Cytoskeletal pathology in non-Alzheimer degenerative dementia: new lesions in Diffuse Lewy body disease, Pick’s disease, and Corticobasal Degeneration

Summary

Increasing use of immunocytochemistry for evaluation of dementia disorders has revealed histopathological alterations that were previously unknown, even with sensitive silver techniques. Disorders [Pick’s disease (PD), diffuse Lewy body disease (DLBD) and corticobasal degeneration (CBD)] in which immunocytochemistry has revealed occult pathology are discussed. All three disorders have neurofilament (NF) immunoreactive neuronal alterations in the neocortex. In DLBD round, eosinophilic cytoplasmic inclusions referred to as cortical Lewy bodies are neurofilament-positive, while in both PD and CBD neurofilament epitopes are expressed in irregularly swollen neurons and their proximal cell processes, which are referred to as ballooned neurons. Interestingly, the cortical neuronal population that is vulnerable to Lewy bodies is similar to that which is vulnerable to ballooned neurons. Furthermore, Lewy bodies can occasionally be detected within the cytoplasm of ballooned neurons. Besides neurofilament-immunoreactivity, Lewy bodies are immunoreactive for ubiquitin, while ballooned neurons are inconsistently stained with antibodies to ubiquitin. Both Lewy bodies and ballooned neurons can be appreciated with routine histology, but they are much easier to detect with immunocytochemistry. In contrast, a new type of neuritic alteration in the hippocampal CA2/3 region has been recognized in DLBD. These dystrophic neurites cannot be appreciated with routine histology and are only optimally seen with immunocytochemistry for ubiquitin. Their presence is a certain indication of the presence of cortical Lewy bodies.

The microtuble associated protein tau is the major constituent of neurofibrillary tangles in Alzheimer’s disease (AD). Biochemical studies have shown that Pick bodies, argyrophilic neuronal inclusions that are highly characteristic of, if not pathognomonic for PD are also composed of abnormal tau protein. Along with Pick bodies, tau has recently been detected in glial cells in PD. Similar so-called “gliofibrillary tangles” are increasingly recognized in progressive supranuclear palsy. Previously, CBD was considered to be free of such lesions, but recent studies have revealed widespread tau-positive neuronal and glial cytoskeletal lesions in CBD. A distinctive type of tau-positive glial lesion in CBD is characterized by annular clusters of grain-like tau immunoreactivity reminiscent of a neuritic plaque in AD, except that the clusters are devoid of amyloid. The tau-positive profiles are consistently located around a central astrocyte cell body. Double labeling studies with glial fibrillary acidic protein, vimentin and CD44, which are markers for reactive astrocytes, demonstrates tau immunoreactivity within astrocytic processes; these “astrocytic plaques” appear to be specific for CBD. Although NF, ubiquitin and tau proteins are present in diverse neuronal and glial inclusions in these disorders, the morphology and distribution of these lesions differentiate non-AD dementias.