Targeting Progressive Neuroaxonal Injury

Abstract

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuroaxonal injury, suggesting a common pathophysiological pathway. Identification and development of neuroprotective therapies for such diseases has proven a major challenge, particularly because of an already substantial neuroaxonal compromise at the time of initial onset of clinical symptoms. Methods for early identification of neurodegeneration are therefore vital to ensure that neuroprotective therapies are applied as early as possible. Recent investigations have enhanced our understanding of the role of neuroaxonal injury in multiple sclerosis (MS). As MS generally manifests earlier in life and can be diagnosed much earlier in the course of the disease than the above-mentioned 'classic' neurodegenerative diseases, it is possible that MS could be used as a model disease to study degeneration and regeneration of the CNS. The mechanism of neuroaxonal injury in MS is believed to be inflammation-led neurodegeneration; however, the reverse may also be true (i.e. neuroaxonal degeneration may precede inflammation). Animal models of PD, AD and ALS have shown that it is likely that most cases of disease are due to initial inflammation, followed by a degenerative process, providing a parallel between MS and the classic neurodegenerative diseases. Other common factors between MS and the neurodegenerative diseases include iron and mitochondrial dysregulation, abnormalities in α-synuclein and tau protein, and a number of immune mediators. Conventional MRI techniques, using markers such as T2-weighted lesions, gadolinium-enhancing lesions and T1-weighted hypointensities, are readily available and routinely used in clinical practice; however, the utility of these MRI measures to predict disease progression in MS is limited. More recently, MRI techniques that provide more pathology-specific data have been applied in MS studies, including magnetic resonance spectroscopy, magnetization transfer ratio and myelin water imaging. Optical coherence tomography (OCT) is a non-MRI technique that quantifies optic nerve integrity and retinal ganglion cell loss as markers of neuroaxonal injury; more research is needed to evaluate whether information obtained from OCT is a reliable marker of axonal injury and long-term disability in MS. Using these advanced techniques, it may become possible to follow degeneration and regeneration longitudinally in patients with MS and to better differentiate the effects of drugs under investigation. Currently available immune-directed therapies that are approved by the US FDA for the first-line treatment of MS (interferon-β and glatiramer acetate) have been shown to decelerate the inflammatory process in MS; however, such therapy is less effective in preventing the progression of the disease and neuroaxonal injury. The use of MS as a clinical model to study modulation of neuroaxonal injury in the brain could have direct implications for the development of treatment strategies in neurodegenerative diseases such as AD, PD and ALS.