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
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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.
Summary
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
16 YEAR OLD SPORADIC FFI ?
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
CREUTZFELDT JAKOB TSE PRION DISEASE HUMANS END OF YEAR REVIEW 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
MEXICO IS UNDER or MIS DIAGNOSING CREUTZFELDT JAKOB DISEASE AND OTHER PRION
DISEASE SOME WITH POSSIBLE nvCJD
*** 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.
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion
poker goes up again $
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
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion
poker goes up again $
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
TSS
