Neurodegeneration and cellular dysfunction may precede the appearance of Lewy bodies in the substantia nigra, shows research that challenges the role of Lewy pathology in Parkinson's disease (PD).
"This report may help to change the view on Lewy pathology," Walter Schulz-Schaeffer (University Medical Center Göttingen, Germany) writes in an editorial accompanying the study in Neurology.
The study, considered together with other recent findings and the clinical effectiveness of dopamine-replacement therapy, "leaves little doubt that the degenerative process must be located at the presynapse," he says.
The autopsy-based results show that total neuron density was significantly reduced, by 39.8%, in the substantia nigra of 33 patients who had incidental Lewy body disease (ILBD) relative to that in 17 patients without Lewy bodies (Braak PD stage 0).
However, neuron density did not differ across Braak PD stages 1 to 6, and the reduced density was also observed in patients with Braak stages PD 1 and 2, ie, before Lewy bodies appeared in the nigrostriatal system.
Neuron density was higher in the ILBD patients than in 13 patients with clinical PD, but the percentage of neurons that were negative for tyrosine hydroxylase (TH), indicating dopaminergic cell dysfunction, was also higher.
The researchers - John Duda (Philadelphia Veterans Affairs Medical Center, Pennsylvania, USA) and colleagues - suggest that these TH-negative cells may be "struggling to survive" in patients with ILBD, but have died in patients with PD, accounting for the low overall neuron density in PD patients (66.7% lower than in patients without Lewy bodies).
Neuronal density in ILBD patients declined in line with increasing burden of α-synuclein, but the proportion of TH-negative cells was not associated with α-synuclein burden, which "further suggests that [Lewy pathology] is not the only cause of nigral neuron loss," comments the team.
Schulz-Schaeffer says: "We should disengage from the notion of Lewy body-associated cell death as the main phenomenon in PD and concentrate on synaptic pathology and axonal degeneration of still-existing cells in our search for therapy and for understanding the pathophysiology of PD."
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