non-motors sympt figs 1-2

At a physiological level, PD is characterised by the loss of neurons in specific regions of the brain and a spreading of Lewy pathology.^{[Halliday et al., 2014]} However, these do not necessarily always go together; many regions with a concentration of Lewy pathology show only mild neuronal loss.^{[Halliday et al., 2014]} The widely-used scheme proposed by Braak and colleagues categorises PD into discrete stages of clinical progression.^{[Braak et al., 2004; Halliday et al., 2014]} The first two stages involve early α-synuclein deposition associated with the appearance of non-motor symptoms, such as olfactory (smell) and autonomic (vital) dysfunction.^{[Halliday et al., 2014]} As the disease progresses, other aspects of brain function may become impaired, causing sleep dysregulation and/or depression in some individuals.^{[Halliday et al., 2014]} Stage 4 is typically the point at which clinical diagnosis occurs, since this stage involves the onset of motor symptoms, such as resting tremor and bradykinesia.^{[Halliday et al., 2014]} Stage 5 is characterised by poor balance and an increased susceptibility to falls, as well as the onset of cognitive impairment.^{[Halliday et al., 2014]} By Stage 6, the patient is likely to be significantly physically disabled and cognitive decline may well have progressed to PD dementia.^{[Braak et al., 2004; Halliday et al., 2014]} The Braak staging scheme is a useful concept to distinguish between the different phases of PD.^{[Braak et al., 2004]} However, in reality, patients vary considerably in the extent to which they conform to this model.^{[Halliday et al., 2014]} In one study, less than half of all patients with PD whose brains were examined post-mortem showed a close fit to the Braak staging scheme.^{[Parkkinen et al., 2008]} Another study found no pathology in the lower brainstem of some individuals (normally affected in Stage 1), even though it was clearly evident in higher regions.^{[Kalaitzakis et al., 2008]} Together, these studies clearly demonstrate that, beneath the over-arching diagnosis of ‘idiopathic PD’, there exists a wide variety of different disease processes, each of which manifests with the clinical and physiological features of PD.^{[Halliday et al., 2014]} References: Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318 (1): 121–134. Halliday GM, Murphy K, Cartwright H. Pathology of Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014. Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of α-synuclein staging. Neuropathol Appl Neurobiol 2008; 34 (3): 284–295. Parkkinen L, Pirttilä T, Alafuzoff I. Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance. Acta Neuropathol 2008; 115 (4): 399–407. 

At a physiological level, PD is characterized by the loss of neurons in specific regions of the brain and the spreading of Lewy pathology.^{[Halliday et al., 2014]} However, these do not necessarily always go together; many regions with a concentration of Lewy pathology show an only mild neuronal loss^{.[Halliday et al., 2014]} The widely-used scheme proposed by Braak and colleagues categorizes PD into discrete stages of clinical progression.^{[Braak et al., 2004; Halliday et al., 2014]} The first two stages involve early α-synuclein deposition associated with the appearance of non-motor symptoms, such as olfactory (smell) and autonomic (vital) dysfunction.^{[Halliday et al., 2014]} As the disease progresses, other aspects of brain function may become impaired, causing sleep dysregulation and/or depression in some individuals^{.[Halliday et al., 2014]} Stage 4 is typically the point at which clinical diagnosis occurs since this stage involves the onset of motor symptoms, such as resting tremor and bradykinesia.^{[Halliday et al., 2014]} Stage 5 is characterized by poor balance and increased susceptibility to falls, as well as the onset of cognitive impairment.^{[Halliday et al., 2014]} By Stage 6, the patient is likely to be significantly physically disabled, and cognitive decline may well have progressed to PD dementia.^{[Braak et al., 2004; Halliday et al., 2014]} The Braak staging scheme is a useful concept to distinguish between the different phases of PD.^{[Braak et al., 2004]} However, in reality, patients vary considerably in the extent to which they conform to this model^{.[Halliday et al., 2014]} In one study, less than half of all patients with PD whose brains were examined post-mortem showed a close fit to the Braak staging scheme.^{[Parkkinen et al., 2008]} Another study found no pathology in the lower brainstem of some individuals (normally affected in Stage 1), even though it was evident in higher regions.^{[Kalaitzakis et al., 2008]} Together, these studies demonstrate that, beneath the overarching diagnosis of ‘idiopathic PD’, there exists a wide variety of different disease processes, each of which manifests with the clinical and physiological features of PD.^{[Halliday et al., 2014]}

References

Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318 (1): 121–134.

Halliday GM, Murphy K, Cartwright H. Pathology of Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson’s Disease and Other Movement Disorders. VU University Press, 2014.

Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of α-synuclein staging. Neuropathol Appl Neurobiol 2008; 34 (3): 284–295.

Parkkinen L, Pirttilä T, Alafuzoff I. Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance. Acta Neuropathol 2008; 115 (4): 399–407.