Effects of Parkinson’s disease and dopamine on digit span measures of working memory

Rationale Parkinson’s disease (PD) impairs working memory (WM)—the ability to maintain items in memory for short periods of time and manipulate them. There is conflicting evidence on the nature of the deficits caused by the disease, and the potential beneficial and detrimental effects of dopaminergic medication on different WM processes. Objectives We hypothesised that PD impairs both maintenance and manipulation of items in WM and dopaminergic medications improve this in PD patients but impair it in healthy older adults. Methods We tested 68 PD patients ON and OFF their dopaminergic medication, 83 healthy age-matched controls, and 30 healthy older adults after placebo and levodopa administration. We used the digit span, a WM test with three components (forwards, backwards, and sequence recall) that differ in the amount of manipulation required. We analysed the maximum spans and the percentage of lists correctly recalled, which probe capacity of WM and the accuracy of the memory processes within this capacity, respectively. Results PD patients had lower WM capacity across all three digit span components, but only showed reduced percentage accuracy on the components requiring manipulation (backwards and sequence spans). Dopaminergic medication did not affect performance in PD patients. In healthy older adults, levodopa did not affect capacity, but did impair accuracy on one of the manipulation components (sequence), without affecting the other (backwards). Conclusions This suggests that the deficit of maintenance capacity and manipulation accuracy in PD patients is not primarily a dopaminergic one and supports a potential “overdosing” of intact manipulation mechanisms in healthy older adults by levodopa

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

The modular architecture of the neglect syndrome: Implications for action control in visual neglect

In our recent review of action control deficits in hemi spatial neglect we concluded that many patients with the disorder have deficits in visuomotor control [Coulthard, E., Parton, A., & Husain, M. (2006). Action control in visual neglect. Neuropsychologia, 44(13), 2717-2733]. This conclusion has been questioned and it has been argued instead that there are no action deficits in neglect [Himmelbach, M., Karnath, H.-O., & Perenin, M.-T. (2007). Action control is not affected by spatial neglect: A comment on Coulthard et al. Neuropsychologia, 45(8), 1979-1981]. We proposed that rather than being specific to the neglect syndrome, action control deficits are more likely to relate to lesion location. Although many of these impairments may contribute to the manifestation of neglect, they may also occur in brain-damaged patients without the condition. In this article, we explore this framework further, discussing how neglect behaviour may emerge from damage to a set of visuomotor or cognitive modules, or their connections. Central to our view is the idea that the critical combination of deficits leading to neglect varies considerably between cases, and that visuomotor or cognitive modules disrupted in the syndrome may not, in fact, be specific to neglect. (c) 2007 Elsevier Ltd. All rights reserved