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Neurodegenerative Disease – a problem caused by protein aggregation?

In the field of neurodegeneration there is a particular need to detect biomarkers in blood that are indicative of the early onset and development of these diseases. Currently the early stages of the major dementias are difficult to diagnose and stratify correctly and so the treatment prescribed, even if it were the correct choice, often begins too late in the progress of the disease; leading to a poor outcome.

The term dementia covers a large class of neurodegenerative disorders with different causes and overlapping symptoms, of which Alzheimer's Disease accounts for 62% of cases. Each disorder benefits from bespoke management and treatment by clinicians, family and carers, but accurate diagnosis and classification is difficult and is usually based on subjective observations. Degenerative diseases can also include systemic forms; an example is amyotrophic lateral sclerosis (ALS) which results from degeneration of the upper and lower motor neurones.

Parkinson’s Disease and Alzheimer’s Disease, for example, have very different symptoms, but at a molecular level they may well have much in common. It is known that aggregates of specific proteins form in the brain during the progress of a neurodegenerative disease1 , hence they are often referred to as protein conformation disorders. The detection of plaques, tangles or Lewy bodies composed of specific aggregated proteins by techniques such as brain imaging in a living subject or by post-mortem histology is considered to be a confirmation of the neurological disease present. Aggregated brain-derived proteins have been detected in cerebrospinal fluid (CSF) and blood. For example the ß-amyloid oligomer content of CSF is a promising biomarker in differentiating early AD from normal aging processes as well as allowing prediction of those patients with mild cognitive impairment (MCI) who will convert later to Alzheimer’s2.

Since CSF sample collection is inconvenient, often painful and cannot easily be performed on a repeat basis it is not a suitable procedure for routine diagnosis and screening. Aggregated biomarker proteins have also been reported to be present in blood but at much lower concentrations, which are at the limit of measurement by the standard immunoassay instruments currently available in clinical biochemistry laboratories. The highly sensitive assay technique of surface enhanced laser desorption time of flight (SELDI-TOF) mass spectrometry has been used to show that higher concentrations of ß-amyloid dimers are present in the blood of some Alzheimer’s patients and the dimers are associated with the membranes of blood cells3.

The plasma levels of various forms of α-synuclein including oligomers have also been shown to have potential value as a diagnostic tool in Parkinson’s Disease4.

References

  1. Soto, C. 2003. Unfolding the role of protein misfolding in neurodegenerative diseases. Nature Reviews, Neuroscience 4:49-60
  2. The Amyloid-Oligomer Count in Cerebrospinal Fluid is a Biomarker for Alzheimer’s Disease. Wang-Dietricha, L, Journal of Alzheimer’s Disease 34 (2013) 985–994, DOI 10.3233/JAD-122047
  3. Blood-Borne Amyloid-Dimer Correlates with Clinical Markers of Alzheimer’s Disease. Villemagne, V, et al. The Journal of Neuroscience, May 5, 2010, 30(18): 6315– 6322
  4. A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson's disease, Foulds P et al Scientific Reports 3, Article number: 2540 doi:10.1038/srep02540