Special LMNN Seminar - Where does Parkinson’s disease start and how does it spread in the brain ?

Six to ten years before a person visits the doctor with the cardinal features of Parkinson’s disease (PD; paucity of movement and rigidity) they will usually have lost their sense of smell. Pathologically, PD is characterised by the accumulation of α-syn in various brain regions and a loss of dopamine cells in the substantia nigra. But, the olfactory bulb is one of the first brain regions affected by the accumulation of α-syn. Apparently, the majority of α-syn accumulates in neurons of the anterior olfactory nucleus in the olfactory bulb. α-syn spreads from the anterior olfactory nucleus to to the olfactory tract, anterior olfactory cortex and then into the substantia nigra. Thus, understanding the early changes in the olfactory bulb could be key in identifying early targets for slowing or stopping the progression of PD-related brain changes before the cardinal features appear. To this end we have performed studies on ethically sourced normal and PD human olfactory bulbs with a focus on characterising glomerular changes, measuring metal accumulation and identifying which cell types accumulate α-syn. To study glomeruli we have performed 3D reconstructions of whole human olfactory bulbs and have identified a ventral glomerular deficit and aberrant placement of many glomeruli in PD. To study metal accumulation we used inductively coupled plasma mass spectrometry, which demonstrated the regional distribution of metals in the bulb and in particular showed increased iron and sodium in the olfactory bulb in PD. Finally we have examined the cell types in which α-syn accumulates in the bulb. Our studies reveal that in PD bulbs, neurons, glia, pericytes and microglia all express α-syn in all cases studied. The results of these studies and implications for PD will be discussed.