2. Background and Rationale
2.1 Joint Programming on Neurodegenerative Diseases (JPND).
The effects of treatments for neurodegenerative diseases are limited, and mainly address the symptoms, rather than the cause. It is widely perceived that the lack of sensitive and specific biomarkers for the diagnosis and the monitoring of progression of neurodegenerative disorders, which are sufficiently robust to be used in large multicentric trials is one of the greatest unmet needs. Therefore, an immediate need to be addressed in order to provide a solid basis for the establishment of risk-stratified cohorts and for upcoming multicentric diagnostic and therapeutic trials is the development of optimally informative biomarkers and stakeholder agreement regarding their use. Fundamental to achieving this is the harmonization of patient sample documentation, collection and storage and biomarker analytical methods between clinical centres.
In response to this, the Joint Programme on Neurodegenerative Diseases (JPND) is an EU initiative established to better coordinate European efforts on the level of research funding organizations on the basis of a joint strategic research agenda.
Through the JPND, a joint trans-national call has therefore been launched to encourage novel approaches to the development of optimally informative biomarkers and harmonisation of their use. Here in Ireland the Health Research Board (HRB) is funding this initiative and are one of many funding organisations across Europe that are contributing to this research.
Overall the JPND initiative aims to establish multi-national, collaborative research projects that will add value to existing research through addressing novel approaches to improve and harmonize the use of biomarkers in the area of neurodegenerative disorders, including:
Alzheimer’s Disease
Parkinson’s Disease and related disorders
Prion Disease
Motor Neuron Disease (MND)
Huntington’s Disease
Spinocerebellar Ataxia (SCA)
Spinal Muscular Atrophy (SMA)
This aim is to establish harmonisation of patient sample documentation, collection and storage and biomarker analytical methods within 3 years.
The BIOMARKAPD project is just one of many projects that is part of this EU initiative.
2.2 BIOMARKAPD
Alzheimer’s and Parkinson’s diseases (AD and PD) are the two most common neurodegenerative
conditions.
The main aim of BIOMARKAPD is to develop evidence-based guidelines for the measurement and the use of biochemical biomarkers for Alzheimer’s disease (AD) and Parkinson’s disease (PD) in clinical practice. [1]
Protocols will be developed for 3 established biomarkers for AD (Aß42, T-tau, and P-tau) and one biomarker for PD (alpha- synuclein). These markers have been selected because they will be of direct clinical use for the diagnosis of AD (Aß42, T-tau, and P-tau) [2] or because they will be crucial for a better understanding of PD pathophysiology and diagnosis (alpha -synuclein)[3].
Aß42 and alpha-synuclein share some biochemical properties and standardization of one of these biomarkers will most likely facilitate standardisation of the other.
Because of the clinical relevance of these markers, a major emphasis of the project will be on implementation of the protocols across Europe.
To reach the main aim, the BIOMARKAPD project has the following objectives:
1. To develop standard operating procedures (SOPs) for pre-analytical sample handling
2. To develop qualification algorithms for commercially available biomarker assays
3. To develop SOPs for analytical procedures
4. To develop SOPs for the use of biomarkers in the diagnosis in clinical practice and for
use in clinical trials
5. To validate the SOPs for pre-analytical and analytical procedures
6. To implement the SOPs among laboratories and clinicians across Europe
2.3 BIOMARKAPD – Collaboration
BIOMARKAPD comprises 51 research centres in 21 countries across Europe and includes one 1 research site in Quebec, Canada.
2.4 Description of Study (Irish population)
The purpose of our Irish study is to explore whether measuring biomarkers of neurodegeneration including protein fragments and other constituents in spinal fluid and in blood of patients with cognitive impairment is helpful in elucidating the underlying cause of their cognitive deficits and for those diagnosed with mild cognitive impairment (MCI), in predicting who will progress to dementia.
We also aim to contribute to the over arching BIOMARKAPD study, by providing a portion of CSF and blood samples to the BIOMARKAPD research biobank in Luxemburg.
Three main cohorts of patients will be investigated:
1.Patients >65 but <90 years, diagnosed with possible/ mild Alzheimer’ s Disease.
2. Patients > 65 but <90 years with mild cognitive impairment (MCI).
3.Patients >45 but <65 years with cognitive deficits/ early onset neurodegeneration.
These patients will be recruited through the Memory Clinic run by Prof Brian Lawlor (Consultant Psychiatrist)and the Cognitive Clinic run by Dr Siobhan Hutchinson (Consultant Neurologist)in St James Hospital and eligible patients will be invited to participate in the study. All patients must retain the capacity to consent to participate in this study.
It can be difficult to predict whether older people with mild cognitive problems have underlying Alzheimer’s disease and whether younger people with memory and cognitive complaints have Alzheimer’s disease or some other neurodegenerative disorder. Recent research indicates that measuring the level of protein fragments (‘biomarkers’) in the spinal fluid in such cases, may be helpful in predicting who will get Alzheimer’s disease or if the presenting features are more likely due to Alzheimer’s disease. Furthermore it would be helpful to measure these biomarkers in the early stages of possible Alzheimer’s disease where a definitive diagnosis may yet be unclear.
Greater certainty about the diagnosis would mean that treatments and advice could potentially be introduced earlier. To develop these tests so that they are useful from a clinical point of view, we need to find out if the biomarkers in the spinal fluid of people with early stages of possible Alzheimer’s disease, mild cognitive impairment (MCI) and early onset cognitive disorders are different to the levels in age-matched people with normal memory and cognition and whether the levels can predict who will develop Alzheimer’s disease in the future.
We need to carry out these studies in the Irish population, as there is currently much variation in the results of biomarker tests between different countries and between different laboratories. Part of the aim of this research study is to understand and account for this variability and rectify it.
Cerebrospinal Fluid (CSF) Samples
We will use CSF samples from people who have no memory complaints to act as a comparison or control. These samples will be made available from a study of normal controls in another Irish centre where ethical approval is in place to allow CSF to be collected from control subjects.
If we can demonstrate that measuring biomarkers of neurodegeneration in patients with cognitive problems is beneficial in detecting the underlying cause of their cognitive impairment and/ or predicting who will go on to develop Alzheimer’s, it will facilitate the establishment of biomarker testing as part of the routine clinical workup for patients presenting with memory or cognitive problems.
Blood Samples
We will also investigate the levels of these biomarkers in blood samples. To date, the measurement of the protein fragment, ß- amyloid in blood has been less promising as a test but it may be possible to look at newer biomarkers to develop a more sensitive test for Alzheimer’s disease in the future.
Genotyping
Blood samples will also undergo genotyping for Apolipoprotein E (APOE) as part of this study.
2.5 Study Background
Alzheimer’s disease (AD) is the most common form of dementia. The prevalence of AD is around 2% at the age of 65 years and increases to about 30% by the age of 85 [4]. The most important risk factor for the development of AD is increasing age; global ageing is associated with a dramatic increased prevalence of AD with the numbers projected to double by the year 2050. The imperative for the scientific community is the discovery of a disease-modifying treatment for AD if there is to be a significant impact on the predicted epidemic numbers of people with AD.
AD remains a clinical diagnosis that can only be confirmed with 100% accuracy by post-mortem examination. Accumulation of the amyloid beta (Aβ) protein and the development of neurofibrillary tangles in the brains of people with AD is associated with neuronal degeneration and the clinical symptoms of dementia [5]. These changes are known to occur decades before the onset of dementia and the identification of a peripheral marker of these pathological processes would allow earlier and more definitive diagnosis of AD.
Mild Cognitive Impairment (MCI) is regarded as a transitional state between normal cognition and that of AD [6]. Around 12-15% of people with MCI will convert to dementia annually. Amnesic MCI type (single domain or multi-domain) has the highest rate of conversion and is most strongly linked with conversion to AD when compared with the other MCI subtype (non-amnesic MCI) [7]. However, not all amnesic MCI subjects progress to AD and it can be difficult, even with the help of neuropsychological testing and neuroimaging to predict which patients with MCI will convert to dementia.
The availability of a valid biomarker for AD would speed up therapeutic advances, allow the diagnosis of AD at an earlier stage and in particular identify those patients with MCI who have underlying AD. Important characteristics of a biomarker for AD are that it reflects the underlying pathological process and can be validated at post-mortem.
One of the most promising biomarkers in this regard has been CSF levels of Aβ1-42, total tau ( T-tau) and phosphorylated tau (P-tau). More that 100 studies have shown that these measures (i.e. low Aβ 42 and high P-tau or the so called ‘AD signature’) have high diagnostic accuracy for AD when compared to normal age-matched controls [8]. Studies are also finding that the AD signature in CSF is predictive of which patients with MCI convert to dementia. As part of the new clinical research criteria from National Institute on Ageing – Alzheimer’s Association (NIA-AA), it has been proposed that a diagnosis of MCI due to AD can be made in the presence of episodic memory deficits with either topographic evidence of medial temporal lobe atrophy or low Aβ 42 and high P-tau [5]. These remain research criteria for the moment and before CSF Aβ, P-tau and topographic imaging biomarkers can be reliably applied to clinical practice on a routine basis, a number of methodological obstacles must be overcome. For example, there is a high inter-laboratory co-efficient of variation and this is a limiting factor for between laboratory comparisons of results. There are many potential reasons for this variability including lack of standardization of pre-assay conditions, sample handling, determination of assay levels and post assay variation, all of which limit multi-centre studies and collaborations in this area.
From the point of view of patient acceptance, the availability of a peripheral blood biomarker for AD would be preferable to CSF sampling. While the advances in the field have been in the area of a spinal fluid biomarker ‘AD signature’, the development of novel biomarkers in peripheral blood will be key to achieving earlier diagnosis and intervention in large numbers of people with AD. A number of recent studies have found that either a reduction of plasma Aβ 42 levels or a change in plasma Aβ42 levels or the ratio of Aβ42/Aβ40 might predict progression from MCI to AD [9] [10] [11]. Much work needs to be carried out with regard to standardisation of how Aβ is measured and which Aβ species are most helpful. With this in mind, this study also proposes to collect blood for amyloid fragment measurement (Aβ40/42) and other novel markers (e.g. Aβ auto-antibodies) that may be of value in predicting progression to AD or in monitoring cognitive decline in these subjects.
TCD is a partner in BIOMARKAPD, a large EC funded consortium to standardise and optimise the use of CSF biomarkers in the diagnosis of AD. This study will be conducted in parallel with BIOMARKAPD and will contribute samples as part of the standardisation and optimisation process for AD biomarker development across Europe.