Parkinson's disease dementia: a neural networks perspective

Abstract

In the long-term, with progression of the illness, Parkinson's disease dementia affects up to 90% of patients with Parkinson's disease. With increasing life expectancy in western countries, Parkinson's disease dementia is set to become even more prevalent in the future. However, current treatments only give modest symptomatic benefit at best. New treatments are slow in development because unlike the pathological processes underlying the motor deficits of Parkinson's disease, the neural mechanisms underlying the dementing process and its associated cognitive deficits are still poorly understood. Recent insights from neuroscience research have begun to unravel the heterogeneous involvement of several distinct neural networks underlying the cognitive deficits in Parkinson's disease dementia, and their modulation by both dopaminergic and non-dopaminergic transmitter systems in the brain. In this review we collate emerging evidence regarding these distinct brain networks to give a novel perspective on the pathological mechanisms underlying Parkinson's disease dementia, and discuss how this may offer new therapeutic opportunities.

Keywords: Parkinson’s disease; acetylcholine; dementia; dopamine; neural networks.

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Dementia is a common late complication of Parkinson’s disease, but the mechanisms underlying this form of dementia are unclear. Gratwicke et al. consider the development of each core cognitive symptom in turn, and argue that Parkinson’s disease dementia reflects dysfunction in seven distinct brain networks, with implications for therapeutic approaches.

Figure 1

The major subcortical neural networks affected in PDD (according to their dominant neurotransmitters). In this 3D representation the medial surface of the right hemisphere of the human brain is closest to the viewer in both images. A = amygdala; AC = anterior commissure (lateral aspect); C = caudate; Cg = cingulate gyrus; DLPFC = dorsolateral prefrontal cortex; GPi = globus pallidus (internus); IN = insular cortex; LC = locus ceruleus; P = putamen; SN = substantia nigra; T = thalamus; VLPFC = ventrolateral prefrontal cortex; VTA = ventral tegmental area.

Figure 2

The major cortical neural networks affected in PDD. Areas of cortical atrophy associated with visuospatial and visuoperceptual deficits in PDD (coloured green and purple, respectively) are based on the data presented in Pereira et al. (2009). Areas of cortical atrophy specifically associated with the presence of visual hallucinations in PDD (coloured blue) are based on the data presented in Goldman et al. (2014a). Functional cortical regions comprising the fronto-parietal attention network (highlighted red) are based on the data presented in Williams-Gray et al. (2008). Cortical regions are identified according to the Allen Brain Atlas for the human brain, and manually drawn onto the corresponding 3D brain image. In this representation the same cortical regions are affected symmetrically in both hemispheres, however in the original studies above the extent of atrophy in these regions was not symmetrical between hemispheres, and varied between individual patients. In the inferior view of the cortex the cerebellum has been removed to expose the fusiform gyri more clearly. DLPFC = dorsolateral prefrontal cortex; PPC = posterior parietal cortex; VLPFC = ventrolateral prefrontal cortex.

Figure 3

Hypothetical model of the neural networks affected in PDD and corresponding cognitive deficits. Solid arrows correspond to direct neural connections and colours are indicative of the primary neurotransmitter involved as shown in the key. Dashed arrows connect the relevant dysfunctional neural network to its putative cognitive effects. Purple arrows indicate that a deficit in one cognitive domain contributes to the development of impairment in another domain. Black crosses indicate damage to a neural pathway. The red dashed arrow represents direct projections from prefrontal cortex to the NBM, permitting top-down control of attention from the fronto-parietal network via recruitment of this latter structure and its cortical projections. The limbic, orbitofrontal and associative circuits in the prefrontal cortex correspond to the dissociable fronto-striatal loops of Alexander et al. (1986). Note effects of levodopa therapy at improving and worsening executive functions reliant on cognitive flexibility and learning from feedback, respectively. Electrocortical activation refers to cortical EEG desynchonization indicative of the awake/alert state as described in the text, and is driven by corticopetal cholinergic input from the NBM only. Both cholinergic input from NBM and noradrenergic input from the locus ceruleus (LC) modulate processing in sensory cortices to facilitate orienting of attention to stimuli. Cx = cortex; DLPFC = dorsolateral prefrontal cortex; fx = function; GPi = globus pallidus (internus); PPC = posterior parietal cortex; SNpc = substantia nigra pars compacta; VLPFC = ventrolateral prefrontal cortex; VTA = ventral tegmental area.