Degeneration of dopaminergic circuitry influences depressive symptoms in Lewy body disorders

Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) are the most common Lewy 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 (LB) and Lewy neurites (LN) 14, 58, the distribution of which is associated with motor and cognitive changes. Comorbid Alzheimer's disease (AD) pathology is commonly observed, particularly in DLB, in the form of extracellular amyloid plaques, of amyloid‐beta (Aβ) peptide, along with neurofibrillary tangles (NFT) and neuropil threads of hyperphosphorylated tau (HPT) protein 42. The prevalence of neuropsychiatric symptoms in LBD is high 77, 81, 102, with depression being the most common prodromal psychiatric symptom in LBD patients, often preceding the onset of motor symptoms 57, 76, 88. Depression is also associated with cognitive impairment 29, 103 and faster rate of cognitive decline in LBD 12, 28. Monoaminergic deficits in depression are well‐established, such as serotonin (5‐HT), norepinephrine (NE) and dopamine 92. PD patients with depression show increased serotonin transporter binding in raphe and limbic regions 75, whereas decreased 5‐HT1A receptor densities in limbic regions including insula, hippocampus and orbitofrontal cortex are seen 6. Selective serotonin reuptake inhibitors (SSRI) are the most commonly prescribed antidepressants in PD patients with depression, although their efficacy in treating depression in PD is not supported by placebo controlled clinical trials 90. 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. Some studies have shown a marked reduction in 5‐HT and NE levels in striatal, cortical and hippocampal regions in AD patients with depression 7, 17, 97, 98, indicating that deficits in these neurotransmitters may relate to depression in AD. The differences between depression in LBD and AD may lie in the neural substrates, with dopamine metabolism being the major neurochemical difference. Dopamine deficiency in the nigrostriatal dopamine pathway caused by progressive α‐syn associated neurodegeneration and loss of dopaminergic neurons in the substantia nigra (SN) pars compacta results in dopamine depletion in the dorsal striatum and the development of motor symptoms in LBD 69. The mesolimbic dopamine pathway sends dopaminergic projections from the ventral tegmental area (VTA) within the midbrain to various cortical and subcortical regions including the nucleus accumbens (NAcc) in the ventral striatum. Consequently, the VTA plays a role in pathophysiology of mood disorders and cognitive deficits 18, 36, 63, 82, 86. The extensive interconnections of the insular cortex with basal ganglia and limbic system, also makes it a key integrator of cognitive and emotional processing 11, 32. Since anhedonia and loss of motivation are core symptoms of depression it is likely that dysfunction of dopaminergic circuitry is involved in mediating depressive behaviors 16, 95. Dopamine depletion is observed in L‐dopa naive PD and DLB cases, which correlates with reduction in attention and cognition 68, 70, 72, and this is likely to derive from changes to the dopaminergic VTA 74. Improved cognition and mood in PD is observed following L‐dopa therapy 56 and correlates with a basal failure to inactivate the default mode network 22. Structural changes to basal ganglia circuitry in LBD are minimal 15 or absent 101 suggesting that changes within specific nuclei may be the major contributors of psychiatric symptoms 2, 15, 20, 46. Some studies have suggested an association of major depression with neuropathological processes in AD, with a higher Aβ plaque and NFT burden within the hippocampus and cortical regions in depressed individuals 64, 78. Therefore, depressive prodromal symptoms in LBD may be directly linked to neuropathological changes in the brain. Neurodegeneration along specific pathways are the neuropathological correlate of distinct clinical phenotypes and this is assumed to be due to prion‐like spread of misfolded proteins (eg, α‐syn and HPT) through anatomically interconnected brain regions 3, 21, 39, 53, 80, 89, 100. Nigrostriatal degeneration occurs early in PD and PDD, where distribution and spreading of α‐syn are closely correlated with clinical symptoms and disease progression, respectively 25, 89. Indeed, current pathological staging of LBD suggests spread of synuclein pathology from specific medullary nuclei to SN and then to allocortical and neocortical regions 14. Grafted fetal nigral neurons in PD patients show LB inclusions years after transplantation, suggesting that physical contacts between susceptible regions, axonal transport and trans‐synaptic transmission of misfolded and aggregated α‐syn might have a role in the pathogenesis and propagation of PD 48, 51. Therefore, specific clinical symptoms in LBD patients may be due to accumulation of misfolded proteins in different brain regions within specific anatomical pathways. Since dopaminergic projections are involved in motor, cognitive and psychiatric deficits in LBD, changes in specific nuclei may relate to specific clinical symptoms. Therefore, we investigated how α‐syn, Aβ and HPT pathology affect nigrostriatal and mesolimbic dopaminergic circuitries in LBD in relation to depressive symptoms.