Huntington's Disease Progression Research Articles

Altered resting‐state connectivity in Huntington's Disease

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Using resting-state fMRI (rs-fMRI) we investigated the functional integrity of resting-state networks (RSN) in HD. 17 HD and 19 matched control participants were examined at a 3 Tesla MR scanner. After controlling for structural degeneration by means of voxel-based morphometry, task-free rs-fMRI data were analyzed using Independent Component Analysis (ICA) and a dual-regression approach in the context of genetic and clinical parameters. Further, we evaluated HD-related differences in interregional connectivity between networks. RSN analysis showed a significant increase in intrinsic functional connectivity in the HD sample compared with controls, including the thalamus, striatum, prefrontal, premotor, and parietal maps. A subset of the Default Mode Network (DMN) was also affected. In the HD cohort, motor impairment correlated with higher network connectivity in mainly motor and parietal cortices. Deteriorating total functional capacity was additionally associated with higher connectivity in the striatum, thalamus, insular and frontal areas. This pattern of increased activity in intrinsic functional networks might suggest a reduced ability of intra-network differentiation with clinical disease progression in HD. Finally, results showed reduced long-range connectivity between parietal ICA components in HD compared to controls, indicating impaired functional coupling between interregional networks in HD. Our data demonstrates that functional connectivity is profoundly altered in HD, both within and between RSN. Rs-fMRI analysis may provide additional valuable insights into neuronal dysfunctions beyond HD-related structural degeneration and disruptions of functional circuits in HD.

The Q175 Mouse Model of Huntington’s Disease Shows Gene Dosage- and Age-Related Decline in Circadian Rhythms of Activity and Sleep

Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington’s disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.

SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

SUMMARYA key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.

In vitro and in vivo models of Huntington's disease show alterations in the endocannabinoid system

In this study, we analyzed the components of the endocannabinoid system (ECS) in R6/2 mice, a widely used model of Huntington's disease (HD). We measured the endogenous content of N-arachidonoylethanolamine and 2-arachidonoylglycerol and the activity of their biosynthetic enzymes (N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and diacylglycerol lipase, respectively) and hydrolytic enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively] and of their target receptors (type 1 cannabinoid receptor, type 2 cannabinoid receptor, and transient receptor potential vanilloid-1) in the brains of wild-type and R6/2 mice of different ages, as well as in the striatum and cortex of 12-week-old animals. In addition, we measured FAAH activity in lymphocytes of R6/2 mice. In the whole brains of 12-week-old R6/2 mice, we found reductions in N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D activity, diacylglycerol lipase activity and cannabinoid receptor binding, mostly associated with changes in the striatum but not in the cortex, as well as an increase in 2-arachidonoylglycerol content as compared with wild-type littermates, without any other change in ECS elements. Then, our analysis was extended to HD43 cells, an inducible cellular model of HD derived from rat ST14A cells. In both induced and noninduced conditions, we demonstrated a fully functional ECS. Overall, our data suggest that the ECS is differently affected in mouse and human HD, and that HD43 cells are suitable for high-throughput screening of FAAH-oriented drugs affecting HD progression.

Cerebellar contribution to anger recognition deficits in Huntington's disease.

Although there is increasing evidence that cerebellar loss of grey matter volume (GMV) is associated with affective deficits, this has not been tested for patients suffering from Huntington's disease (HD), who show a pronounced impairment in the recognition of anger. We assessed GMV in 18 symptomatic HD patients and 18 healthy controls using voxel-based morphometry. The GMV of cerebellar subregions was correlated with participants' intensity and accuracy ratings for facial expressions of basic emotions from the Karolinska Directed Emotional Faces (Lundqvist et al. 1998). The patients gave lower and less accurate anger ratings for angry faces than controls. This anger recognition deficit was correlated with atrophy of selected hemispheric and vermal regions of the cerebellum. Furthermore, cerebellar volume reductions of the HD patients were associated with longer disease duration and greater functional impairment. The data imply that anger recognition deficits could potentially serve as indicators of disease onset and progression in HD. Furthermore, the patients might profit from specific affect trainings.

Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease

5-Hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine. While the dynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington's disease (HD). We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificial chromosome transgene with 128 CAG repeats) HD mouse brain tissues when compared with age-matched wild-type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains during postnatal development. Genome-wide distribution analysis of 5-hmC further confirmed the diminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions. Intriguingly, we have identified disease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuity pathway analysis (IPA) of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/β-catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset of HD. Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that this aberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain. Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscape may have the potential to slow/halt the progression of HD.

Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data

TRACK-HD is a multinational prospective observational study of Huntington's disease (HD) that examines clinical and biological findings of disease progression in individuals with premanifest HD (preHD) and early-stage HD. We aimed to describe phenotypic changes in these participants over 36 months and identify baseline predictors of progression. Individuals without HD but carrying the mutant huntingtin gene (classed as preHD-A if ≥10·8 years and preHD-B if <10·8 years from predicted onset), participants with early HD (classed as HD1 if they had a total functional capacity score of 11-13 and HD2 if they had a score of 7-10), and healthy control individuals were assessed at four study sites in the Netherlands, the UK, France, and Canada. We measured 36-month change for 3T MRI, clinical, cognitive, quantitative motor, and neuropsychiatric assessments and examined their prognostic value. We also assessed the relation between disease progression and the combined effect of CAG repeat length and age. All participants were analysed according to their baseline subgroups. Longitudinal results were analysed using a combination of repeated-measure weighted least squares models and, when examining risk of new diagnosis, survival analysis. At baseline, 366 participants were enrolled between Jan 17, and Aug 26, 2008, and of these 298 completed 36-month follow-up: 97 controls, 58 participants with preHD-A, 46 with preHD-B, 66 with HD1, and 31 with HD2. In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months. Of the cognitive measures, the symbol digit modality test was especially sensitive (adjusted mean loss 4·11 points [95% CI 1·49-6·73] greater than controls; p=0·003). Among psychiatric indicators, apathy ratings specifically showed significant increases (0·34 points [95% CI 0·02-0·66] greater than controls; p=0·038). There was little evidence of reliable change in non-imaging measures in the preHD-A group, with the exception of the speeded tapping inter-tap interval (0·01 s [95% CI 0·01-0·02] longer than controls; p=0·0001). Several baseline imaging, quantitative motor, and cognitive measures had prognostic value, independent of age and CAG repeat length, for predicting subsequent clinical diagnosis in preHD. Of these, grey-matter volume and inter-tap interval were particularly sensitive (p=0·013 and 0·002, respectively). Longitudinal change in these two measures was also greater in participants with preHD who received a diagnosis of HD during the study compared with those who did not, after controlling for CAG repeat length and age-related risk (p=0·006 and 0·0003, respectively). In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change; also, neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity (problem behaviours assessment composite behaviour score p<0·0001). Age and CAG repeat length explained variance in longitudinal change of multimodal measures, with the effect more prominent in preHD. We have shown changes in several outcome measures in individuals with preHD over 36 months. These findings further our understanding of HD progression and have implications for clinical trial design. CHDI Foundation.

8OHdG is not a biomarker for Huntington disease state or progression

To evaluate plasma 8-hydroxy-deoxy-guanosine (8OHdG) levels as a potential biomarker of premanifest and early Huntington disease (HD). Personnel from 2 independent laboratories quantified 8OHdG in blinded longitudinal plasma samples taken 24 months apart from 160 TRACK-HD participants, as well as samples containing control plasma with added ("spiked") 8OHdG. One laboratory used a liquid chromatography-electrochemical array (LCECA) assay, and the other used liquid chromatography-mass spectrometry (LCMS). The LCMS assay was more accurate than the LCECA assay for measurements of "spiked" 8OHdG levels in plasma. Neither assay demonstrated cross-sectional differences in plasma 8OHdG among controls, premanifest HD, and early symptomatic HD. Similarly, neither assay showed longitudinal changes in any disease group over 24 months. Plasma concentration of 8OHdG is not a biomarker of disease state or progression in HD. We recommend that future putative biomarker studies use blinded sample analysis, standard curves, independent analytical methods, and strict quality control of sample collection and storage.

Decreased expression of GLT‐1 in the R6/2 model of Huntington's disease does not worsen disease progression

Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease (HD). Glutamate is the predominant excitatory neurotransmitter in the brain, and excess activation of glutamate receptors can cause neuronal dysfunction and death. Glutamate transporters regulate the extracellular concentration of glutamate. GLT-1 is the most abundant glutamate transporter, and accounts for most of the glutamate transport in the brain. Administration of ceftriaxone, an antibiotic that increases the functional expression of GLT-1, can improve the behavioral phenotype of the R6/2 mouse model of HD. To test the hypothesis that GLT-1 expression critically affects the HD disease process, we generated a novel mouse model that is heterozygous for the null allele of GLT-1 and carries the R6/2 transgene (double mutation). We demonstrated that the protein expression of total GLT-1, as well as two of its isoforms, is decreased within the cortex and striatum of 12-week-old R6/2 mice, and that the expression of EAAC1 was decreased in the striatum. Protein expression of GLT-1 was further decreased in the cortex and striatum of the double mutation mice compared with the R6/2 mice at 11 weeks. However, the effects of the R6/2 transgene on weight loss, accelerating rotarod, climbing and paw-clasping were not exacerbated in these double mutants. Na(+) -dependent glutamate uptake into synapatosomes isolated from the striatum and cortex of 11-week-old R6/2 mice was unchanged compared with controls. These results suggest that changes in GLT-1 expression or function per se are unlikely to potentiate or ameliorate the progression of HD.

Diffusion weighted imaging of prefrontal cortex in prodromal huntington's disease

Huntington's disease (HD) is a devastating neurodegenerative disease with no effective disease-modifying treatments. There is considerable interest in finding reliable indicators of disease progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion-weighted imaging (DWI) may provide a reliable marker of disease progression by characterizing diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connections and documented role in executive function. This study uses DWI to characterize diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. Prodromal HD individuals were separated into three CAG-Age Product (CAP) groups (16 low, 22 medium, 15 high) that indexed baseline progression. Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. For MD and RD, differences among controls and HD participants tracked with baseline disease progression. The smallest difference was for the low group and the largest for the high group. Significant correlations between Trail Making Test B (TMTB) and mean fractional anisotropy (FA) and/or RD paralleled group differences in mean MD and/or RD in several right hemisphere regions. The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression in future longitudinal studies as increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals.

Plasma 24S-hydroxycholesterol correlation with markers of Huntington disease progression

24S-hydroxycholesterol (24OHC) is involved in the conversion of excess cholesterol in the brain, and its level in plasma is related to the number of metabolically active neuronal cells. Previous research suggests that plasma 24OHC is substantially reduced in the presence of neurodegenerative disease. Huntington disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by a cytosine–adenine–guanine (CAG) triplet repeat expansion in the coding region of the huntingtin (HTT) gene. The current study focused on the relative importance of 24OHC as a marker of HD progression. Using mass spectrometry methods, we examined plasma 24OHC levels in three groups of gene-expanded individuals (Low, Medium, High) characterized by their progression at entry into the parent PREDICT-HD study, along with a group of non-gene-expanded controls (total N=150). In addition, the correlation of 24OHC with a number of motor, cognitive, and imagining markers was examined, and effect sizes for group differences among the markers were computed for comparison with 24OHC. Results show a progression gradient as 24OHC levels decreased as the progression group increased (Low to High). The effect size of group differences for 24OHC was larger than all the other variables, except striatal volume. 24OHC was significantly correlated with many of the other key variables. The results are interpreted in terms of cholesterol synthesis and neuronal degeneration. This study provides evidence that 24OHC is a relatively important marker of HD progression.

Measuring Executive Dysfunction Longitudinally and in Relation to Genetic Burden, Brain Volumetrics, and Depression in Prodromal Huntington Disease

Executive dysfunction (ED) is a characteristic of Huntington disease (HD), but its severity and progression is less understood in the prodromal phase, e.g., before gross motor abnormalities. We examined planning and problem-solving abilities using the Towers Task in HD mutation-positive individuals without motor symptoms (n = 781) and controls (n = 212). Participants with greater disease progression (determined using mutation size and current age) performed more slowly and with less accuracy on the Towers Task. Performance accuracy was negatively related to striatal volume while both accuracy and working memory were negatively related to frontal white matter volume. Disease progression at baseline was not associated with longitudinal performance over 4 years. Whereas the baseline findings indicate that ED becomes more prevalent with greater disease progression in prodromal HD and can be quantified using the Towers task, the absence of notable longitudinal findings indicates that the Towers Task exhibits limited sensitivity to cognitive decline in this population.

Differential effects of early environmental enrichment on emotionality related behaviours in Huntington's disease transgenic mice

Psychiatric disorders such as depression and anxiety are reported in patients with Huntington's disease (HD). Recent studies suggest beneficial effects of environmental enrichment (EE) on HD progression possibly through the serotonergic system. We investigated the potential effectiveness of EE in correcting the affective-like phenotype of female R6/1 HD mice. In addition to a behavioural battery of tests assessing depression and anxiety-related endophenotypes, we recorded physiological measures, including body temperature regulation and defecation rate as indices of stress reactivity. Finally, following identification of changes in serotonin (5-HT) receptor gene expression we measured the function of 5-HT(1A) auto- and hetero-receptors. We found that 8-week-old female HD mice exhibited higher immobility time in the forced swimming test and a decreased preference for saccharin solution. EE did not correct those depressive-like behaviours but reduced anxiety-related measures in unconditioned approach/avoidance conflict situations. Defecation rate in a large open field and change in temperature during exposure to the tail suspension test were both enhanced in HD compared to wild-type animals. Despite the enhanced hypothermic response to the 5-HT(1A) receptor agonist 8-OH-DPAT exhibited by HD mice, we found a reduction in 5-HT(1A) receptor-mediated stimulation of [(35)S]GTP-γ-S binding in the dorsal raphe nucleus and the hippocampus of HD animals. EE did not change 5-HT(1A) receptor function. Our data suggest that early EE has beneficial effects on the anxiety-like, but not on depression-like, behaviours in HD. This is the first evidence that these affective endophenotypes can be dissociated via this form of environmental stimulation. As 5-HT(1A) receptor dysfunction was not affected by EE, this receptor is unlikely to underlie the anxiety-related phenotype of HD. However, the specific regulatory role of the 5-HT(1A) autoreceptor in mediating depressive-like behaviour in HD remains to be elucidated. Interestingly, by comparing in vivo and in vitro results, our findings suggest that 8-OH-DPAT-induced hypothermia could be mediated by other targets besides the 5-HT(1A) autoreceptor, including hippocampal 5-HT(7) receptors.

OCULOMOTOR DEFICITS IN PREMANIFEST AND EARLY HUNTINGTON'S DISEASE AND THEIR STRUCTURAL BRAIN CORRELATES: THE LONGITUDINAL TRACK-HD STUDY

BackgroundOculomotor deficits are a potential predictor of Huntington's Disease (HD). Saccadic abnormalities include delayed initiation, low velocity and a lack of inhibition and can be partially explained by HD's stereotypical...

Androgen Function in the Pathophysiology and Treatment of Male Huntington’s Disease Patients

Low concentrations of circulating testosterone have been associated with dementia manifesting with advancing age and in neurodegenerative conditions. Huntington's disease (HD) is a dominantly inherited neurodegenerative disease with an invariably fatal outcome. Severe motor symptoms, psychosis and dementia are symptomatic hallmarks of the progression of HD that result from the dysfunction and death of neocortical and basal ganglia neurones. Treatments are directed toward manifest symptoms, although they are largely ineffectual in slowing or preventing disease progression. Emerging data have identified hypothamic pathologies in HD that result in endocrine disturbances. Clinically defined primary or secondary hypogonadism elicit low circulating testosterone concentrations and have been linked to the development of Alzheimer's disease in men. Examining similar neuroendocrine dysfunction in HD including the nature of manifest hypogonadism in male patients could allow an elucidation of the complex pathophysiology of HD and provide an impetus for hitherto untested testosterone replacement therapy.

Evidence from the R6/2 Mouse Model of Huntington's Disease for Using Abnormal Brain Metabolism as a Biomarker for Evaluating Therapeutic Approaches for Treatment.

Huntington's disease (HD) is an autosomal dominant genetic disorder characterized by a progression of motor abnormalities as well as cognitive and psychiatric symptoms [1]. Presently, there is no cure for HD and no treatment to reverse its course or prevent its onset. HD has been characterized primarily by significant degeneration of the striatum. In addition, imaging studies have shown alterations in extra-striatal regions including the cortex [2, 3], hippocampus, and hypothalamus [4]. Although previous functional magnetic resonance imaging (fMRI) studies in patients have yielded complex and heterogeneous findings, identifying functional alterations may serve as a useful tool for tracking the progression of HD and assessing the effects of therapeutic interventions. In a recent article Cepeda-Prado et el. use novel and groundbreaking fMRI methods to elucidate functional, structural, and metabolic alterations in the R6/2 mouse model of HD. Based on changes in relative cerebral brain volume (rCBV), neuronal activity, and glucose utilization, the authors suggest that R6/2 mice have impaired neurometabolic coupling. They propose the use of rCBV as a biomarker of HD progression, providing a basis for future research examining functional alterations in animal models.

Euglycemic Agent-mediated Hypothalamic Transcriptomic Manipulation in the N171–82Q Model of Huntington Disease Is Related to Their Physiological Efficacy

Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171-82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD.

F05 Mutant huntingtin fragmentation in immune cells tracks Huntington's disease progression

F05 Mutant huntingtin fragmentation in immune cells tracks Huntington's disease progression

F14 8OHdG is not a biomarker for Huntington's disease; lessons for future biomarker studies

<h3>Background</h3> No candidate blood, CSF or urine biomarkers for HD have been clinically validated. 8-hydroxy-deoxy-guanosine (8OHdG) has been proposed as a candidate biomarker. Increased levels of 8OHdG have been reported in post-mortem brains^{1 2} and in serum,³ leucocytes⁴ and plasma⁵ of HD patients. All of the published studies on 8OHdG utilised a liquid chromatography electrochemical array (LCECA) assay. <h3>Aims</h3> To evaluate the potential of plasma 8-OHdG as a biomarker of HD state or progression and to develop a general set of procedures to test potential biomarkers. <h3>Methods</h3> We established a new liquid chromatography-mass spectrometry (LCMS) assay for 8OHdG and used it to measure 8OHdG levels in a cross-sectional plasma collection from the PREDICT-HD study. Next, longitudinal plasma samples taken 24 months apart from 160 TRACK-HD subjects, along with control plasma with added (“spiked”) 8OHdG, were sent blindly to two laboratories for measurement of 8OHdG using either the LCECA or the LCMS assay. <h3>Results</h3> We found no differences in 8OHdG levels between controls, premanifest HD and clinically diagnosed HD subjects from the PREDICT-HD study using the LCMS assay. A blinded head to head comparison showed the LCMS assay to be more accurate than the LCECA assay at measuring 8OHdG from spiked control plasma. Both assays were consistent in demonstrating no cross sectional differences in plasma 8OHdG between TRACK-HD controls, premanifest HD and early symptomatic HD subjects, and no longitudinal changes in any of the disease groups over 24 month. <h3>Conclusions</h3> Plasma concentration of 8-OHdG should not be considered a potential biomarker of disease state or disease progression in HD. To avoid the errors that have plagued such analyses, studies of all putative biomarkers should employ (1) blinded sample analyses; (2) verification of measurements by independent analytic methods; (3) standard curves; and (4) collection and storage of biological fluids under strict quality control. <h3>References</h3> 1. <b>Browne SE</b>, Bowling AC, MacGarvey U, <i>et al.</i> Oxidative damage and metabolic dysfunction in Huntington9s disease: selective vulnerability of the basal ganglia. <i>Ann Neurol</i> 1997;<b>41</b>:646–53. 2. <b>Polidori MC</b>, Mecocci P, Browne SE, <i>et al.</i> Oxidative damage to mitochondrial DNA in Huntington9s disease parietal cortex. <i>Neurosci Lett</i> 1999;<b>272</b>:53–6. 3. <b>Hersch SM</b>, Gevorkian S, Marder K, <i>et al.</i> Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH29dG. <i>Neurology</i> 2006;<b>66</b>:250–2. 4. <b>Chen C</b>, Wu Y, Cheng M, <i>et al.</i> Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington9s disease patients. <i>Biochem Biophys Res Commun</i> 2007;<b>359</b>:335–40. 5. <b>Long JD</b>, Matson WR, Juhl AR, <i>et al</i>; PREDICT-HD Investigators and Coordinators of the Huntington Study Group. 8OHdG as a marker for Huntington disease progression. <i>Neurobiol Dis</i> 2012;<b>46</b>:625–34.

I04 Palm-size oculomotor laboratory for field testing of saccadic system potentially applicable for monitoring of HD development

Saccadic eye movement measurement is reported as potential sensitive biomarker of Huntington's disease (HD), in both pre-manifest and manifest stages. While definitely less specific than imagining techniques, it possess potential for quick, low cost and non invasive quantitative assessment of brain functional status. It is also less prone to neuronal compensation mechanism which continues to conceal the evidence of functional motor impairment, especially when voluntary component is involved in saccadic test paradigm (antisaccade-peripherial-conflict). According to recent findings, the changes of saccadic metrics accompany HD progression and they can be considered as a means of tracking the current patient condition and outcome of new therapeutic interventions. Authors present portable, integrated diagnostic environment, Saccadometer Clinical. The system is designed as minimal-setup for evaluation of saccadic metrics, allowing to establish subjects functional deterioration profile based on the repetitive measurements (status samples) accumulated over the time. The key component is small factor, battery powered, head-mounted intelligent sensor, capable of generating laser dot stimuli for both reflex and volitional decision based saccadic tests, and performing automated eye movement acquisition and classification. Due to portability, ease of use, and build-in telemetry link for wireless communication, the measurement can be carried by patient her/himself in home environment, providing facility for continuous, remote monitoring of patient's functional status. In order to broaden the spectrum of measured parameters, current development efforts aim to include the smooth pursuit and the vestibule-ocular (postural sway) tests within the same miniaturised system, serving as complementary biomarkers of HD.