Degeneration of dopaminergic circuitry influences depressive symptoms in Lewy body disorders

Abstract

Aims: Depression is commonly observed even in prodromal stages of Lewy body disorders (LBD), and is associated with cognitive impairment and a faster rate of cognitive decline. Given the role of dopamine in the development of movement disorders, but also in motivation and reward, we investigated neurodegenerative pathology in dopaminergic circuitry in Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) patients in relation to depressive symptoms.

Methods: α-synuclein, hyperphosphorylated tau and amyloid-beta pathology was assessed in 17 DLB, 14 PDD and 8 PD cases within striatal and midbrain subregions, with neuronal cell density assessed in substantia nigra and ventral tegmental area. Additionally, we used a structural equation modeling (SEM) approach to investigate the extent to which brain connectivity might influence the deposition of pathological proteins within dopaminergic pathways.

Results: A significantly higher α-synuclein burden was observed in the substantia nigra (P = 0.006), ventral tegmental area (P = 0.011) and nucleus accumbens (P = 0.031) in LBD patients with depression. Significant negative correlations were observed between cell density in substantia nigra with Lewy body (LB) Braak stage (P = 0.013), whereas cell density in ventral tegmental area showed negative correlations with LB Braak stage (P = 0.026) and neurofibrillary tangle Braak stage (P = 0.007).

Conclusions: Dopaminergic α-synuclein pathology appears to drive depression. Selective targeting of dopaminergic pathways may therefore provide symptomatic relief for depressive symptoms in LBD patients.

Keywords: dementia with Lewy bodies; depression; dopaminergic pathways; α-synuclein.

Figure 1

α‐synuclein pathology distribution . Photomicrographs of α‐synuclein pathology distribution in substantia nigra (SN), ventral tegmental area (VTA), putamen and insula in DLB (case #4, LB Braak stage 6), PDD (case #26, LB Braak stage 6) and PD (case #34, LB Braak stage 4). α‐synuclein immunohistochemistry with KM51 antibody, ×20. Scale bar 300 µm.

Figure 2

Levels of α‐synuclein pathology in LBD . α‐synuclein pathology (% area stained) was assessed in substantia nigra (SN), ventral tegmental area (VTA), nucleus accumbens (NAcc), caudate (Cd), anterior and posterior putamen (Pu), globus pallidus internus (GPi) and externus (GPe) and insula between DLB, PDD and PD groups. *P < 0.05, DLB vs. PD.

Figure 3

Tau pathology distribution . Photomicrographs of tau pathology distribution in substantia nigra (SN), ventral tegmental area (VTA), putamen and insula in DLB (case #4, NFT Braak stage 6), PDD (case #26, NFT Braak stage 6) and PD (case #34, NFT Braak stage 4). HPT immunohistochemistry with AT8 antibody, ×20. Scale bar 300 µm.

Figure 4

Levels of tau pathology in LBD . Tau pathology (% area stained) was assessed in substantia nigra (SN), ventral tegmental area (VTA), nucleus accumbens (NAcc), caudate (Cd), anterior and posterior putamen (Pu), globus pallidus internus (GPi) and externus (GPe) and insula between DLB, PDD and PD groups. *P < 0.05, DLB vs. PDD; **P < 0.01, DLB vs. PDD; ^## P < 0.01, DLB vs. PD.

Figure 5

Amyloid‐beta distribution . Photomicrographs of Aβ pathology distribution in substantia nigra (SN), ventral tegmental area (VTA), putamen and insula in DLB (case #4), PDD (case #26) and PD (case #34). Aβ immunohistochemistry with 4G8 antibody, ×20. Scale bar 300 µm.

Figure 6

Amyloid‐beta pathology in LBD . Aβ pathology (% area stained) was assessed in substantia nigra (SN), ventral tegmental area (VTA), nucleus accumbens (NAcc), caudate (Cd), anterior and posterior putamen (Pu), globus pallidus internus (GPi) and externus (GPe) and insula between DLB, PDD and PD groups. *P < 0.05, DLB vs. PD; **P < 0.01, DLB vs. PD; ***P < 0.001, DLB vs. PD.

Figure 7

Dopaminergic cell loss in the midbrain in LBD. Pigmented dopaminergic neuron counts in substantia nigra (SN) and ventral tegmental area (VTA) (cells/mm²) in controls, DLB, PDD and PD cases. *P < 0.05, controls vs. PD; **P < 0.01, controls vs. DLB; ***P < 0.001, controls vs. PDD; ^### P < 0.001, controls vs. DLB and controls vs. PDD.

Figure 8

α‐synuclein burden in depressed vs. non‐depressed LBD cases . Significant pathological changes (% area stained) in depressed vs. nondepressed LBD cases. Significance levels set at *P < 0.05, **P < 0.01 and ***P < 0.001.

Figure 9

Canonical correspondence analysis . Pathological protein burden across brain regions in relation to age, Braak NFT stage and disease group. Note, DLB is the reference in this plot against which PD and PDD are compared.

Figure 10

Modeling of pathology spread in LBD . Structural Equation Model suggesting significant spread along pathways between brain regions based on levels of protein deposition in each region. Arrows indicate significant linkages between brain regions for α‐synuclein, tau and Aβ, where the levels of protein in one region (end of arrow) were significantly related to levels in the other region from which the arrow starts (in this case assumed to be source).