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Biomarkers for Alzheimer's Disease – Where are we now and Where are we going?

Last July, the Alzheimer's disease community gathered in Toronto for the Alzheimer's Association International Conference (AAIC) to share the latest advances in AD research and clinical trials.

Dementia is a global health issue as it affects over 45 million people worldwide and is recognized as a public health priority by the World Health Organization (WHO). Alzheimer's disease (AD) is a fatal degenerative brain disease and is the most common cause of dementia, accounting for an estimated 60 to 80% of cases1.

AD is characterized by the pathologic accumulation of the amyloid-β peptide (Aβ), forming extracellular amyloid plaques and the deposition of neurofibrillary tangles (NTFs), composed of the hyperphosphorylated microtubule-associated protein tau2,3. These two main pathological hallmarks are thought to contribute to neuronal damages resulting in AD symptoms, such as memory loss. Currently, the only available treatments for AD aim to reduce these symptoms and new drugs are desperately needed to prevent, halt the progression or delay the clinical onset of AD. Indeed, failures of trials testing anti-Aβ modifying drugs on AD patients in the dementia phase raised the question of initiating these treatments in earlier AD stages. Identifying AD patients early in the disease progress (before clinical onset) and including them in clinical trials may improve the capability to demonstrate the clinical efficacy of such candidate drugs.

That is one of the reasons why AD research community has focused their work on better characterizing early mechanisms of AD. The identification and the development of imaging and cerebrospinal fluid (CSF) biomarkers allowed researchers to establish the pathological cascade of AD, ranging from asymptomatic, to mild cognitive impairment (MCI), to dementia. Indeed, it has been shown that the CSF proteins Aβ1-42, total-tau and p-tau181, directly reflect the core hallmarks of AD and can be detected prior to clinical symptom onset. The CSF levels of these three proteins correlate closely with post-mortem Alzheimer's pathology and significantly increase the accuracy of AD diagnosis. That's the reason why these CSF biomarkers have been integrated into the core diagnostic framework of the IWG-2 criteria4.

New CSF and blood AD biomarkers
Despite the fact that core CSF biomarkers reflect the main pathological mechanisms of AD, new biomarkers are needed to monitor other molecular events such as synaptic damage and degeneration. It is against this background that several research teams presented promising results about emerging fluid biomarkers in AD. Blennow, Zetterberg and colleagues presented exciting data showing the small protein neurogranin as a promising CSF biomarker for AD. Mainly localized in dendritic spines, neurogranin is important for synaptic signalling and LTP induction. CSF neurogranin levels have been shown to increase specifically in AD, even at the early clinical stage, and to be associated with disease intensity5–7. Other CSF proteins, such as NfL and H-FABP are intensively studied to determine their role in AD and their use as biomarkers.

Even if CSF is the most relevant matrix to analyze brain biochemistry, it remains hardly accessible due to the need of a lumbar puncture. Blood biomarkers rationally appear as a good alternative as they are less invasive and cost- and time-efficient. Deters and colleagues showed that plasma tau levels are increased in AD patients compared to cognitively normal participants and are negatively associated with the ADNI-Memory score. These results correlate with Mielke's team findings, showing that plasma tau is associated with cortical thickness and memory performance8. However, plasma tau levels largely overlap between AD patients and controls participants, making its use difficult for population screening9. Martins et al., together with the AIBL Research Group presented a panel of candidate plasma biomarkers to assess cognitive decline and progression to AD. sVCAM1, PPY, I309, ApoJ, SAA and CRP along with APOE4 and age gave a sensitivity and specificity of 78-79% for AD, which is promising but doesn't reach values obtained with CSF biomarkers yet. Despite these very exciting results, further studies will be needed to evaluate plasma proteins as relevant tools for clinical diagnosis or screening.

Urgent need for standardization and establishing cut-off levels
If researchers and clinicians want to use biomarkers in AD clinical trials or for patient's diagnosis, all of the sources of variability have to be identified and minimized, to avoid any misdiagnosis. During this AAIC, standardization was actually the key word, especially to define cut-off levels. Indeed, since no reference method has been yet approved, published cut-offs are Center and procedure-specific. For CSF biomarkers analysis, variability has various origins, from pre-analytical procedures, such as how the lumbar puncture is performed and how samples are handled, to analytical methods used in laboratories, such as the different assays used for biomarker assessment. Drs Peskind and Dean explain us how to reduce pre-analytical sources of variability: the CSF collection is always performed during the same timeslot and in the same position. Samples are collected with polypropylene (PP) syringe, as amyloid have been shown to absorb onto polystyrene and glass, and are immediately aliquoted and frozen in PP cryotubes. Vanderstichele et al., went further into the optimization of standardization procedures by showing that using the ratio Aβ1-42 /Aβ1-40 eliminated effects of tube type, freeze/thaw cycles or volume of CSF in PP storage tubes10. This study, among others, provides guidelines for optimized standard operating procedures for CSF collection, storage and analysis, an essential step for standardization.

Aligned with these efforts, Bioclinica Lab

  • developed standardized methods for CSF sample collection, handling and storage to improve the reproducibility of your data,
  • takes part to the AAQC program for CSF biomarkers and are part of the ADNI biomarker initiative,
  • established an efficient, quality-driven, fit-for-purpose approach to analyze CSF biomarkers in clinical trials.

Bioclinica Lab established a strong relationship with ADx Neurosciences, in order to offer to our clients fully-validated assays to measure core biomarkers of AD (Aβ1-40, Aβ1-42, and total Tau) along with markers of neuropathological processes such as synaptic damage (neurogranin), or neuroinflammation (inflammatory cytokines) in human CSF and blood samples.

 

Bibliography

  1. Alzheimer's Association. 2015 Alzheimer's Disease Facts and Figures. (2015).
  2. Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).
  3. Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U. S. A. 82, 4245–4249 (1985).
  4. Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014).
  5. Kvartsberg, H. et al. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease. Alzheimers Dement. J. Alzheimers Assoc. 11, 1180–1190 (2015).
  6. Portelius, E. et al. Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease. Brain J. Neurol. 138, 3373–3385 (2015).
  7. Wellington, H. et al. Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835 (2016).
  8. Dage, J. L. et al. Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort. Alzheimers Dement. J. Alzheimers Assoc. (2016). doi:10.1016/j.jalz.2016.06.001
  9. Zetterberg, H. et al. Plasma tau levels in Alzheimer's disease. Alzheimers Res. Ther. 5, 9 (2013).
  10. Vanderstichele, H. M. J. et al. Optimized Standard Operating Procedures for the Analysis of Cerebrospinal Fluid Aβ42 and the Ratios of Aβ Isoforms Using Low Protein Binding Tubes. J. Alzheimers Dis. JAD (2016). doi:10.3233/JAD-160286

Fit-for-Purpose Validation of the Cerebrospinal Fluid Markers Aβ1-40, Aβ1-42 and Total Tau

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