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Nonmotor symptoms in sporadic versus familial forms of Parkinson’s disease

Yin Xia Chao1,2, Lai Mun Chew1,3, Xiao Deng1,3 & Eng-King Tan*,1,2,3 Practice points ●●

Nonmotor symptoms (NMS), which include neuropsychiatric, autonomic, sleep and sensory dysfunction, are common in both sporadic and genetic forms of Parkinson’s disease (PD).

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The genetic background may affect the pathophysiological and clinical features of NMS in PD. However, to draw a conclusion, more studies are needed. The function of PD risk molecules also need to be further investigated.

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NMS seem to be worse in GBA-PD comparing with sporadic PD while less severe in others such as Lrrk2- and Parkin-PD.

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Treatment of NMS has a major improvement on patients’ quality of life.

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Multiple and tailored treatment according to the factors involved in different genetic background of PD are required.

SUMMARY Besides the classical motor symptoms, Parkinson’s disease (PD) patients experience a wide range of nonmotor symptoms (NMS) throughout the disease course. However, due to the lack of recognition and understanding of the pathogenesis, NMS symptoms may be overlooked. Familial PD is a well-defined group that can provide a good model to investigate the mechanisms for both motor and NMS in PD. Some studies suggest that the frequency of NMS is not different between genetic and sporadic form of PD while others suggest that specific domains (such as neuropsychiatric symptoms) are more common in the genetic form. Early recognition of NMS may facilitate early diagnosis and monitoring of both sporadic and genetic PD. Parkinson’s disease (PD) is characterized by tremor, bradykinesia, muscle rigidity and gait instability. Although the motor symptoms of PD are well-defined, the subtypes and severity of nonmotor symptoms (NMS) of this disorder are less well recognized and consequently, undertreated [1,2] . This is mainly due to the lack of inclusion of NMS in the current diagnostic criteria for the clinical diagnosis of PD as well as limited knowledge of pathogenesis of NMS in PD [3–5] . Since the first mutation responsible for PD was reported in 1996 [6,7] , 28 distinct chromosomal regions among which at least six genes are confirmed to be pathogenic in PD (including SNCA, LRRK2, Parkin, PINK1, DJ-1 and ATP13A2) [8,9] . The mechanisms leading to cell degeneration are variable in the

KEYWORDS 

• clinical symptoms • genetic background • Parkinson’s disease • pathophysiology • management

National Neuroscience Institute, Singapore 308433, Singapore Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore 3 Department of Neurology, Singapore General Hospital, Singapore 169608, Singapore *Author for correspondence: National Neuroscience Institute (SGH Campus), 20 College Road, Academia Level 4, Singapore 169856; Tel.: +65 6321 4006; Fax: +65 6220 3321; [email protected] 1 2

10.2217/NMT.14.57 © 2015 Future Medicine Ltd

Neurodegener. Dis. Manag. (2015) 5(2), 147–153

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ISSN 1758-2024

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Review  Chao, Chew, Deng & Tan different subtypes of PD and this may also be true for NMS development in PD [10] . The existence of genetic forms of PD patients together with the availability of corresponding animal models provides powerful tools to understand the mechanisms for the disease development. This review is a concise summary of NMS in both genetic and idiopathic PD patients, highlighting the importance of NMS in research and clinical practice of PD together with some of the potential differences in pathophysiology and clinical features. Common NMS seen in sporadic versus genetic forms of PD NMS are increasingly recognized in both idiopathic and genetic PD. The most commonly described primary NMS of PD (summarized in Table 1) are cognitive impairments, sleep disorders, autonomic symptoms, olfactory d­ysfunction and mood disorders [11,12] . NMS can occur at all stages of PD, including prodromal symptoms and at the time of diagnosis when motor symptoms are already present. Some symptoms such as olfactory deficit, constipation, rapid eye movement (REM) sleep behavior disorder (RBD) and depression might precede the expression of motor symptoms by more than a decade [13,14] . Dementia and psychosis are more commonly seen in late stage PD. Approximately 75% of the PD patients who survive for more than 10 years will develop dementia [15] . There are also NMS that are secondary to pharmacotherapy treatment in PD. The potential clinical differences between genetic and idiopathic PD have been far less recognized, complicated by the wide spectrum of the phenotype and genotype in genetic PD. In a review of published literature involving 55 sporadic PD and 27 genetic PD, Kasten et al. did not find differences in NMS between the two groups [16] . Healy and colleagues reported that in LRRK2 G2019S PD, both motor symptoms (e.g., disease severity, rate of progression, occurrence of falls and dyskinesia) and NMS (e.g., cognition and olfaction) were milder than those of idiopathic PD in a worldwide study with 21 centers involved [17] . Asian populations have different variants of LRRK2 among which G2385R and R1628P are more common. NMS are also prevalent in Asian PD patients. Similar to the study with LRRK2 G2019S PD, studies indicate there are no differences in the NMS phenotype between G2385R, R1628P and

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wild-type LRRK2 patients but with milder NMS in the LRRK2 mutation patients [18,19] . Apart from anxiety, NMS also appear to be less prevalent in Parkin gene-related Parkinsonism  [20,21] . The data are in keeping with a different pathological disease process in Parkin gene related Parkinsonism. In contrast, olfaction differed between carriers with one and two mutations in Parkin/PINK1-associated PD. Parkin PD with two mutations showed higher UPSIT percentiles than IPD while Parkin PD with only one mutation had UPSIT percentiles closer to those of the IPD. Similar findings were reported in PINK1 carriers [22] . However, the small sample limited any firm conclusions. Compared with idiopathic PD and LRRK2-PD, GBA-PD patients had a significantly younger age at onset and higher Unified Parkinson’s Disease Rating Scale (UPDRS) scores. NMS such as cognitive decline, hallucination, sexual dysfunction and constipation were more common in GBA-PD than in LRRK2-PD and idiopathic PD patients [23] . In addition, GBA-PD patients had a worse performance for social functioning and role-emotional scores  [18,19] . The GBA mutation has also been reported to be a risk factor for cognitive impairment in PD patients [24] . GBA-positive individuals with or without PD as well as GBA-negative PD patients have a significant deficit in memory precision compared with healthy controls with the GBA-positive cases with PD the worst. This is potentially important in GBA-positive individuals as it might help to identify individuals at risk of developing PD [25] . The differences of NMS phenotype in idiopathic and genetic forms of PD (summarized in Table 2 ) perhaps reflect varying pathological mechanisms. Pathophysiological pathways of NMS in PD In the past, most would view PD as a predominant dopaminergic neuron neurodegeneration followed by dopamine deficiency in the substantia nigra [26] . However, PD is increasingly recognized as a multisystem neurodegeneration affecting multiple systems which include both inside and outside brain [27] . Research on both idiopathic and genetic forms of PD recently has helped us to understand more on the p­athophysiology of motor and NMS. The relative contribution of LB formation and synuclein pathology in dementia in PD remains under investigation but a shared pathway between

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Nonmotor symptoms in sporadic versus familial forms of Parkinson’s disease 

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Table 1. Summary of reported nonmotor symptoms idiopathic and genetic forms of Parkinson’s disease. Category

Idiopathic PD

Genetic forms of PD

 

 

SNCA

Parkin

LRRK2

PINK1

ATP13A2 GBA

DJ-1

UCHL1

Cognitive impairment REM sleep behavior disorder Orthostatic hypotension Constipation Olfactory dysfunction Pain Mood disorders Neuropsychiatric features

+ + + + + + + +

+ + + – + ? + +

+ + + + – ? + +

+ + + + + + + +

+ – ? ? + – + +

+ ? ? ? ? ? + +

? ? – – – ? + –

? ? ? ? ? ? ? ?

+ + ? + ? ? + +

+ Present; – Absent; ? Not reported/unknown; PD: Parkinson’s disease; REM: Rapid eye movement.

PD and AD is plausible [28] . Recently, abnormal α-synuclein accumulation in regions other than substantia nigra in the brain has been reported to be responsible for NMS in PD [4] . The mechanism may involve multiple subcellular failures in selected cell populations which is difficult to reconcile with a reductionistic scenario of a single causative cascade of events leading to NMS in PD [29] . The generation of new-born neurons in the adult hippocampus and in the subventricular zone/olfactory bulb system is affected by many different regulators and possibly involved in memory processing, depression and olfaction symptoms which commonly occur in PD [30] . Degeneration of the cholinergic system has been postulated to occur in PD. There is accumulating evidence that cholinergic system degeneration not only contributes to cognitive but also to other nonmotor features and motor impairments in PD, which include cognition, olfaction, mood, REM sleep behavior disorder and balance and gait functions due to selected cortical and thalamic cholinergic denervation [31–34] . Kehagia and colleagues suggest that those with dopaminergically mediated fronto-striatal executive impairments from a dementia syndrome with distinctive prodromal visuospatial deficits may benefit from cholinergic treatment [35] . Male gender has been found to be a risk factor for dribbling and nocturia, irrespective of therapy and clinical features in PD. It is possible that extra CNS are involved [36] . Adrenal synucleinopathy has also been reported to cause anxiety, constipation and loss of olfaction in a mouse model [37] . The possibility of novel etiological hypotheses such as the environmental toxicants or viruses may initiate PD pathogenesis in the GI tract or olfactory bulb has also been proposed [38] . Besides CNS, dopamine receptors have also been reported to express in other cells such as

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gastric and immune cells [39–41] . The administration of the D2 receptor antagonist domperidone relieved gastric dysmotility in 6-OHDA rats, possibly as a result of the enhanced activity of dopamine system and reduced Ach in gastric tissue [41] . In animal models, the D3R deficiency results in anxiety-like and depressive-like symptoms which are not associated with motor dysfunction [42] . Recent findings that PD genes are also associated to other disease situations highlight the importance of other system involvement in PD pathogenesis. GWAS results show that LRRK2 is also a risk factor for various disorders which include inflammatory bowel disease [43,44] . However, whether the NMS are due to shared pathology needs to be further evaluated. Severity of motor function & NMS in PD NMS have been reported by patient surveys to be more disabling than the motor symptoms and can cyclically interact and exacerbate each other when they coexist [45,46] . Due to the heterogeneity in terms of progression, the relevance of defining PD subtypes is to understand the shared pathophysiology which will be i­mportant in individual tailored therapies/trials. Some have classified PD patients based on differences in the severity of nondopaminergic features and motor complications [47] . Other PD subtypes such as rapid disease progression subtype, young-onset subtype, nontremor-dominant subtype with psychopathology and a tremordominant subtype have been proposed. Of particular interest, cognitive deterioration, depressive and apathetic symptoms and hallucinations all cluster within the nontremor-dominant motor subtype, which is characterized by hypokinesia, rigidity, postural instability and gait disorder [48] .

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Review  Chao, Chew, Deng & Tan Table 2. Correlations of nonmotor symptoms with LRRK2- and GBA- and Parkin/PINK1-PD in comparison with sporadic Parkinson’s disease.  

Parkin/PINK1

LRRK2

GBA

Cognitive impairment Restless leg symptoms Nocturia Constipation Sexual dysfunction Pain Double vision Dribbling Loss of smell Anxiety Social functioning

? – – – ? – – – – + ?

? ? – ? ? ? – ? ? ? ?

+ ? ? + + ? ? ? ? + –

+ Positively correlated – Negatively correlated? Not correlated/unknown

Olfactory dysfunction differed among the clinical subtypes of PD and impaired sense of smell were significantly higher in nontremor-dominant PD. This suggests that NMS might relate to prognosis of patients with PD [49] . Subjects with idiopathic RBD have an increased risk of incident mild cognitive impairment, dementia (usually dementia with Lewy bodies), and PD. A high frequency of RBD (REM sleep behavior disorder) was found in early-stage PD patients. Severity of clinical RBD has been reported to correlate with clinical severity (UPDRS and the Hoehn-Yahr) of PD [50] . Plomhause and colleagues found RBD was not associated with other sleep disorders or cognitive decline but suggest follow-up is needed to assess the risk for developing dementia in earlystage PD patients with RBD [51] . In a population-based cohort study, Boot and colleagues observed that pRBD confers a 2.2-fold increased risk of developing mild cognitive impairment/ PD over 4 years [52] . While the relationship between RBD and cognitive impairment has been debated, it is generally accepted that presence of comorbid sleep disorders predicted more NMS including increased sleep complaints, more depressive symptoms, lower quality of life and poorer cognition. RBD was a factor of overall increased NMS [53,54] . NMS were also reported to be more prominent in patients with pain compared with that of controls and PD patients without pain [55–57] . As have been discussed previously, the motor symptoms and nonmotor of LRRK2-associated PD were no different or even more benign than those of idiopathic PD [17–19] . Similar results were reported with Parkin-related PD [20] . In contrast, GBA-PD patients had a significantly

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higher Unified Parkinson’s Disease Rating Scale scores and more common NMS than LRRK2-PD and IPD patients [18–19,23] . The management of NMS in PD NMS present during the full course of PD and some of them (constipation, depressive status, hyposmia and anxiety) could even exist as nonspecific symptoms before the diagnosis of PD. At the advanced stage of disease, NMS make the disease severity worse. The proper management of these situations will greatly improve the quality of patients’ life. However, to date, no neuroprotective interventions able to modify PD progression are identified [58] . This may partially due to the limited recognition of the pathogenesis of these NMS [46] . As having been mentioned above, the mechanisms leading to cell degeneration are variable in the different subtypes of PD and this may also be true for NMS development in PD, treatment should, thus, be multiple and tailored according to the factors involved in different genetic background [10] . Research on genetic forms of PD no doubt will provide good models to understand the pathogenesis of both motor and NMS and potential therapies. Similar to the treatment of motor symptoms, it is generally accepted that clinicians should adopt a multidisciplinary approach to control NMS by combining pharmacological treatments with psycho/occupational therapy with PD [59] . As being proposed, the most important indication for an early initiation of treatment should aim to maintain the quality of PD patients’ life and to prolong their socioeconomic status [60] . Both pharmacotherapy and deep brain stimulation have been reported to improve the NMS and have a major impact on patients’ quality of life [61–64] .

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Nonmotor symptoms in sporadic versus familial forms of Parkinson’s disease  However, the lack of report on the NMS management in genetic forms of PD made it difficult to compare the efficiency of these therapeutic methods. Conclusion & future perspective Although the frequency of NMS may not be different between genetic and sporadic forms of PD, some specific domains (such as neuropsychiatric symptoms) are more common in the genetic form. As published data are still limited, it is difficult to draw definite conclusions. With increasing awareness, early recognition of NMS may facilitate early diagnosis and monitoring of both sporadic and genetic PD. PD is a complex disease that develops over many years, and was not diagnosed until motor symptoms indicated irreversible damage had already occurred in the brain. The function of the proteins coded by the PD risk genes has been investigated, whether alterations of these proteins lead to different entities of PD or whether they interact with each other and finally converge at a point is not clear. The current therapies are mostly symptomatic. NMS not only affect the quality of patients’ life in advanced PD, but also predict PD development at early stage. Preclinical diagnosis can help modify lifestyle and exposure to reduce risk. High-risk populations can also be References

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Nonmotor symptoms in sporadic versus familial forms of Parkinson's disease.

Besides the classical motor symptoms, Parkinson's disease (PD) patients experience a wide range of nonmotor symptoms (NMS) throughout the disease cour...
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