journal articles
THE ROAD AHEAD TO CURE ALZHEIMER\'S DISEASE: DEVELOPMENT OF BIOLOGICAL MARKERS AND NEUROIMAGING METHODS FOR PREVENTION TRIALS ACROSS ALL STAGES AND TARGET POPULATIONS
E. Cavedo , S. Lista, Z. Khachaturian, P. Aisen, P. Amouyel, K. Herholz, C.R. Jack Jr, R. Sperling, J. Cummings, K. Blennow, S. O’Bryant, G.B. Frisoni, A. Khachaturian , M. Kivipelto, W. Klunk, K. Broich, S. Andrieu, M. Thiebaut de Schotten, J.-F. Mangin, A.A. Lammertsma, K. Johnson, S. Teipel , A. Drzezga , A. Bokde , O. Colliot , H. Bakardjian , H. Zetterberg , B. Dubois , B. Vellas, L.S. Schneider, H. Hampel
J Prev Alz Dis 2014;1(3):181-202
Alzheimer's disease (AD) is a slowly progressing non-linear
dynamic brain disease in which pathophysiological
abnormalities, detectable in vivo by biological markers, precede
overt clinical symptoms by many years to decades. Use of these
biomarkers for the detection of early and preclinical AD has
become of central importance following publication of two
international expert working group's revised criteria for the
diagnosis of AD dementia, mild cognitive impairment (MCI)
due to AD, prodromal AD and preclinical AD. As a
consequence of matured research evidence six AD biomarkers
are sufficiently validated and partly qualified to be incorporated
into operationalized clinical diagnostic criteria and use in
primary and secondary prevention trials. These biomarkers fall
into two molecular categories: biomarkers of amyloid-beta (Aβ)
deposition and plaque formation as well as of tau-protein
related hyperphosphorylation and neurodegeneration. Three of
the six gold-standard ("core feasible) biomarkers are
neuroimaging measures and three are cerebrospinal fluid (CSF)
analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1-
40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven
diagnostic accuracy and risk enhancement in prodromal MCI
and AD dementia. Conversely, having all three biomarkers in
the normal range rules out AD. Intermediate conditions require
further patient follow-up. Magnetic resonance imaging (MRI) at
increasing field strength and resolution allows detecting the
evolution of distinct types of structural and functional
abnormality pattern throughout early to late AD stages.
Anatomical or volumetric MRI is the most widely used
technique and provides local and global measures of atrophy.
The revised diagnostic criteria for “prodromal AD” and "mild
cognitive impairment due to AD" include hippocampal atrophy
(as the fourth validated biomarker), which is considered an
indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both
in regions of interest, such as the hippocampus and in an
exploratory fashion, observer and hypothesis-indedendent,
throughout the entire brain. Evolving modalities such as
diffusion-tensor imaging (DTI) and advanced tractography as
well as resting-state functional MRI provide useful additionally
useful measures indicating the degree of fiber tract and neural
network disintegration (structural, effective and functional
connectivity) that may substantially contribute to early
detection and the mapping of progression. These modalities
require further standardization and validation. The use of
molecular in vivo amyloid imaging agents (the fifth validated
biomarker), such as the Pittsburgh Compound-B and markers of
neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as
the sixth validated biomarker) support the detection of early AD
pathological processes and associated neurodegeneration. How
to use, interpret, and disclose biomarker results drives the need
for optimized standardization. Multimodal AD biomarkers do
not evolve in an identical manner but rather in a sequential but
temporally overlapping fashion. Models of the temporal
evolution of AD biomarkers can take the form of plots of
biomarker severity (degree of abnormality) versus time. AD
biomarkers can be combined to increase accuracy or risk. A list
of genetic risk factors is increasingly included in secondary
prevention trials to stratify and select individuals at genetic risk
of AD. Although most of these biomarker candidates are not yet
qualified and approved by regulatory authorities for their
intended use in drug trials, they are nonetheless applied in
ongoing clinical studies for the following functions: (i)
inclusion/exclusion criteria, (ii) patient stratification, (iii)
evaluation of treatment effect, (iv) drug target engagement, and
(v) safety. Moreover, novel promising hypothesis-driven, as
well as exploratory biochemical, genetic, electrophysiological,
and neuroimaging markers for use in clinical trials are being
developed. The current state-of-the-art and future perspectives
on both biological and neuroimaging derived biomarker
discovery and development as well as the intended application
in prevention trials is outlined in the present publication.
CITATION:
E. Cavedo ; S. Lista ; Z. Khachaturian ; P. Aisen ; P. Amouyel ; K. Herholz ; C.R. Jack Jr ; R. Sperling ; J. Cummings ; K. Blennow ; S. O’Bryant ; G.B. Frisoni ; A. Khachaturian ; M. Kivipelto ; W. Klunk ; K. Broich ; S. Andrieu ; M. Thiebaut de Schotten ; J.-F. Mangin ; A.A. Lammertsma ; K. Johnson ; S. Teipel ; A. Drzezga ; A. Bokde ; O. Colliot ; H. Bakardjian ; H. Zetterberg ; B. Dubois ; B. Vellas ; L.S. Schneider ; H. Hampel (2014): THE ROAD AHEAD TO CURE ALZHEIMER'S DISEASE: DEVELOPMENT OF BIOLOGICAL MARKERS AND NEUROIMAGING METHODS FOR PREVENTION TRIALS ACROSS ALL STAGES AND TARGET POPULATIONS. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.32