Menéndez González, Manuel

PubMed

Repositorio Institucional de la Universidad de Oviedo

OPINION ARTICLEpublished: 18 March 2014doi: 10.3389/fnagi.2014.00045The many questions on the use of biomarkers forneurodegenerative diseases in clinical practiceManuel Menéndez-González1,2,3*1 Neurología, Hospital Álvarez-Buylla, Mieres, Spain2 Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain3 Instituto de Neurociencias, Oviedo, Spain*Correspondence: manuelmenendezgonzalez@gmail.comEdited by:Oscar López, University of Pittsburgh School of Medicine, USAKeywords: biomarker, dementia, clinical practice, mild cognitive impairment, treatment outcomeThere are two basic questions alwaysraised when biomarkers are proposed tobe used for diagnosing neurodegenerativediseases (ND) in clinical practice (Wilner,2010). The first question is, do biomarkersenhance the diagnostic accuracy? Clinical-based diagnosis accuracy of ND variesdepending on the disease, stage and thecriteria used, but in general terms it isabout 75–90% accuracy. Today, there isconsensus that several biomarkers, com-bined with the traditional clinical process,may allow a more accurate diagnosis inmany ND (Galluzzi et al., 2013). This factis particularly important in early stages,when the diagnosis is specially challeng-ing. For most patients with mild deficitsconcerned about the development of ND,a careful history, and a physical, neuro-logical and neuropsychological evaluationwith a close follow-up (a “wait and see”approach) used to be the standard prac-tice. Today we can offer a more proactiveapproach for discerning whether there isan underlying neurodegenerative processbehind these mild deficits (Heister et al.,2011). The National Institute on Aging-Alzheimer’s Association criteria for AD orMCI recommend the use of amyloid lig-ands with caution, and only in exceptionalcircumstances they should be used in clin-ical practice (Albert et al., 2011; Sperlinget al., 2011). The use of different biomark-ers for differential diagnosis should notbe discouraged. On the other hand, useof biomarkers as predictive instrumentsshould be discouraged.The second question is, does the addi-tional diagnostic accuracy provided bybiomarkers really matter? In clinical prac-tice, a test that confirmed or ruled out aNDwould remove uncertainty. This wouldalso disregard or reinforce the need toconsider other diseases that may presentsymptoms similar to those of ND. In someof these diseases, prompt diagnosis canlead to earlier effective treatment, suchas shunting for normal pressure hydro-cephalus, supplementation with thyroidhormones in hypothyroidism or antide-pressive medications for depression.The best argument for using biomark-ers in clinical practice would be thepossibility of treating patients with adisease-modifying therapy that prevents ordelays the progression of the disease. Inother words, putting patients on drugswith neuroprotective effect. However, nodrug have proven prevention of any NDyet.The current therapies only providesymptomatic improvement at best so thereis an urgent need to discover neuroprotec-tive treatments. But how can we conductclinical trials for testing such drugs whendiagnosing ND at its very early stages is sodifficult? Again, the support of biomark-ers should be mandatory for enrollingpatients in research studies.Then, if there is not a disease-modifying therapy yet, what is theimportance of an early diagnosis in routineclinical practice today? There are severalreasons to make an early diagnosis evenwhen we cannot modify the course of thedisease. For instance, once people becomedemented, they can no longer plan fortheir future or dictate their end-of-lifecare. An early diagnosis of Alzheimer’sdisease gives a person the opportunity todecide on important questions before heor she gets demented (Martínez-Riveraet al., 2008). It also has important conse-quences for the patient’s family. However,an early diagnosis of a ND may also havenegative psychological consequences in anotherwise well-functioning person whomust now consider an inexorable declinetowards a state of illness and dependency.Consequently, the pros and cons of earlydiagnosis must be carefully weighed upin each individual prior to perform aconfirmatory test.And even if we have decided to usebiomarkers for supporting the diagnosis ofa ND, there are many questions to face. Itis important to emphasize that standard-ization of these biomarkers is currentlylimited, and results often vary from labo-ratory to laboratory. Ultimately, it will benecessary to interpret biomarker data inthe context of well-established normativevalues. Moreover, procedures for acquisi-tion and analysis of samples need to beestablished to implement these biomarkercriteria on a broad scale. Although weconsider biomarkers as “negative” or “pos-itive” for purposes of classification, it isrecognized that varying severities of anabnormality may confer different likeli-hoods or prognoses, which is difficult toquantify accurately for broad application.Currently it is difficult to understand therelative importance of different biomark-ers when used together, and to interpretresults when biomarker data conflict withone another.Equally important, there is a dearth oftruly predictive studies at the individualsubject level or in unselected populations.The use of biomarkers in the clinical prac-tice will require the ability to assign alikelihood of progression in an individ-ual person over a specific time intervalthrough the use of a single or multiplebiomarkers. Another major limitation isknowledge about the timing of declineFrontiers in Aging Neuroscience www.frontiersin.org March 2014 | Volume 6 | Article 45 | 1AGING NEUROSCIENCEMenéndez-González Biomarkers for neurodegenerative diseasesbecause the ability to detect change isdependent on the period of observationor prediction. A complete understandingof the role of biomarkers in prediction ofdecline will require both short and long-term periods of observation.Finally, little is known about out-come when biomarkers provide conflict-ing results. When a panel of biomarkers isused, it is possible that for some individu-als, one biomarker will be positive, one willbe negative, and one equivocal. The long-term significance of such findings may alsovary with the length of follow-up.Therefore, questions such as “whatbiomarker is better for making the earlydiagnosis of each ND?,” or “which oneis better for the follow up,” “which onefor making the differential diagnosis withother disease?”, “how to interpret theresults of these tests in coordination withclinical or genetic findings” and “howto combine the results from differentbiomarkers?” have important repercussionon the management of patients suspectedof suffering from ND and still remainunresponsed. The answers to these ques-tions are not always easy and rely onupcoming science.We need more data and more net-working to find appropriate conclusions.Collaboration between basic, translationaland clinic researchers is paramount forgiving answers relevant to everyday clin-ical practice. In this regard, the topicresearch issue accompanying this edito-rial letter gathers together a bunch ofreview and original articles exploring theuse of biomarkers for ND from differentperspectives.REFERENCESAlbert, M. S., DeKosky, S. T., Dickson, D., Dubois,B., Feldman, H. H., Fox, N. C., et al. (2011).The diagnosis of mild cognitive impairmentdue to Alzheimer’s disease: recommendationsfrom the National Institute on Aging-Alzheimer’sAssociation workgroups on diagnostic guide-lines for Alzheimer’s disease. AlzheimersDement. 7, 270–279. doi: 10.1016/j.jalz.2011.03.008Galluzzi, S., Geroldi, C., Amicucci, G., Bocchio-Chiavetto, L., Bonetti, M., Bonvicini, C., et al.(2013). Translational outpatient memory clinicworking group. Supporting evidence for usingbiomarkers in the diagnosis of MCI due to AD.J. Neurol. 260, 640–650. doi: 10.1007/s00415-012-6694-0Heister, D., Brewer, J. B., Magda, S., Blennow, K.,and McEvoy, L. K. (2011). Alzheimer’s dis-ease neuroimaging initiative. Predicting MCIoutcome with clinically available MRI and CSFbiomarkers. Neurology 77, 1619–1628. doi:10.1212/WNL.0b013e3182343314Martínez-Rivera, M., Menénedez-González, M., andPérez-Piñera, P. (2008). Biomarcadores para laEnfermedad de Alzheimer y otras demenciasdegenerativas. Archivos de Medicina 4:3.Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D.A., Craft, S., Fagan, A. M., et al. (2011). Towarddefining the preclinical stages of Alzheimer’sdisease: recommendations from the NationalInstitute on Aging-Alzheimer’s Association work-groups on diagnostic guidelines for Alzheimer’sdisease. Alzheimers Dement. 7, 280–292. doi:10.1016/j.jalz.2011.03.003Wilner, A. N. (2010). Alzheimer’s CSF test: useful oruseless? Medscape.Received: 10 December 2013; accepted: 01 March 2014;published online: 18 March 2014.Citation: Menéndez-González M (2014) The manyquestions on the use of biomarkers for neurodegenera-tive diseases in clinical practice. Front. Aging Neurosci.6:45. doi: 10.3389/fnagi.2014.00045This article was submitted to the journal Frontiers inAging Neuroscience.Copyright © 2014 Menéndez-González. This is anopen-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.Frontiers in Aging Neuroscience www.frontiersin.org March 2014 | Volume 6 | Article 45 | 2

Frontiers in Aging Neuroscience

The many questions on the use of biomarkers for neurodegenerative diseases in clinical practice

Manuel MenÃ©ndez-GonzÃ¡lez

Frontiers - Publisher Connector

OPINION ARTICLE
published: 18 March 2014
doi: 10.3389/fnagi.2014.00045
The many questions on the use of biomarkers for
neurodegenerative diseases in clinical practice
Manuel Menéndez-González1,2,3*
1 Neurología, Hospital Álvarez-Buylla, Mieres, Spain
2 Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain
3 Instituto de Neurociencias, Oviedo, Spain
*Correspondence: manuelmenendezgonzalez@gmail.com
Edited by:
Oscar López, University of Pittsburgh School of Medicine, USA
Keywords: biomarker, dementia, clinical practice, mild cognitive impairment, treatment outcome
There are two basic questions always
raised when biomarkers are proposed to
be used for diagnosing neurodegenerative
diseases (ND) in clinical practice (Wilner,
2010). The first question is, do biomarkers
enhance the diagnostic accuracy? Clinical-
based diagnosis accuracy of ND varies
depending on the disease, stage and the
criteria used, but in general terms it is
about 75–90% accuracy. Today, there is
consensus that several biomarkers, com-
bined with the traditional clinical process,
may allow a more accurate diagnosis in
many ND (Galluzzi et al., 2013). This fact
is particularly important in early stages,
when the diagnosis is specially challeng-
ing. For most patients with mild deficits
concerned about the development of ND,
a careful history, and a physical, neuro-
logical and neuropsychological evaluation
with a close follow-up (a “wait and see”
approach) used to be the standard prac-
tice. Today we can offer a more proactive
approach for discerning whether there is
an underlying neurodegenerative process
behind these mild deficits (Heister et al.,
2011). The National Institute on Aging-
Alzheimer’s Association criteria for AD or
MCI recommend the use of amyloid lig-
ands with caution, and only in exceptional
circumstances they should be used in clin-
ical practice (Albert et al., 2011; Sperling
et al., 2011). The use of different biomark-
ers for differential diagnosis should not
be discouraged. On the other hand, use
of biomarkers as predictive instruments
should be discouraged.
The second question is, does the addi-
tional diagnostic accuracy provided by
biomarkers really matter? In clinical prac-
tice, a test that confirmed or ruled out a
NDwould remove uncertainty. This would
also disregard or reinforce the need to
consider other diseases that may present
symptoms similar to those of ND. In some
of these diseases, prompt diagnosis can
lead to earlier effective treatment, such
as shunting for normal pressure hydro-
cephalus, supplementation with thyroid
hormones in hypothyroidism or antide-
pressive medications for depression.
The best argument for using biomark-
ers in clinical practice would be the
possibility of treating patients with a
disease-modifying therapy that prevents or
delays the progression of the disease. In
other words, putting patients on drugs
with neuroprotective effect. However, no
drug have proven prevention of any ND
yet.The current therapies only provide
symptomatic improvement at best so there
is an urgent need to discover neuroprotec-
tive treatments. But how can we conduct
clinical trials for testing such drugs when
diagnosing ND at its very early stages is so
difficult? Again, the support of biomark-
ers should be mandatory for enrolling
patients in research studies.
Then, if there is not a disease-
modifying therapy yet, what is the
importance of an early diagnosis in routine
clinical practice today? There are several
reasons to make an early diagnosis even
when we cannot modify the course of the
disease. For instance, once people become
demented, they can no longer plan for
their future or dictate their end-of-life
care. An early diagnosis of Alzheimer’s
disease gives a person the opportunity to
decide on important questions before he
or she gets demented (Martínez-Rivera
et al., 2008). It also has important conse-
quences for the patient’s family. However,
an early diagnosis of a ND may also have
negative psychological consequences in an
otherwise well-functioning person who
must now consider an inexorable decline
towards a state of illness and dependency.
Consequently, the pros and cons of early
diagnosis must be carefully weighed up
in each individual prior to perform a
confirmatory test.
And even if we have decided to use
biomarkers for supporting the diagnosis of
a ND, there are many questions to face. It
is important to emphasize that standard-
ization of these biomarkers is currently
limited, and results often vary from labo-
ratory to laboratory. Ultimately, it will be
necessary to interpret biomarker data in
the context of well-established normative
values. Moreover, procedures for acquisi-
tion and analysis of samples need to be
established to implement these biomarker
criteria on a broad scale. Although we
consider biomarkers as “negative” or “pos-
itive” for purposes of classification, it is
recognized that varying severities of an
abnormality may confer different likeli-
hoods or prognoses, which is difficult to
quantify accurately for broad application.
Currently it is difficult to understand the
relative importance of different biomark-
ers when used together, and to interpret
results when biomarker data conflict with
one another.
Equally important, there is a dearth of
truly predictive studies at the individual
subject level or in unselected populations.
The use of biomarkers in the clinical prac-
tice will require the ability to assign a
likelihood of progression in an individ-
ual person over a specific time interval
through the use of a single or multiple
biomarkers. Another major limitation is
knowledge about the timing of decline
Frontiers in Aging Neuroscience www.frontiersin.org March 2014 | Volume 6 | Article 45 | 1
AGING NEUROSCIENCE
Menéndez-González Biomarkers for neurodegenerative diseases
because the ability to detect change is
dependent on the period of observation
or prediction. A complete understanding
of the role of biomarkers in prediction of
decline will require both short and long-
term periods of observation.
Finally, little is known about out-
come when biomarkers provide conflict-
ing results. When a panel of biomarkers is
used, it is possible that for some individu-
als, one biomarker will be positive, one will
be negative, and one equivocal. The long-
term significance of such findings may also
vary with the length of follow-up.
Therefore, questions such as “what
biomarker is better for making the early
diagnosis of each ND?,” or “which one
is better for the follow up,” “which one
for making the differential diagnosis with
other disease?”, “how to interpret the
results of these tests in coordination with
clinical or genetic findings” and “how
to combine the results from different
biomarkers?” have important repercussion
on the management of patients suspected
of suffering from ND and still remain
unresponsed. The answers to these ques-
tions are not always easy and rely on
upcoming science.
We need more data and more net-
working to find appropriate conclusions.
Collaboration between basic, translational
and clinic researchers is paramount for
giving answers relevant to everyday clin-
ical practice. In this regard, the topic
research issue accompanying this edito-
rial letter gathers together a bunch of
review and original articles exploring the
use of biomarkers for ND from different
perspectives.
REFERENCES
Albert, M. S., DeKosky, S. T., Dickson, D., Dubois,
B., Feldman, H. H., Fox, N. C., et al. (2011).
The diagnosis of mild cognitive impairment
due to Alzheimer’s disease: recommendations
from the National Institute on Aging-Alzheimer’s
Association workgroups on diagnostic guide-
lines for Alzheimer’s disease. Alzheimers
Dement. 7, 270–279. doi: 10.1016/j.jalz.2011.
03.008
Galluzzi, S., Geroldi, C., Amicucci, G., Bocchio-
Chiavetto, L., Bonetti, M., Bonvicini, C., et al.
(2013). Translational outpatient memory clinic
working group. Supporting evidence for using
biomarkers in the diagnosis of MCI due to AD.
J. Neurol. 260, 640–650. doi: 10.1007/s00415-012-
6694-0
Heister, D., Brewer, J. B., Magda, S., Blennow, K.,
and McEvoy, L. K. (2011). Alzheimer’s dis-
ease neuroimaging initiative. Predicting MCI
outcome with clinically available MRI and CSF
biomarkers. Neurology 77, 1619–1628. doi:
10.1212/WNL.0b013e3182343314
Martínez-Rivera, M., Menénedez-González, M., and
Pérez-Piñera, P. (2008). Biomarcadores para la
Enfermedad de Alzheimer y otras demencias
degenerativas. Archivos de Medicina 4:3.
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D.
A., Craft, S., Fagan, A. M., et al. (2011). Toward
defining the preclinical stages of Alzheimer’s
disease: recommendations from the National
Institute on Aging-Alzheimer’s Association work-
groups on diagnostic guidelines for Alzheimer’s
disease. Alzheimers Dement. 7, 280–292. doi:
10.1016/j.jalz.2011.03.003
Wilner, A. N. (2010). Alzheimer’s CSF test: useful or
useless? Medscape.
Received: 10 December 2013; accepted: 01 March 2014;
published online: 18 March 2014.
Citation: Menéndez-González M (2014) The many
questions on the use of biomarkers for neurodegenera-
tive diseases in clinical practice. Front. Aging Neurosci.
6:45. doi: 10.3389/fnagi.2014.00045
This article was submitted to the journal Frontiers in
Aging Neuroscience.
Copyright © 2014 Menéndez-González. This is an
open-access article distributed under the terms of the
Creative Commons Attribution License (CC BY). The
use, distribution or reproduction in other forums is per-
mitted, provided the original author(s) or licensor are
credited and that the original publication in this journal
is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which
does not comply with these terms.
Frontiers in Aging Neuroscience www.frontiersin.org March 2014 | Volume 6 | Article 45 | 2


Crossref

http://digibuo.uniovi.es/dspace/bitstream/10651/26816/1/FrontiersinAgingNeuroscience_2014.pdf

The many questions on the use of biomarkers for neurodegenerative diseases in clinical practice

Abstract

Similar works

Full text

Available Versions

Repositorio Institucional de la Universidad de Oviedo

Frontiers - Publisher Connector

Frontiers - Publisher Connector

Crossref