Whether individual prodromal NMS can be grouped together to further enhance their predictive power, with or without the addition of other markers – including the presence of genes that enhance the risk of developing PD – is a pressing question considered below. So too is the potential of NMS in helping differentiate between subtypes of PD.
Patients differ in the nature and severity of their NMS. In part, these differences are predictable on the basis of etiological factors. This is clear, for example, with certain glucocerebrosidase (GBA) polymorphisms and mutations that increase risk of dementia.
In a large Italian study, GBA mutation carriers were more likely than non-carriers to have severe motor disease, and also more likely to have dementia (HR=3.16).12 This was especially so for carriers of severe GBA mutations: presence of the L444P variant was associated with a more aggressive phenotype akin to that of Dementia with Lewy Bodies. In a more recent study from Scandinavia, half of the 12% of incident PD patients who had GBA variants progressed to dementia within seven years.13 This rate of progression was faster than that seen in non-carriers.
Studies of GBA mutation carriers show convincingly that PD risk genes can influence the severity of non-motor symptoms
The presence of one non-motor feature can also be predictive of the presence of others. Thus, PD patients with RBD are more likely than those without sleep disorder to have cognitive impairment.14 This led some investigators to think that PD with RBD might represent a distinct PD phenotype. Being able to identify a PD subtype (whether related to gene mutation or other factors) that conferred enhanced risk of cognitive decline would in principle be clinically useful, since cognitive training might be implemented at an early stage.15
In a prospective study of 113 people with PD (mean age 67 years) attending two Montreal movement disorder clinics, Fereshtehnejad et al used cluster analysis to group patients according to clinical features.16 Investigators were able to re-assess 76 patients after a median of 4.5 years.
Analysis suggested patients could be divided into three groups: those with mainly motor disease and slow progression; those with diffuse/malignant disease; and those with an intermediate phenotype and disease course. Patients in the diffuse/malignant group were more likely than the others to have had mild cognitive impairment, orthostatic hypotension and RBD at baseline.
This distinct phenotype was present despite similar age and disease duration, suggesting that it represented a true subgroup and not a more advanced stage of the same pathophysiological entity. Based on the evidence that this cluster of NMS indicated risk of rapid progression in both motor and non-motor symptoms, the authors recommended baseline screening of all PD patients for cognitive impairment, hypotension and sleep disorder.
The possibility that urinary symptoms might serve as a simple clinical marker of more rapid disease progression was suggested by Erro and colleagues.17 The median time from diagnosis to introduction of L-dopa was significantly shorter for patients with urinary problems (median 20 months) than those without this feature (37 months).
Sauerbier et al found a more complex picture in a study that identified seven distinct subtypes of PD characterized by the most dominant NMS present. Their analysis suggested subgroups in which the most salient symptoms were cognitive impairment, or apathy, or depression and anxiety, or sleep disturbance, or pain, or fatigue, or autonomic dysfunction.18 The authors further suggested that sleep-dominant and autonomic-dominant subtypes might be considered together as a phenotype deriving from underlying brainstem and olfactory system pathology, while the subtype dominated by cognitive problems represented a group suffering from mainly cortical involvement.
Another group of researchers cluster analyzed symptoms experienced by a large international cohort including 904 patients from the range of motor stages. The study identified four subtypes: those mildy affected in both motor and non-motor domains; those with severe NMS but mild motor symptoms; those with mild NMS but severe motor features; and those severely affected in both domains.19
This study used validated scales to assess NMS. However, a wide consensus on which scales should be used has yet to emerge. And the 2015 MDS diagnostic criteria made clear that at that stage we were not able to reliably identify subtypes of PD in a way that would be clinically useful.20
If “PD” is reached via several different pathological pathways, finding common markers of progression will be difficult
Indeed, as Marras and Chaudhuri point out, the subtyping project is likely to prove challenging since each disease-associated feature lies somewhere along a spectrum, and features are not likely to cluster in distinct, non-overlapping groups.21 The problem will be compounded if Alberto Espay et al are correct in arguing that PD is at least twenty different diseases.22 On this view, degeneration in the nigral dopamine system is common to a range of conditions, but these conditions differ in their molecular and genetic etiologies, and clinical pathology.
That said, there is considerable impetus in this direction, and much research effort is being directed towards the identification of subtype “signatures” that reflect a distinct pathophysiology relevant to prognosis and the much-needed individualization of management.23
NMS have potential to contribute – along with other clinical, imaging and biofluid markers – to the identification of people in the prodromal phase of PD who are at high risk of developing classical motor symptoms. The ability to do this offers opportunities for early intervention, and perhaps prevention – assuming that we can develop neuroprotective, disease-modifying agents that are well tolerated.
Hyposmia plus DAT deficit is highly predictive of conversion to PD within 4 years;24 RBD is highly predictive of synucleinopathy over 12 years25
The potential for such an approach is illustrated by the Parkinson Associated Risk Study (PARS) which showed that the combined presence of hyposmia and a deficit on dopamine transporter (DAT) imaging is highly predictive of conversion to PD within four years.24 At the outset of the study, olfactory screening in the community identified 203 people with hyposmia who were subsequently invited for DAT imaging. Among 21 subjects who were hyposmic and had a DAT deficit at baseline (65% or less of expected binding), 67% had been diagnosed with PD by four years. The RR compared with people with an intermediate or no baseline DAT deficit was 17.5.
The fact that idiopathic RBD is also a powerful predictor of synucleinopathies is being used to advantage in a parallel initiative.25 Data contributed by the 24 centers belonging to the international RBD Study Group were used to identify factors relevant to phenoconversion among people with sleep disorder at baseline. In this major study of 1280 subjects with RBD at the outset, the rate of conversion to PD, DLB or MSA was 74% at twelve years. Risk of phenoconversion was significantly increased by a range of motor and non-motor features (Table 2).