Molecular biomarkers of neurodegeneration

Abstract

Neuronal dysfunction and degeneration are central events of a number of major diseases with significant unmet need. Neuronal dysfunction may not necessarily be the result of cell death, but may also be due to synaptic damage leading to impaired neuronal cell signaling or long-term potentiation. Once degeneration occurs, it is unclear whether axonal or synaptic loss comes first or whether this precedes neuronal cell death. In this review we summarize the pathophysiology of four major neurodegenerative diseases; Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease) For each of these diseases, we describe how biochemical biomarkers are currently understood in relation to the pathophysiology and in terms of neuronal biology, and we discuss the clinical and diagnostic utility of these potential tools, which are at present limited. We discuss how markers may be used to drive drug development and clinical practice.

Keywords::

• Alzheimer’s disease
• amyotrophic lateral sclerosis
• axon
• biomarkers
• cerebrospinal fluid
• clinical trials
• multiple sclerosis
• neurodegeneration
• Parkinson’s disease
• plasma
• synapse.

Financial & competing interests disclosure

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.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Synaptic damage is common to the major neurodegenerative diseases.

• • Biochemical biomarkers of synaptic damage exist, and can be measured in cerebrospinal fluid.

• • The exact relationship between underlying disease and biomarker levels is relatively unknown.

• • Key biomarkers include (structural proteins [ex actin, tubulin, tau and neurofilaments]).

• • Proteins involved in transmitter release (ex Rab3a, synaptotagmin, synaptophysin, synapsin, SNARE’s).

• • Pre- and post-synaptic proteins (ex GAP43, synaptodpodin, drebrin).

• • Because synaptic status functionally aligns to cognitive symptoms, synaptic biomarkers have the possibility to select patients for emerging therapies, both prognostically and diagnostically.

• • Synaptic status also has the possibility to be used a surrogate markers for monitoring treatment effects.

• • Integrated biomarker programs monitoring multiple modalities, including synaptic markers, are expected to increase the quality of future biomarker programs.

• • Peripheral correlates of cerebrospinal fluid markers is a relatively unexplored field, but one with the possibility to open up diagnostics into clinical practice.

Notes