J Clin Neurol.  2016 Oct;12(4):381-392. 10.3988/jcn.2016.12.4.381.

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

• Kim D
• Kim YS
• Shin DW
• Park CS
• Kang JH

• KMID: 2385100
• DOI: http://doi.org/10.3988/jcn.2016.12.4.381

Abstract

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.

Keyword

cerebrospinal fluid; Alzheimer's disease; Parkinson's disease; biomarker; clinical trial; disease-modifying therapy

MeSH Terms

Alzheimer Disease
Biomarkers*
Cerebrospinal Fluid*
Humans
Models, Animal
Neurodegenerative Diseases
Parkinson Disease
Pathology
Therapeutic Uses
Biomarkers
Therapeutic Uses

Figure

• 

  Fig. 1 Illustration of the pathogenesis of neurodegeneration induced by proteinopathy, and the development of drugs targeting this pathogenesis. Amyloid beta (Aβ)-, hyperphosphorylated-tau-, or alpha-synuclein (α-syn)-mediated neurotoxicity is caused by the overproduction of toxic species of the protein from splicing of precursor protein (i.e., amyloid precursor protein) or protein modification (e.g., tau hyperphosphorylation), and/or a decreased clearance of detrimental proteins followed by the production of toxic oligomers and inflammatory microglial activation. Examples of developing drugs targeting the proteinopathy-mediated neurotoxicity are shown. Drugs that are currently being developed include an inhibitor of protein aggregation and antioxidants.

• 

  Fig. 2 Clinical trials of drugs in Alzheimer's disease (AD) that used cerebrospinal fluid (CSF) biomarkers and are ongoing or were completed within the past 5 years. Each of the developed drugs is arranged according to the estimated study completion date in descending order in each phase. The superscripted letters indicate the specific clinical trials as follows: among solanezumab trials (superscripts d, g, i, and j), (d) and (g) are ongoing prevention trials being performed by the Dominantly Inherited Alzheimer Network (DIAN) Trials Unit and Anti-Amyloid treatment in Asymptomatic AD study (A4 study), respectively, and (i) is another solanezumab trial (EXPEDITION 3) with mild AD that is currently underway after the completion of two double-blind trials (EXPEDITION 1 and 2; superscript j) involving patients with mild-to-moderate AD. One of gantenerumab trials (superscript e) belongs to the DIAN Trials Unit and involves subjects in the preclinical phase of AD, while another (superscript h) is a separate trial of mild AD. Two ongoing trials of IVIG (intravenous immunoglobulin; superscripts a and f) are independent studies supported by different sponsors. Therapeutic targets are presented using different symbols: stars (★) indicate Aβ-producing enzyme, diamonds (♦) indicate Aβ immunotherapy, triangles (►) indicate tau modification or aggregation, cruciform symbols (✚) indicate Aβ aggregation, and closed circles (●) indicate repositioned drug. NCT numbers in the references list indicate the identifiers at www.clinicaltrials.gov. Bars with two colors indicate trials that used CSF biomarkers for two purposes. CD: cluster of differentiation, MCI: mild cognitive impairment, NS: not specified, p-tau: phosphorylated tau, sAPP: soluble amyloid precursor protein, TNF: tumor necrosis factor, t-tau: total tau.

• 

  Fig. 3 Consideration of a "gray zone" for cutoff values of CSF biomarkers for sample enrichment in clinical trials. The application of a gray zone in which the biomarker values are considered to be inconclusive could be a more realistic approach than the application of single cutoff point in the design of clinical trials. The upper and lower values delimiting the gray zone indicate the 95% confidence interval (95% CI) values calculated using the ADNI-1 cohort (n=116 for controls and n=100 for AD) with cutoff values of 183.5 pg/mL for amyloid beta1–42 (Aβ42) and 86.5 pg/mL for t-tau that were measured using the xMAP-Luminex multiplex platform. The gray zones contain 19% and 19.9% of the biomarker values for CSF Aβ42 and ttau, respectively. Data in the graphs were presented by Coart et al.83 at AAIC 2015 in Washington DC (USA). AD: Alzheimer's disease, CSF: cerebrospinal fluid.

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