Korean J Physiol Pharmacol.  2014 Dec;18(6):447-456. 10.4196/kjpp.2014.18.6.447.

Role of Cerebrospinal Fluid Biomarkers in Clinical Trials for Alzheimer's Disease Modifying Therapies

Affiliations
  • 1Department of Pharmacology and Clinical Pharmacology, Inha University School of Medicine, Incheon 400-712, Korea. johykang@inha.ac.kr
  • 2Hypoxia-related Disease Research Center, Inha University School of Medicine, Incheon 400-712, Korea.
  • 3Department of Anatomy, Inha University School of Medicine, Incheon 400-712, Korea.
  • 4Department of Emergency Medicine, Inje University Ilsan Paik Hospital, Ilsan 411-706, Korea.
  • 5Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. Les.Shaw@uphs.upenn.edu
  • 6Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Abstract

Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Abeta1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the

Keyword

Alzheimer's disease; Abeta1-42; Cerebrospinal fluid biomarker; Clinical trial; Tau

MeSH Terms

Alzheimer Disease*
Biomarkers*
Cerebrospinal Fluid*
Consensus
Decision Making
Dementia
Humans
Pathology
Quality Control

Figure

  • Fig. 1 Chronological relationship among pathology, clinical symptoms and biomarkers. Based on biomarker studies, Ab accumulation appears to start more than 20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in CSF Aβ1-42 levels may indicate Ab accumulation in the brain, even in preclinical stage of AD. Neocortical tau pathology correlates with the timing of symptom onset and start approximately 10 years before the onset of dementia. However, these findings need to be reconciled with reports that tau pathology is observed in the prior to Ab pathology. FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.

  • Fig. 2 Sequential process of amyloid precursor protein (APP) metabolism and production of amyloid beta species. Transmembrane APP is cleaved by α-secretase followed by γ-secretase to produce non-toxic amyloid species (non-amyloidogenic pathway, left blue thick arrow), while, through the amyloidogenic pathway (right red thick arrow), toxic Aβ species are generated by β-and γ-secretase. The toxic Aβ species including Aβ1-42 and Aβ1-40 are easily aggregated and produce highly toxic Aβ oligomers. Both processes produce soluble ectodomains [soluble APPα (sAPPα) and sAPPβ] and identical intracellular C-terminal fragment of APP (AICD). RAGE and LRP-1 located in bloodbrain barrier (BBB) are involved in the transport of the Ab between the brain and peripheral blood.

  • Fig. 3 Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the stability of microtubule. Hyperphosphorylation of tau induces disassembly of mitrotubules, causing axonal transport failure. Unbound tau produces oligomers or aggregates which congest axonal transport, and the tau pathology is synaptically transmitted. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.


Cited by  1 articles

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges
Dana Kim, Young-Sam Kim, Dong Wun Shin, Chang-Shin Park, Ju-Hee Kang
J Clin Neurol. 2016;12(4):381-392.    doi: 10.3988/jcn.2016.12.4.381.


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