Figure 3. Principles for progression of neuropathological changes.

a | Intracellular protein aggregates can be released from neurons by exocytosis or cell death. The aggregates are taken up by, for example, adjacent neuronal cell bodies and are either retained in the cell soma (local spread of pathology) or transported anterogradely by axons. Alternatively, they are taken up by axon terminals and transported retrogradely to the cell soma. The protein aggregates can spread between brain regions by axonal transport. b–d | Three drawings propose principles for how neuropathological changes in Parkinson’s, Alzheimer’s and Huntington’s diseases spread spatiotemporally during disease progression. The earlier the neuropathology develops in a given brain region, the darker the shading in the diagram. As only one view (mid-sagittal for Parkinson’s and Alzheimer’s diseases; lateral for Huntington’s disease) of the brain is depicted for each disorder, not all relevant anatomical structures and details of the spreading patterns (indicated by arrows) are presented. b | in Parkinson’s disease, α-synuclein aggregates (Lewy neurites and Lewy bodies) are suggested to first appear in the dorsal motor nucleus of the vagal nerve in the brainstem and anterior olfactory structures (darkest green), and then to spread stereotypically to finally occupy large parts of the brain⁴,⁵. c | in Alzheimer’s disease, neurofibrillary tangles first appear in the hippocampus (and closely associated structures), the basal nucleus of Meynert and the brainstem¹⁵–¹⁸ (darkest green). They spread to other brain regions, including the neocortex, in a stereotypical manner, correlating with symptomatic progression. d | in Huntington’s disease, the putamen and caudate nucleus, and related basal ganglia structures deep inside the brain (darkest green), have been suggested to degenerate first²⁵–²⁷. However, recent imaging studies suggest that primary motor and sensory cortices already undergo atrophy in pre-symptomatic gene carriers²⁸. Therefore we propose that cortical involvement precedes basal ganglia pathology.