Ubiquitin immunoreactive structures in normal human brains. Distribution and developmental aspects

Ubiquitin-immunoreactive structures in normal human brains ranging in age from 2 months to 91 years were studied with light and electron microscopy. Antibodies to ubiquitin immunostained structures in both neurons and glia. In the cerebrum, ubiquitin-immunoreactive, coarsely granular structures were most consistent with dystrophic neurites. They were most numerous in middle and upper cortical layers, especially lamina II of the entorhinal cortex and the cortical and accessory basal nuclei of the amygdala. Dystrophic neurites were first detected in brains of young adults, increased with age, and were numerous in the oldest brains. One of the normal elderly subjects had a small number of senile plaques with dystrophic neurites similar to those in the gray matter of the other brains, except for their location adjacent to amyloid deposits. With immunoelectron microscopy, dystrophic neurites were nonmyelinated neuronal processes containing dense, lamellar bodies, and finely granular material. White matter consistently had more immunoreactive structures than gray matter at all ages. The immunoreactive structures in white matter were smaller, less coarsely granular "dot-like" structures. With immunoelectron microscopy, dot-like structures were composed of dense inclusions within glial cells and focal swellings in myelin lamellae containing heterogeneous dense material. Only rarely were axons immunostained. Axonal spheroids in the basal ganglia, substantia nigra, and dorsal medulla were ubiquitin-immunoreactive. Spheroids were detected in these locations as early as the second decade, and they increased in number with age. A few dystrophic axons could be detected in spinal nerve roots of the oldest subjects. Other ubiquitin-immunoreactive structures included nuclei of small granular neurons, especially those in lamina II of the neocortex of the youngest brains; round cytoplasmic inclusions in tanycytes of all brains; and intranuclear Marinesco bodies in the substantia nigra and eosinophilic cytoplasmic inclusions in inferior olivary neurons in the oldest brains. These results demonstrate the spectrum of ubiquitinated structures in normal brains and suggest that progressive axonal dystrophy may be a more common age-related pathologic alteration of the brain than formerly recognized.