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Brain MRI in juvenile Huntington's disease (case 1). Neuroimaging demonstrates diffuse volume loss involving the caudate nucleus with associated ventriculomegaly (T2) as well as mild cerebellar volume loss, particularly of the vermis (T1).
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Magnetic resonance imaging (MRI) of the brain showed diffuse volume loss involving the caudate nucleus with associated ventriculomegaly, as well as mild cerebellar volume loss (Fig. 1).
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Four-generation pedigree. Case 1 (IV-1) is the affected son of case 2 (III-2). Family history indicates that members of earlier generations also had Huntington's disease, including the father and paternal grandmother of case 2.
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Huntington's disease. His father died at age 52 from HD and his paternal grandmother died in her 40s of presumed HD (Fig 2). Atrophy of the caudate and putamen was moderate and assigned a Vonsattel grade of 3 (Fig. 2D). The cerebellum was grossly unremarkable (Fig. 2E,F).
Gross pathology. The juvenile (A) and the adult onset (D) case both demonstrate moderate atrophy of the caudate nucleus and putamen (Vonsattel grade 3). Sagittal sections of the cerebellum in the juvenile case also highlight the mild medial, predominantly vermian, atrophy (B) with thinning of the folia (C). In contrast, the cerebellum in the late onset case lacks significant cerebellar atrophy (E, F).
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Atrophy of the caudate and putamen was mild to mostly moderate, appropriate for grade 3 neostriatal atrophy using the Vonsattel criteria (Fig. 3A). Mild cerebellar atrophy, primarily involving the midline/vermis, was present (Fig. 3B, C).
Histopathology of the cortex and neostriatum (caudate nucleus). There is no significant loss of neocortical neurons in the juvenile case (A) compared to mild to focally moderate neuron loss in the adult onset case (D) (H&E) associated with increased astrogliosis in both cases (B, E) (GFAP). Huntingtin-positive intranuclear and cytoplasmic neuronal inclusions are present in the cerebral cortex of both cases (C, F). There is significant neostriatal neuron loss (G, J) (H&E) and associated astrogliosis (H, K) (GFAP). Striatal Huntingtin-positive neuronal intranuclear and cytoplasmic inclusions are present in both cases (I, L).
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Cerebral cortex had normal hexalaminar architecture with no definite neuron loss (Fig. 4A) and unremarkable white matter. There was mild diffuse gliosis of the cerebral cortex (confirmed with GFAP IHC; Fig. 4B). The caudate nucleus, putamen, and globus pallidus had gliotic gray matter with moderate neuron loss corresponding to histologic Vonsattel grade 3 HD (Fig. 4G,H). Prominent intranuclear huntingtin-immunopositive inclusions were identified by immunohistochemistry in cerebral cortical and striatal neurons (Fig. 4 C, I). Cerebral cortex had normal hexalaminar architecture with mild to focally moderate neuron loss (Fig. 4D) and patchy gliosis of the cerebral cortex (confirmed with GFAP immunostains; Fig. 5E). There was moderate to focally severe astrogliosis in association with moderate to focally severe neuron loss in the caudate nucleus and putamen (Fig. 4 J, K) as well as globus pallidus. Huntingtin-positive intranuclear and cytoplasmic inclusions as well as scattered extracellular inclusions were confirmed by immunohistochemistry in the frontal cortex and striatum (Fig. 4F,L); intranuclear and cytoplasmic inclusions were not identified in cerebellum (Fig 5 L).
Histopathology of the cerebellum. Marked atrophy of cerebellar cortex with associated severe gliosis is evident in H&E, Bielschowsky, and GFAP-stained sections in JHD (A-E) but not in the adult onset case (G-K). Rare huntingtin-positive intranuclear inclusions are identified in the cerebellum of the JHD brain (F) that are not identified in the AOHD case (L).
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There was also marked atrophy of cerebellar cortex characterized by severe thinning of the molecular layer and prominent loss of Purkinje cells with associated Bergmann gliosis (Fig. 5A-E). GFAP in particular highlighted the increased gliosis (Fig. 5C). Granule neurons were relatively preserved. Of the remaining Purkinje cells, many were small with irregular cytoplasmic borders and pyknotic nuclei with rare huntingtin-immunopositive intranuclear inclusions (Fig. 5F). The cerebellum was relatively uninvolved; Purkinje neurons were intact and significant Bergmann gliosis was not noted (Fig. 5 G-K). Huntingtin-positive intranuclear and cytoplasmic inclusions as well as scattered extracellular inclusions were confirmed by immunohistochemistry in the frontal cortex and striatum (Fig. 4F,L); intranuclear and cytoplasmic inclusions were not identified in cerebellum (Fig 5 L).