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.

Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat

“…Likewise, pathological α-synuclein aggregates found in the hippocampus could impair both working and episodic memory, as observed with the BSSG systemic administration [78]. Depressive-like behavior can be explained by dopaminergic denervation of nucleus accumbens from VTA neurons, and the presence of pathological α-synuclein aggregates in those nuclei [55]. Moreover, nigral dopaminergic innervation of the forebrain, which is part of the mesolimbic system, is well documented in humans [76] and experimental animals [14,48,84].…”

“…The presence of those aggregates in the striatum was associated with sensorimotor impairments, in the olfactory bulb with hyposmia, in the hippocampus with memory alteration, and in VTA with TH (+) cell loss and the development of depressive-like behavior. Those areas are anatomically and physiologically interconnected, thus explaining the spreading of α-synuclein pathology in a prion-like manner [3,19,35,37,55,81]. The mechanisms of α-synuclein aggregation are still in the characterization process, including those underlying the genetic causes [10].…”

“…α-Synucleinopathies are neurodegenerative diseases characterized by misfolded α-synuclein aggregates, which are the major component of Lewy bodies in neurons and Lewy neurites in neuronal terminals [55,69,82]. Of the three main types of α-synucleinopathy, Parkinson's disease (PD) is the most common and pure αsynucleinopathy phenotype [29].…”

Neuropathological Changes in Dementia With Lewy Bodies and the Cingulate Island Sign

“…Immunolabeling was detected using the Menarini X-Cell-Plus HRP Detection Kit (Menarini, Wokingham, UK) and visualized using diaminobenzidine (Menarini) substrate. Neuronal cell number within the regions of interest was assessed using 3 10-µm sections stained with Cresyl fast violet (26).…”

“…The mean percentage area stained per case was calculated from the mean values obtained across all images taken. For Cresyl fast violet-stained sections the same regions of interest were used as for quantification of neuropathological lesions, with the images captured using 63x oil immersion objective (26). Three 10-μm sections were used for each case to ensure adequate sampling.…”