Neuroimaging studies have consistently shown cortical and basal ganglia atrophy in individuals with HDL2, even in relatively early cases [11, 20, 26]. Qualitatively, MRI images cannot be distinguished from those of HD patients (Fig. 2). While quantitative studies have not been performed, there is no consistent qualitative evidence of atrophy outside of the cortex and basal ganglia.

The neuropathology of 4 HDL2 cases has been published. The case from the index HDL2 family came to autopsy 20 years after disease onset. Gross examination showed mild frontal, temporal, and mesial parietal and occipital atrophy, with severe atrophy of the caudate and putamen. White matter appeared normal. Microscopic examination showed marked neuronal loss with relative sparing of

Fig. 2 Striatal and cerebral cortex atrophy in HDL2 resembles HD. (a, d) HDL2 case, age 36, 10 year disease duration. (b, e) HD case, age 48 years, 12 year, disease duration. (c, f) Normal control, age 43. (Reprinted, with permission, from Margolis et al. [11].)

larger neurons, astrocytosis, and neuropil vacuolation of the striatum (caudate worse than putamen), in a dorsal to ventral gradient. The globus pallidus was affected to a lesser extent, and neurodegeneration without Lewy bodies was observed in the substantia nigra. There was no evidence of neurofibrillary tangles or amyloid plaques. Intranuclear inclusion bodies are typically found in various regions, discussed in more detail below.

An unrelated individual [26], autopsied about 23 years after disease onset and retrospectively determined to have the HDL2 mutation, displayed similar, but not identical, findings. Cortical atrophy was diffuse, except for sparing of the hippocampus and medial temporal lobe. The striatum was severely atrophic, with much less atrophy of the globus pallidum. Pigmentation of the locus ceruleus and the substantia nigra was reduced. Substantial gliosis and neuronal loss, sparing large somatostatin-positive inter-neurons, was apparent in the striatum, with milder neuronal loss detected in multiple other brain regions, including substantia nigra, locus ceruleus, and amygdala. The frequency of scattered neurofibrillary tangles was considered to be within the normal range for age.

Two cases recently reported showed similar findings with a few interesting differences [3]. In the first case, mild atrophy was detected in the acumbens, and isolated regions of parietal and occipital cortex showed loss of large neurons in layers V and VI. There was evidence of mild neurodegeneration in the substantia nigra and the locus ceruleus, and mild AD-type findings in paralimbic and allocortical regions. The second case was notable, in addition to marked striatal neurodegeneration, for very prominent occipital lobe involvement, particularly in the primary visual cortex. Substantia nigra was mildly affected.

One conclusion from these preliminary findings is that HDL2 and HD cannot be distinguished on pathological grounds in any given case, but there may be more occipital lobe involvement, and perhaps substantia nigra involvement, in HDL2.

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