The End Is the Beginning: Parkinson's Disease in the Light of Brain Imaging

Abstract

Parkinson's disease (PD), the most common neurodegenerative disorder, is characterized by abnormal accumulation of α-synuclein aggregates known as Lewy bodies (LB) and loss of nigrostriatal dopaminergic neurons. Recent neuroimaging studies suggest that in the early phases of PD, synaptic and axonal damage anticipate the onset of a frank neuronal death. Paralleling, even post mortem studies on the brain of affected patients and on animal models support that synapses might represent the primary sites of functional and pathological changes. Indeed, α-synuclein microaggregation and spreading at terminals, by dysregulating the synaptic junction, would block neurotransmitter release, thus triggering a retrograde neurodegenerative process ending with neuronal cell loss by proceeding through the axons. Rather than neurodegeneration, loss of dopaminergic neuronal endings and axons could thus underlie the onset of connectome dysfunction and symptoms in PD and parkinsonisms. However, the manifold biases deriving from the interpretation of human brain imaging data hinder the validation of this hypothesis. Here, we present pivotal evidence supporting that novel comparative brain imaging studies, in patients and experimental models of PD in preliminary stages of disease, could be instrumental for proving whether synaptic endings are the sites where degeneration begins and initiating the factual achievement of disease modifying approaches. The need for such investigations is timely to define an early therapeutic window of intervention to attempt disease halting by terminal and/or axonal healing.

Keywords: Parkinson’s disease; axonal damage; brain imaging; synaptic terminal loss; α-synuclein.

Figure 1

The putative organization of the dopaminergic synapse in healthy condition and in Parkinson’s disease (PD) is presented in relation with nigrostriatal neuron degeneration, connectome function and the disease staging. (A) Correct organization of synaptic vesicle pools in a dopaminergic striatal terminal in the healthy brain. (B) Retrograde synapse-to-cell-body degeneration initiating and perpetrating nigrostriatal connectome dysfunction in PD. In the prodromal phases of PD, microaggregation of α-synuclein at synaptic terminals progressively changes the organization of synaptic vesicle pools, reduces dopamine release, alters dopamine turnover and decreases dopamine transporter (DAT) membrane content but nigral neuron loss is negligible. Alpha-synuclein can also spread from terminals. DAT binding is reduced with mild to absent alterations of diffusion tensor imaging (DTI) and lack of Nigrosome-1 decrease. This synaptic impairment may initiate connectome dysfunctions in the absence of marked synapse loss or axonal and cell body degeneration. In the early stages of PD, the onset of symptoms is related to the beginning of connectome deficits that mainly arise from synaptic and axonal loss and only to a lesser extent to nigral cell loss. DAT binding and DTI abnormalities are accompanied by a partial or unilateral decrease of Nigrosome-1. Finally, in the advanced phases of the disease, broad synaptic, axonal and cell body degeneration that can be detected by integrating multiple imaging techniques, concomitantly participate to disease progression. PP, Proximal pool; RRP, ready releasable pool, RP, reserve pool.