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Eighteen patients with early Huntington's disease were compared with age- and IQ-matched control volunteers on tests of executive and mnemonic function taken from the Cambridge Neuropsychological Test Automated Battery. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, spatial planning and visual discrimination learning/attentional set shifting were employed. These tests have previously been found to be sensitive to the later stages of Huntington's disease. Patients with early Huntington's disease were found to have a wide range of cognitive impairments encompassing both visuospatial memory and executive functions, a pattern distinct from those seen in other basal ganglia disorders. In contrast to patients with more advanced Huntington's disease, early Huntington's disease patients were not impaired at simple reversal learning, but were impaired at performing an extradimensional shift (EDS). The results will be discussed in relation to the hypothesized neuropathological staging of Huntington's disease and to the anatomical connectivity of the striatum.

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The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells.