Since Parkinson’s disease (PD) takes years to develop and progress, the damage to neurons is already extensive, by the time motor symptoms appear. In order to treat patients as early as possible, it is imperative to find accurate early diagnostic tools or biomarkers. Understanding this urgency, IBBL (Integrated BioBank of Luxembourg) participates in both, national and international, PD biomarker studies.
Worldwide, approximately 6.3 million people live with Parkinson’s disease, a chronic and progressive neurodegenerative disease. Even though the risk of developing a neurodegenerative disease goes up as we get older, up to 10% of PD patients are diagnosed before they turn 50. At the time of diagnosis, PD patients usually exhibit the motor symptoms including rigidity, tremors and bradykinesia (slowness in initiating movement). As the disease progresses, these can be accompanied by cognitive and sensory decline, as well as problems with the autonomic nervous system. Importantly, some of the symptoms affecting the autonomic nervous system can start showing up long before motor symptoms do. Indeed, up to 10-20 years before experiencing tremors or rigidity, most patients will exhibit problems with their vision, constipation, sleep disorders, or a reduction in their sense of smell. These symptoms are today considered pre-motor risk factors for developing PD.
Multiple cellular dysfunctions
Although researchers have identified a number of familial genes that can cause PD, most patients do not present with any familial history or PD-associated mutations. Like many of today’s greatest health burdens, PD is a multi-factorial disease; caused by a combination of environmental and genetic factors. However, there is still a lot to learn, especially about the influence of the environment on the development of PD. Similarly, on a cellular level, we know that a number of pathways and mechanism are disrupted in PD patients, but the whole picture remains rather foggy. Some of the mechanisms known to underlie PD pathology include: aggregation and misfolding of the α-synclein protein, failure of the protein degradation machinery, mitochondrial and synaptic dysfunctions, oxidative stress and neuroinflammation. These dysfunctions ultimately lead to the characteristic loss of dopamine in the striatum and loss of dopaminergic neurons in the substantia nigra of the midbrain. Typically, cell death in these neurons is caused, at least in part, by an accumulation of the protein α-synuclein in inclusions called Lewy bodies, one of the hallmarks of PD.
Looking for alternatives
The diagnosis of PD is essentially based on clinical symptoms. Unfortunately it can be inaccurate in up to 20% of cases, due to a number of other, rarer, neurodegenerative diseases with similar symptoms. The rate of misdiagnosis, in addition to the fact that PD starts developing years before motor symptoms appear, underlines the need for new, more accurate, and earlier diagnostic tools. Further, up to 80% of dopaminergic neurons can already be damaged when motor symptoms start developing. So if the disease were diagnosed earlier, treatment could be started before substantial neuronal cell death has occurred.This is the main motivation behind researchers all around the world working on the development and implementation of diagnostic and progression biomarkers for PD.
In addition to the more traditional biomarkers in cerebrospinal fluid, a lot of effort is focused on developing biomarkers based on alternative tissues and fluids, or on neuroimaging techniques. Indeed, today, imaging of the dopamine metabolism is already employed to support PD diagnosis. Another imaging technique showing great potential as a diagnostic tool for PD is diffusion tensor imaging (DTI), a type of MRI that maps the diffusion process of molecules. Recently, Prodoehl and his colleagues combined DTI measures from multiple basal ganglia and cerebellar target regions known to be affected by movement disorders [1]. On the basis of these combined measures, the researchers were able to distinguish between healthy controls, PD patients and patients with other movement disorders, with high specificity and sensitivity.
Since PD also affects the autonomous nervous system (ANS), researchers have been investigating the use of biopsies of the ANS as potential PD biomarkers. A study published last October in the journal Neurology, found that skin biopsies of the thigh may be a minimally invasive method to diagnose PD [2]. The researchers from Boston found that α-synuclein is increased in certain autonomic nerves (for sweat glands and piloerector muscles) of PD patients compared to healthy controls. Although these results represent a promising first step, a larger cohort and longitudinal study will be essential to determine if skin biopsies can be used, alone or in combination with other techniques, to differentially diagnose PD. Importantly, it will be interesting to investigate whether this method may allow earlier diagnosis. Indeed, similar small-scale pilot studies showed that α-synuclein pathology can be detected in colonic biopsies of PD patients 2 to 5 years before the development of typical motor symptoms.
IBBL supports PD research on multiple levels
Despite enormous efforts and substantial progress, to date, there is no validated and established biomarker for diagnosis, prognosis or progression of PD. One of the common problems in biomarker research is the lack of standardization and the variation between studies. This is where the EU Joint Programme for Neurodegenerative Disease Research (JPND) comes into play. Their new BIOMARKAPD project, supported by IBBL (Integrated BioBank of Luxembourg), aims to standardize Alzheimer’s and Parkinson’s biomarker measurements across Europe. The collaborators from 19 different countries are on the one hand focusing on existing biomarkers in the cerebrospinal fluid. On the other hand they support the development of new biomarkers. This will be greatly facilitated by IBBL as the biobank will host the collection of patients’ samples from the project, which will be made available to the scientific community.
As part of the Personalised Medicine Consortium (PMC) of Luxembourg, IBBL also collaborates closely with Luxembourgish researchers and clinicians on PD research. In particular, neurologist Dr Nico Diederich of the Centre Hospitalier de Luxembourg (CHL), as well as the Luxembourg Centre for Systems Biomedicine (LCSB), are renowned for their high quality PD research, combining systems and molecular approaches. The collaboration with these institutes, as well as the Centre de Recherche Public – Santé (CRP-Santé ), will be further strengthened by their possible participation in a new research programme created by the FNR, Luxembourg’s funding agency. This programme, the National Centre of Excellence in Research (NCER), launched its first call for “Early Diagnosis and Stratification of Parkinson’s Disease” last year, an initiative that should greatly advance PD research in Luxembourg.
[1] doi: 10.1002/mds.25491
[2] doi: 10.1212/WNL.0b013e3182a9f449
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