Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder primarily characterised by motor symptoms such as bradykinesia, tremor, rigidity, and postural instability. However, PD is far from being solely a motor disorder. It involves a wide spectrum of non-motor symptoms (NMS) including olfactory dysfunction, neuropsychiatric dysfunction, REM sleep disorder and importantly cognitive deficits that significantly impact patients’ quality of life (Schrag, 2004; Chaudhuri & Odin, 2010). Since the symptoms develop almost independently of each other, these NMS can be attributed to other causes, leading to delayed diagnosis and suboptimal management. Furthermore, they may go unrecognised or increase in intensity such that the symptoms culminate in dementia (Goetz et al., 2009).

Cognitive impairment is a prominent NMS in PD and can manifest across a spectrum, ranging from mild cognitive impairment (MCI) to dementia. It is one of the top 10 overarching research priorities for the management of PD (Deane et al., 2015) as no effective treatments exist, meaning this remains an unmet medical need. The primary pathology of PD is loss of nigrostriatal and to a lesser extent, mesolimbic and meso-corticolimbic dopamine which is known to play a key role in cognitive processes (Williams & Goldman-Rakic, 1995). Early studies by Brown and Marsden (1984) and Brown et al. (1984) estimated that between 15 and 20% of patients with PD develop dementia which can be recapitulated by full nigrostriatal lesions in MPTP treated primates. In this PD model, dopaminergic loss represents the primary neuropathology, while to a lesser extent the ventral tegmental area, nucleus accumbens and prefrontal cortex are also affected (Iravani et al., 2005). However, such a full lesion of the nigrostriatal system reflects more an “end-stage” model of PD and may miss the subtle changes in the fluctuations of neurotransmitters such as dopamine, serotonin and acetylcholine that occur throughout the progression of idiopathic PD. Therefore, appropriate models must be employed for the various stages of cognitive dysfunction.

Patients with early PD are more prone to attentional interference in the presence of distractors and experience difficulty in shifting and sustaining attention (Sharpe, 1990). This failure is likely related to the early loss of dopamine in the meso-corticolimbic region but in advanced stages of the disease other anatomical areas such as the temporal lobe and the hippocampal formation may also be affected resulting in different forms of cognitive impairment, including visuospatial learning and memory problems (Owen et al., 1997). Cognitive deficits are largely untreated and dopamine replacement, given for relief of the motor symptoms, may improve, worsen, or indeed do nothing for cognition (Chaudhuri & Schapira, 2009). The often-noted lack of cognitive enhancement by dopamine replacement therapies (Gotham et al., 1988, Swainson et al., 2000) suggests that alongside the loss of dopamine dysfunction, other neurotransmitter systems such as acetylcholine, noradrenaline and serotonin (Scatton et al., 1982, Agid and Blin, 1987) may play important roles in the pathogenesis of cognitive impairment associated with PD, and thus serve as potential therapeutic targets as the disease progresses. PD patients experience some form of cognitive impairment during the course of the disease and epidemiologic estimates of the prevalence and incidence of cognitive disorders in PD varies between 30 and 40% depending on differences in diagnostic criteria and the type of cognitive impairment (Petersen et al., 1999, Aarsland, 2016, Aarsland et al., 2021). This number could be greater as the disease progresses (Santangelo et al., 2015) but not all PD patients, even those in the later stages of the disease and showing cognitive impairment, are overwhelmingly demented although they have an increased risk of its development (Brown and Marsden, 1988b, Brown and Marsden, 1988a).