Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices - fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences

Measuring cognitive impairment and monitoring cognitive decline in Huntington's disease:a comparison of assessment instruments

Background Progressive cognitive decline is an inevitable feature of Huntington’s disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. Methods We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. Results The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. Conclusion The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Language disintegration in spontaneous speech in Huntington’s disease: a more fine-grained analysis

Huntington’s disease (HD) is a neurodegenerative disease causing motor symptoms along with cognitive and affective problems. Recent evidence suggests that HD also affects language across core levels of linguistic organization, including at stages of the disease when standardized neuropsychological test profiles are still normal and motor symptoms do not yet reach clinical thresholds (‘pre-manifest HD’). The present study aimed to subject spontaneous speech to a more fine-grained linguistic analysis in a sample of 20 identified HD gene-carriers, 10 with pre-manifest and 10 with early manifest HD. We further explored how language performance related to non-linguistic cognitive impairment, using standardized neuropsychological measures. A distinctive pattern of linguistic impairments marked off participants with both pre-manifest and manifest HD from healthy controls and each other. Fluency patterns in premanifest HD were marked by prolongations, filled pauses, and repetitions, which shifted to a pattern marked by empty (unfilled) pauses, re-phrasings, and truncations in manifest HD. Both HD groups also significantly differed from controls and each other in how they grammatically connected clauses and used noun phrases referentially. Functional deficits in language occurred in pre-manifest HD in the absence of any non-linguistic neuropsychological impairment and did largely not correlate with standardized neuropsychological measures in manifest HD. These results further corroborate that language can act as a fine-grained clinical marker in HD, which can track disease progression from the pre-manifest stage, define critical remediation targets, and inform the role of the basal ganglia in language processing.This research was supported by the Ministerio de Economía y Competitividad (MINECO, Spanish Government), grant FFI2013-40526P, and the Generalitat de Catalunya, Grant SGR-1265, both to W.H

Measuring cognitive impairment and monitoring cognitive decline in Huntington's disease : a comparison of assessment instruments

Altres ajuts: acords transformatius de la UABBackground: Progressive cognitive decline is an inevitable feature of Huntington's disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. Methods: We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. Results: The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. Conclusion: The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients