Introduction
Parkinson's disease (PD) is an example for a complex field of research, which is driven
by the multifactorial etiology, the heterogeneity in phenotype and the variability
in disease progression, as well as the presence of a long pre-diagnostic period, called
prodromal PD, lasting up to decades (Postuma et al., 2010). The very slow, so far
inevitably progressive, neurodegenerative process and the multidimensional heterogeneity
of symptoms in kind (motor and non-motor), time of onset and speed of progression
call for prediction markers and progression markers to understand the onset of neurodegeneration
and its course. These markers would also help to establish endpoints for neuroprotective
treatment strategies aiming to modify disease progression. Because of the complexity,
heterogeneity, and the progressive nature of PD, such predictive and progression markers
can only be identified in large cohorts and in studies with a longitudinal design.
A considerable number of longitudinal cohort studies in PD patients, as well as in
individuals at risk, are currently being performed, and extensive effort has gone
into the characterization of the individuals assessed. Although each study has its
own value and merits, many important research questions cannot be answered as the
numbers of participants are too small (e.g., when studying conversion to PD in at-risk
populations). Moreover, the pivotal combination of data and findings across studies
is hampered by the lack of comparability of symptoms/factors that are being assessed
and the specific assessments that are being applied. Therefore, a common approach
is needed to enable harmonization and combination of data across studies to define
and validate predictive and progression markers.
Based on the need for harmonized assessments of symptoms/markers in PD, the working
group: Harmonization of biomarker assessment in longitudinal cohort studies in Parkinson's
Disease (BioLoC-PD) of the Joint Programme for Neurodegenerative Diseases (JPND),
set out to develop an assessment battery that includes the most useful clinical, laboratory,
and brain imaging assessments for (longitudinal) studies in PD.
We here describe the result of the process to find a way to harmonize assessments
across studies and propose a modular set of biomarker assessments agreed upon by the
group of experts who were included in the working group (all authors of this manuscript).
Materials and methods
As a first step, information about the design, markers, and assessments of 21 ongoing
cohort studies in various phases of PD represented by members of the JPND working
group were collected using a detailed questionnaire. These data served as a basis
for the project. Detailed results have been reported previously in Lerche et al. (2015).
In a second step, a systematic literature search on assessments and markers in the
prodromal and clinical phases of PD was conducted to determine the most useful predictive
and progression markers in PD. The outcome of this literature search was combined
with the study information derived from the BioLoC-PD studies and the expert clinical
knowledge of the principal investigators in their clinical routine. This information
were used to establish the proposed assessment battery. A common modular set of biomarker
assessments was defined that includes a basic module and different modules for extension,
in order to account for the differences in research focus between studies.
Results
Composition of a modular set of biomarker assessments
Based on the analyses, the JPND BioLoC-PD working group suggests the following three-level
modular assessment battery to be implemented in new and whenever possible ongoing
longitudinal studies for PD (Figure 1). The set comprises a basic module (demographics,
diagnosis, etc.), a minimum function and assessment module and several optional extension
modules.
Figure 1
Suggestion for a modular set of biomarker assessments to be used in longitudinal studies
in PD. The number of studies using the assessment in the BioLoC-PD consortium are
given in brackets.
The basic module is meant to be applied to all participants in longitudinal studies
in PD. It may also be applied to existing registers and patients seen routinely in
outpatient clinics irrespective of whether they are currently recruited for a longitudinal
study. It may also be used for retrospective analyses or identification of potential
eligible participants for future randomized controlled trials.
The minimum module is suitable for all individuals participating in at risk, prodromal,
and clinical longitudinal studies of PD. The functions of the minimum module are in
a descending order (sorted by their use within the BioLoC-PD working group). Functions
used in all (risk, prodromal, and clinical) PD studies are at the beginning of each
of the lists (in the minimum and extension modules). Modes of assessment of these
symptoms are based on the frequency and applicability within studies (easy to apply
assessments, which still provide sufficient information were preferred). Each of the
assessments suggested for the minimum module (Figure 1) takes no more than 10 min,
depending on the cognitive capacity of the study participant. For some functions (neuropsychiatric
and olfactory), two optional assessments are suggested from which one can be chosen.
This is because they are used in almost equal proportion in ongoing studies and are
similarly tolerable for the participants. For the neuropsychiatric function we recommend
to use the BDI in prodromal studies and in early stage PD studies and the GDS in late
stage PD studies. For olfaction two assessments are given because they are used in
almost equal proportion in ongoing studies are similarly tolerable for the participants.
However, the first mentioned suggestion, is slightly preferred by the BioLoC-PD consortium
(used more often). Regarding the use of the MMSE or MoCA, we found that the MMSE is
more often applied in existing studies but for new studies we clearly recommend to
use the MoCA.
The optional extension module can be applied to evaluate study participants in more
detail. The selection of the additional function modules depends on the main research
focus of the study, on the number of study participants and on the available staff
and finance. Optional modules can be applied to interesting sub-groups of participants,
if financial or pragmatic/practical factors hinder administration to the whole cohort.
The assessments included in the extension modules were chosen based on their implementation
in the ongoing BioLoC-PD studies. For each subdomain within the extension modules,
the most commonly used assessment is suggested in addition to the minimum module (e.g.,
motor → gait and balance → accelerometer). In case of the imaging module the methods
are in a descending order with the one on the top preferred by the BioLoC-PD consortium.
Application of the modular set of biomarker assessments
We propose, that each study should as a minimum requirement collect the data specified
in the basic module. The basic module is valuable also for genetic or other non-clinical
analyses. Once individuals are clinically examined, several motor and non-motor domains
should be covered, as suggested in the minimum module which also comprises additional
data about medical history. Finally, according to the main research aim of the study,
different extension modules can be added.
In general, we provide researchers with suggestions for specific assessment tools/scales
to allow comparison across studies. For the cognition module, however, it is less
important which assessments are used rather, it is important to take a minimum of
two tests per domain for a sensitive and specific diagnosis of dementia and Mild Cognitive
Impairment (MCI) level II (Goldman et al., 2015). For cognitive analyses, a comparison
of studies with different assessments will then be possible by comparing the domain
z-scores (Aarsland et al., 2010), equipercentile or item response theory modeling
or by using existing conversion algorithms (e.g., conversion between the MMSE and
MOCA tests (Lawton et al., 2016)). A list of neuropsychological tests suitable for
the optional cognitive extension module can be found in Goldman et al. (2015) and
Litvan et al. (2012).
Discussion
The inventory of assessments used in ongoing longitudinal studies within the working
group revealed that there is a consensus about the functions/domains that should be
assessed in PD cohort studies, but not about the nature of specific assessments used.
The variability in the choice of the assessments may be explained by a number of different
factors: (i) Not all scales/questionnaires are available and validated in all languages.
(ii) Study designs vary with regard to outcome variables which influences the choice
of assessments. (iii) Some assessments require more resources than others (more time-consuming,
more costly or requiring trained staff members), which also influenced the selection
and composition of the selected assessment battery. (iv) Advances in knowledge about
assessments and biomarkers have led to revision or expansion of assessments after
the respective study was initiated. (v) Preference for a specific assessment based
on previous experience of the individual researchers involved.
With our proposed modular set of biomarker assessments, we propose a concept by which
we hope to overcome the problem of data comparison due to lack of harmonization and
set the stage for broad data sharing, joint data analyses and acceleration of biomarker
research.
Author contributions
SL, SH, GA, PB, SB, YBS, HB, BRB, DBu, RD, DG, GH, MH, MK, RK, ILS, WM, MM, BM, WO,
BR, UW, KW, DBe substantial contributed to the conception and design of the work;
SL, SH, DBe drafted the work; GA, PB, SB, YBS, HB, BRB, DBu, RD, DG, GH, MH, MK, RK,
ILS, WM, MM, BM, WO, BR, UW, KW revised the work critically for important intellectual
content; SL, SH, GA, PB, SB, YBS, HB, BRB, DBu, RD, DG, GH, MH, MK, RK, ILS, WM, MM,
BM, WO, BR, UW, KW, DBe gave their final approval to the version to be published;
SL, SH, GA, PB, SB, YBS, HB, BRB, DBu, RD, DG, GH, MH, MK, RK, ILS, WM, MM, BM, WO,
BR, UW, KW, DBe agreed to be accountable for all aspects of the work.
Funding
The work was funded by the EU Joint Programme—Neurodegenerative Disease Research (JPND)
program (BMBF No:01ED1410).
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.