HD Insights™

HD INSIGHTS Research Round-Up By: Lise Munsie and Mahmoud Pouladi, PhD In the scanner... Huntington disease (HD) imaging data is providing new insights into the mechanism of disease, and is also providing sensitive biomarkers. Identification of biomarkers is critical to the success of clinical trials of disease-modifying therapeutic agents. Imaging techniques include magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and functional MRI (fMRI). The TRACK-HD team led by Prof. Sarah Tabrizi has now published its 24-month data, which supports the 12-month data from the team's previous report, showing that imaging markers are the most effective method to detect disease-related group differences in premanifest and early HD patient groups.1 The team's data also indicates that striatal and total white matter atrophy are the most sensitive anatomical measures of premanifest HD. Di Paola and colleagues used MRI to investigate changes in the corpus callosum, which has the largest white matter tract in the human brain.2 Their findings complement those of the TRACK-HD study; white matter changes in the corpus callosum in premanifest and early HD suggest that the corpus callosum may be a key structure in the development of the neuropathology of HD. MRI-observable changes in corpus callosum white matter may be a biomarker in the progression of HD. Zacharoff and colleagues published data on the R6/2 mouse model of HD.3 They used MRS to investigate changes in brain metabolites, and MRI to assess changes in brain volume. They found that changes in brain metabolites manifest before changes in brain volume. This data aids in validating HD mouse models for use in drug discovery and target design. 1 Tabrizi SJ, Reilman R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012;11(1): 42-53. 2 Di Paola M, Luders E, Cherubini A, et al. Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington's disease. Cerebral Cortex. 2012 Jan 5 [Epub] doi:10.1093/ cercor/bhr360 3 Zacharoff L, Tkac I, Song Q, et al. Cortical metabolites as biomarkers in the R6/2 model of Huntington's disease. Journal of Cerebral Blood Flow & Metabolism. 2011 1-13. HD Insights, Vol. 2 In the lab... Two studies in the December 2011 issue of Nature highlight Sirt1, an NAD-dependent protein deacetylase implicated in the regulation of cellular metabolism, as a potential therapeutic target for HD. Jiang and colleagues demonstrated that mutant huntingtin (mHTT) inhibits Sirt1 deacetylase activity, which alters the acetylation status of a number of its substrates such as FoxO3a, and influences their function.4 Knockdown of Sirt1 in vitro exacerbated mHTT-mediated toxicity, whereas overexpression of Sirt1 restored the concentrations of acetylated FoxO3a and p53 to baseline levels and protected against mHTT toxicity. The authors reported that in N171-82Q and BACHD mice, overexpression of Sirt1 improved motor function and reduced neuropathology, including striatal and cortical atrophy. In N171-82Q mice some metabolic parameters were improved, including improved insulin sensitivity as shown by attenuated hyperglycaemia and decreased plasma insulin levels; improved glucose tolerance; and attenuated body weight loss. Jeong and colleagues examined the effect of modulation of Sirt1 levels in R6/2 mice.5 Brain- specific knockdown of Sirt1 worsened motor dysfunction and exacerbated striatal atrophy. Conversely, global overexpression of Sirt1 attenuated striatal atrophy and was associated with restoration of BDNF levels. Although there is a disconnect in the impact of Sirt1 overexpression on survival, body weight, and mHTT aggregates in the N171-82Q and R6/2 mice, these studies highlight a role for Sirt1 in the pathogenesis of HD. The neuroprotective effects of Sirt1 show that it is a potential therapeutic target for HD. In the clinic... Neuropsychiatric disturbances are common in HD patients, and two recent studies explore depression and apathy. Richards and colleagues exploited the richness of the data repository assembled as part of the European Huntington's Disease Network REGISTRY Study, to examine the discriminant value of items on two depression rating scales, namely the Beck Depression Inventory (BDI), and the Hamilton Rating Scale for Depression (HAM-D).6 Using a discriminant analysis method, the authors found that items from the BDI were more likely than items from the HAM-D to discriminate depressed mood HD patients from those without depressed mood. Loss of interest, guilt, and suicidal thoughts were the best discriminators of depressed mood. Weight loss, measures of sleep disturbances, and irritability were poor discriminators of depressed mood. This study can assist in the development of refined measures of depression in HD patients. Reedeker and colleagues examined the incidence, course and predictors of apathy in HD in a prospective study.7 Patients were assessed using a modified version of the Apathy Evaluation Scale at baseline, and re-assessed after two years. Of the patients who completed the study, 14% who were free of apathy at baseline later developed apathy. The development of apathy in these patients was associated with a lower baseline Mini-Mental State Exam score, supporting a role for cognitive dysfunction in the development of apathy in HD. Of 34 patients with apathy at baseline, 14 subjects were no longer apathetic at follow-up, indicating that apathy in HD is reversible, and suggesting that targeting treatable causes of apathy may aid in combating apathy in HD. 4 Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med. 2011 Dec 18;18(1):153-8. 5 Jeong H, Cohen DE, Cui L, Supinski A, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med. 2011 Dec 18;18(1):159-65. 6 Rickards H, Souza JD, Crooks J, et al. Discriminant Analysis of Beck Depression Inventory and Hamilton Rating Scale for Depression in Huntington's Disease. J Neuropsychiatry Clin Neurosci. 2011 Sep 1;23(4):399-402.. 7 Reedeker N, Bouwens JA, van Duijn E, et al. Incidence, Course, and Predictors of Apathy in Huntington's Disease: A Two-Year Prospective Study. J Neuropsychiatry Clin Neurosci. 2011 Sep 1;23(4):434-41. Copyright © Huntington Study Group 2012. All rights reserved. 3

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