Novel Therapeutics in the Search for Disease Modification in Parkinson’s Disease – a Rapid Review of the Literature

Sporadic Parkinson’s Disease (PD) affects 3% of people over 65 years of age. People are living longer, thanks in large part to improvements in global health technology and health access for non-neurological diseases. Consequently, neurological diseases of senescence such as PD are represent-ing an ever- increasing share of global disease burden. There is an intensifying research focus on the processes which underlie these conditions in the hope that neurological decay may be arrested at the earliest timepoint. The concept of neuronal death linked to ageing- neural senescence- first emerged in the 1800s. By the late 20th century, it was recognised that neurodegeneration was common to all ageing human brains, but in most cases this process did not lead to clinical disease during life. Conditions such as PD are the result of accelerated neurodegeneration in particular brain foci. In the case of PD, de-generation of the substantia nigra pars compacta (SNpc) is especially implicated. Exactly why neu-ral degeneration accelerates in such specific regions remains a point of contention though current evidence implicates a complex interplay between a vast array of neuronal cell functions, neuron bio-energetic failure, and a dysfunctional brain immunological response. Their complexity is a consider-able barrier to disease modification trials which seek to intercept these maladaptive cell processes. This paper reviews current evidence in the domain of neurodegeneration in Parkinson’s disease, with a focus on alpha-synuclein accumulation and deposition and the role of oxidative stress and inflammation in progressive brain changes. Recent approaches to disease modification are discussed, including the prevention or reversal of alpha-synuclein accumulation and deposition, modification of oxidative stress, alteration of maladaptive innate immune processes and reactive cascades, and regeneration of lost neurons using stem cells and growth factors. The limitations of past research methodologies are interrogated, including the difficulty of recruiting patients in the clinically quies-cent prodromal phase of sporadic Parkinson’s disease. Recommendations are provided for future studies seeking to identify novel therapeutics with disease modifying properties.