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We performed a detailed study of swollen neurite aggregation surrounding extracellular neurofibrillary tangles (ghost tangles, GTs) in brains of patients with progressive supranuclear palsy (PSP) by immunohistochemistry and electron microscopy (EM). The complex structures, designated as tangle-associated neuritic clusters (TANCs), were found in the hippocampus and parahippocampal cortex in all five PSP brains examined. TANCs measured from 20 to 40 microm across; twice as large as nearby neurons. Each neurite was globular or fusiform in shape, measured up to 10 microm in diameter, and was found between loosened fascicles of GTs or along their outer rims. There were several subsets of neurites that were argyrophilic or immunoreactive against antibodies to either phosphorylated tau protein, phosphorylated neurofilaments, ubiquitin, or synaptophysin. On EM, TANCs consisted of numerous axon terminals of varying size, which were filled with flocculate dense bodies, vesicular profiles, and synaptic vesicles, as well as normal-looking and degenerating cell organelles. Some axons had 13- to 15-nm-thick straight tubules that showed tau immunoreactivity; however, there was little neurofilament accumulation. Most of the swollen axon terminals conformed to the ultrastructural features of either reactive or degenerating terminals. The neurites identified by immunohistochemistry only represented a minority of the swollen axons visualized by EM. Tubules of GTs were dispersed in the extracellular space, but no amyloid fibrils were found. TANCs may constitute a distinctive form of neuronal degeneration in PSP cortices. We hypothesize that axon terminal accumulation may occur in response to GT-formation.

We examined neuronal cytoplasmic inclusions (NCIs) and oligodendrocytic glial cytoplasmic inclusions (GCIs) in the pontine nuclei in multiple system atrophy (MSA) using antibodies against the non-amyloid beta component of Alzheimer's disease amyloid precursor protein (NACP/alpha-synuclein). Our immunohistochemical study revealed that anti-NACP antibodies labeled both NCIs and GCIs. Immunoelectron microscopy showed that positive reaction products were localized on the 15- to 30-nm-thick filamentous components of NCIs and GCIs. The present study demonstrates that NACP is associated with cytoplasmic inclusions of MSA, and suggests a role of NACP in abnormal filament aggregation in neuronal degeneration.

We found eosinophilic fibrillary neuronal inclusions (EFNI) that were argyrophilic and immunoreactive for anti-ubiquitin in the cerebral cortex of a patient with sporadic amyotrophic lateral sclerosis (ALS) and mild personality changes. Both hematoxylin and eosin and Bodian's preparations revealed the EFNI to be rod-, flame-shaped, or spherical structures existing within the swollen neuronal perinuclear region in the third, fifth, and sixth layers of the fronto-parieto-temporal cortices including the primary motor cortex. On electron microscopy, filamentous profiles aggregated and formed a single bundle or globule in the neuronal perikaryon without any limiting membrane. Most EFNI had a characteristic multiple layer arrangement. The inner core consisted of randomly oriented granule-free tubules with a fuzzy outer contour, measuring 15-20 nm in diameter. The surrounding layer was made up of granule-associated filaments, electrondense free granules, and small vesicular profiles. Large autolysosome-like membrane-bound vesicular profiles were found scattered at the periphery. Neurofilaments were usually mingled with in the surrounding cytoplasm. Many EFNI were also found in dendrites, but only a few in axons. Both granule-free tubules and granule-associated filaments expressed ubiquitin protein epitopes. Aberrant phosphorylation of neurofilament protein and induction of alphaB-crystallin were shown to exist in EFNI-bearing swollen neurons. Despite having a variety of histological appearances, our observations revealed that EFNI all have common immunocytochemical and ultrastructural characteristics, and thus we assume that EFNI represent a series of cytological alterations in the motor and extra-motor cortices of ALS patients.

Coiled bodies and interfascicular threads are conspicuous white matter abnormalities of brains of patients with progressive supranuclear palsy (PSP). Both structures are argyrophilic and immunoreactive for the microtubule-binding protein tau. This report concerns the ultrastructural localization of interfascicular threads and their relationship to coiled bodies in five PSP patients. We showed for the first time that abnormal tubules with a 13- to 15-nm diameter and fuzzy outer contours were the common structures of coiled bodies in the oligodendroglial perikarya and of interfascicular threads. Moreover, the tubules were immunolabeled by anti-tau antibodies. The abnormal tau-positive tubules of interfascicular threads were located in the inner loop of the myelin sheath. Our study further indicated that the thread-like structures in the white matter comprised, at least in part, oligodendroglial processes, and that they were also present in gray matter. We consider that the formation of coiled bodies in the perikarya and of interfascicular threads represents a common cytoskeletal abnormality of the oligodendroglia of PSP patients. Moreover, even though the white matter alterations of PSP resemble those of corticobasal degeneration, there are certain ultrastructural differences in the abnormal oligodendroglial tubules of the two diseases.

Myotonic dystrophy (DM) is genetically characterized by abnormal expansion of an unstable CTG trinucleotide repeat, located in the 3'-untranslated region of mRNA encoding the family of serine-threonine protein kinases. DNA extracted from various organs of patients with DM was analyzed by the Southern blotting method. We identified differently expanded bands in DNAs from various tissues from patients with DM. In studying the length of the CTG repeat in different regions of the brain, we found a noticeably small increase in repeat length in the cerebellum compared with other tissues. While this phenomenon has been reported in other triplet repeat diseases such as Huntington disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy, we are the first to describe it in DM. Although the mechanism of expansion of the triplet repeat remains to be defined, the tissue-dependent somatic mosaicism suggests that its occurrence may depend on the differentiated state of each tissue.

A 42-year-old woman with distal myopathy with rimmed vacuoles had intracytoplasmic inclusion bodies similar to those described in reducing body myopathy. Since these inclusions were found in fibers with high acid phosphatase activity and occasional rimmed vacuoles, their formation appeared to correlate with active myofibrillar degeneration, but their origin remains unknown.

Four patients with mitochondrial abnormality had multiple muscle biopsies at several year intervals during which respiratory chain enzyme activities were shown to be quite variable. In three patients, progression of the disease paralleled the decrease in respiratory chain enzyme activity. In one patient, the clinical and pathological findings improved with age as is seen in the benign infantile form of cytochrome c oxidase (CCO) deficiency. The variability in these mitochondrial disorders may result from the varied proportions of normal and abnormal mitochondria in the muscle cells in which the mitochondria are said to be randomly replicated from numerous mitochondrial DNA copies.