Meaningful and measurable health domains in Huntington’s: large-scale validation of the Huntington’s disease health-related quality of life questionnaire (HDQoL) across severity stages

Objectives: While health-related quality of life is key for patients with long-term neurodegenerative conditions, measuring this is less straightforward and complex in Huntington’s disease. This study aimed to refine and validate a fully patient-derived instrument, the Huntington’s Disease health-related Quality of Life questionnaire (HDQoL), and to elucidate health domains that are meaningful to patients’ lived experience. Methods: Five-hundred and forty-one participants, from pre-manifest to end-stage disease completed the HDQoL, together with generic quality of life measures, and in-person motor, cognitive and behavioural assessments. The psychometric properties of the HDQoL were examined using factor analysis and Rasch analysis. Results: Four HDQoL domains emerged reflecting the classical triad of HD features - they were Physical-Functional, Cognitive, and two different behavioural aspects i.e. Mood-Self domain, as well as a distinct Worries domain. These domains clarify the behavioural sequelae as experienced by patients, and all showed good to excellent internal consistency. Known groups analyses illustrated significant and graded changes in clinical assesments and corresponding HDQoL domains across severity levels. Convergent and discriminant validity was demonstrated by the expected pattern of correlations between specific HDQoL domains and corresponding domain-relevant clinical assesments as well as patient-reported measures. The data demonstrate robust support for the refined HDQoL across disease stages. Conclusions: The HDQoL with its two distinct behavioural domains of Mood-Self and of Worries, as well as a Physical-Functional and a Cognitive domain, is a relevant, reliable and valid patient-derived instrument to measure the impact of Huntington’s disease across all severity stages

Adaptive Equalization and Capacity Analysis for Amplify-and-Forward Relays

Recent research has shown that multiple-input multiple-output (MIMO) systems provide high spectral efficiencies and error performance gains. However, the use of multiple antennas in mobile terminals may not be very practical. Certainly there is limited space and other implementation issues which make this a challenging problem. Therefore, to harness the diversity gains afforded by MIMO transmitter diversity techniques, while maintaining a minimal number of antennas on each handset, cooperative diversity techniques have been proposed. In addition, attention has also been given to combining wireless relaying systems with MIMO techniques to improve capacity, coverage, and obtain better diversity at the expense of increased node complexity. This thesis considers the design and analysis of cooperative diversity systems and MIMO amplify-and-forward relaying systems. In particular, we investigate adaptive time- and frequency-domain equalization techniques for cooperative diversity systems using space-time block codes (STBC). For MIMO relaying systems, we analyze the ergodic capacity of various systems and compare different amplify-and-forward methods in terms of system capacity performance. We propose a new block time-domain adaptive equalization structure for time reversal-space time block coding (TR-STBC) systems, which eliminates the separate decoder and also the need for explicit channel state information (CSI) estimation at the receiver. Our simulation results show that the time-domain adaptive block equalizer performs better than the frequency-domain counterpart but at the cost of increased complexity. Then, we extend this time-domain adaptive equalization scheme to distributed TR-STBC systems. We also develop a frequency-domain counterpart for the distributed systems. Our simulation results show that the adaptive algorithms work well for Protocols I and III proposed by Nabar et al. The time-domain adaptive algorithms perform better than the frequency-domain algorithms, and overall the Protocol I receivers outperform the Protocol III receivers. We also show that, if only the Protocol III receiver is used, it can be susceptible to noise amplification due to a weaker source-to-relay link compared to the relay-to-destination link. This problem can be mitigated by using the Protocol I receivers with some extra complexity but much superior diversity performance. We also present an ergodic capacity analysis of an amplify-and-forward (AF) MIMO two-hop system including the direct link and validate the analysis with simulations. We show that having the direct link improves the capacity due to diversity and quantify this improvement. We also present an ergodic capacity analysis of an AF MIMO two-hop, two relay system. Our results verify the capacity gain of relaying systems with two relays due to the extra diversity compared to a single relaying system. However, the results also show that when one of the source-to-relay links has a markedly higher SNR compared to the other, a single relay system has better capacity than a two relay system. Finally, we compare three types of relay amplification methods: a) average amplification, b) instantaneous channel amplification, and c) instantaneous power amplification. The instantaneous power amplification method has a higher mean capacity but with a higher variance. Also, it requires additional information at the destination and would create enormous overheads compared to the other methods. We also find that the instantaneous channel amplification method has almost no advantage in terms of the mean capacity but its capacity is less variable than the average amplification method. On the other hand, the average amplification method is simpler to implement as it does not require channel estimation at the relaying terminal

Plasmodynamic synthesis of product based on aluminum in the oxygen atmosphere of a reactor-chamber

In this paper, the possibility is shown to synthesize oxide aluminum using a high-speed electro discharge plasma jet. The synthesized products were characterized by X-Ray diffractometry and transmission electron microscopy

Evaluation of multi-modal, multi-site neuroimaging measures in Huntington's disease: Baseline results from the PADDINGTON study.

BACKGROUND: Macro- and micro-structural neuroimaging measures provide valuable information on the pathophysiology of Huntington's disease (HD) and are proposed as biomarkers. Despite theoretical advantages of microstructural measures in terms of sensitivity to pathology, there is little evidence directly comparing the two. METHODS: 40 controls and 61 early HD subjects underwent 3 T MRI (T1- and diffusion-weighted), as part of the PADDINGTON study. Macrostructural volumetrics were obtained for the whole brain, caudate, putamen, corpus callosum (CC) and ventricles. Microstructural diffusion metrics of fractional anisotropy (FA), mean-, radial- and axial-diffusivity (MD, RD, AD) were computed for white matter (WM), CC, caudate and putamen. Group differences were examined adjusting for age, gender and site. A formal comparison of effect sizes determined which modality and metrics provided a statistically significant advantage over others. RESULTS: Macrostructural measures showed decreased regional and global volume in HD (p < 0.001); except the ventricles which were enlarged (p < 0.01). In HD, FA was increased in the deep grey-matter structures (p < 0.001), and decreased in the WM (CC, p = 0.035; WM, p = 0.053); diffusivity metrics (MD, RD, AD) were increased for all brain regions (p < 0.001). The largest effect sizes were for putamen volume, caudate volume and putamen diffusivity (AD, RD and MD); each was significantly larger than those for all other metrics (p < 0.05). CONCLUSION: The highest performing macro- and micro-structural metrics had similar sensitivity to HD pathology quantified via effect sizes. Region-of-interest may be more important than imaging modality, with deep grey-matter regions outperforming the CC and global measures, for both volume and diffusivity. FA appears to be relatively insensitive to disease effects

Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study

BACKGROUND: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. METHODS: We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. FINDINGS: Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. INTERPRETATION: Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy

Validating automated segmentation tools in the assessment of caudate atrophy in Huntington's disease

Background: Neuroimaging shows considerable promise in generating sensitive and objective outcome measures for therapeutic trials across a range of neurodegenerative conditions. For volumetric measures the current gold standard is manual delineation, which is unfeasible for samples sizes required for large clinical trials.Methods: Using a cohort of early Huntington's disease (HD) patients (n = 46) and controls (n = 35), we compared the performance of four automated segmentation tools (FIRST, FreeSurfer, STEPS, MALP-EM) with manual delineation for generating cross-sectional caudate volume, a region known to be vulnerable in HD. We then examined the effect of each of these baseline regions on the ability to detect change over 15 months using the established longitudinal Caudate Boundary Shift Integral (cBSI) method, an automated longitudinal pipeline requiring a baseline caudate region as an input.Results: All tools, except Freesurfer, generated significantly smaller caudate volumes than the manually derived regions. Jaccard indices showed poorer levels of overlap between each automated segmentation and manual delineation in the HD patients compared with controls. Nevertheless, each method was able to demonstrate significant group differences in volume (p < 0.001). STEPS performed best qualitatively as well as quantitively in the baseline analysis. Caudate atrophy measures generated by the cBSI using automated baseline regions were largely consistent with those derived from a manually segmented baseline, with STEPS providing the most robust cBSI values across both control and HD groups.Conclusions: Atrophy measures from the cBSI were relatively robust to differences in baseline segmentation technique, suggesting that fully automated pipelines could be used to generate outcome measures for clinical trials.Neurological Motor Disorder

Relationship of serum beta-synuclein with blood biomarkers and brain atrophy

Background: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). Methods: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. Results: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. Discussion: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. Highlights: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL)

Predicting disease progression in behavioral variant frontotemporal dementia

Introduction: The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline. Methods: One hundred five bvFTD patients were recruited from the German frontotemporal lobar degeneration (FTLD) consortium study. After defining two groups ("fast progressors" vs. "slow progressors"), we investigated the predictive value of MR brain volumes for disease progression rates performing exhaustive screenings with multivariate classification models. Results: We identified areas that predict disease progression rate within 1 year. Prediction measures revealed an overall accuracy of 80% across our 50 top classification models. Especially the pallidum, middle temporal gyrus, inferior frontal gyrus, cingulate gyrus, middle orbitofrontal gyrus, and insula occurred in these models. Discussion: Based on the revealed marker combinations an individual prognosis seems to be feasible. This might be used in clinical studies on an individualized progression model

Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis

IMPORTANCE: Predictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTT gene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first. OBJECTIVE: To determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis. DESIGN, SETTING AND PARTICIPANTS: This study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017. MAIN OUTCOMES AND MEASURES: The primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test. RESULTS: Of Track’s 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For required sample size, PFS with a motor diagnosis or total motor score progression required about 4 times fewer participants than a motor diagnosis alone. Including additional cognitive progression events further reduced the number. For example, a 3-year trial with 10% attrition and a treatment effect of 50% requires a total of 661 with motor diagnosis as the survival end point but only 177 with a total motor score PFS. CONCLUSIONS AND RELEVANCE: Reasonably sized prediagnosis Huntington disease trials can be planned with PFS, and there is evidence of generalizability of this approach

White matter predicts functional connectivity in premanifest Huntington's disease

Objectives The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD. The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD