Posted in Journal Reviews on 20th Sep 2013
The TRACK to clinical trials in Huntington’s disease
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder classically described as a triad of motor, cognitive and psychiatric features. Given the monogenic nature of this disease and the availability of suitable animal models, finding potential therapies or even a cure should be theoretically feasible particularly since a number of treatments have shown preclinical promise. However, a major challenge facing such clinical trials is the longitudinal assessment of disease progression. Defining tests that are sensitive enough to detect a longitudinal decline over a short period of time in this slowly progressive disease is of utmost importance as it is likely that initial therapies developed for HD will aim to slow down the pathological process and hence hinder decline rather than restoring pathology.
The aim of TRACK HD,a multicentre longitudinal observational natural history study, is to identify a battery of potential outcome measures to be used in future therapeutic trials. Over the past few years, they have followed up a group of 366 participants divided into groups of premanifest gene carriers (preHD), early manifest HD patients,and controls. In a recent paper in Lancet Neurology, Tabrizi and colleagues reported findings from the 298 participants that completed the 36 month follow up period of the TRACK HD study. The study was specifically extended beyond 24 months due to the paucity of findings in the preHD cohort. However, by the 36 months visit they were able to demonstrate longitudinal changes in several imaging, quantitative motor and cognitive measures in the preHD group that were close to manifesting disease. In contrast, despite striatal and white matter loss, very little change could be seen clinically in the preHD group estimated to be far from disease onset. In addition, the authors also noted a variety of changes in early HD in accordance with the 12 and 24 month report of the TRACK HD study. Several baseline imaging and cognitive measures could also predict disease progression in preHD, and functional decline in manifest disease.
HD is unique in the respect that a population which will almost certainly develop disease can be identified prior to the onset of clinically meaningful symptoms. This has led to the ambitious goal of developing a preventative therapy for this disease. However, despite the longitudinal changes in the preHD group estimated to be close to onset in this study,such trials will certainly face many practicality challenges in the preHD population, including identification of a “close to onset” group, lengthy follow up and large sample sizes. Such trials may be more feasible in manifest HD where TRACK HD has shown that disease progression can be detected reliably at 24 months, with some measurements showing changes as early as 12 months,which will prove useful in planning future clinical trials in HD. – FB
Tabrizi SJ, Scahill RI, Owen G, et al.
Predictors of phenotypic progression and disease onset in premanifest and early.stage Huntington’s disease in the TRACK.HD study: analysis of 36 month observational data.
Lancet Neurol. 2013;12:637.49.
Tabrizi SJ, Reilmann R, Roos RA, et al.
Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK HD study: analysis of 24 month observational data.
Lancet Neurol. 2012;11:42.53.
Tabrizi SJ, Scahill RI, Durr A, et al.
Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACKHD study: the 12 month longitudinal analysis.
The Lancet Neurology. 2011;10:31.42.
Consider Earlier Surgical Intervention in people with intractable Frontal Lobe Epilepsy
Frontal lobe epilepsy (FLE) is the second most common type of focal.onset epilepsy treated surgically. Seizure outcomes reported from cohort studies are generally inferior to those reported from temporal lobe surgery, and in particular compared with outcomes from those with mesial temporal lobe epilepsy.
A recent paper from the Cleveland clinic examined potential prognostic factors following frontal lobe surgery.Simasathien and colleagues reviewed 158 people who underwent FLE surgery between 1995 and 2010 with the primary outcome being complete seizure freedom at last follow up. The mean age at surgery was 20.4 years (SD 1.2) with a mean age of epilepsy onset of 8.4 years (SD 0.7) and mean epilepsy duration of 12.0 years (SD 0.9). The mean duration of follow.up post.operatively was 4.3 years. The predominant underlying pathology identified was malformations of cortical development (MCD) in almost 60% of cases overall. Non lesional resections (normal MRI) were performed in 38 patients (24%).
Overall, half of the people who underwent surgery for FLE were seizure free at last follow-up. The probability of being seizure free was 66% (95% CI 62.68) at 1 year post-operatively, 52% (95% CI 48.56) at 2 years and 44% (95% CI 39.49) at five years and beyond. The majority (70%) of seizure recurrences occurred in the absence of any provoking factors.
Three factors were identified that predicted (unprovoked) seizure recurrence on univariate analysis:longer epilepsy duration (> 10 years), left (as opposed to right) sided surgery, and the occurrence of seizures in the first postoperative week.All 3 factors remained statistically significant on multivariate analysis with a risk ratio of 1.82 for left sided surgery, 2.61 for epilepsy duration ≥5 years, and a risk ratio of 3.35 for acute postoperative seizures.
The novel finding in this study is the importance of epilepsy duration in determining postoperative seizure prognosis. Sub-analysis of seizure outcome in various pathologies underlies the importance of seizure duration: 68% of people with MCD and epilepsy duration < 5 years were seizure free at last follow-up compared to 40% with duration of ≥5 years with 100% vs 37% seizure free rates in people with FL tumour resection.
This study highlights the importance of early consideration and referral for evaluation of surgery in people with established intractable FLE. It may be that the poorer outcome associated with FLE surgery compared to TLE surgery may be in part explained that TLE surgery, is typically considered earlier in people with refractory TLE (given it’s longer surgical pedigree and also the increased number of procedures performed in a typical epilepsy centre) compared to people with refractory FLE. – AN
Simasathien T, Vadera S, Najm I et al.
Improved Outcomes with Earlier Surgery for Intractable Frontal Lobe Epilepsy.
Ann Neurol 2013;73:646.54.
IST-3: Live not longer, but better?
The third International Stroke Trial (IST-3) was designed to test alteplase administered to a wide range of patients, including those aged over 80, and up to six hours after stroke onset. Most previous trials assessing IV alteplase versus control within 6 hours of ischaemic stroke were limited to reported outcomes at 90 days, with none reporting outcomes beyond one year. The Lancet Neurology recently published useful long term clinical data regarding patient outcomes in this cohort at eighteen months post thrombolysis.
3035 patients were originally randomised to receive either alteplase or standard care alone. At 18 months, outcomes from 2,348 patients were analysed, revealing there was no significant difference in mortality between treated patients and controls (35%). The number of patients alive and independent, as assessed by an Oxford Handicap Scale (OHS) score of 0 to 2, had not been significantly improved at the 6 month time point in the trial,published last year. At 18 months however,this endpoint was significant. Furthermore,there were statistically significant and clinically relevant improvements in the health related quality of life of treated survivors as assessed by the Euro QoL instrument, with them having better functional outcomes, and requiring less help with ADL’s. Mobility,self-care,ability to perform usual activities,and pain and discomfort were all improved. However, this did not translate into a difference in the proportion of patients living at home as opposed to in care facilities post stroke.
Limitations in study design conceded by authors were that the patients weren’t blinded as to whether they had received thrombolysis or not, which could have led to recall bias when they reported outcomes on quality of life. A high proportion of the health-related quality of life forms were completed by a proxy in the trial due to the severity of stroke in some patients, although we know from other studies that proxies tend to assign worse health status than do patients.
The IST-3 trial corroborates evidence from several other previous trials that stroke thrombolysis with IV alteplase within 6h of acute stroke onset does not significantly improve the number of patients who are alive and living independently following treatment at 6 months when compared with controls. The primary endpoint of the trial was therefore negative. Caution is of course needed when a secondary exploratory analysis is used to claim efficacy.
On a more positive note, we now have evidence that thrombolysis can lead to a sustained and meaningful improvement in the quality of life of patients, including the elderly. There are also potentially significant economic gains to be made from using a treatment that keeps patients independent (albeit not necessarily in their own homes) at 18 months. As the authors point out, in 2002 the estimated cost of longterm care of an independent stroke survivor was £876 per year as compared to the £11,292 price of care for a dependent survivor. Although thrombolysis did not improve survival at 18 months in this large cohort, the fact it can make a difference to the lives of individual patients at extended followup, as well as lessening societal costs, is encouraging. – GC
The IST-3 collaborative group.
Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long.term outcomes (the third International Stroke Trial [IST.3]): 18.month follow-up of a randomised controlled trial.
The Lancet Neurology 2013;12:768–76.
The IST-3 collaborative group.
The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.
Can Sudoku save your marbles?
Iris Murdoch is one of many towering intellects who sadly succumbed to the ravages of dementia in their later years. Yet the mass media is replete with headlines exhorting us to“use or lose it”claiming that everything from crossword puzzles to Nintendo games can stave off “The Big D”. With no disease modifying medications available to treat dementia, the idea of being able to modify our lifestyle factors in this way to prevent it, seems like an enticing yet somewhat implausible one.
Wilson et al sought to determine whether childhood (6–12 years),young adulthood (age 18),middle age (age 40),and late life (current) engagement in cognitively stimulating activities delays late life cognitive decline and if it is not linked to common neuropathologic measures of amyloid, tangles, cerebral infarcts and lewy bodies. Utilising neuropathologic assessments on 294 individuals followed clinically every year on average 5.8 years before death, they were able to test the cognitive reserve hypothesis.Interestingly,their results supported the cognitive reserve hypothesis as people with current and early.life engagement in cognitively stimulating activities showed slower decline in cognition, despite the presence of underlying pathology. This raises the intriguing question of how cognitive reserve actually exerts an effect,if not through ameliorating the burden of pathology. – GC
Wilson RS, Boyle PA, Yu L et al.
Lifespan cognitive activity, neuropathologic burden, and cognitive aging.
Neurology. 2013 Jul 23; 81:314.21.
Is ALS a prion like disorder?
Neurodegenerative diseases are characterised by pathological protein inclusions.The age old question remains as to whether these inclusions are mechanistically involved in disease or not.In the case of ALS,the hallmark protein in 95% of cases is TDP43. There has been much interest in the possibility that a prionlike process could explain the pathogenicity of this promiscuous RNA/DNA binding protein. A self templating, prion like process is attractive given that patients with ALS initially develop symptoms/signs at a single locus, and that the disease appears to ‘spread’ to contiguous anatomical regions. Such spread might also explain the clinicopathological overlap with FTLD TDP: the primary motor cortex is of course part of the frontal lobe. Indeed,recent evidence has implicated axons as potential conduits for the spread of TDP43 pathology (Brettschneider et al 2013). Furthermore, TDP43 does have modest sequence similarity to the prion protein (Guo et al 2011), and a growing list of proteins linked to ALS appear to be prion like (Kim et al 2013).However,this data does not show that TDP43 inclusions actually beget TDP43 inclusions. Establishing whether this is the case or not could have massive implications for the kind of drugs we decide to develop for ALS.
It is interesting, therefore, to see the biochemical studies conducted by Nonaka et al (2013). They actually took human ALS and FTLD brain tissue, mashed it up and purified an insoluble fraction, which they then introduced into cultured cells in vitro. What they found was that if the cultured cells were already forced to express large amounts of TDP43 using genetic constructs, the addition of the ALS brain solution caused TDP43 aggregation within those cells. If the brain solution was first treated to remove TDP43,it no longer caused TDP43 aggregation. This result, together with further cellular studies suggests that TDP43 aggregates can ‘seed’ further TDP43 aggregation.Similar experiments with brain extracts from Pick’s disease and DLB did not cause TDP43 aggregation, demonstrating a specific effect of ALS brains in causing TDP43 aggregation.
What is far less convincing is their ‘self templating’ conclusion. They argue that the pattern of protein aggregation in their cell cultures is determined by the protein fingerprint seen in the brain samples they add. However, they do not really convince us that TDP43 ‘self templates’ in the way that true prion protein strains do (have a quick look at their cartoon in figure 3C and come to your own conclusion).The fact remains that ALS is not a true prion disease (even ‘prion like’ is a term that still remains unclear) and TDP43 proteinopathy has not been found to be infectious between humans.This last point is important as some have suggested that ALS patients should not be allowed to do one last good deed and donate their organs after death for fear of spreading disease (Holmes and Diamond 2013)! We still need to better understand how TDP43 causes disease, and protein toxicity alone is unlikely to be the answer. – JS
Brettschneider J, Del Tredici K, Toledo JB et al.
Stages of pTDP.43 pathology in amyotrophic lateral sclerosis.
Ann Neurol. 2013 May 20. (E.pub ahead of print)
Guo W, Chen Y, Zhou X et al.
An ALS associated mutation affecting TDP43 enhances protein aggregation, fibril formation and neurotoxicity.
Nat Struct Mol Biol. 2011 Jun 12; 18:822.30.
Kim HJ, Kim NC, Wang YD et al.
Mutations in prion like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.
Nature. 2013 Mar 28; 495:467.73.
Nonaka T, Masuda.Suzukake M, Arai T et al.
Prion like Properties of Pathological TDP43 Aggregates from Diseased Brains.
Cell Rep. 2013 Jul 11;4(1):124.34.
Holmes BB, Diamond MI.
Amyotrophic lateral sclerosis and organ donation: is there risk of disease transmission?
Ann Neurol. 2012 Dec;72:832.6
Panel of reviewers
Faye Begeti, Van Geest Centre for Brain Repair, Cambridge University, UK.
Gemma Cummins, Van Geest Centre for Brain Repair, Cambridge University.
Aidan Neligan, UCL Institute of Neurology, Queen Square, London, UK
Jemeen Sreedharan, Dept of Neurobiology/ Neurology, University of Massachusetts Medical School, Worcester, USA.
ACNR 2013: 13: 38-39
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