Huntington's disease like-2 neuropathology.

Huntington's disease like-2 (HDL-2) neurodegeneration is a recently described autosomal dominant disorder with features similar to Huntington's disease (HD). Only one case report has described neuropathology from an affected patient. We describe the clinical presentation and illustrate the pathology in two additional molecularly confirmed patients, compare these with the previously published case, and contrast them with HD. We examined two patients with HDL-2. Their charts were reviewed, their brains were examined using standard neuropathology techniques, including immunoperoxidase stains, and their diagnoses were confirmed with a PCR-based assay for repeat length. The first patient presented with obsessive suspiciousness, while the second had depression and decreased visual acuity. Both patients developed increased tone and cogwheel rigidity, but neither developed choreoathetosis. Extensive degeneration affected the caudate nucleus and putamen, especially dorsally and laterally. In addition, the first patient showed lateral temporal, lateral frontal, and orbitofrontal cortical atrophy, while the second patient displayed marked degeneration in the occipital and parietal cortices. Neither patient showed significant changes in the cerebellum or brainstem. Both cases had ubiquitin-immunoreactive neuronal intranuclear inclusions (NII). The patients with of HDL-2 reviewed here were remarkable for significant frontal inhibition with parkinsonism, a lack of choreiform movements, and African ancestry. Pathologically, HDL-2 is similar to HD in its effect on the neostriatum but may differ, at least in some cases, in its degree of focal cortical involvement, including the occipital lobe.     

Sex differences in sleep architecture in a mouse model of Huntington's disease

Sleep and circadian rhythm disturbances are common features of Huntington's disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies as well as preclinical work indicate there may be sex differences in disease presentation and progression. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s), we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in sleep/wake cycles are detectable in an animal model of the disease. Electroencephalography/electromyography (EEG/EMG) was used to measure sleep/wake states and polysomnographic patterns in young adult (12-week-old) male and female wild-type and BACHD mice. Our findings show that male, but not female, BACHD mice exhibited increased variation in phases of the rhythms as compared to age- and sex-matched wild-types. For both rapid-eye movement (REM) and non-rapid eye movement (NREM) sleep, genotypic and sex differences were detected. In particular, the BACHD males spent less time in NREM sleep and exhibited a more fragmented sleep than the other groups. Finally, in response to 6 h of sleep deprivation, both genotypes and sexes displayed the predicted homeostatic responses to sleep loss. These findings suggest that females are relatively protected early in disease progression in this HD model.     

Lack of association between PSA‐NCAM expression and migration in the rostral migratory stream of a Huntington's disease transgenic mouse model

Huntington's disease is a neurodegenerative autosomal disorder characterized by selective loss of striatal and cortical neurons. The mammalian brain subventricular zone contains a population of neural precursors involved in postnatal neurogenesis. These newly generated cells migrate from the subventricular zone along the rostral migratory stream and differentiate into mature olfactory bulb neurons throughout adulthood. The establishment of this pathway depends upon a variety of molecules, including polysialylated neural cell adhesion molecule (PSA‐NCAM). We used a murine model of Huntington's disease, the R6/2 transgenic mouse, and in vivo bromodeoxyuridine administration to label cells undergoing proliferation and to follow their migration along the rostral migratory stream. Bromodeoxyuridine labeling did not show any significant increase in proliferation of progenitor cells in symptomatic R6/2 mice, but migration of neuroblasts along the rostral migratory stream was significantly diminished. The decrease in neuroblast migration was not due to an alteration in the expression of PSA‐NCAM along the rostral migratory stream since immunohistochemical analysis showed no significant differences between R6/2 and wild type mice. In addition, we used Fluoro‐Jade C to evaluate apoptosis and demonstrated that the number of apoptotic cells in the rostral migratory stream is similar in affected and wild type animals, suggesting that cell death is not responsible for the differences observed in neuroblast migration. We conclude that in R6/2 mice, progenitor cells have an impaired migration in their route to the olfactory bulb, with accumulation of cells in the caudal rostral migratory stream that does not result from changes in PSA‐NCAM expression and/or cell death.     

Impaired modulation of the vestibulo‐ocular reflex in Huntington's disease

The vestibulo‐ocular reflex (VOR) stabilizes gaze during movement, in conjunction with other afferent information: visual, proprioceptive, and somaesthetic. The reflex can either be augmented or suppressed, depending on visual requirements, and undergoes long‐term adaptation to compensate for physical changes in the subject. Importantly, over relatively short periods of time, the VOR should function consistently under the same circumstances. This study examines VOR function in patients with Huntington's disease (HD), with a view to investigating cortical influences on the reflex. Horizontal eye movements were recorded in 9 patients with HD and 7 normal subjects, using the scleral search coil technique, in response to high frequency, unpredictable head rotations imposed manually. To establish base VOR function, recordings were made in darkness, without instruction, before and after wearing ×2 magnifying lenses for a period of 2 hours to adapt the reflex. Recordings were also made before adaptation, while fixating a stationary visual target (VOR augmentation), and while fixating a target moving with the head (VOR suppression). Although results suggest that the VOR is preserved in HD, with relatively normal gain values and appropriate augmentation and suppression of the reflex with visual input, patients were unable to adapt the VOR to altered visual conditions. This represents a novel finding in HD and suggests that cortical structures compromised in HD exert influences on the long‐term adaptation of the VOR. © 2003 Movement Disorder Society     

Neuronal vulnerability in mouse models of Huntington's disease: membrane channel protein changes

Huntington's disease (HD) is caused by a polyglutamine expansion that results in atrophy of the striatum and frontal cortex during disease progression. HD-susceptible striatal neurons are affected chronologically with initial degeneration of the striatopallidal neurons then the striatonigral projections, whereas large aspiny striatal interneurons (LAN) survive. Two classes of critical membrane proteins were evaluated in transgenic mouse models to determine their association with HD susceptibility, which leads to dysfunction and death in selected striatal neuron populations. We examined potassium (K+) channel protein subunits that form membrane ionophores conducting inwardly and outwardly rectifying K+ currents. K+ channel protein staining was diminished substantially in the HD striatal projection neurons but was not expressed in the HD-resistant LAN. Because loss of K+ channel subunits depolarizes neurons, other voltage-gated ionophores will be affected. N-methyl-D-aspartate (NMDA) receptors and their phosphorylation by cyclic AMP were studied as a mechanism contributing to excitotoxic vulnerability in striatal projection neurons that would lose voltage regulation after diminished K+ channels. NR1 subunits showed significant elevation in the HD transgenic projection systems but were expressed at very low levels in LAN. NR1 subunit phosphorylation by cyclic AMP also was enhanced in striatal projection neurons but not in LAN. Cyclic AMP-driven phosphorylation of NMDA receptors increases the channel open time and elevates neuronal glutamate responsiveness, which may lead to excitotoxicity. Together our data suggest that changes in these proteins and their modification may predispose striatal projection neurons to dysfunction and then degeneratation in HD and provide a mechanism for LAN resistance in the disease.     

Ghrelin‐mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease

Huntington's disease (HD) is a heritable neurodegenerative disorder, characterised by metabolic disturbances, along with cognitive and psychiatric impairments. Targeting metabolic HD dysfunction via the maintenance of body weight and fat mass and restoration of peripheral energy metabolism can improve the progression of neurological symptoms. In this respect, we focused on the therapeutic potential of the orexigenic peptide hormone ghrelin, which plays an important role in promoting a positive energy balance. In the present study, we found a significant disruption of circadian metabolic regulation in a R6/2 mouse HD model in the late stage of disease. Daily circadian rhythms of activity, energy expenditure, respiratory exchange ratio and feeding were strongly attenuated in R6/2 mice. During the rest phase, R6/2 mice had a higher total activity, elevated energy expenditure and excessive water consumption compared to control mice. We also found that, in the late stage of disease, R6/2 mice had ghrelin axis deficiency as a result of low circulating ghrelin levels, in addition to down‐regulation of the ghrelin receptor and several key signalling molecules in the hypothalamus, as well as a reduced responsiveness to exogenous peripheral ghrelin. We demonstrated that, in pre‐symptomatic mice, responsiveness to ghrelin is preserved. Chronic ghrelin treatment efficiently increased lean body mass and decreased the energy expenditure and fat utilisation of R6/2 mice in the early stage of disease. In addition, ghrelin treatment was also effective in the normalisation of drinking behaviour and the rest activity of these mice. Ghrelin treatment could provide a novel therapeutic possibility for delaying disease progression; however, deficiency in ghrelin receptor expression could limit its therapeutic potential in the late stage of disease.     

MR‐spectroscopic findings in juvenile‐onset Huntington's disease

Seven HD gene positive individuals under the age of 21 years are described with clinical examination and proton‐MR‐spectroscopy (¹H‐MRS) profiles of the putamen. Despite clinical variability, the predominate ¹H‐MRS abnormality is elevated glutamate, expressed well beyond the confines of the basal ganglia, and low striatal creatine. © 2008 Movement Disorder Society     

Huntington's disease‐like 2 in Brazil—Report of 4 patients

Huntington's disease‐like 2 (HDL2) is a neurodegenerative disorder found in people of African ancestry with clinical, radiological, and neuropathological manifestations similar to Huntington's disease (HD). HDL2 is caused by a pathological expansion of CAG/CTG triplets in exon 2A of the JPH3 gene. We describe four cases of HDL2 from four unrelated families, and discuss their clinical findings. HDL2 should be considered in every patient with an HD‐like phenotype who tests negative for the HD mutation, even if African ancestry is not immediately apparent. © 2008 Movement Disorder Society     

Motor abnormalities in premanifest persons with Huntington's disease: The PREDICT‐HD study

The PREDICT‐HD study seeks to identify clinical and biological markers of Huntington's disease in premanifest individuals who have undergone predictive genetic testing. We compared baseline motor data between gene‐expansion carriers (cases) and nongene‐expansion carriers (controls) using t‐tests and Chi‐square. Cases were categorized as near, mid, or far from diagnosis using a CAG‐based formula. Striatal volumes were calculated using volumetric magnetic resonance imaging measurements. Multiple linear regression associated total motor score, motor domains, and individual motor items with estimated diagnosis and striatal volumes. Elevated total motor scores at baseline were associated with higher genetic probability of disease diagnosis in the near future (partial R² 0.14, P < 0.0001) and smaller striatal volumes (partial R² 0.15, P < 0.0001). Nearly all motor domain scores showed greater abnormality with increasing proximity to diagnosis, although bradykinesia and chorea were most highly associated with diagnostic immediacy. Among individual motor items, worse scores on finger tapping, tandem gait, Luria, saccade initiation, and chorea show unique association with diagnosis probability. Even in this premanifest population, subtle motor abnormalities were associated with a higher probability of disease diagnosis and smaller striatal volumes. Longitudinal assessment will help inform whether motor items will be useful measures in preventive clinical trials. © 2009 Movement Disorder Society     

Exosomes from adipose‐derived stem cells ameliorate phenotype of Huntington's disease in vitro model

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the aggregation of mutant Huntingtin (mHtt). Adipose‐derived stem cells (ASCs) have a potential for use in the treatment of incurable disorders, including HD. ASCs secrete various neurotrophic factors and microvesicles, and modulate hostile microenvironments affected by disease through paracrine mechanisms. Exosomes are small vesicles that transport nucleic acid and protein between cells. Here, we investigated the therapeutic role of exosomes from ASCs (ASC‐exo) using in vitro HD model by examining pathological phenotypes of this model. Immunocytochemistry result showed that ASC‐exo significantly decreases mHtt aggregates in R6/2 mice‐derived neuronal cells. Western blot result further confirmed the reduction in mHtt aggregates level by ASC‐exo treatment. ASC‐exo up‐regulates PGC‐1, phospho‐CREB and ameliorates abnormal apoptotic protein level in an in vitro HD model. In addition, MitoSOX Red, JC‐1 and cell viability assay showed that ASC‐exo reduces mitochondrial dysfunction and cell apoptosis of in vitro HD model. These findings suggest that ASC‐exo has a therapeutic potential for treating HD by modulating representative cellular phenotypes of HD.     

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. Hum Brain Mapp 35:2582–2593, 2014. © 2013 Wiley Periodicals, Inc .     

Seizures in juvenile Huntington's disease: Frequency and characterization in a multicenter cohort

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult‐onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic‐clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required. © 2012 Movement Disorder Society     

Validation of self‐report depression rating scales in Huntington's disease

The aim of this study was to assess the criterion validity of three self‐report measures of depression in a sample of patients with Huntington's disease (HD). Fifty patients with HD completed the Beck Depression Inventory‐II (BDI‐II), the Hospital Anxiety and Depression Scale (HADS), and the Depression Intensity Scale Circles (DISCs). Current psychiatric status was assessed using the schedules for clinical assessment in neuropsychiatry (SCAN), and ICD‐10 diagnosis was used as the gold standard. Receiver operating characteristics (ROC) curves were obtained and the sensitivity, specificity, positive, and negative predictive values were calculated for different cut‐off scores on each rating scale. Twelve patients (24%) met ICD‐10 criteria for depressive disorder. The depression sub‐scale of the HADS (HADS‐D) at an optimal cut‐off of 6/7 was found to discriminate maximally between depressed and nondepressed patients in this population. The DISCs at a cut‐off of 1/2 also performed well at detecting possible “cases” of depression, whereas the BDI‐II performed the least satisfactorily of all scales. The HADS‐D and DISCs are good screening measures for depression in the HD population and the DISCs may be particularly useful in those patients with more severe communicative and cognitive deficits. © 2009 Movement Disorder Society     

Rate and acceleration of whole‐brain atrophy in premanifest and early Huntington's disease

Huntington's disease (HD) produces progressive and ultimately widespread impairment of brain function. Neostriatal atrophy alone cannot account for whole‐brain losses seen postmortem, and the mutant huntingtin protein and its neuropathologic sequelae are evident throughout the brain. Whole‐brain atrophy quantification encompasses the totality of mutant huntingtin's effects on brain volume and may be useful in tracking progression in trials. We studied whole‐brain atrophy in HD using a 2‐year follow‐up design, with three annual MRI scans. We recruited 20 control subjects, 21 premanifest mutation carriers, and 40 patients with early HD and used the brain boundary shift integral to study rate and acceleration of atrophy. Among subjects with an acceptable quality 2‐year scan pair, age‐ and gender‐standardized mean brain atrophy rate was greater (P < 0.001) in the patients with HD (n = 21; 0.88%/yr; 95% confidence interval: 0.62–1.13%/yr) than that in controls (n = 13; 0.16%/yr; 0.00–0.32%/yr). In the 12 patients with early HD in whom acceleration could be directly assessed there was evidence (P= 0.048) of acceleration year‐on‐year (mean acceleration = 0.69% yr^?2; 95% confidence interval: 0.01% yr^?2 to 1.37% yr^?2), although this was not formally significantly different from that in controls (n = 7, P = 0.055). Statistically significantly increased atrophy rates and acceleration were not seen overall in the premanifest group, who were on average 18 years from predicted disease onset. We conclude that the study of whole‐brain atrophy has the potential to inform our understanding of the neurobiology of HD and warrants further study as one means of assessing the outcomes of future clinical trials. © 2009 Movement Disorder Society     

Variability in interval production is due to timing‐dependent deficits in Huntington's disease

In Huntington's disease (HD), increased variability is seen in performance of motor tasks that require implicit control of timing. We examined whether timing variability was also evident in an explicit interval‐timing task. Sixty subjects (21 controls, 19 manifest HD, and 20 pre‐manifest HD) performed a single‐interval production task with three target intervals (1.1 s, 2.2 s, 3.3 s). We analyzed accuracy (proportional error) and precision (standard deviation) across groups and intervals. No differences were seen in accuracy across groups or intervals. Precision was significantly lower in manifest (P = 0.0001) and pre‐manifest HD (P = 0.04) compared with controls. This was particularly true for pre‐manifest subjects close to diagnosis (based on probability of diagnosis in 5 years). Precision was correlated with proximity to diagnosis (r² = 0.3, P < 0.01). To examine the source of reduced precision, we conducted linear regression of standard deviation with interval duration. Slope of the regression was significantly higher in manifest HD (P = 0.02) and in pre‐manifest HD close to diagnosis (P = 0.04) compared with controls and pre‐manifest participants far from diagnosis. Timing precision is impaired before clinical diagnosis in Huntington's disease. Slope analysis suggests that timing variability (decreased precision) was attributable to deficits in timing‐dependent processes. Our results provide additional support for the proposal that the basal ganglia are implicated in central timekeeping functions. Because the single interval production task was sensitive to deficits in pre‐manifest HD, temporal precision may be a useful outcome measure in future clinical trials. © 2014 International Parkinson and Movement Disorder Society     

HD‐CAB: A cognitive assessment battery for clinical trials in Huntington's disease1,2,3

Cognitive dysfunction is central to Huntington's disease (HD) and undermines quality of life. Clinical trials are now targeting cognitive outcomes in HD; however, no cognitive battery has been optimized for HD clinical trials. We evaluated 16 cognitive tests in a 20‐site, five‐country, observational study designed to mimic aspects of a clinical trial (e.g., data collection managed by a contract research organization, repeated testing, prespecified statistical analyses). Fifty‐five early HD, 103 premanifest HD (pre‐HD), and 105 controls were tested at visit 1, visit 2 (1‐3 days later), and visit 3 (5‐7 weeks after visit 1). For inclusion in a recommended battery, tests were evaluated for sensitivity, practice effects, reliability, domain coverage, feasibility, and tolerability. Most tests differentiated controls from pre‐HD and early HD and showed excellent psychometric properties. We selected six tests to constitute the Huntington's Disease Cognitive Assessment Battery (HD‐CAB): Symbol Digit Modalities Test, Paced Tapping, One Touch Stockings of Cambridge (abbreviated), Emotion Recognition, Trail Making B, and the Hopkins Verbal Learning Test. These tests demonstrated sensitivity to disease status (Cohen's d effect sizes: early HD= ?1.38 to ?1.90 and pre‐HD= ?0.41 to ?0.78), and acceptable reliability (r's 0.73‐0.93). A composite score yielded large effect sizes (early HD = ?2.44 and pre‐HD = ?0.87) and high reliability (r = 0.95). HD‐CAB is the first cognitive battery designed specifically for use in late premanifest and early HD clinical trials. Adoption of the HD‐CAB will facilitate evaluation of treatments to improve cognition in HD. © 2014 International Parkinson and Movement Disorder Society