Tuesday, April 2, 2013

Human prion diseases: progress in clinical trials

Human prion diseases: progress in clinical trials

Inga Zerr, MD

+ Author Affiliations

National TSE Reference Centre Clinical Dementia Centre Department of Neurology University Medical School Georg-August University Goettingen, Germany

Correspondence to: Inga Zerr. E-mail: epicjd@med.uni-goettingen.de

The progress made in understanding disease pathology and phenomenology in prion disorders and recent advances in diagnostic techniques might encourage researchers now to consider therapeutic trials in patients with Creutzfeldt–Jakob disease. Although attempts have been made in the past (Trevitt and Collinge, 2006; Stewart et al., 2008), the drugs tested involved a variety of compounds that belong to antimicrobial, anti-inflammatory or analgesic substance classes and most of the studies are limited to extremely small series or single case reports. Controlled trials are rare but progress in diagnostic techniques, such as imaging, CSF biomarkers and recently developed methods to detect abnormal prion protein in easily accessible body fluids, will hopefully lead to early diagnosis of the disease. Although clinical trials are difficult to perform, they are feasible and clinicians must contemplate several specific problems when evaluating the efficacy of a drug in Creutzfeldt-Jakob disease.

Sporadic Creutzfeldt–Jakob disease is the most common human prion disease form, but still rare, with an annual incidence range between one and two cases per million per year worldwide (Ladogana et al., 2005). Any potential benefit of a drug must be proven on a large number of patients. Low disease incidence and prevalence are therefore problematic in terms of sample size. The median disease duration reported for all forms of sporadic Creutzfeldt–Jakob disease is ∼6 months (Pocchiari et al., 2004; Heinemann et al., 2007). The disease duration varies, and major determinants of survival such as age at onset, gender and PRNP codon 129 genotype have been identified (Ladogana et al., 2005). Unlike more chronic neurological disorders, prolonging survival from time of diagnosis offers one obvious and tractable outcome for a clinical trial. However, because of rapid disease progression, the clinical diagnosis of Creutzfeldt–Jakob disease is frequently not made until middle and late disease stages.

There is a wide scope of clinical phenomenology in human prion disease with respect to presenting features, rate of progression and appearance of other clinical manifestation (Parchi et al., 1999; Zerr et al., 2000; Heinemann et al., 2007). Phenotypic variability in the clinical syndrome and neuropathological changes in sporadic Creutzfeldt-Jakob disease were recognized long ago and some attempts have been made to define disease subtypes based on a molecular disease classification (Parchi et al., 1999). But as with many neurological disorders, heterogeneity of the clinical and pathological phenotype may reduce power even if an adequate sample can be recruited for a particular study.

Taking these considerations into account, clinicians face important decisions when designing a trial to assess efficacy and safety in the context of Creutzfeldt–Jakob disease. Scales have been designed to monitor disease progression in Alzheimer’s disease; and for vascular dementia and frontotemporal dementia (Braaten et al., 2006). Unfortunately, these systems are not suitable for monitoring cognitive decline in patients with Creutzfeldt-Jakob disease because of the different neuropsychological profiles. Also, neurological abnormalities such as ataxia, rigidity or myoclonus need to be monitored in a standard way. Because of the variability in clinical syndromes across molecular Creutzfeldt–Jakob disease subtypes, specific scales, weighted for particular subtypes, would be needed. Anticipating this issue, trial protocols need to include a variety of rating scales designed to probe neurological, cognitive, psychiatric and general functional status.

The paper by Andrew Thompson and colleagues in the current issue of Brain directly addresses these issues. The goal was to develop a rating scale for the progression of symptoms in prion diseases (the MRC Prion Disease Rating Scale) that could be used as an outcome measure in future clinical trials, as no single scale has been able to capture progression across the full range of functional domains affected in patients with prion diseases. The analysis was performed on data obtained from 437 clinical trial participants over a period of several years. Scale development included semi-quantitative and qualitative carer interviews, item response modelling, inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point MRC Prion Disease Rating Scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence. An important point is that the items are weighted according to their relative importance documented by interview with carers. Another advantage is easy application; the scale can be used over the telephone and will allow frequent assessments, which are necessary because of the rapid progression of the disease.

This is an important and timely study and analysis was carried out in a large cohort. The study addresses a fundamental issue in clinical trials of prion diseases: which scales can be used to monitor the rapid change in several domains including cognitive, motor and global decline? The scales need to be validated in future prospective studies on prion diseases but potentially other rapid progressive neurological conditions too (including Alzheimer’s disease or dementia with Lewy bodies with rapid progression). Clinical research in rare diseases is extremely challenging for logistic, statistical and financial reasons and systematic data collection in a multi-centre/multi-national setting is required to obtain sufficient information in a reasonable time frame. The work presented here is one important step towards achieving the challenging goal to find and then evaluate an effective treatment, or even a cure, for this devastating disorder. © The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

References ↵

Braaten AJ, Parsons TD, McCue R, Sellers A, Burns WJ . Neurocognitive differential diagnosis of dementing disease: Alzheimer's dementia, vascular dementia, frontotemporal dementia, and major depressive disorder. Int J Neurosci 2006;116:1271-93. CrossRefMedline

Heinemann U, Krasnianski A, Meissner B, Varges D, Bartl M, Stoeck K, et al . Creutzfeldt-Jakob disease in Germany: a prospective 12-year surveillance. Brain 2007;130:1350-9. Abstract/FREE Full Text

Ladogana A, Puopolo M, Croes EA, Budka H, Jarius C, Collins S, et al . Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada. Neurology 2005;64:1586-91. CrossRef

Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al . Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224-33. CrossRefMedlineWeb of Science

Pocchiari M, Poupolo M, Croes EA, Budka H, Gelpi E, Collins S, et al . Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Brain 2004;10:2348-59. Search Google Scholar

Stewart LA, Rydzewska LH, Keogh GF, Knight RS . Systematic review of therapeutic interventions in human prion diseases. Neurology 2008;70:1272-81. CrossRef

Trevitt CR, Collinge J . A systematic review of prion therapeutics in experimental models. Brain 2006;129:2241-65. Abstract/FREE Full Text

Zerr I, Schulz-Schaeffer WJ, Giese A, Bodemer M, Schröter A, Henkel K, et al . Current clinical diagnosis in CJD: identification of uncommon variants. Ann Neurol 2000;48:323-9.

The Medical Research Council Prion Disease Rating Scale: a new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies

Andrew G.B. Thompson1,2, Jessica Lowe1,2, Zoe Fox3, Ana Lukic1,2, Marie-Claire Porter1,2, Liz Ford2, Michele Gorham2, Gosala S. Gopalakrishnan2, Peter Rudge1,2, A. Sarah Walker4, John Collinge1,2 and Simon Mead1,2

+ Author Affiliations

1 MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, UCLH NHS Trust, Queen Square, London, UK

2 National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH NHS Trust, Queen Square, London, UK

3 Joint Research Office Biostatistics Unit, UCL, and Education Unit, UCL Institute of Neurology, London, UK

4 MRC Clinical Trials Unit, London, UK

Correspondence to: Professor John Collinge, MD, FRS, FRCP, MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK E-mail: j.collinge@prion.ucl.ac.uk Received October 31, 2012. Revision received December 18, 2012. Accepted January 31, 2013.


Progress in therapeutics for rare disorders like prion disease is impeded by the lack of validated outcome measures and a paucity of natural history data derived from prospective observational studies. The first analysis of the UK National Prion Monitoring Cohort involved 1337 scheduled clinical assessments and 479 telephone assessments in 437 participants over 373 patient-years of follow-up. Scale development has included semi-quantitative and qualitative carer interviews, item response modelling (Rasch analysis), inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point Medical Research Council Prion Disease Rating Scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence, according to their relative importance documented by carer interviews. It is quick and simple to administer, and has been validated for use by doctors and nurses and for use over the telephone, allowing for frequent assessments that capture the rapid change typical of these diseases. The Medical Research Council Scale correlates highly with widely used cognitive and single item scales, but has substantial advantages over these including minimal floor effects. Three clear patterns of decline were observed using the scale: fast linear decline, slow linear decline (usually inherited prion disease) and in some patients, decline followed by a prolonged preterminal plateau at very low functional levels. Rates of decline and progress through milestones measured using the scale vary between sporadic, acquired and inherited prion diseases following clinical expectations. We have developed and validated a new functionally-oriented outcome measure and propose that future clinical trials in prion disease should collect data compatible with this scale, to allow for combined and comparative analyses. Such approaches may be advantageous in orphan conditions, where single studies of feasible duration will often struggle to achieve statistical power.

Key words prion cohort rating scale outcome measure CJD

Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray

'Pray por Cristina' video highlights prayer movement for girl with degenerative disease

Date: 2013-03-31 08:00:00

March 31, 2013. (ROMEREPORTS.COM) (-VIDEO ONLY-) A social network that allows users to ask and give prayers, MayFeelings.com, published the story of one of its youngest members. Her name is Cristina and is the youngest person in the world that suffers from a degenerative neurological disease called Creutzfeldt-Jakob, a fatal condition that attacks the brain.

Her parents have tried all they can to try to save her, but no known cure of the disease has been developed. As a result, his father Juan Perican uploaded her story to the social network, which has drawn support from thousands throughout the world.

Using the hashtag #prayporcristina on Twitter, they ask for prayers. “People call us asking if we need anything, money, if they could help us... but we only want to be with Cristina. We thank them a lot of their support, but we always tell them the same thing: the only thing they can do is pray,” her mother explains in the video.

sporadic CJD, 11 year old victim, 2 year clinical course to date ???

Saturday, March 23, 2013

CJD Incidents Panel to be disbanded

Thursday, February 21, 2013

National Prion Disease Pathology Surveillance Center Cases Examined January 16, 2013


Monday, January 14, 2013

Gambetti et al USA Prion Unit change another highly suspect USA mad cow victim to another fake name i.e. sporadic FFI at age 16 CJD Foundation goes along with this BSe

Monday, December 31, 2012

Creutzfeldt Jakob Disease and Human TSE Prion Disease in Washington State, 2006–2011-2012

Tuesday, December 25, 2012


Tuesday, June 26, 2012

Creutzfeldt Jakob Disease Human TSE report update North America, Canada, Mexico, and USDA PRION UNIT as of May 18, 2012

type determination pending Creutzfeldt Jakob Disease (tdpCJD), is on the rise in Canada and the USA

Wednesday, June 13, 2012


*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.


OR-10: Variably protease-sensitive prionopathy is transmissible in bank voles

Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve University; Cleveland, OH USA

Background. Variably protease-sensitive prionopathy (VPSPr) is a recently described “sporadic”neurodegenerative disease involving prion protein aggregation, which has clinical similarities with non-Alzheimer dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern similar to that described in GSS cases. The clinical and pathological features of VPSPr raised the question of the correct classification of VPSPr among prion diseases or other forms of neurodegenerative disorders. Here we report preliminary data on the transmissibility and pathological features of VPSPr cases in bank voles.

Materials and Methods. Seven VPSPr cases were inoculated in two genetic lines of bank voles, carrying either methionine or isoleucine at codon 109 of the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain pathological assessment and western blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.

Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission in BvM109. Overall, 3 voles were positive with survival time between 290 and 588 d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form of the typical PrP27–30, which was indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1 cases.

In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until now. Overall, 5 voles were positive with survival time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus and the N-terminus. Second passages are in progress from these first successful transmissions.

Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109.

The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.

Wednesday, March 28, 2012


Tuesday, March 5, 2013

Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)

FDA believes current regulation protects the public from BSE but reopens comment period due to new studies

Tuesday, March 05, 2013

A closer look at prion strains Characterization and important implications Prion

7:2, 99–108; March/April 2013; © 2013 Landes Bioscience

Wednesday, March 20, 2013

GAO-13-244, Mar 18, 2013 Dietary Supplements FDA May Have Opportunities to Expand Its Use of Reported Health Problems to Oversee Product

From: Terry S. Singeltary Sr.

Sent: Tuesday, March 19, 2013 2:46 PM

To: gomezj@gao.gov

Cc: siggerudk@gao.gov ; youngc1@gao.gov ; oighotline@gao.gov

Wednesday, February 20, 2013

World Organization for Animal Health Recommends United States' BSE Risk Status Be Upgraded

Statement from Agriculture Secretary Tom Vilsack:

Thursday, February 14, 2013

The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease

Sunday, March 31, 2013

Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray


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