Parkinson's: a syndrome rather than a disease?

Abstract

Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson's disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson's to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently. Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson's is a multi-organ disorder. The Parkinson's phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease.

Keywords: Individualized medicine; Neurotransmitter; Non-motor subtypes; Non-motor symptoms; Parkinson’s disease; Parkinson’s syndrome.

Fig. 1

Multi-system and multi-neurotransmitter dysfunction in PD. NMS non-motor symptoms; OH orthostatic hypotension, MCI mild cognitive impairment Adapted from Chaudhuri and Fung (2016)

Fig. 2

Cardiac meta-(123)I-iodobenzylguanedine (MIBG) imaging. a Shows a subject with normal visualisation of the heart (arrowed), while b shows non-visualisation of the heart as in PD as evidence of postganglionic peripheral sympathetic dysfunction Picture courtesy nuclear imaging department, Kings College Hospital, London

Fig. 3

5-[11C]-methoxy-donepezil PET-imaging in normal subjects (a) and Parkinson’s disease (b). b Showing reduced uptake of pancreas and intestine Taken from Gjerløff et al. (2015)

Fig. 4

Peripheral sympathetic and parasympathetic dysfunction of the Parkinson’s syndrome as shown by in vivo imaging. MIBG meta-(123)I-iodobenzylguanedine, PET positron emission tomography

Fig. 5

Submandibular gland needle biopsy from a subject with PD with immune-histochemical staining for phosphorylated alpha-synuclein showing positive inclusion. Arrow points to an immunoreactive nerve fiber within a stromal nerve fascicle. Asterisks indicate nonspecific immunoperoxidase staining of gland cell cytoplasm Taken from Adler et al. (2016)

Fig. 6

Proposed flowchart showing the various selective (does not exclude overlap) neurotransmitter pathway dysfunction as delineated by in vivo imaging or clinical tests and the resulting clinical phenotype of NMS dominant subtypes. Dopamine deficiency underpins the whole condition. The imaging correlates could emerge as possible biomarkers in future MS motor syndrome. NMS non-motor syndrome