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Pathophysiology of neuropsychiatric symptoms

Although there is extensive literature on the pathophysiology of both NPS and cognitive impairment in PD, there has been almost no research on the pathophysiology of these symptoms in PD-D specifically.

In general, the high frequency of depression in PD has been explained by dysfunction in: (1) subcortical nuclei and the frontal lobes; (2) striatal-thalamic-frontal cortex circuits and limbic circuits; and (3) brainstem monoamine and indolamine systems (i.e. dopamine, serotonin, norepinephrine, and acetylcholine). Impairments in the pathways connecting subcortical structures and the frontal cortex also are thought to be important [92]. Functional brain imaging studies have reported simultaneous hypometabolism in the pan-frontal cortex and caudate in depressed PD patients, changes which are presumed to reflect neurodegeneration of the cortical-striatal- thalamic-cortical circuits [93, 94]. Regarding neurotransmitters, disproportionate degeneration of dopamine neurons in the ventral tegmental area (VTA) has been reported in PD patients with a history of depression [95]. Functional imaging studies in depressed PD patients have found both a decrease in signal intensity of neural pathways originating from monoaminergic brainstem nuclei [96] and a negative correlation between depression scores and dorsal midbrain serotonin transporter (5-HTT) densities [97].

Goal-directed behaviour is associated with dopaminergic and noradrenergic function as well as with activation of the prefrontal cortex and basal ganglia [98]. Supporting the role of the frontal cortical-striatal impairments in the development of diminished goal-directed behaviour (i.e. apathy), studies of apathy in PD have reported associations with executive deficits, impairment of verbal memory, and bradyphrenia [23, 99].

A recent study looking at cerebral metabolism and apathy found that areas involved in reward, emotion, and cognition are implicated in PD patients with apathy. Positive correlations were found between the following Brodmann areas (BA) and higher scores on the Apathy Evaluation Scale (AES): right inferior frontal gyrus (BA47), right middle frontal gyrus (BA10), right cuneus (BA18), and left anterior insula (BA13). The left and right cerebellum, posterior lobe, and inferior semilunar lobule were found to be negatively correlated with high AES scores [100].

As previously mentioned, the aetiology of psychosis in PD is complex and probably includes a complex interaction between medication exposure, PD pathology, aberrant REM-related phenomena, and co-morbid conditions, particularly cognitive impairment and visual disturbances. Dopaminergic medication may lead to excessive stimulation or hypersensitivity of mesocorticolimbic D2/D3 receptors and induce psychosis [101]. However, the association between psychosis, cognitive impairment, and mood disorders suggests more widespread involvement of other neurotransmitter systems or neural pathways. In this context, cholinergic deficits and serotonergic/dopaminergic imbalance have also been implicated in the development of psychosis in PD [82, 83, 101-104].

RBD and other sleep disturbances in PD have been attributed to both progressive degeneration of the cholinergic pedunculopontine nucleus [105] and reduced striatal dopaminergic activity [106]. With regard to the pathophysiology of PBA, a final common pathway seems to be disinhibi- tion of the brainstem bulbar nuclei that control the expression of crying and laughing. PBA in PD probably results from impairment in neural pathways connecting the cortex and brainstem [107].

 
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