Neuronal intranuclear and neuropil inclusions for pathological assessment of Huntington's disease

Abstract

To evaluate the usefulness of neuronal intranuclear inclusions and neuropil inclusions for the pathological assessment of Huntington's disease (HD), their presence in neocortex was assessed by ubiquitin and N-terminal huntingtin immunohistochemistry in a consecutive series of 195 autopsy brains of individuals with a positive or tentative clinical diagnosis of, or at risk for, HD. The findings were correlated with striatal pathology (n = 190), CAG repeat length (n = 85) and original pathological diagnosis (n = 186). The antibodies detected both these inclusions in 181 patients with HD pathology > or = Vonsattel et al's grade I, five patients lacking striatal tissue for review, and two at-risk individuals with grade 0 and grade I HD pathology, respectively. One patient with HD-like pathology and two patients and four at-risk individuals without HD pathology lacked HD inclusions. In the genetically analyzed cases, the inclusions were exclusively and consistently observed in association with repeat expansion [(CAG)(n) > or = 39, n = 81]. Thirteen inclusion-positive cases, including the grade 0 at-risk individual, had a false negative original pathological diagnosis of HD and four had an unjustly questionable diagnosis. A false positive diagnosis was made in the inclusion-negative case with HD-like pathology. These results indicate that immunohistochemical analysis for HD inclusions facilitates the pathological evaluation of HD and enhances its accuracy.

Figure 1

Neuronal intranuclear inclusions (A–C) and neuropil inclusions (D–F) in the neocortex of the brains of two at‐risk individuals with grade I (A,B,D,E) and grade 0 (C,F) HD pathology, respectively. Immunostaining was performed with an antibody against ubiquitin (A,D) and antiserum H7 (B,E) and antibody 5374 (C,F) both directed to the N‐terminus of huntingtin. Scale bar (A–F) 10 µm.

Figure 2

Neuronal intranuclear inclusion (A) and neuropil inclusion (B) in the tail of the caudate of the brain of the at‐risk individual with grade 0 HD pathology. Immunostaining was performed with antibody 5374 directed to the N‐terminus of huntingtin. Scale bar (A,B) 10 µm.