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.
Highlights
Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) are the most commonLewy body disorders (LBD) [91], sharing many clinical and pathological characteristics [59, 60]
The decline in Mini-Mental State Examination (MMSE) scores with time was slower in PD patients compared to PDD and DLB (t = 6.490, P < 0.001), with no significant difference observed between PDD and DLB patients (t = 0.619, P = 0.54)
There was no difference between Unified Parkinson’s Disease Rating Scale (UPDRS) scores for PD and DLB (t = 0.256, P = 0.799), scores were significantly higher in patients diagnosed with PDD (t = 3.332, P = 0.002)
Summary
Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) are the most commonLewy body disorders (LBD) [91], sharing many clinical and pathological characteristics [59, 60]. LBD are pathologically characterized by abnormal aggregation of misfolded α-synuclein (α-syn) protein, which is the major component of Lewy bodies. In PD, there are noradrenergic deficits due to loss of neurons in the locus coeruleus (LC), with reductions in noradrenaline found in caudate, putamen and cortical regions [33, 34]. These changes are suggested to be related to the presence of depression as an early indication of LBD, since staging of pathology suggests degeneration of the LC before SN degeneration [96]. The differences between depression in LBD and AD may lie in the neural substrates, with dopamine metabolism being the major neurochemical difference
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