormal tau proteins formed flat twisted ribbons with a maximum diameter of 20 nanometers (nm) and a periodicity of about 200 nm, resembling those reported in CBD. Based on this, we conclude that PPND is a hereditary neurodegenerative disorder characterized by neuronal and glial tau-rich inclusions formed from aggregated filaments and hyperphosphorylated tau proteins and, hence, can be subcategorized into the tauopathy group of chromosome 17-linked neurodegenerative disorders. Further, since the morphologic and biochemical lesions of PPND overlap with those seen in sporadic CBD and PSP, we speculate that these disorders share common pathogenetic mechanisms.

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Between 1984 and 1996, seven patients with symptomatic masses located posterior to the odontoid process and containing calcium pyrophosphate dihydrate crystals were evaluated by the senior author (A.H.M). All patients presented with distal paresthesias and myelopathy and underwent transoral-transpharyngeal resection of the anterior arch of C-I, the odontoid process, and the compressing mass. Histological examination revealed the characteristic changes of calcium pyrophosphate dihydrate (CPPD) deposition disease, with nodular deposits of birefringent rhomboid crystals. On magnetic resonance imaging, the masses appeared predominantly isointense with neural tissue on T1-weighted images and iso-to hyperintense on T2-weighted images. On computerized tomography scans, small area of calcifications within the masses were apparent in all cases. All patients improved postoperatively, with six of seven patients requiring posterior fixation for instability as a second procedure. Calcium pyrophosphate dihydrate deposition causing periodontoid mass lesions is a distinct clinical disease entity that probably is underdiagnosed. In the authors' l opinion, the diagnosis can often be established preoperatively by the distinctive neuroradiological appearance of the masses. Therefore, CPPD deposition disease should be considered in the differential diagnosis of masses of the craniocervical junction, because it is amenable to early surgical intervention. The consulting neuropathologist should be made aware of this diagnostic possibility at the time of surgery.

Background: Velocardiofacial syndrome (VCFS) is one of the most common multiple anomaly syndromes in humans. Pharyngeal hypotonia, one of the most common findings in VCFS, contributes to hypernasal speech, which occurs in approximately 75% of individuals with VCFS. Objective: To evaluate the thickness and histologic and histochemical properties of the superior pharyngeal constrictor (SPC) muscle in patients with VCFS to determine whether a muscle abnormality exists that might contribute to the hypotonia seen in these patients. Subjects: The SPC muscle thickness in 26 VCFS patients (18 male and 8 female; age range, 3-29 years) was compared with SPC muscle thickness in age-and sex-matched controls using magnetic resonance images. The histologic and histochemical properties of the SPC muscle in 9 VCFS patients (6 male and 3 female; age range, 4-12 years) were compared with SPC muscle in 3 adult cadavers without VCFS (all male; age range, 80-86 years) using specimens obtained during pharyngeal flap surgery. Results: The thickness of the SPC muscle was significantly less in patients with VCFS (2.03 mm) than in patients without VCFS (2.85 mm). The SPC muscle contained a significantly greater proportion of type 1 fibers in patients with VCFS (27.7%) than in adults without VCFS (17.9%), and the diameter of the type 1 fibers was significantly smaller in patients with VCFS (21.6 µm) than in adults without VCFS (26.6 µm). Conclusions: Differences in the thickness and histologic and histochemical properties of the SPC muscle found in patients with VCFS compared with individuals without VCFS may offer insight into the cause of pharyngeal hypotonia and hypernasal speech seen in these patients.

Neoplastic angioendotheliomatosis (NAE) is a rare entity characterized by multifocal, intravascular proliferation of large pleomorphic cells within small vessels of most organs, with a particular affinity for the central nervous system. Clinically, patients with NAE present with focal neurologic signs and a progressive decline in mental status, followed by death in a few months. The histogenesis of NAE is controversial but has been previously thought to represent a malignant proliferation of endothelial cells. Three autopsy cases with clinical and histologic features of NAE were investigated by electron microscopic, standard histochemical, and immunohistochemical technics that included the use of three panleukocyte monoclonal antibodies (PLA), the endothelial-cell-specific reagents, FVIII-RAG anti-sera and Ulex europaeus agglutinin (UEA), and muramidase. The NAE cells in all three cases were stained positively by the PLA, whereas the adjacent endothelial cells and not the NAE cells were stained by FVIII-RAG and UEA. Muramidase by immunoperoxidase technic and nonspecific esterase (chloracetate) were not present in NAE cells. These results indicate that NAE is a leukocyte-derived neoplasm and not a malignant endothelial cell neoplasm. Based on these findings and on a review of the literature, it is proposed that NAE represents intravascular malignant lymphomatosis (IML). IML appears to be a primary manifestation and/or a major secondary form of disseminated malignant lymphoma. This would explain the spectrum of findings in previously reported cases.