Rating Apathy in Huntington’s Disease: Patients and Companions Agree.

BACKGROUND: Apathy is a common feature of Huntington’s disease (HD), even from early disease. However, patients are believed to lack insight into their own apathy and therefore clinicians and/or companions are relied upon to estimate the extent of a patient’s apathy. In addition, the evolution of apathy over time in HD has not been unequivocally established. OBJECTIVEs: The purpose of this study was to determine whether HD patient’s self-rated apathy scores were consistent with the scores given by companions who were also asked to rate the patients apathy. Furthermore, the clinical correlates of apathy and its stability over time were examined for both self-rated and companion-rated scores. METHODs: Apathy was measured in a large cross-sectional population of HD patients ranging from early to late stage disease (n = 106) using the Apathy Evaluation Scale; a subgroup of whom were followed longitudinally (n = 62) on average 18.7 (1.2 SD) months later. Comparisons were made between self-rated and companion-rated apathy and the relationship between apathy and motor, cognitive and functional performance was explored. RESULTS: Analysis of the cross-sectional data revealed that self-rated and companion-rated apathy were highly correlated, establishing the validity of using self-rated instead of, or in combination with, companion-rated assessments of apathy in future studies. Both self-rated and companion-rated scores had a relationship with motor and functional impairment, but had a complex relationship with cognition. The results of the longitudinal comparison revealed that apathy did not change over time in this cohort.CONCLUSIONs: Apathy can be equally well assessed by either patients or companions and does not change significantly over an18 month period. These findings have implications in the design of studies looking at treating this important aspect of HD.The work included in this manuscript has been partially funded by financial support from the NIHR Cambridge Biomedical Research Centre and the Cambridge University NHS Foundation Trust.This is the accepted manuscript of a paper published in the Journal of Huntington's Disease (Mason S, Barker RA, Journal of Huntington's Disease 2015, 4, 49-59, doi:10.3233/JHD-140133). The final version is available at http://dx.doi.org/10.3233/JHD-14013

Cell replacement therapy for Parkinson's disease

AbstractParkinson's disease (PD) is a progressive neurodegenerative disorder in which the degeneration of dopaminergic neurons projecting from the substantia nigra to the striatum is a key pathological feature of the disease. Although pharmacological dopamine replacement is generally very effective in early disease, it is only a symptomatic therapy and can have significant side effects with long term use. One of the key strategies in a more restorative approach to PD therapy involves replacement of this degenerating nigro-striatal dopaminergic network with cells and several possible cell sources are being explored. While much experience and some success have been gained with fetal ventral mesencephalic (FVM) tissue transplants, the rapidly advancing stem cell field is providing attractive alternative options which circumvent many of the ethical and practical problems inherent in trials with FVM tissue. Of these embryonic stem cells and induced pluripotent stem cells seem the most promising. However further development and optimisation of the safety and efficacy of the techniques involved in generating and manipulating these, as well as other, cell sources will be essential before any further clinical trials are carried out

Progress in Huntington's disease: the search for markers of disease onset and progression.

Unlike most neurodegenerative disorders, individuals at risk from Huntington's disease can be identified prior to the onset of clinical signs of the disease by virtue of it being an autosomal dominant condition. This provides the hypothetical opportunity to delay disease onset and/or slow down the progression of the disease in the very early stages ahead of overt features of disease. To help prepare for therapeutic trials of disease-modifying compounds, extensive work has gone into (1) finding ways of better predicting the onset of disease in pre-manifest HD gene carriers (PMGC), (2) defining the extent of non-motor features of HD and (3) identifying robust and reliable tests by which to measure disease progression. In this short review, we summarise some of the major findings in this area of clinical research.The work included in this manuscript has been partially funded by financial support from the NIHR Cambridge Biomedical Research Centre and the Cambridge University NHS Foundation Trust.This is the accepted manuscript of an article published by Springer. The final version is available at http://dx.doi.org/10.1007/s00415-015-7700-0

Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i) what constitutes an iN cell, ii) which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii) whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.This research has received funding from the New York Stem Cell Foundation, the European Research Council under the European Union's Seventh Framework Programme: FP/2007-2013 Neuro Stem Cell Repair (no. 602278), ERC Grant Agreement no. 30971, the Swedish Research Council treatment of the future grant agreement K2012-99X-22324-01-5, the Swedish Research Council 70862601/Bagadilico, Swedish Parkinson Foundation (Parkinsonfonden), the Strategic Research Area at Lund University Multipark and StemTherapy. JJ is supported by the Swedish Foundation for Strategic Research (#FFL12-0074). JD is supported by a Canadian Institutes of Health Research (CIHR) fellowship (#358492), and RB is supported by an NIHR Biomedical Research Centre grant to the University of Cambridge/Addenbrooke's Hospital. MP is a New York Stem Cell Foundation—Robertson Investigator

Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease.

Clinical studies of Parkinson's disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO ( NCT01898390 ), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.This study was supported by an EU FP7 grant (242003) as well as funding from the Cure Parkinson’s Trust (RG81537), John Black Charitable Trust and Multipark. The work was also supported by NIHR funding of Biomedical Research Centres at UCL and Cambridge (146281). RAB is an NIHR Senior Investigator (NF-SI-0616-10011) and a PI in the MRC/WT Stem Cell Institute (203151/Z/16/Z)

Current Understanding of the Glial Response to Disorders of the Aging CNS

In this special issue of Frontiers in Pharmacology, we have asked leading experts to comment and review the evidence that inflammatory cells play a leading role in the pathological processes underlying neurodegenerative disorders. We now seek to draw these various observations together into a conclusion, with the hope that this will inform further work in this area and result in the identification of new therapeutic targets that will have a disease modifying effect

The Current Status of Neural Grafting in the Treatment of Huntington’s Disease. A Review

Huntington’s disease (HD) is a devastating, fatal, autosomal dominant condition in which the abnormal gene codes for a mutant form of huntingtin that causes widespread neuronal dysfunction and death. This leads to a clinical presentation, typically in midlife, with a combination of motor, psychiatric, cognitive, metabolic, and sleep abnormalities, for which there are some effective symptomatic therapies that can produce some transient benefits. The disease, though, runs a progressive course over a 20-year period ultimately leading to death, and there are currently no proven disease modifying therapies. However whilst the neuronal dysfunction and loss affects much of the central nervous system, the striatum is affected early on in the disease and is one of the areas most affected by the pathogenic process. As a result the prospect of treating HD using neural transplants of striatal tissue has been explored and to date the clinical data is inconclusive. In this review we discuss the rationale for treating HD using this approach, before discussing the clinical trial data and what we have learnt to date using this therapeutic strategy

Animal Models of Parkinson's Disease: Are They Useful or Not?

The use of animal models in Parkinson's disease research has been controversial in terms of how well they relate to the clinical condition and thus their utility for translating therapies from the lab to the clinic. In this article, two researchers debate this issue with Roger Barker taking the view that such models are not useful and may even be misleading, while Anders Björklund defends their use and highlights their value in better understanding and treating this condition.This is just a discussion piece, so no funding acknowledged

Disease-Modification in Huntington's Disease: Moving Away from a Single-Target Approach.

To date, no candidate intervention has demonstrated a disease-modifying effect in Huntington's disease, despite promising results in preclinical studies. In this commentary we discuss disease-modifying therapies that have been trialled in Huntington's disease and speculate that these failures may be attributed, in part, to the assumption that a single drug selectively targeting one aspect of disease pathology will be universally effective, regardless of disease stage or "subtype". We therefore propose an alternative approach for effective disease-modification that uses 1) a combination approach rather than monotherapy, and 2) targets the disease process early on - before it is clinically manifest. Finally, we will consider whether this change in approach that we propose will be relevant in the future given the recent shift to targeting more proximal disease processes-e.g., huntingtin gene expression; a timely question given Roche's recent decision to take on the clinical development of a promising new drug candidate in Huntington's disease, IONIS-HTTRx.MPJ’s work is supported by the Newton College Masters Award and Trinity Hall Studentship. The work is also supported by an NIHR award of a Biomedical Research Centre to Addenbrooke’s NHS Trust/University of Cambridge (NIHR BRC award: RG85367). RAB is also an NIHR senior investigator (NIHR senior Investigator Award: RG86498)