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

In vivo characterization of white matter pathology in pre‐manifest Huntington's disease

OBJECTIVE: Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder, providing an ideal model for understanding brain changes occurring in the years prior to disease onset. Diffusion tensor imaging (DTI) studies show widespread white matter disorganization in the early pre-manifest stages (pre-HD). However, while DTI has proved informative, it provides only limited information about underlying changes in tissue properties. Neurite Orientation Dispersion and Density Imaging (NODDI) is a novel MRI technique for characterizing axonal pathology more specifically, providing metrics that separately quantify axonal density and axonal organization. Here, we provide the first in vivo characterization of white matter pathology in pre-HD using NODDI. METHODS: Diffusion-weighted MRI data that support DTI and NODDI were acquired from 38 pre-HD and 45 control participants. Using whole-brain and region-of-interest analyses, NODDI metrics were compared between groups and correlated with clinical scores of disease progression. Whole-brain changes in DTI metrics were also examined. RESULTS: The pre-HD group displayed widespread reductions in axonal density compared with control participants; this correlated with measures of clinical disease progression in the body and genu of the corpus callosum. There was also evidence in the pre-HD group of increased coherence of axonal packing in the white matter surrounding the basal ganglia. INTERPRETATION: Our findings suggest that reduced axonal density is one of the major factors underlying white matter pathology in pre-HD, coupled with increased local organization in areas surrounding the basal ganglia. NODDI metrics show promise in providing more specific information about the biological processes underlying HD and neurodegeneration per se

Testing a longitudinal compensation model in premanifest Huntington's disease

Neurological Motor Disorder

International Fragility Fracture Network Delphi consensus statement on the principles of anaesthesia for patients with hip fracture

Globally, the number of hip fractures is expected to double between 2017 and 2050, from ~2.2 million to ~4.5 million. For the purposes of analgesia and remobilisation, ~ 99% of hip fractures should be fixed surgically, requiring anaesthesia. Surgery for hip fracture has become increasingly standardised, but peri‐operative medical and anaesthetic care varies considerably. Peri‐operative morbidity and mortality remain high. Guidelines exist for the anaesthetic management of patients with hip fracture, but are specific to the healthcare systems of Western nations. This consensus statement (advises basic standards of anaesthetic care that hip fracture patients should expect to receive in any country, regardless of resources. On behalf of the Fragility Fracture Network (FFN), the Anaesthesia Working Group (SW) invited internationally recognised experts in hip fracture anaesthesia and national professional leaders to contribute to a Consensus Com-mittee

White matter predicts functional connectivity in premanifest Huntington's disease

Neurological Motor Disorder

Brain Regions Showing White Matter Loss in Huntington’s Disease Are Enriched for Synaptic and Metabolic Genes

and the Track-On HD InvestigatorsInternational audienceBackground: The earliest white matter changes in Huntington’s disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability.Methods: Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington’s disease relative to control participants. The baseline cohort included 72 premanifest Huntington’s disease participants and 85 healthy control participants.Results: We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington’s disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington’s disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles.Conclusions: These findings suggest a dual mechanism of white matter vulnerability in Huntington’s disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss

Topological length of white matter connections predicts their rate of atrophy in premanifest Huntington's disease

Neurological Motor Disorder

Testing a longitudinal compensation model in premanifest Huntington's disease

The initial stages of neurodegeneration are commonly marked by normal levels of cognitive and motor performance despite the presence of structural brain pathology. Compensation is widely assumed to account for this preserved behaviour, but despite the apparent simplicity of such a concept, it has proven incredibly difficult to demonstrate such a phenomenon and distinguish it from disease-related pathology. Recently, we developed a model of compensation whereby brain activation, behaviour and pathology, components key to understanding compensation, have specific longitudinal trajectories over three phases of progression. Here, we empirically validate our explicit mathematical model by testing for the presence of compensation over time in neurodegeneration. Huntington’s disease is an ideal model for examining longitudinal compensation in neurodegeneration as it is both monogenic and fully penetrant, so disease progression and potential compensation can be monitored many years prior to diagnosis. We defined our conditions for compensation as non-linear longitudinal trajectories of brain activity and performance in the presence of linear neuronal degeneration and applied our model of compensation to a large longitudinal cohort of premanifest and early-stage Huntington’s disease patients from the multisite Track-On HD study. Focusing on cognitive and motor networks, we integrated progressive volume loss, task and resting state functional MRI and cognitive and motor behaviour across three sequential phases of neurodegenerative disease progression, adjusted for genetic disease load. Multivariate linear mixed models were fitted and trajectories for each variable tested. Our conceptualization of compensation was partially realized across certain motor and cognitive networks at differing levels. We found several significant network trends that were more complex than that hypothesized in our model. These trends suggest changes to our theoretical model where the network effects are delayed relative to performance effects. There was evidence of compensation primarily in the prefrontal component of the cognitive network, with increased effective connectivity between the left and right dorsolateral prefrontal cortex. Having developed an operational model for the explicit testing of longitudinal compensation in neurodegeneration, it appears that general patterns of our framework are consistent with the empirical data. With the proposed modifications, our operational model of compensation can be used to test for both cross-sectional and longitudinal compensation in neurodegenerative disease with similar patterns to Huntington’s disease