Non motor subtypes and Parkinson's disease
Introduction
Motor symptoms of Parkinson's disease (PD) such as tremor, bradykinesia and rigidity are the hallmark based on which diagnosis and treatment are started and are now known to be preceded by the “pre-motor” phase of PD largely dominated by a range of different non motor symptoms (NMS) [1], [2], [3].
Virtually every PD patient has NMS, which are now widely recognized as an important unmet need in PD [3] and a major determinant of health related quality of life (HrQoL) of patients with PD and their carers [4]. In a survey by Parkinson's UK, patients listed NMS such as pain, sleep disorders and anxiety ahead of motor problems in clinical importance, and two further studies have outlined the key impact of NMS as declared by patients themselves [3], [32].
Despite this importance, little has been done to establish NMS clinical phenotypes in the context of the multi-morbid PD patient even though several workers have reported clinical phenotypes driven by specific NMS such as pain, cognitive problems, apathy and sleep dysfunction. Additionally, cluster analysis from several large early and untreated PD cohorts have all suggested specific NMS dominant or only NMS driven clustering [12], [13], [14]. This review aims to highlight these phenotypic variants that have been described within the rubric of Parkinson's disease.
NMS based subtyping of PD is plausible from a clinical point of view that in some PD patients, but not all, specific NMS are predominantly expressed, while in others NMS may not be evident or are less relevant. The clinical expression of a range of NMS highlights the fact that the phenotype of PD results from varying rates of Lewy body deposition and neurodegeneration in PD and represents the effects of widespread brain and peripheral Lewy body pathology instead of a single neural structure affected or the loss of the monoamine neurotransmitter such as dopamine [3], [5]. This convergence of deficits in multiple transmitter systems and pathways, including the cholinergic, noradrenergic, and serotonergic systems, may all be associated with clinical expression of NMS. In addition, glial pathology, neuroimmune responses, and proinflammatory cytokines may also play a key pathogenic role adding to the heterogeneity of PD [5], [6]. Furthermore, non-dopaminergic areas in the brainstem may be affected and involved ahead of dopaminergic involvement as recently reviewed by Todorova et al. [3], [5], [6], [7]. Jellinger has suggested that neuropathological spread of the neurodegenerative process may be initiated via the olfactory bulb and thereafter through the limbic or brainstem areas while spread via the enteric nervous system via the nervus vagus has also been suggested [5], [6], [7], [8]. A limbic, brainstem and cortical dominant pathophysiological process as proposed by Braak et al. [11], Jellinger et al. [5], Beach et al. [9] or Halliday et al. [7] is the basis of our proposal as shown in Fig. 1. All of these processes would lead to dominant expression of NMS over motor symptoms as also underpinned by the Braak hypothesis of α-synuclein accumulation starting in the lower brainstem and the olfactory bundle well before there is significant involvement of substantia nigra [11].
NMS subtyping is thus based on the evidence that early and substantial neuronal loss occurs in many non-dopaminergic nuclei in the limbic and brainstem areas, either before or concomitantly with involvement of dopaminergic projections [5], [9], [10]. The dorsal motor nucleus of the vagus (DMV) is a key area for control of autonomic signaling responsible for symptoms such as constipation. Neuronal loss in the DMV could be as profound as that in the substantia nigra (SN), and large (43–57% loss) cholinergic and substance P expressing neurons are preferentially lost while tyrosine hydroxylase neurons may be relatively spared in PD [5], [10].
A further contributor in the pathophysiology of non motor subtypes within PD is the age of onset of PD. Preferential Lewy body deposition in the brainstem in young onset PD versus a cortical dominant pathology in late onset PD has been described, the latter being associated with Alzheimer's disease type pathology [7], [11].
It is likely therefore, in these subjects patterns of NMS, dependent on relevant neuropathological involvement of non-dopaminergic areas, will underpin the clinical expression of specific NMS such as sleep problems, apathy, pain, depression/anxiety, ahead of and dominating the typical motor deficit of PD.
Untreated PD patients represent a suitable model to study the expression of NMS in comparison to motor symptoms. Erro et al. have conducted a cluster analysis coupled with validated cognitive, motor and nonmotor assessments in a untreated PD cohort and found 4 discrete clusters within the cohort termed benign pure motor, benign mixed motor-non-motor, nonmotor dominant and motor dominant [12]. The non motor dominant cluster reported higher urinary dysfuction and a rapid progression rate compared to the benign mixed motor, nonmotor cluster.
In the recently reported ONSET-PD study, the authors highlighted specific non motor clusters of PD ranging from cognitive and mood clusters to sensory, RBD dominant and autonomic dysfunction related cluster further supporting our attempt of NM subtying of PD [13]. Studies have also identified specific clinical phenotypes in untreated PD underpinned by NMS such as sleep dysfunction, cognitive and neurosychiatric disturbances (depression, apathy), fatigue, dysautonomia, pain and olfaction recently reviewed by Zis et al. [14]. These observations fit well with the neuropathological studies, which have suggested a differential rate of neuronal degeneration and Lewy body deposition in the non-dopaminergic brainstem and limbic areas in PD, with consequent expression of a variety of related NMS.
Section snippets
The literature descriptions of specific NMS dominant subtypes of PD
A proposal of at least six different NMS dominant clinical phenotypes within PD mainly in early and untreated phase has been proposed based on clinical observation and in this review we discuss the patterns that have been reported and published so far [15].
The problems of non-motor subtyping
As PD is a heterogeneous disorder there is considerable possibility that these subtypes will overlap and are likely to be present only in a proportion of patients. Comparable with the instability of motor subtypes, non-motor subtypes will change throughout the course of disease and at the end several types will merge and overlap. As such we accept that the classification is a simplification with heterogeneity and overlapping probably existing within these proposed major subtypes.
Selection bias
Conclusion
NMS subtyping in PD is a new concept and as shown in this paper, is clinically relevant and possible. The process emphasizes the value of incorporating NMS as an obligatory clinic assessment which aims to ensure that NMS are not missed in the clinic currently dominated by motor assessment and leads to sub-optimal care. Subtyping of clinically heterogeneous conditions is possible and regarded as routine clinical practice in conditions such as multiple sclerosis, motor neuron disease, and
Conflict of interest statement
The authors do not report any conflicts of interest.
Author declaration
The author declaration will be submitted offline.
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