Symptomatic Huntington's Disease Subjects Research Articles

Customized Dietary Intervention Avoids Unintentional Weight Loss and Modulates Circulating miRNAs Footprint in Huntington's Disease

Huntington's disease (HD) is a rare progressive neurodegenerative disorder of genetic origin, with no definitive treatment. Unintentional weight loss (UWL) is a clinical feature of symptomatic HD subjects. To prevent UWL, a customized HD diet is designed and its impact on plasma miRNA HD footprint and neurological parameters is examined. Eleven participants are included, BMI≤18 kgm-2 or UWL of 5% in 6 months or 10% in a year. Diet design is based on nutritional surveys and interviews of participants and caregivers and on published literature review. Twelve-month dietary intervention, with follow-up every 3 months, induces high diet adherence, which manages to curb UWL in all participants (73% gained weight). Noticeable increases in fat mass and leptin levels are obtained. The results also show significant decrease in the expression of 19 miRNAs, which are previously reported to be upregulated in HD-patients versus healthy controls: revealing hsa-miR-338-3p, hsa-miR-128-3p, hsa-miR-23a-3p, and hsa-miR-24-3p as potential HD-biomarkers. The diminished expression of hsa-miR-100-5p reflects the general maintenance of the functional status. Cognitive status is improved in six of 11 participants, while only three present better motor-score values. A customized HD-diet prevents UWL and modified miRNAs HD-footprint. The normalization of miRNA values suggests its potentially use as HD-biomarkers.

A Computational Cognitive Biomarker for Early-Stage Huntington's Disease.

Huntington’s disease (HD) is genetically determined but with variability in symptom onset, leading to uncertainty as to when pharmacological intervention should be initiated. Here we take a computational approach based on neurocognitive phenotyping, computational modeling, and classification, in an effort to provide quantitative predictors of HD before symptom onset. A large sample of subjects—consisting of both pre-manifest individuals carrying the HD mutation (pre-HD), and early symptomatic—as well as healthy controls performed the antisaccade conflict task, which requires executive control and response inhibition. While symptomatic HD subjects differed substantially from controls in behavioral measures [reaction time (RT) and error rates], there was no such clear behavioral differences in pre-HD. RT distributions and error rates were fit with an accumulator-based model which summarizes the computational processes involved and which are related to identified mechanisms in more detailed neural models of prefrontal cortex and basal ganglia. Classification based on fitted model parameters revealed a key parameter related to executive control differentiated pre-HD from controls, whereas the response inhibition parameter declined only after symptom onset. These findings demonstrate the utility of computational approaches for classification and prediction of brain disorders, and provide clues as to the underlying neural mechanisms.

The Corticospinal Tract in Huntington's Disease

Huntington's disease (HD) is characterized by progressive motor impairment. Therefore, the connectivity of the corticospinal tract (CST), which is the main white matter (WM) pathway that conducts motor impulses from the primary motor cortex to the spinal cord, merits particular attention. WM abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using magnetic resonance imaging (MRI). In the present study, we examined CST microstructure using diffusion tensor imaging (DTI)-based tractography in 30-direction DTI data collected from 100 subjects: Pre-HD subjects (n = 25), HD patients (n = 25) and control subjects (n = 50), and T2*-weighted (iron sensitive) imaging. Results show decreased fractional anisotropy (FA) and increased axial (AD), and radial diffusivity (RD) in the bilateral CST of HD patients. Pre-HD subjects had elevated iron in the left CST, regionally localized between the brainstem and thalamus. CAG repeat length in conjunction with age, as well as motor (UHDRS) assessment were correlated with CST FA, AD, and RD both in Pre-HD and HD. In the presymptomatic phase, increased iron in the inferior portion supports the "dying back" hypothesis that axonal damage advances in a retrograde fashion. Furthermore, early iron alteration may cause a high level of toxicity, which may contribute to further damage.

44. Features of laser evoked potentials in pre-symptomatic Huntington disease patients

We evaluated pain perception and evoked responses by laser stimuli (LEPs) in presymptomatic Huntington disease (HD) patients. We recorded mismatch negativity (MMN) and P3a also to esplorate attention in HD subjects. 6 Presymptomatic gene mutation carriers (pHDs) 7 subjects at risk and 10 healthy controls were compared with 10 symptomatic HDs subjects. LEPs were obtained by four scalp electrodes, (Fz, Cz, referred to the nasion; T3, T4, referred to Fz), stimulating the dorsum of both hands. The MMN was measured in the difference waveshapes of deviant minus standard The P3a was the most positive peak between 300 and 500 ms. A delay in nociceptive input processing emerged in pHDs with CAG replication suggesting a forthcoming onset of the disease, in absence of clinical evidence of abnormalities in pain perception or attention delay. Neurophysiological measurements, such as event-related potentials (ERPs), have been suggested to provide a biological substrate for some aspects of cognitive disturbance. This experimental model is interesting for the evaluation of attention to salient stimuli, potentially relevant for a motor response, studying also the cognitive mechanisms able to compensate the reduced function of the motor cortex in these patients.

Poster 14: Evaluation of Novel Radiotracers Targeting Non-Dopaminergic Striatal Biomarkers in HD: 18F-FPEB and PET Imaging for Metabotropic Glutamate Receptor Type 5 (mGluR5) Expression in Healthy Subjects and Subjects with Huntington Disease (HD)

Objective Presented here is a first-in-human study of 3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile ( 18 F-FPEB) and PET imaging of mGluR5 in subjects with HD and healthy controls Background mGluR5 is highly expressed on enkephalinergic striatal neurons and in other neocortical structures. mGluR5 expression may be reduced because of neuron loss or alteration of gene expression. Therefore, mGluR5 may be a useful biomarker for early brain changes in HD, HD progression, or for drug development in HD. 18 F-FPEB binds mGluR5 with high affinity and specificity. Prior studies in non-human primates demonstrated 18 F-FPEB uptake consistent with the known distribution of mGluR5 expression. Methods Early HD patients ( n = 2) and healthy controls (HC, n = 2) underwent imaging. Subjects received 5 mCi 18 F-FPEB i.v. and serial dynamic PET projection data were acquired for 3 to 6 hours. Regional equilibrium tissue distribution volume measurements were assessed in striatal, neocortical, thalamic, and cerebellar regions. The standardized uptake value (SUV) ratios of targets to a cerebellar reference region were compared in HD and HC. Results Both HD subjects were female with Htt repeat expansions ≥35. HD_1: age 54 yr, UHDRS subscores motor 13 and TFC 13. HD_2: age 44 yr, UHDRS motor 6 and TFC 11. The HCs were both male, ages 57 and 43 yr. The HCs revealed intense uptake in striatal and cortical gray matter areas, moderate uptake in thalamus, and low, but not absent, uptake in cerebellum. For HCs, mean SUV ratios to cerebellum were, for anterior cingulate, 6.79; for temporal lobe, 6.15; for caudate, 5.44; and for putamen, 4.89. The HD subjects revealed a mean reduction in 18 F-FPEB uptake in striatal regions of 25–30% and temporal lobe and limbic cortical areas of 20–35%. Conclusions 18 F-FPEB is a promising PET radiotracer for evaluating mGluR5 with excellent characteristics for human imaging. This first-in-human study indicates that 18 F-FPEB PET may detect early reductions in striatal and neocortical mGluR5 in relatively mildly symptomatic HD subjects. Future studies are ongoing to evaluate these objectives and other nondopaminergic striatal markers further.

Cortical dopamine dysfunction in symptomatic and premanifest Huntington's disease gene carriers

We used 11C-raclopride PET, a marker of D 2 dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D 2 receptor dysfunction in individual Huntington's disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clinical significance. 62.5% of symptomatic HD patients and 54.5% of premanifest carriers showed cortical reductions in D 2 binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D 2 binding had worse scores on neuropsychological tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable reduction in striatal D 2 binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiology and could contribute to the impairment in neuropsychological performance in these patients.

Altered white matter microstructure in the corpus callosum in Huntington's disease: Implications for cortical “disconnection”

The corpus callosum (CC) is the major conduit for information transfer between the cerebral hemispheres and plays an integral role in relaying sensory, motor and cognitive information between homologous cortical regions. The majority of fibers that make up the CC arise from large pyramidal neurons in layers III and V, which project contra-laterally. These neurons degenerate in Huntington's disease (HD) in a topographically and temporally selective way. Since any focus of cortical degeneration could be expected to secondarily de-afferent homologous regions of cortex, we hypothesized that regionally selective cortical degeneration would be reflected in regionally selective degeneration of the CC. We used conventional T1-weighted, diffusion tensor imaging (DTI), and a modified corpus callosum segmentation scheme to examine the CC in healthy controls, huntingtin gene-carriers and symptomatic HD subjects. We measured mid-sagittal callosal cross-sectional thickness and several DTI parameters, including fractional anisotropy (FA), which reflects the degree of white matter organization, radial diffusivity, a suggested index of myelin integrity, and axial diffusivity, a suggested index of axonal damage of the CC. We found a topologically selective pattern of alterations in these measures in pre-manifest subjects that were more extensive in early symptomatic HD subjects and that correlated with performance on distinct cognitive measures, suggesting an important role for disrupted inter-hemispheric transfer in the clinical symptoms of HD. Our findings provide evidence for early degeneration of commissural pyramidal neurons in the neocortex, loss of cortico-cortical connectivity, and functional compromise of associative cortical processing.

Spectrum of gait impairments in presymptomatic and symptomatic Huntington's disease

The purpose of this study was to quantify gait impairments in presymptomatic and symptomatic Huntington's disease (HD) subjects, and examine sensitivity of gait measures. Our sample (n = 65) included presymptomatic mutation carriers (PMC) (n = 15), symptomatic HD subjects (SHD) (n = 30) and healthy controls (n = 20). Participants were requested to walk at their preferred speed on a computerized walkway that recorded spatiotemporal variables. We administered the Unified HD Rating Scale (UHDRS) for PMC and SHD. PMC demonstrated decreased gait velocity (P < 0.01), stride length (P < 0.008), and increased time in double support (P < 0.001); and demonstrated higher variability in stride length (P < 0.01) and step time (P < 0.004) compared with controls. These impairments worsened with increasing disease severity for SHD. Gait impairments were correlated with predicted years to onset in PMC (velocity = -0.65; cadence = -0.70, step time = 0.71) and demonstrated high sensitivity and specificity in distinguishing between controls and mutation carriers. In contrast, UHDRS scores did not reveal impairments in gait and balance. Gait bradykinesia and dynamic balance impairments begin in the presymptomatic stage of HD and continue to worsen in the symptomatic stages. Gait measures are sensitive in differentiating between mutation positive and negative individuals even when impairments were not detected by clinical neurological examination. (c) 2008 Movement Disorder Society.

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

The ultimate goal for Huntington's disease (HD) therapeutics is to develop disease-modifying neuroprotective therapies that can delay or prevent illness in those who are at genetic risk and can slow progression in those who are affected clinically. Neuroprotection is the preservation of neuronal structure, function, and viability, and neuroprotective therapy is thus targeted at the underlying pathology of HD, rather than at its specific symptoms. Preclinical target discovery research in HD is identifying numerous distinct targets, along with options for modulating them, with some proceeding into large-scale efficacy studies in early symptomatic HD subjects. The first pilot studies of neuroprotective compounds in premanifest HD are also soon to begin. This review discusses the opportunities for neuroprotection in HD, clinical methodology in premanifest and manifest HD, the clinical assessment of neuroprotection, molecular targets and therapeutic leads, and the current state of clinical development.

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

Mutated huntingtin (htt) is ubiquitously expressed in tissues of Huntington's disease (HD) patients. In the brain, the mutated protein leads to neuronal cell dysfunction and death, associated with formation of htt-positive inclusions. Given increasing evidence of abnormalities in HD skeletal muscle, we extensively analyzed primary muscle cell cultures from seven HD subjects (including two unaffected mutation carriers). Myoblasts from presymptomatic and symptomatic HD subjects showed cellular abnormalities in vitro, namely mitochondrial depolarization, cytochrome c release, increased caspase-3, -8, and -9 activities, and defective cell differentiation. Another notable feature was the formation of htt inclusions in differentiated myotubes. This study helps to advance current knowledge about the downstream effects of the htt mutation in human tissues. Further applications may include drug screening using this human cellular model.