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
