Huntington's Disease Cohort Research Articles

Dysphagia in Huntington's Disease: Correlation with Clinical Features

Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by motor impairment, cognitive decline and psychiatric disorders. Dysphagia is a pathologic condition that increases morbidity and mortality of the affected people. Our aim was to evaluate dysphagia in a group of HD patients in view of motor, cognitive and functional decline. Thirty-seven genetically confirmed HD patients were submitted to clinical evaluations of swallowing. Bedside Swallowing Assessment Scale (BSAS) was used. Dysphagia Outcome and Severity Scale (DOSS) was applied for a preliminary classification of swallowing difficulties. All patients were also evaluated by the Unified Huntington's Disease Rating Scale (UHDRS). A group of 39 controls comparable for sex and age were recruited for BSAS scores normalisation. The BSAS scores indicated that in our HD cohort, 32.4% presented relevant or severe dysphagia. The DOSS levels were significantly correlated with main clinical features, such as age, disease duration and motor impairment, with special regard to lingual protrusion ability, dysarthria and bradykinesia. The total functional capacity (TFC) and cognitive scales did not show significant correlation with DOSS levels. The results of clinical examination of swallowing indicated that dysphagia is a prevalent motor symptom of HD.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease and its association with depressive symptoms and suicidality.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington's disease (HD). In non-HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre-motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi ) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre-motor, early and advanced disease stages, β values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre-motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity and deserves further longitudinal study.

I21 Causes Of Death In A European Huntington's Disease Cohort (registry)

<h3>Background</h3> Huntington’s disease (HD) is a genetic neurodegenerative disease that leads to premature death. However little evidence is available regarding late-stage HD including causes and places of death. <h3>Aims</h3> This retrospective study aims to ascertain HD causes and places of death in a European Huntington’s disease cohort – the REGISTRY. <h3>Methods</h3> REGISTRY, the European HD Network’s prospective observational study, was used for data collection from 2001 to 2013. Our study population consisted of manifest HD patients having attended more than one study visit. For deceased subjects data was extracted from the death report form and incorporated information such as cause and place of death. Statistical analysis included descriptive statistics and survival analysis through Kaplan Meier estimates of median survival time using SPSS and R software. <h3>Results</h3> A total of 5164 participants were analysed (50.9% women and 98.1% Caucasians). At the end of the study period there were 533 deaths (10.3% of cases). For deceased subjects, the median age of diagnosis was 49 years (9–85) and the median age of death was 58 years (16–93). The most frequent cause of death was pneumonia (25.6%) followed by: other infections (9.1%), suicide (8.6%), cancer (4.4%), stroke (3.4%), and trauma (1.2%). The cause of death was undetermined in 47.7% of deaths. The most frequent place of death was the hospital (29.8%) followed by: home (23.9%), nursing houses (19.8%), and hospice care facilities (3.3%). The place of death was undetermined in 23.1% of deaths. The median survival time as time from diagnosis to death was 24 years (95% CI: 20.8–27.2); and as time from symptom onset to death was 35 years (95% CI: 29.2–40.8). <h3>Conclusion</h3> In the REGISTRY cohort HD patients succumb to the same conditions shown in former HD and other neurodegenerative diseases studies. Still, our results show HD has its own natural history, being the age of death and the survival after the diagnosis unique among neurodegeneration.

Neuropsychiatric symptoms in a European Huntington's disease cohort (REGISTRY)

BackgroundThe majority of Huntington's disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study...

Late-onset Huntington's disease: Diagnostic and prognostic considerations

To address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD). We analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20-59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale. Late-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046). A positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD.

Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease

Huntington's disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellular dysfunctions culminating in neuronal loss and consequent motor, cognitive and psychiatric disturbances in HD patients. The length of the CAG repeat is inversely correlated with age of onset (AO) in HD patients, while environmental and genetic factors can further modulate this parameter. Here, we explored whether the recently described copy-number variation (CNV) of the gene SLC2A3—which encodes the neuronal glucose transporter GLUT3—could modulate AO in HD. Strikingly, we found that increased dosage of SLC2A3 delayed AO in an HD cohort of 987 individuals, and that this correlated with increased levels of GLUT3 in HD patient cells. To our knowledge this is the first time that CNV of a candidate gene has been found to modulate HD pathogenesis. Furthermore, we found that increasing dosage of Glut1—the Drosophila melanogaster homologue of this glucose transporter—ameliorated HD-relevant phenotypes in fruit flies, including neurodegeneration and life expectancy. As alterations in glucose metabolism have been implicated in HD pathogenesis, this study may have important therapeutic relevance for 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.

The V471A Polymorphism in Autophagy-Related Gene ATG7 Modifies Age at Onset Specifically in Italian Huntington Disease Patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

The challenge of juvenile Huntington disease

In a cohort of patients with suspected juvenile-onset Huntington disease (HD), we compared HD expansion-positive and -negative cases in order to identify parameters that may allow differentiating between them and may act as a guide to clinicians contemplating genetic testing. We analyzed the clinical and genetic characteristics of 76 juvenile-onset patients referred consecutively for HD genetic testing over a 16-year period. In total, 24 patients were positive for the HD expansion (7.8% of our HD cohort). Mean age at onset of expanded cases was similar to unexpanded cases. All expanded cases had a family history of genetically confirmed HD compared to only 13.5% of unexpanded cases (p = 0.000). Clinical symptoms at onset or at presentation could not differentiate between expanded and unexpanded patients. Although criteria suggested by previous reports allowed statistical differentiation between the 2 groups, they were not sufficiently sensitive and specific to be used in clinical context and performed less satisfactorily than presence of a family history of HD alone. A diagnosis of juvenile HD should be primarily contemplated in symptomatic children with a family history of HD, although a proportion of these will test negative. With no family history of HD, juvenile HD is very unlikely and genetic testing should never delay searching for other causes. The specific nature of symptoms at onset or at presentation is of limited value in guiding the decision to test or not to test.

E02 Novel SNPs in the expanded PPARGC1A gene locus modify age of onset in a large HD cohort

Background Huntington disease (HD) is caused by an autosomal dominant CAG repeat expansion in the htt gene. HD symptoms include neurologic, psychiatric and cognitive and metabolic abnormalities. In addition to the CAG repeat mutation other genetic factors termed disease modifiers determine symptom onset and disease progression. Some evidence suggests that the metabolic master regulator is such a modifier. We showed that the PPARGCA1A gene locus is larger than previously thought. Aims We sought to determine whether SNPs in the expanded PPARGC1A gene locus modify age of onset in HD patients. Results We report that a novel SNP located in the expanded PPARGC1A gene locus is associated with a delayed age of onset of motor symptoms in a large European HD cohort (REGISTRY cohort). Conclusions This finding provides further support for a role of the PGC-1A signalling axis in the pathogenesis of HD and as a potential therapeutic target.

M02 Enroll-HD: a prospective observational study in a global huntington's disease cohort

BackgroundEnroll-HD is a global, observational, longitudinal study that combines two existing Huntington's disease (HD) observational studies, “REGISTRY” conducted in Europe and “COHORT” in North America and Australia. Enroll-HD will also...

E03 Association study of cannabinoid receptor gene (CNR1) polymorphisms and age at onset in HD

<h3>Background</h3> Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene. Although the variation in age at onset (AO) is partly explained by the lengths of the expanded repeat, the unexplained variation in AO is heritable, emphasising the role of modifier genes on disease expression. Identification of modifier genes can confirm intracellular pathways already suspected to be involved in pathophysiological processes related to HD pathogenesis. Since down regulation of type 1 cannabinoid (CB1) receptors is a key pathogenic event in HD, it has been suggested that activation of these receptors in patients may attenuate disease progression. <h3>Aims</h3> In order to evaluate whether variations in the cannabinoid receptor 1 (CNR1) gene encoding the CB1 receptor have modifying effects on the AO of HD we performed an association study between CNR1 polymorphisms and AO in HD patients. <h3>Results/outcome</h3> AO was significantly associated with the longest alleles (≥17 AAT) of the (AAT)n triplet repeat polymorphism downstream of the CNR1 gene (p=0.02), as well as with one single nucleotide polymorphism (SNP) in the 3′UTR of CNR1 (rs4707436, p=0.05). <h3>Methods/techniques</h3> A total of nine SNPs in the CNR1 gene were selected for genotyping in a German HD cohort of more than 500 patients recruited from the Huntington Center NRW in Bochum. Genotyping was performed by restriction fragment length polymorphism (RFLP). The (AAT)n repeat polymorphism was genotyped by capillary electrophoresis using Beckman-Coulter CEQT 8000 Genetic Analysis System. Variability in AO was assessed by linear regression using logarithmically transformed AO as dependent and respective genotypes as independent variables. <h3>Conclusions</h3> These data support the idea that variation in CNR1 may have modifying effects on the AO in HD.

M04 European huntington's disease network registry: current status

BackgroundThe European Huntington's disease Network's (EHDN) REGISTRY is an observational, prospective, longitudinal, multi-national, multi-centre cohort study of Huntington's disease (HD). It is the largest study of HD to date, and...

Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease

Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

An event-based model for disease progression and its application in familial Alzheimer's disease and Huntington's disease

Understanding the progression of neurological diseases is vital for accurate and early diagnosis and treatment planning. We introduce a new characterization of disease progression, which describes the disease as a series of events, each comprising a significant change in patient state. We provide novel algorithms to learn the event ordering from heterogeneous measurements over a whole patient cohort and demonstrate using combined imaging and clinical data from familial Alzheimer's and Huntington's disease cohorts. Results provide new detail in the progression pattern of these diseases, while confirming known features, and give unique insight into the variability of progression over the cohort. The key advantage of the new model and algorithms over previous progression models is that they do not require a priori division of the patients into clinical stages. The model and its formulation extend naturally to a wide range of other diseases and developmental processes and accommodate cross-sectional and longitudinal input data.

F01 The European HD Network REGISTRY: Current status and future directions

BackgroundThe European Huntington's Disease Network's (EHDN) REGISTRY is an observational, prospective, longitudinal, multi-national, multi-centre cohort study of Huntington's disease (HD). It is the largest study of HD to date, and...

QEEG Measures in Huntington’s Disease: A Pilot Study

Structural brain changes as measured with Magnetic Resonance Imaging (MRI) are associated with progression of Huntington’s Disease (HD), a trinucleotide repeat neurodegenerative disorder. Neurophysiological measures may offer additional biomarkers of the onset and progression of brain disease. We used quantitative electroencephalography (QEEG) power measures to assess resting state brain function in 27 HD subjects and 15 healthy controls. Those QEEG features that distinguished between HD subjects and healthy controls were examined in relation to illness severity, using Unified Huntington Disease Rating Scale (UHDRS) subscales, as well as to the number of CAG repeats in the HD cohort. HD subjects showed a global increase in delta power as compared to controls, even when examining unmedicated HD subjects only (n = 13), or premanifest HD subjects only (n = 3). HD subjects also showed loss of the normal anterior-posterior (AP) gradient of relative alpha and delta power. Relative alpha AP gradient loss was associated with lower Total Functional Capacity (TFC) and greater cognitive dysfunction. Relative delta AP gradient loss was associated with lower TFC, more severe motor symptoms, and greater number of CAG repeats. Overall, results suggest that QEEG power measures may capture perturbations of brain function that are related to functional status as well as to underlying genetic repeat expansion in HD. Pilot data in the three premanifest HD subjects are consistent with the hypothesis that brain functional abnormalities may be detectable even in premanifest gene carriers. Cross-sectional findings suggest that QEEG measures may be biomarkers of HD progression; prospective studies in larger samples are needed to confirm these findings and test hypotheses regarding underlying mechanisms.

ASK1 and MAP2K6 as modifiers of age at onset in Huntington’s disease

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease associated with abnormal expansions of a stretch of perfect CAG repeats in the HD gene. The number of repeat units is predictive for the age at onset (AO) of neurological symptoms. Part of the remaining variation in AO is attributed to modifier genes. In this study, genes involved in apoptosis were investigated as candidates for modulating AO in HD. A panel of 304 candidate genes was screened for allelic associations with motor AO via linked micro-satellite markers by pooling the DNAs of HD individuals from opposite ends of the AO distribution. After genotyping promising markers from the pooling experiment individually, markers revealed consolidated evidence for association in a candidate region comprising the genes MAP3K5 (ASK1)/PEX7 at 6q23.3 and in the gene MAP2K6 at 17q24.3. Fine-mapping of these candidate regions in a cohort of 250 Caucasian HD patients using single nucleotide polymorphism (SNP) markers delimitated the precise locations of association. Certain variations in an ASK1-PEX7 haplotype block explain 2.6% of additional variance in AO in our HD cohort. In males, 4.9% additional variance could be attributed to MAP2K6 genotype variations. Altogether, ASK1-PEX7 haplotypes and MAP2K2 genotype variations explain 6.3% additional variance in AO for HD. We hypothesise that sequence variations of ASK1 and MAP2K6 lead to partially sex-specific changes in the levels and/or phosphorylation states of p38 and p38-regulated proteins that might contribute to the observed delaying effects in the AO of HD.

11C-diprenorphine binding in Huntington's disease: a comparison of region of interest analysis with statistical parametric mapping.

We compare region of interest (ROI) analytical approaches with statistical parametric mapping (SPM) of 11C-diprenorphine positron emission tomography findings in five patients with Huntington's disease (HD) and nine age-matched controls. The ROI were placed on caudate, putamen, and an occipital reference area. Ratios of striatal-occipital uptake from averaged static images centered at 60 minutes showed a mean 20% reduction in caudate (P = 0.034) and 15% reduction in putamen (P = 0.095) receptor binding in the HD patients. Dynamic data from caudate and putamen ROI, together with a plasma tracer input function, were analyzed using spectral analysis to give regional impulse response functions. Regional data at 60 minutes after impulse showed a mean 29% decrease in caudate (P = 0.006) and 23% decrease in putamen (P = 0.029) opioid binding in the HD cohort. Parametric images of tracer binding also were produced with spectral analysis on a voxel basis. The images of the unit impulse response function at 60 minutes showed a mean 31% decrease in caudate (P = 0.005) and a 26% decrease in putamen binding (P = 0.011) in HD. The voxel-based parametric images were transformed into standard stereotactic space, and a between-group comparison (patient versus controls) was performed with SPM. This approach revealed symmetrical decreases in caudate (peak 40% decrease, z score = 4.38) and putamen opioid binding (peak 24% decrease, z score = 4.686) with additional nonhypothesized changes in cingulate, prefrontal, and thalamic areas. The significance and precision of changes measured with spectral analysis applied to dynamic data sets were superior to ROI-based ratio analysis on static images. The SPM replicated the striatal reductions in opioid binding in HD and detected additional nonpredicted changes. This study suggests that SPM is a valid alternative to conventional ROI analytical approaches for determining binding changes with positron emission tomography and may have advantages over region-based analyses in exploratory studies.