Additional malfunctioning of the complex fronto-subcortical circuits of the basal ganglia in PD is almost invariably associated with relatively subtle dysexecutive cognitive impairment reminiscent of frontal lobe lesions. This type of cognitive impairment in PD is variably associated to dopamine depletion in the ventral and dorsal striatum and in the dorsolateral prefrontal lobe, arising from additional degeneration of dopamine neurons in the ventral tegmental area (VTA) (area A-10) of the midbrain. Besides subtle cognitive deficits, epidemiological studies have shown that dementia associated to PD (PDD), which was once thought to be rare, may eventually develop in up to 75% of patients with PD. Progress in understanding the core components of Lewy bodies and alphasynuclein staining lead to pathological studies evidencing that PDD is variably linked with cortical Lewy body topography and density. Accordingly, recent studies also indicate that degeneration of the midbrain dopaminergic neurons is only a part of PD and that alpha-synuclein pathologies accumulate throughout the central nervous system in areas that also undergo progressive neurodegeneration, leading to clinical symptoms that go far beyond motor parkinsonism. These include abnormalities in the regulation of mood, alterations in personality, impairments in olfactory discrimination and identification, impaired colour vision discrimination, decreased autonomic function and rapid eye movement (REM) sleep behaviour disorder.

When PD is clinically diagnosed, degeneration of dopaminergic neurons involves motor structures and also structures of the limbic system, affecting dopaminergic cognitive, learning and reward mechanisms that can lead to subtle cognitive impairment, anhedonia, loss of motivation and apathy. With the progression of the disease, further involvement of other neuronal circuits such as noradrenergic, serotonergic and cholinergic, and the influence of nonphysiological dopaminergic replacement may contribute to the variable presentation of other mental symptoms such as anxiety, depression, dementia and psychosis. Dopamine replacement therapy (DRT) with levodopa and other dopaminergic agents is a widely used and effective treatment for the motor symptoms of PD and, at least in the initial stages of the disease, has been shown to also benefit mood and certain cognitive functions. However, in chronically treated patients, DRT was variably associated to subtle cognitive impairment and to disabling behavioural side effects such as psychosis, hypersexuality, addiction, pathological gambling and punding. Dopaminergic-related neuropsychiatric problems in PD patients may be mild and underrecognised, or combined with premorbid personality traits can produce a complex and distressing clinical picture. With the progression of the disease, the behavioural and cognitive manifestations of PD are often more disabling than its motor complications.

Overall, PD should be viewed nowadays as a complex disorder, characterised by motor signs and by a broad and challenging range of neurological and psychiatric symptoms. This article highlights some of these aspects that emerge as the most difficult challenges of advanced disease, often limiting effective treatment of motor symptoms and leading to increased disability, worse quality of life, poorer outcomes and caregiver distress.