The role of the cingulate cortex in depression in dementia with Lewy bodies

Abstract

Dementia with Lewy bodies (DLB) is a significant cause of dementia in the older population with a core set of clinical symptoms that help to distinguish DLB from other forms of dementia such as Alzheimer’s disease (AD). The core symptoms of DLB include fluctuating cognition, recurrent complex visual hallucinations and parkinsonism. Additionally, depression is experienced in around half of DLB patients and is associated with faster rate of cognitive decline, higher mortality rates and a poor response to treatment. The subgenual anterior cingulate cortex (sgACC) is integral in mood regulation, displaying structural, functional and metabolic abnormalities in depression, and shows early and extensive pathological changes in DLB. However, little is known about how any pathological or neurochemical changes in sgACC contribute to the aetiology of depression in DLB. Post-mortem tissue from cingulate cortex subregions was used to quantify neuropathological lesions in DLB cases with and without depression, and cognitively normal controls. Neurochemical analysis was performed to assess disease and depression specific changes in the sgACC in GABAergic, glutamatergic and monoaminergic transmission. Synaptic changes were assessed using confocal and stimulated emission depletion (STED) microscopy. Neuropathological burden in cingulate subregions showed disease, but not depression specific changes in DLB. Abnormalities in GABAergic and glutamatergic neurotransmission were observed in DLB cases with depression, showing greater dysregulation compared to DLB cases without depression. Dopaminergic deficits were observed in sgACC in DLB cases, with a greater reduction in DLB cases with depression, whereas no major changes in serotonergic or noradrenergic neurotransmission were observed in DLB. The results demonstrate that neurodegenerative neuropathological changes within the cingulate cortex do not appear to influence the development of depression in DLB. An imbalance in GABAergic/glutamatergic transmission within the sgACC was greater in DLB cases with depression, which may suggest greater dysregulation in excitation and inhibition, possibly contributing to the development of depression in DLB. This work also demonstrates the major role of dopaminergic neurotransmission in the aetiology of depression in DLB. Overall, this work indicates that treatment of depressive symptoms in DLB could benefit from modulation of dopaminergic, glutamatergic, or GABAergic transmission.