Current and future clinical utilities of Parkinson’s disease and dementia biomarkers: can they help us conquer the disease?

ABSTRACT

Introduction: Biomarkers for Parkinson’s disease and Alzheimer’s disease are essential, not only for disease detection, but also provide insight into potential disease relationships leading to better detection and therapy. As metabolic disease is known to increase neurodegeneration risk, such mechanisms may reveal such novel targets for PD and AD. Moreover, metabolic disease, including insulin resistance, offer novel biomarker and therapeutic targets for neurodegeneration, including glucagon-like-peptide-1, dipeptidyl peptidase-4 and adiponectin.

Areas covered: The authors reviewed PubMed-listed research articles, including ours, on a number of putative PD, AD and neurodegenerative disease targets of interest, focusing on the relevance of metabolic syndrome and insulin resistance mechanisms, especially type II diabetes, to PD and AD. We highlighted various issues surrounding the current state of knowledge and propose avenues for future development.

Expert opinion: Biomarkers for PD and AD are indispensable for disease diagnosis, prognostication and tracking disease severity, especially for clinical therapy trials. Although no validated PD biomarkers exist, their potential utility has generated tremendous interest. Combining insulin-resistance biomarkers with other core biomarkers or using them to predict non-motor symptoms of PD may be clinically useful. Collectively, although still unclear, potential biomarkers and therapies can aid in shedding new light on novel aspects of both PD and AD.

KEYWORDS:

• Parkinson’s disease
• Alzheimer’s disease
• biomarker
• therapy
• diabetes mellitus
• neurodegeneration
• glucagon-like-peptide-1
• dipeptidyl peptidase-4
• diponectin
• synuclein
• leucine-rich repeat kinase 2
• miRNA
• therapy

Article highlights

• Biomarkers are indispensable for PD and AD diagnosis, assessment of disease severity, disease prognostication and also for inclusion/exclusion and tracking during disease-modifying clinical trials for neurodegeneration.

• For PD, no validated clinical biomarkers are established, while in AD, they may be somewhat invasive and have limited clinical utility.

• Among many possible PD and neurodegeneration candidate molecules with a novel pathogenetic basis, those derived from diabetic and insulin-resistance mechanisms appear promising both therapeutically and for developing relevant sensitive and specific biomarkers.

• Central to insulin resistance, GLP-1, DPP-4 and APN appear mechanistically linked to protection against either αS or Aβ-induced neurodegeneration, providing a rationale for use as novel therapeutic targets and in new biomarker discovery.

• Several PD non-motor symptoms (NMS) including behavioral and cognitive changes are related to insulin resistance and others mechanisms, and can be reversed by stimulating GLP-1 and inhibiting DPP-4.

• Multiple approved incretins (GLP-1R agonists) and gliptins (DPP-4 inhibitors) are already in widespread use for T2DM, making them attractive for repurposing for PD and neurodegeneration clinical trials, while APN clinical development remains in preclinical research.

• Genomic methods, especially miRNA, will have great impact on PD and neurodegeneration detection and possible treatment.

• As with the cancer diagnosis and therapy model, combined biomarkers whether using diabetes-related molecules such as GLP-1, DPP-4 or APN, or core molecules including αS, Aβ and others, may, in future, be used to better identify subsets of patients for individualized PD and dementia therapy with combined anti-diabetes, anti-aggregation or other future novel targeted treatments.

Acknowledgments

The authors are grateful for the continuous encouragement of Dr. Eliezer Masliah (National Institute on Aging).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.