A biomarker is “A specific physical trait used to measure or indicate the effects or progress of a disease or condition“. The role of a biomarker is to provide doctors with an accurate and a reliable tool to make a diagnosis of Alzheimer’s disease. With degenerative diseases such as Alzheimer’s a biomarker should ideally, many doctors believe, meet a number of criteria.
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Cognitive reserve and Alzheimer's disease biomarkers are independent determinants of cognition
Cognitive reserve and Alzheimer’s disease biomarkers are independent determinants of cognition Brain (2011) awr049 first published online April 7, 2011 doi:10.1093/brain/awr049
The link to this article in Brain is here.
The objective of the study above was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer’s disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-? load via cerebral spinal fluid amyloid-?1–42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. They included very large samples – 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer’s disease, from the Alzheimer’s Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer’s disease in a group labelled ‘cognitively impaired’ subjects.
Their main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer’s disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-?1–42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer’s disease pathology.
A new way of diagnosing the earliest stages of Alzheimer's Disease?
Alzheimer’s disease is the most common form of dementia in the UK, characterized by profound memory problems in affected individuals. Currently there is no single test or cure for dementia, a condition that affects over 800,000 people in the UK. The prospect of disease modification has intensified the need to diagnose very early Alzheimer’s Disease with high accuracy. The ultimate goal is possibly to identify and treat asymptomatic individuals with early stages of Alzheimer’s Disease, or those at high risk of developing the disease. By definition, such individuals will be asymptomatic, and disease biomarkers or high-risk traits will be require identification. For pre-symptomatic treatment trials, demonstration of disease modification will ultimately require evidence of delay to symptom-onset or conversion to Alzheimer’s Disease.
In a paper reported recently, UK experts say they may have found a way to check for Alzheimer’s years before symptoms appear. A lumbar puncture test (a test to get spinal fluid from an individual via his back) combined with a brain scan can identify patients with early tell-tale signs of dementia, they believe. Ultimately, doctors could use this to select patients to try out drugs that may slow or halt the disease. Although there are many candidate drugs and vaccines in the pipeline, it is hard for doctors to test how well these work because dementia is usually diagnosed only once the disease is moreadvanced. Researchers at the Institute of Neurology, University College of London, working with the National Hospital for Neurosurgery and Neurosurgery, Queen Square, London, believe they can now detect the most common form of dementia – Alzheimer’s disease – at its earliest stage, many years before symptoms appear.
Their approach checks for two things – shrinkage of the brain and lower than normal levels of a protein, called amyloid, in the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. Experts already know that in Alzheimer’s there is loss of brain volume and an unusual build up of amyloid in the brain, meaning on the whole less amyloid in the CSF. There is, however, rather conflicting evidence for a relationship between measures of amyloid burden and brain volume in healthy controls, The research team reasoned that looking for these changes might offer a way of detecting the condition long before than is currently possible. To confirm this, they recruited 105 healthy volunteers to underwent a series of checks. All subjects were drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a multi-centre publicly/privately-funded longitudinal study investigating adult subjects with Alzheimer’s Disease, ‘mild cognitive impairment’ of the memory variety, and normal cognition. Participants undergo baseline and periodic clinical and neuropsychometric assessments and serial MRI.
The volunteers had lumbar puncture tests to check their spinal cerebrospinal fluid (CSF) for levels of amyloid and MRI brain scans to calculate brain shrinkage. The results, published in Annals of Neurology (reference provided below), revealed that the brains of those normal individuals with low CSF levels of amyloid (38% of the group), shrank twice as quickly as the other group. They were also five times more likely to possess the APOE4 cholesterol risk gene and had higher levels of another culprit Alzheimer’s protein, tau. Crucially, the results may allow doctors to pursue avenues to test which drugs might be beneficial in delaying or preventing dementia.
Potential limitations of the study include the relatively high percentage of amyloid-positive normal controls, which may or may not reflect the true population prevalence of individuals with significant amyloid pathology in this age range. There are also a number of issues relating to the reproducibility, reliability, and reporting of biomarker levels in spinal fluid, which need to be standardized to allow for cross-study comparisons.
Notwithstanding that, the scope for further research is enormous. Whether excess rates of brain atrophy in apparently cognitively normal aged patients with CSF profiles suggestive of AD inevitably lead to cognitive impairment, and if so over what time frame, needs to be established. If this proves to be the case, the results we present have significant implications for very early intervention, demonstrating that biomarkers may be used not only to identify Alzheimer’s Disease pathology in asymptomatic individuals, but also to demonstrate and quantify pr-esymptomatic clinical dementia. This suggests that disease-modifying trials in asymptomatic individuals with the aim of preventing progression to cognitive impairment and dementia may be feasible one day.
Reference:
Increased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid A?1-42. Jonathan M. Schott MD, Jonathan W. Bartlett PhD, Nick C. Fox MD, Josephine Barnes, for the Alzheimer’s Disease Neuroimaging Initiative Investigators Article first published online: 22 DEC 2010 DOI: 10.1002/ana.22315
You can view this paper here.
(c) Dr Shibley Rahman 2010
Biomarkers in dementia
The National Institute of Aging has initiated the Alzheimer’s Disease Neuroimaging Initiative, a large observational study of patients with Alzheimer’s Disease (AD), patients with mild cognitive impairment and cognitively normal volunteers to assess longitudinal changes in AD. Because cognitive measures do not easily correlate disease-modifying effects of treatment, current trials of investigational compounds require large sample sizes and long treatment duration. Therefore the use of biomarkers in such trials can help in the understanding of disease progression and drug effect.
Biomarkers allow new therapies to be developed more quickly and can be directly associated with a drug treatment as companion diagnostic. Since a clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, biomarkers might improve the accuracy of diagnosis. Indeed it is mandatory in a diagnosis to exclude other forms of dementia as fronto-temporal lobe degeneration (FTLD), dementia with Lewy bodies (DLB) and vascular dementia (VaD). In addition biomarkers might also serve as indirect measures of AD severity and could help to follow the evolution of the disease during a drug treatment. There are two directions in developing biomarkers of AD: (i) neuroimaging techniques which provide both structural and metabolic information about the brain, (ii) and cerebrospinal fluid (CSF) biomarkers which correlate the intensity of the disease. Cerebrospinal fluid (CSF) collection is a test to look at the fluid that surrounds the brain and spinal cord, and is performed through a ‘lumbar puncture’. The CSF acts as a cushion, protecting the brain and spine from injury. The fluid is normally clear.
According to a recent review, the identification and validation of biomarkers for diagnosing Alzheimer’s disease and other forms of dementia are increasingly important. To date, biochemical measurements of ?-amyloid(1-42), total tau and phospho-tau-181 in cerebrospinal fluid (CSF) is the most advanced and accepted method to diagnose probable AD with high specificity and sensitivity. Specificity means that a test can pick up an abormality in that particular condition, rather than other conditions; sensitivity means that it’s very adept at doing so. Biomarkers should be totally reliable, obtaining the sample should be simple, should have few side effects, and should be cheap.
However, it is a great challenge to search for novel biomarkers in CSF and blood by using modern mega-sophisticated biochemical methods, such as microarrays and mass spectrometry, and to optimize the handling of samples (e.g. collection, transport, processing, and storage), as well as the interpretation using biological metrics.
It seems likely that only a combined analysis of several biomarkers will define a patient-specific signature to diagnose AD in the future.
