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1.  Motor onset and diagnosis in Huntington disease using the diagnostic confidence level 
Journal of neurology  2015;262(12):2691-2698.
Background
Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments.
Methods
Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine-adenine-guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington's Disease Rating Scale.
Results
HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, were associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11% (95% CI: 7-15%) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47% (95% CI: 27-69%).
Conclusions
Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models.
doi:10.1007/s00415-015-7900-7
PMCID: PMC4666501  PMID: 26410751
Huntington disease; hidden Markov model; diagnostic confidence level; prediction; diagnosis; onset
2.  Prefrontal cortex white matter tracts in prodromal Huntington disease 
Human brain mapping  2015;36(10):3717-3732.
Huntington disease (HD) is most widely known for its selective degeneration of striatal neurons but there is also growing evidence for white matter (WM) deterioration. The primary objective of this research was to conduct a large-scale analysis using multisite diffusion-weighted imaging (DWI) tractography data to quantify diffusivity properties along major prefrontal cortex WM tracts in prodromal HD. Fifteen international sites participating in the PREDICT-HD study collected imaging and neuropsychological data on gene-positive HD participants without a clinical diagnosis (i.e. prodromal) and gene-negative control participants. The anatomical prefrontal WM tracts of the corpus callosum (PFCC), anterior thalamic radiations (ATR), inferior fronto-occipital fasciculi (IFO), and uncinate fasciculi (UNC) were identified using streamline tractography of DWI. Within each of these tracts, tensor scalars for fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity coefficients were calculated. We divided prodromal HD subjects into three CAG-age product (CAP) groups having Low, Medium, or High probabilities of onset indexed by genetic exposure. We observed significant differences in WM properties for each of the four anatomical tracts for the High CAP group in comparison to controls. Additionally, the Medium CAP group presented differences in the ATR and IFO in comparison to controls. Furthermore, WM alterations in the PFCC, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. These results suggest long-range tracts essential for cross-region information transfer show early vulnerability in HD and may explain cognitive problems often present in the prodromal stage.
doi:10.1002/hbm.22835
PMCID: PMC4583330  PMID: 26179962
diffusion weighted MRI; diffusion tractography; diffusion tensor imaging; Huntington's disease; prefrontal cortex; multicenter studies; cross sectional analysis
3.  Multivariate prediction of motor diagnosis in Huntington disease: 12 years of PREDICT-HD 
Background
It is well known in Huntington disease that cytosine-adenine-guanine expansion and age at study entry are predictive of the timing of motor diagnosis. The goal was to assess whether additional motor, imaging, cognitive, functional, psychiatric, and demographic variables measured at study entry increase the ability to predict the risk of motor diagnosis over 12 years.
Methods
There were 1078 Huntington disease gene expanded carriers (64% female) from the Neurobiological Predictors of Huntington's Disease study who were followed for up to 12 years (mean = 5, standard deviation = 3.3) covering 2002-2014. No one had a motor diagnosis at study entry, but 225 (21%) carriers prospectively received a motor diagnosis. Analysis was performed with random survival forests, which is a machine learning method for right-censored data.
Results
Adding 34 variables along with cytosine-adenine-guanine and age substantially increased predictive accuracy relative to cytosine-adenine-guanine and age alone. Adding six of the common motor and cognitive variables (total motor score, diagnostic confidence level, Symbol Digit Modalities Test, three Stroop tests) resulted in lower predictive accuracy than the full set, but still had twice the 5-year predictive accuracy than when using cytosine-adenine-guanine and age alone. Additional analysis suggested interactions and non-linear effects that were characterized in a post hoc Cox regression model.
Conclusions
Measurement of clinical variables can substantially increase the accuracy of predicting motor diagnosis over and above cytosine-adenine-guanine and age (and their interaction). Estimated probabilities can be used to characterize progression level and aid in future studies' sample selection.
doi:10.1002/mds.26364
PMCID: PMC4795466  PMID: 26340420
Huntington disease; prognosis; clinical trials methodology/study design; assessment of cognitive disorders/dementia
4.  Patterns of Co-Occurring Gray Matter Concentration Loss across the Huntington Disease Prodrome 
Huntington disease (HD) is caused by an abnormally expanded cytosine–adenine–guanine (CAG) trinucleotide repeat in the HTT gene. Age and CAG-expansion number are related to age at diagnosis and can be used to index disease progression. However, observed onset-age variability suggests that other factors also modulate progression. Indexing prodromal (pre-diagnosis) progression may highlight therapeutic targets by isolating the earliest-affected factors. We present the largest prodromal HD application of the univariate method voxel-based morphometry (VBM) and the first application of the multivariate method source-based morphometry (SBM) to, respectively, compare gray matter concentration (GMC) and capture co-occurring GMC patterns in control and prodromal participants. Using structural MRI data from 1050 (831 prodromal, 219 control) participants, we characterize control-prodromal, whole-brain GMC differences at various prodromal stages. Our results provide evidence for (1) regional co-occurrence and differential patterns of decline across the prodrome, with parietal and occipital differences commonly co-occurring, and frontal and temporal differences being relatively independent from one another, (2) fronto-striatal circuits being among the earliest and most consistently affected in the prodrome, (3) delayed degradation in some movement-related regions, with increasing subcortical and occipital differences with later progression, (4) an overall superior-to-inferior gradient of GMC reduction in frontal, parietal, and temporal lobes, and (5) the appropriateness of SBM for studying the prodromal HD population and its enhanced sensitivity to early prodromal and regionally concurrent differences.
doi:10.3389/fneur.2016.00147
PMCID: PMC5030293  PMID: 27708610
disease progression; gray matter concentration; humans; magnetic resonance imaging; movement disorders; multivariate methods; prodromal symptoms
5.  Validity of the 12-Item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) in individuals with Huntington disease (HD) 
Purpose
The reliability and construct validity of the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) was examined in individuals with Huntington disease (HD).
Methods
We examined factor structure (confirmatory factor analysis), internal consistency reliability (Cronbach’s alpha), floor and ceiling effects, convergent validity (Pearson correlations), and known-groups validity (multivariate analysis).
Results
Results of a confirmatory factor analysis replicated the six factor latent model that reflects the six separate scales within the WHODAS 2.0 (understanding and communicating; getting around; self-care; getting along with others, life activities; participation). Cronbach’s alpha for the scale was 0.94, suggesting good internal consistency reliability. The WHODAS demonstrated a ceiling effect for 19.5% of participants; there were no floor effects. There was evidence for convergent validity; the WHODAS demonstrated moderate significant correlations with other general measures of health-related quality of life (HRQOL; i.e., RAND-12, EQ5D). Multivariate analyses indicated that late-stage HD participants indicated poorer HRQOL than both early-stage HD and prodromal HD participants for all HRQOL measures.
Conclusions
Findings provide support for both the reliability and validity of the WHODAS 2.0 in individuals with HD.
doi:10.1007/s11136-015-0930-x
PMCID: PMC4497948  PMID: 25636661
Neuropsychology; Neuropsychological Assessment; World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0); Confirmatory Factor Analysis; Psychometrics
6.  Network topology and functional connectivity disturbances precede the onset of Huntington’s disease 
Brain  2015;138(8):2332-2346.
Early intervention trials in Huntington’s disease would benefit from markers of prodromal disease progression. By applying graph theory analyses and network-based statistics to whole-brain resting-state fMRI data, Harrington et al. reveal decreased connectivity of rich-club network hubs, plus weakening of frontostriatal and strengthening of frontal-posterior connections with increasing disease burden.
Early intervention trials in Huntington’s disease would benefit from markers of prodromal disease progression. By applying graph theory analyses and network-based statistics to whole-brain resting-state fMRI data, Harrington et al. reveal decreased connectivity of rich-club network hubs, plus weakening of frontostriatal and strengthening of frontal-posterior connections with increasing disease burden.
Cognitive, motor and psychiatric changes in prodromal Huntington’s disease have nurtured the emergent need for early interventions. Preventive clinical trials for Huntington’s disease, however, are limited by a shortage of suitable measures that could serve as surrogate outcomes. Measures of intrinsic functional connectivity from resting-state functional magnetic resonance imaging are of keen interest. Yet recent studies suggest circumscribed abnormalities in resting-state functional magnetic resonance imaging connectivity in prodromal Huntington’s disease, despite the spectrum of behavioural changes preceding a manifest diagnosis. The present study used two complementary analytical approaches to examine whole-brain resting-state functional magnetic resonance imaging connectivity in prodromal Huntington’s disease. Network topology was studied using graph theory and simple functional connectivity amongst brain regions was explored using the network-based statistic. Participants consisted of gene-negative controls (n = 16) and prodromal Huntington’s disease individuals (n = 48) with various stages of disease progression to examine the influence of disease burden on intrinsic connectivity. Graph theory analyses showed that global network interconnectivity approximated a random network topology as proximity to diagnosis neared and this was associated with decreased connectivity amongst highly-connected rich-club network hubs, which integrate processing from diverse brain regions. However, functional segregation within the global network (average clustering) was preserved. Functional segregation was also largely maintained at the local level, except for the notable decrease in the diversity of anterior insula intermodular-interconnections (participation coefficient), irrespective of disease burden. In contrast, network-based statistic analyses revealed patterns of weakened frontostriatal connections and strengthened frontal-posterior connections that evolved as disease burden increased. These disturbances were often related to long-range connections involving peripheral nodes and interhemispheric connections. A strong association was found between weaker connectivity and decreased rich-club organization, indicating that whole-brain simple connectivity partially expressed disturbances in the communication of highly-connected hubs. However, network topology and network-based statistic connectivity metrics did not correlate with key markers of executive dysfunction (Stroop Test, Trail Making Test) in prodromal Huntington’s disease, which instead were related to whole-brain connectivity disturbances in nodes (right inferior parietal, right thalamus, left anterior cingulate) that exhibited multiple aberrant connections and that mediate executive control. Altogether, our results show for the first time a largely disease burden-dependent functional reorganization of whole-brain networks in prodromal Huntington’s disease. Both analytic approaches provided a unique window into brain reorganization that was not related to brain atrophy or motor symptoms. Longitudinal studies currently in progress will chart the course of functional changes to determine the most sensitive markers of disease progression.
doi:10.1093/brain/awv145
PMCID: PMC5022662  PMID: 26059655
Huntington disease; resting-state connectivity; network topology; graph theory; network based statistic
7.  T1ρ Imaging in Premanifest Huntington Disease Reveals Changes Associated with Disease Progression 
Background
Imaging biomarkers sensitive to Huntington’s disease (HD) during the premanifest phase preceding motor diagnosis may accelerate identification and evaluation of potential therapies. For this purpose, quantitative MRI sensitive to tissue microstructure and metabolism may hold great potential. We investigated the potential value of T1ρ relaxation to detect pathological changes in premanifest HD (preHD) relative to other quantitative relaxation parameters.
Methods
Quantitative MR parametric mapping was used to assess differences between 50 preHD subjects and 26 age- and sex-matched controls. Subjects with preHD were classified into two progression groups based on their CAG-age product (CAP) score; a high and a low/moderate CAP group. Voxel-wise and region-of-interest analyses were used to assess changes in the quantitative relaxation times.
Results
T1ρ showed a significant increase in the relaxation times in the high-CAP group, as compared to controls, largely in the striatum. The T1ρ changes in the preHD subjects showed a significant relationship with CAP score. No significant changes in T2 or T2* relaxation times were found in the striatum. T2* relaxation changes were found in the globus pallidus, but no significant changes with disease progression were found.
Conclusion
These data suggest that quantitative T1ρ mapping may provide a useful marker for assessing disease progression in HD. The absence of T2 changes suggests that the T1ρ abnormalities are unlikely owing to altered water content or tissue structure. The established sensitivity of T1ρ to pH and glucose suggests that these factors are altered in HD perhaps owing to abnormal mitochondrial function.
doi:10.1002/mds.26203
PMCID: PMC4751081  PMID: 25820773
premanifest Huntington disease; magnetic resonance imaging; imaging biomarkers; T1rho; quantitative imaging
8.  Longitudinal Changes in the Motor Learning-Related Brain Activation Response in Presymptomatic Huntington's Disease 
PLoS ONE  2016;11(5):e0154742.
Neurocognitive decline, including deficits in motor learning, occurs in the presymptomatic phase of Huntington’s disease (HD) and precedes the onset of motor symptoms. Findings from recent neuroimaging studies have linked these deficits to alterations in fronto-striatal and fronto-parietal brain networks. However, little is known about the temporal dynamics of these networks when subjects approach phenoconversion. Here, 10 subjects with presymptomatic HD were scanned with 15O-labeled water at baseline and again 1.5 years later while performing a motor sequence learning task and a kinematically matched control task. Spatial covariance analysis was utilized to characterize patterns of change in learning-related neural activation occurring over time in these individuals. Pattern expression was compared to corresponding values in 10 age-matched healthy control subjects. Spatial covariance analysis revealed significant longitudinal changes in the expression of a specific learning-related activation pattern characterized by increasing activity in the right orbitofrontal cortex, with concurrent reductions in the right medial prefrontal and posterior cingulate regions, the left insula, left precuneus, and left cerebellum. Changes in the expression of this pattern over time correlated with baseline measurements of disease burden and learning performance. The network changes were accompanied by modest improvement in learning performance that took place concurrently in the gene carriers. The presence of increased network activity in the setting of stable task performance is consistent with a discrete compensatory mechanism. The findings suggest that this effect is most pronounced in the late presymptomatic phase of HD, as subjects approach clinical onset.
doi:10.1371/journal.pone.0154742
PMCID: PMC4871440  PMID: 27192167
9.  Is There an Association of Physical Activity with Brain Volume, Behavior, and Day-to-day Functioning? A Cross Sectional Design in Prodromal and Early Huntington Disease 
PLoS Currents  2016;8:ecurrents.hd.cba6ea74972cf8412a73ce52eb018c1e.
Background: Huntington disease (HD) is a genetic neurodegenerative disease leading to progressive motor, cognitive, and behavioral decline. Subtle changes in these domains are detectable up to 15 years before a definitive motor diagnosis is made. This period, called prodromal HD, provides an opportunity to examine lifestyle behaviors that may impact disease progression. Theoretical Framework: Physical activity relates to decreased rates of brain atrophy and improved cognitive and day-to-day functioning in Alzheimer disease and healthy aging populations. Previous research has yielded mixed results regarding the impact of physical activity on disease progression in HD and paid little attention to the prodromal phase.
Methods: We conducted analyses of associations among current physical activity level, current and retrospective rate of change for hippocampus and striatum volume, and cognitive, motor, and day-to-day functioning variables. Participants were 48 gene-expanded cases with prodromal and early-diagnosed HD and 27 nongene-expanded control participants. Participants wore Fitbit Ultra activity monitors for three days and completed the self-reported International Physical Activity Questionnaire (IPAQ). Hippocampal and striatal white matter volumes were measured using magnetic resonance imaging. Cognitive tests included the Stroop Color and Word Test, and the Symbol Digit Modalities Test (SDMT). Motor function was assessed using the Unified Huntington’s Disease Rating Scale total motor score (TMS). Day-to-day functioning was measured using the World Health Organization Disability Assessment Schedule (WHODAS) version 2.0.
Results: Higher Fitbit activity scores were significantly related to better scores on the SDMT and WHODAS in case participants but not in controls. Fitbit activity scores tracked better with TMS scores in the group as a whole, though the association did not reach statistical significance in the case participants. Higher Fitbit activity scores related to less day-to-day functioning decline in retrospective slope analyses. Fitbit activity scores did not differ significantly between cases and controls.
Conclusions: This is the first known study examining the associations between activity level and imaging, motor, cognitive, and day-to-day functioning outcomes in prodromal and early HD. Preliminary results suggest physical activity positively correlates with improved cognitive and day-to-day functioning and possibly motor function in individuals in the prodromal and early phase of the condition.
doi:10.1371/currents.hd.cba6ea74972cf8412a73ce52eb018c1e
PMCID: PMC4866530  PMID: 27818843
10.  Everyday Cognition in Prodromal Huntington Disease 
Neuropsychology  2014;29(2):255-267.
Objective
Assessment of daily functions affected by cognitive loss in prodromal Huntington disease (HD) is necessary in practice and clinical trials. We evaluated baseline and longitudinal sensitivity of the Everyday Cognition (ECog) scales in prodromal HD and compared self- and companion-ratings.
Method
Everyday cognition was self-assessed by 850 participants with prodromal HD and 768 companions. We examined internal structure using confirmatory factor analysis (CFA) on baseline data. For longitudinal analysis, we stratified participants into Low, Medium, and High disease progression groups. We examined ECog scores for group differences and participant-and-companion differences using linear mixed effects regression (LMER). Comparison with the Total Functional Capacity (TFC) scale was made.
Results
CFA revealed good fit of a 5-factor model having a global factor (total score), and sub factors (subscales) of memory, language, visuospatial perception, and executive function. At study entry, participants and companions in the Medium and High groups reported significantly worsened everyday cognition as well as significant functional decline over time. Losses became more pronounced and participant and companion ratings diverged as individuals progressed. TFC showed significant functional loss over time in the High group but not in the Medium group.
Conclusions
Disease progression is associated with reduced self- and companion-reported everyday cognition in prodromal HD participants who are less than 13 years to estimated motor onset. Our findings suggest companion ratings are more sensitive than participants’ for detecting longitudinal change in daily cognitive function. ECog appears more sensitive to specific functional changes in the prodrome of HD than the TFC.
doi:10.1037/neu0000102
PMCID: PMC4286521  PMID: 25000321
Prodromal Huntington disease; cognition; ECog; TFC; everyday functioning; activities of daily living (ADLs)
11.  Cognitive changes associated with switching to frequent nocturnal hemodialysis or renal transplantation 
BMC Nephrology  2016;17:12.
Background
It is uncertain whether switching to frequent nocturnal hemodialysis improves cognitive function in well-dialyzed patients and how this compares to patients who receive a kidney transplant.
Methods
We conducted a multicenter observational study with longitudinal follow-up of the effect on cognitive performance of switching dialysis treatment modality from conventional thrice-weekly hemodialysis to frequent nocturnal hemodialysis, a functioning renal transplant or remaining on thrice-weekly conventional hemodialysis. Neuropsychological tests of memory, attention, psychomotor processing speed, executive function and fluency as well as measures of solute clearance were performed at baseline and again after switching modality. The change in cognitive performance measured by neuropsychological tests assessing multiple cognitive domains at baseline, 4 and 12 months after switching dialysis modality were analyzed using a linear mixed model.
Results
Seventy-seven patients were enrolled; 21 of these 77 patients were recruited from the randomized Frequent Hemodialysis Network (FHN) Nocturnal Trial. Of these, 18 patients started frequent nocturnal hemodialysis, 28 patients received a kidney transplant and 31 patients remained on conventional thrice-weekly hemodialysis. Forty-eight patients (62 %) returned for the 12-month follow-up. Despite a significant improvement in solute clearance, 12 months treatment with frequent nocturnal hemodialysis was not associated with substantial improvement in cognitive performance. By contrast, renal transplantation, which led to near normalization of solute clearance was associated with clinically relevant and significant improvements in verbal learning and memory with a trend towards improvements in psychomotor processing speed. Cognitive performance in patients on conventional hemodialysis remained stable with the exception of an improvement in psychomotor processing speed and a decline in verbal fluency.
Conclusions
In patients on conventional thrice-weekly hemodialysis, receiving a functioning renal transplant was associated with improvement in auditory-verbal memory and psychomotor processing speed, which was not observed after 12 months of frequent nocturnal hemodialysis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-016-0223-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12882-016-0223-9
PMCID: PMC4722762  PMID: 26801094
Renal replacement therapy; Frequent nocturnal hemodialysis; Renal transplantation; Cognitive impairment; Cognition; Neuropsychological testing
12.  Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin 
Molecular psychiatry  2015;20(11):1286-1293.
Huntington’s disease, a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid from BACHD transgenic rats and from human Huntington’s subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes Huntington’s subjects from healthy and non-Huntington dementia controls without overlap (blinded samples). Ultimately this seeding property in Huntington’s patient cerebrospinal fluid may form the basis of a molecular biomarker assay to monitor Huntington’s disease and evaluate therapies that target mutant huntingtin protein.
doi:10.1038/mp.2015.81
PMCID: PMC4718563  PMID: 26100538
13.  An Open-Source Label Atlas Correction Tool and Preliminary Results on Huntingtons Disease Whole-Brain MRI Atlases 
The creation of high-quality medical imaging reference atlas datasets with consistent dense anatomical region labels is a challenging task. Reference atlases have many uses in medical image applications and are essential components of atlas-based segmentation tools commonly used for producing personalized anatomical measurements for individual subjects. The process of manual identification of anatomical regions by experts is regarded as a so-called gold standard; however, it is usually impractical because of the labor-intensive costs. Further, as the number of regions of interest increases, these manually created atlases often contain many small inconsistently labeled or disconnected regions that need to be identified and corrected. This project proposes an efficient process to drastically reduce the time necessary for manual revision in order to improve atlas label quality. We introduce the LabelAtlasEditor tool, a SimpleITK-based open-source label atlas correction tool distributed within the image visualization software 3D Slicer. LabelAtlasEditor incorporates several 3D Slicer widgets into one consistent interface and provides label-specific correction tools, allowing for rapid identification, navigation, and modification of the small, disconnected erroneous labels within an atlas. The technical details for the implementation and performance of LabelAtlasEditor are demonstrated using an application of improving a set of 20 Huntingtons Disease-specific multi-modal brain atlases. Additionally, we present the advantages and limitations of automatic atlas correction. After the correction of atlas inconsistencies and small, disconnected regions, the number of unidentified voxels for each dataset was reduced on average by 68.48%.
doi:10.3389/fninf.2016.00029
PMCID: PMC4971025  PMID: 27536233
brain MRI; label atlas; open-source; multi-modal; ITK; Huntingtons Disease; multi-atlas
14.  Prediction of manifest Huntington disease with clinical and imaging measures: A 12-year prospective observational study 
The Lancet. Neurology  2014;13(12):1193-1201.
BACKGROUND
Although correlation between cytosine-adenine-guanine (CAG) repeat length and age of Huntington disease (HD) onset is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counseling. We compared genetic, demographic, motor, cognitive, psychiatric, functional and imaging measures for tracking progression and predicting conversion to manifest HD.
METHODS
N=1078 research participants with the gene mutation for HD, but without a rating of 4 on the Diagnostic Confidence Level (DCL) following administration of the 15-item motor assessment of the Unified Huntington’s Disease Rating Scale. Participants were from 33 world wide sites and followed for up to 12 years (mean=5, SD=3·3) over the period 2001–2013. A subset of 225 participants prospectively converted to manifest HD according to the DCL (“meets the operational definition of the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder in a subject at risk for HD” with ≥99% confidence). Joint modeling of longitudinal and survival data was used to examine the extent to which baseline and change of 40 variables analyzed separately was predictive of CAG-adjusted age at motor diagnosis.
FINDINGS
Cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors in the top three phenotypic domains were total motor score (motor), putamen volume (imaging), and Stroop word test (cognitive). A one standard deviation (SD) difference in total motor score increased the risk of a motor diagnosis by 3·1 times (95% CI=[2·3,4·2]), one SD loss in putamen volume increased risk by 3·3 times ([2·4,4·7]) and one SD cognitive decline increased risk by 2·3 ([1·9,2·9]).
INTERPRETATION
Prediction of HD diagnosis can be considerably improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest HD should inform discussions about revisions to guidelines for diagnosis, and prognosis, and counselling, and might be useful in guiding selection of participants and outcome measures for clinical trials.
FUNDING
National Institutes of Health, National Institute of Neurological Disorders and Stroke, and CHDI Foundation, Inc.
doi:10.1016/S1474-4422(14)70238-8
PMCID: PMC4373455  PMID: 25453459
15.  Multivariate clustering of progression profiles reveals different depression patterns in prodromal Huntington disease 
Neuropsychology  2015;29(6):949-960.
Objective
Although Huntington disease (HD) is caused by an autosomal dominant mutation, its phenotypic presentation differs widely. Variability in clinical phenotypes of HD may reflect the existence of disease subtypes. This hypothesis was tested in prodromal participants from the longitudinal Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study.
Method
We performed clustering using longitudinal data assessing motor, cognitive, and depression symptoms. Using data from 521 participants with 2716 data points, we fit growth mixture models (GMM) that identify groups based on multivariate trajectories.
Results
In various GMM, different phases of disease progression were partitioned by progression trajectories of motor and cognitive signs, and by overall level of depression symptoms. More progressed motor signs were accompanied by more progressed cognitive signs, but not always by higher levels of depressive symptoms. In several models, there were at least two groups with similar trajectories for motor and cognitive signs that showed different levels for depression symptoms - one with a very low level of depression and the other with a higher level of depression.
Conclusions
Findings indicate that at least intermediate HD progression might be associated with different levels of depression. Depression is one of the few symptoms that is treatable in HD and has implications for clinical care. Identification of potential depression subtypes may also help to select appropriate patients for clinical trials.
doi:10.1037/neu0000199
PMCID: PMC4640959  PMID: 26011117
Depression; Huntington disease; genetics; cognition; movement disorders
16.  Performance of the 12-item WHODAS 2.0 in prodromal Huntington disease 
European Journal of Human Genetics  2015;23(11):1584-1587.
The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5), recommends the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 for routine clinical use. We tested the utility of the 12-item WHODAS 2.0 in prodromal Huntington disease. Using data from 726 participants and 630 companions over a 3-year follow-up, linear mixed models were fitted to test (1) baseline and longitudinal differences by progression group; (2) participant and companion differences within each group; and (3) sensitivity of the 12-item WHODAS in comparison to the 36-item WHODAS and the Total Functional Capacity (TFC) score from the Unified Huntington's Disease Rating Scale. Participants showed baseline group differences whereas companions showed baseline and longitudinal group differences. Companions reported worse functional decline over time than participants as the disease progresses. The 12-item WHODAS detected longitudinal change better than the 36-item WHODAS and the TFC in the medium progression group. Results suggest the 12-item WHODAS 2.0 can detect baseline and longitudinal differences in prodromal HD and may be useful in HD clinical trials.
doi:10.1038/ejhg.2015.11
PMCID: PMC4613468  PMID: 25735480
17.  Onset of Huntington disease: Can it be purely cognitive? 
Knowledge of the cognitive manifestation of Huntington disease has burgeoned over the past two decades. Many studies from independent datasets have shown cognitive impairment is evident prior to motor diagnosis and annual cognitive decline is a robust marker of disease progression. Additionally, cognition is a critical concern to patients and families and is associated with meaningful outcomes including functional capacity, driving, loss of accustomed work and quality of life. In the past few years, Huntington disease animal models of cognition have increased, preparing for preclinical experimental therapeutics with cognitive endpoints. A longitudinal analysis of cognitive variables was conducted with 559 gene-positive cases and 233 controls showing no signs of motor abnormalities over approximately a three year period. Results show there were statistically significant differences in rate of annual change for some cognitive variables, such that the cases group had worsening performance over time. These findings show cognitive deterioration can be seen in persons with the Huntington disease gene expansion with no overt motor signs or symptoms, suggesting that cognitive onset of Huntington disease may precede motor.
doi:10.1002/mds.25997
PMCID: PMC4193504  PMID: 25142616
Huntington disease; cognition; non-motor; onset; diagnosis
18.  Functional Connectivity of Primary Motor Cortex Is Dependent on Genetic Burden in Prodromal Huntington Disease 
Brain Connectivity  2014;4(7):535-546.
Abstract
Subtle changes in motor function have been observed in individuals with prodromal Huntington disease (prHD), but the underlying neural mechanisms are not well understood nor is the cumulative effect of the disease (disease burden) on functional connectivity. The present study examined the resting-state functional magnetic resonance imaging (rs-fMRI) connectivity of the primary motor cortex (M1) in 16 gene-negative (NEG) controls and 48 gene-positive prHD participants with various levels of disease burden. The results showed that the strength of the left M1 connectivity with the ipsilateral M1 and somatosensory areas decreased as disease burden increased and correlated with motor symptoms. Weakened M1 connectivity within the motor areas was also associated with abnormalities in long-range connections that evolved with disease burden. In this study, M1 connectivity was decreased with visual centers (bilateral cuneus), but increased with a hub of the default mode network (DMN; posterior cingulate cortex). Changes in connectivity measures were associated with worse performance on measures of cognitive–motor functioning. Short- and long-range functional connectivity disturbances were also associated with volume loss in the basal ganglia, suggesting that weakened M1 connectivity is partly a manifestation of striatal atrophy. Altogether, the results indicate that the prodromal phase of HD is associated with abnormal interhemispheric interactions among motor areas and disturbances in the connectivity of M1 with visual centers and the DMN. These changes may, respectively, contribute to increased motor symptoms, visuomotor integration problems, and deficits in the executive control of movement as individuals approach a manifest diagnosis.
doi:10.1089/brain.2014.0271
PMCID: PMC4146393  PMID: 25072408
functional connectivity; Huntington disease; motor cortex; motor system; seed voxel analysis
19.  Disruption of response inhibition circuits in prodromal Huntington disease 
Cognitive changes in the prodromal phase of Huntington disease (prHD) are found in multiple domains, yet their neural bases are not well understood. One component process that supports cognition is inhibitory control. In the present fMRI study, we examined brain circuits involved in response inhibition in 65 prHD participants and 36 gene-negative (NEG) controls using the stop signal task (SST). PrHD participants were subdivided into three groups (LOW, MEDIUM, HIGH) based on their CAG-Age Product (CAP) score, an index of genetic exposure and a proxy for expected time to diagnosis. Poorer response inhibition (stop signal duration) correlated with CAP scores. When response inhibition was successful, activation of the classic frontal inhibitory-network was normal in prHD, yet stepwise reductions in activation with proximity to diagnosis were found in the posterior ventral attention network (inferior parietal and temporal cortices). Failures in response inhibition in prHD were related to changes in inhibition centers (supplementary motor area (SMA)/anterior cingulate and inferior frontal cortex/insula) and ventral attention networks, where activation decreased with proximity to diagnosis. The LOW group showed evidence of early compensatory activation (hyperactivation) of right-hemisphere inhibition and attention reorienting centers, despite an absence of cortical atrophy or deficits on tests of executive functioning. Moreover, greater activation for failed than successful inhibitions in an ipsilateral motor-control network was found in the control group, whereas such differences were markedly attenuated in all prHD groups. The results were not related to changes in cortical volume and thickness, which did not differ among the groups. However, greater hypoactivation of classic right-hemisphere inhibition centers [inferior frontal gyrus (IFG)/insula, SMA/anterior cingulate cortex (ACC)] during inhibition failures correlated with greater globus pallidus atrophy. These results are the first to demonstrate that response inhibition in prHD is associated with altered functioning in brain networks that govern inhibition, attention, and motor control.
doi:10.1016/j.cortex.2014.04.018
PMCID: PMC4227536  PMID: 24959703
fMRI; Response inhibition; Huntington's disease; Brain activation; Brain atrophy; Neuropsychological testing
20.  Intra-individual Variability in Prodromal Huntington Disease and Its Relationship to Genetic Burden 
The current study sought to examine the utility of intra-individual variability (IIV) in distinguishing participants with prodromal Huntington disease (HD) from nongene-expanded controls. IIV across 15 neuropsychological tasks and within-task IIV using a self-paced timing task were compared as a single measure of processing speed (Symbol Digit Modalities Test [SDMT]) in 693 gene-expanded and 191 nongene-expanded participants from the PREDICT-HD study. After adjusting for depressive symptoms and motor functioning, individuals estimated to be closest to HD diagnosis displayed higher levels of across- and within-task variability when compared to controls and those prodromal HD participants far from disease onset (FICV(3,877) = 11.25; p < .0001; FPacedTiming(3,877) = 22.89; p < .0001). When prodromal HD participants closest to HD diagnosis were compared to controls, Cohen’s d effect sizes were larger in magnitude for the within-task variability measure, paced timing (− 1.01), and the SDMT (− 0.79) and paced tapping coefficient of variation (CV) (− 0.79) compared to the measures of across-task variability [CV (0.55); intra-individual standard deviation (0.26)]. Across-task variability may be a sensitive marker of cognitive decline in individuals with prodromal HD approaching disease onset. However, individual neuropsychological tasks, including a measure of within-task variability, produced larger effect sizes than an index of across-task IIV in this sample.
doi:10.1017/S1355617714001076
PMCID: PMC4549971  PMID: 26304055
Huntington disease; Neuropsychological tests; Executive function; Attention; Adult; Cognition disorders/diagnosis; Cognition disorders/genetics; Prodromal symptoms; Intra-individual variability
21.  Diagnostic criteria for vascular cognitive disorders: a VASCOG statement 
Background
Several sets of diagnostic criteria have been published for vascular dementia (VaD) since the 1960s. The continuing ambiguity in VaD definition warrants a critical re-examination.
Methods
Participants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the DSM-5 Task Force.
Results
Cognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent co-occurrence of Alzheimer’s disease pathology emphasized.
Conclusions
The proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathological validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.
doi:10.1097/WAD.0000000000000034
PMCID: PMC4139434  PMID: 24632990
Vascular dementia; vascular cognitive disorder; vascular cognitive impairment; diagnostic criteria; cerebrovascular disease; multi-infarct dementia; post-stroke dementia; subcortical dementia
22.  Diffeomorphic Shape Trajectories for Improved Longitudinal Segmentation and Statistics 
Longitudinal imaging studies involve tracking changes in individuals by repeated image acquisition over time. The goal of these studies is to quantify biological shape variability within and across individuals, and also to distinguish between normal and disease populations. However, data variability is influenced by outside sources such as image acquisition, image calibration, human expert judgment, and limited robustness of segmentation and registration algorithms. In this paper, we propose a two-stage method for the statistical analysis of longitudinal shape. In the first stage, we estimate diffeomorphic shape trajectories for each individual that minimize inconsistencies in segmented shapes across time. This is followed by a longitudinal mixed-effects statistical model in the second stage for testing differences in shape trajectories between groups. We apply our method to a longitudinal database from PREDICT-HD and demonstrate our approach reduces unwanted variability for both shape and derived measures, such as volume. This leads to greater statistical power to distinguish differences in shape trajectory between healthy subjects and subjects with a genetic biomarker for Huntington’s disease (HD).
PMCID: PMC4486086  PMID: 25320781
23.  Regional Atrophy Associated with Cognitive and Motor Function in Prodromal Huntington Disease 
Journal of Huntington's disease  2013;2(4):477-489.
Background
Neuroimaging studies suggest that volumetric MRI measures of specific brain structures may serve as excellent biomarkers in future clinical trials of Huntington disease (HD).
Objective
Demonstration of the clinical significance of these measures is an important step in determining their appropriateness as potential outcome measures.
Methods
Measures of gray- and white-matter lobular volumes and subcortical volumes (caudate, putamen, globus pallidus, thalamus, nucleus accumbens, hippocampus) were obtained from MRI scans of 516 individuals who tested positive for the HD gene expansion, but were not yet exhibiting signs or symptoms severe enough to warrant diagnosis (“pre-HD”). MRI volumes (corrected for intracranial volume) were correlated with cognitive, motor, psychiatric, and functional measures known to be sensitive to subtle changes in pre-HD.
Results
Caudate, putamen, and globus pallidus volumes consistently correlated with cognitive and motor, but not psychiatric or functional measures in pre-HD. Volumes of white matter, nucleus accumbens, and thalamus, but not cortical gray matter, also correlated with some of the motor and cognitive measures.
Conclusions
Results of regression analyses suggest that volumes of basal ganglia structures contributed more highly to the prediction of most motor and cognitive variables than volumes of other brain regions. These results support the use of volumetric measures, especially of the basal ganglia, as outcome measures in future clinical trials in pre-HD. Results may also assist investigators in selecting the most appropriate measures for treatment trials that target specific clinical features or regions of neuropathology.
doi:10.3233/JHD-130076
PMCID: PMC4412155  PMID: 25062732
Huntington disease; magnetic resonance imaging; cognitive; psychiatric; motor
24.  Movement sequencing in Huntington disease 
Objectives
To examine longitudinal changes in movement sequencing in prodromal Huntington’s disease (HD) participants (795 prodromal HD; 225 controls) from the PREDICT-HD study.
Methods
Prodromal HD participants were tested over seven annual visits and were stratified into three groups (low, medium, high) based on their CAG-Age Product (CAP) score, which indicates likely increasing proximity to diagnosis. A cued movement sequence task assessed the impact of advance cueing on response initiation and execution via three levels of advance information.
Results
Compared to controls, all CAP groups showed longer initiation and movement times across all conditions at baseline, demonstrating a disease gradient for the majority of outcomes. Across all conditions, the high CAP group had the highest mean for baseline testing, but also demonstrated an increase in movement time across the study. For initiation time, the high CAP group showed the highest mean baseline time across all conditions, but also faster decreasing rates of change over time.
Conclusions
With progress to diagnosis, participants may increasingly use compensatory strategies, as evidenced by faster initiation. However, this occurred in conjunction with slowed execution times, suggesting a decline in effectively accessing control processes required to translate movement into effective execution.
doi:10.3109/15622975.2014.895042
PMCID: PMC4389285  PMID: 24678867
Huntington disease; sequencing; movement; basal ganglia; predictive testing
25.  Diffusion weighted imaging of prefrontal cortex in prodromal Huntington’s disease 
Human brain mapping  2013;35(4):1562-1573.
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.
doi:10.1002/hbm.22273
PMCID: PMC3775984  PMID: 23568433
Executive function; diffusion tensor imaging; frontal lobe; Trail Making Test

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