According to the 2nd item of NMS Quest, PD patients were classified as PD without and with olfactory dysfunction, and the latter were then classified as olfactory dysfunction occurring before or after MS. Results are shown in Table 4.
3.2 Rapid eye movement sleep behavior disorder screening scale (RBD)
According to the 25th item of NMS screening scale, PD patients were classified as PD without RBD and PD with RBD, and the latter were further classified as RBD occurring before MS or after MS. Results were shown in Table 5.
Our study showed that the incidence of PD was slightly higher in male than in female, the ratio was close to 1:1, the average age of PD patients was about 60 years, which was consistent with the domestic and international reports. Education level of patients with PD was paralleled with that of age-matched (40–70 years old) citizens in our country, suggesting that it was not an associated factor for PD.
By investigating into the clinical manifestations, we found that the majority PD patients were initiated from unilateral side, for which, the right side was slightly more than the left. The most common type of onset was the mixed type (which meant rigidity and resting tremor often occurred simultaneously); static tremor predominant type was less but still seen common, while the akinetic-rigidity type was rare. This implied that most PD patients presented comprehensive MS in the early stage, which was consistent with the domestic and international reports.
There are still no curable anti-Parkinson medicines thus far, although our knowledge about the pathogenesis and symptom-improving drugs of PD has increased. In the past decades, several agents targeting different pathways have been explored as treatments to slow down disease progression, but promising successes are limited. In this investigation, the most widely used drug was dopamine standard tablets; the 2nd was dopamine receptor agonist, which meets PD treatment guideline. Because the average disease duration of our patients was approximately only 4 years, nearly half of patients could get satisfactory therapeutic effects when taking 3 kinds of anti-Parkinson drugs. However, there were still 25.5% of patients who did not receive standard treatment when first diagnosed PD, indicating insufficient understanding of diagnosis and treatment of PD in basic hospitals in our country.
For the assessment of MS, the average H-Y staging of our patients was 2.0, which meant bilateral limbs were involved, but the postural balance was not affected, and the average score of Unified Parkinson disease Rating Scale III was 25.8 ± 13.8.
Screening of NMS suggested that the decline of smell or taste ranked top of NMS, followed by the nervous system symptoms (such as memory loss, depression, apathy, and anxiety) and autonomic symptoms (including salivation, dysphagia, constipation, nocturia, urgency to urinate, excessive sweating, and sexual dysfunction). Sleep disorders (such as insomnia, RBD, and daytime sleepiness) were also common seen, and psychiatric symptoms (such as hallucinations, delusions) ranked the last. So more attention should be paid to the decline of memory, emotion disorders, autonomic disorders, and their treatment options in PD patients.
Braak classified the pathological degree of PD into 6 stages, according to the sequential presence of Lewy bodies. The presence of Lewy bodies at apophysis mamillaris and anterior olfactory nucleus, nuclei originis dorsalis, reticular formation, dorsal raphe nucleus and locus coerule, nuclei pontis, hypothalamic, neocortex, and limbic system may be connected to NMSs, as olfactory sensation, sleep, autonomic nerve, mental and behavioral disorders, respectively. In addition, the effects of anti-Parkinson drugs on dopamine and non-dopamine pathways may, directly or indirectly, result in NMS.
Cognitive disorder is one of the cardinal features of NMS that influences the life quality of PD patients. Detailed assessments displayed that more than half patients with PD were diagnosed mild cognitive impairment, but only 12% of patients reached the degree of dementia, which was consistent with the domestic and international reports. Executive dysfunction of PD is thought to be link to DA pathway abnormalities in the frontal striatum. Progressive degeneration and subsequential loss of cholinergic neurons in nucleus basalis of Meynert, and the reduction of hippocampal volume, results in dementia in PD patients.
Among the emotion disturbances, the most common is depression, the 2nd is anxiety. We found that the detection rate of depression using Hamilton Depression scale was higher than NMS screening scale, this might due to depression in PD was usually accompanied by numerous somatic symptoms. Thus, the Hamilton Depression scale exhibited superiority in recognizing depression because its more complicated questionnaire design paying attention to somatic symptoms. PD patients may present depression early in the Braak stage II, when Lewy bodies deposit in dorsal raphe nucleus and locus ceruleus. The probable biochemical mechanisms are related to serotonin system, also mixed with norepinephrine and dopaminergic abnormalities in limbic lobe. Anxiety is another common affective disturbance in patients with PD, the reported incidence of anxiety varies from 5% to 69%. The mechanism underlying anxiety in PD remains unclear. Currently, anxiety is believed not only an emotional response to MS but also a manifestation of PD itself. A case–control study showed that anxiety features had existed for several years prior to the emergence of MS.
According to NPI scale, the incidence of mental and behavioral disorders in PD patients was generally low except depression (41.5%), apathy (40.9%), and anxiety (39.4%), changes in sleep and eating condition were most common (such as nocturnal behavior disorders, appetite loss, and eating disorders), personality changes ranked the 2nd place (such as irritability, disinhibition), while illusion appeared far less. The incidence of apathy was also high. The pathogenesis of apathy is associated with the functional dysregulation of the facies orbitalis frontal lobe-ventral striatum circuit. A previous study observed that, PD related apathy was more prone to occur at “off” stage, suggesting it may be correlated with the DA level of brain.
Somnipathy is a common NMS for PD patients, it could be the result of the disease itself, or secondary to other NMS, the side effect of medicine, and it may emerge over different phases of PD. It was reported that the most common somnipathy was sleep disruption, referring to interfered or disrupted sleep caused by other nocturnal NMS. Previous studies showed 50% of PD patients had prolonged daytime sleepiness or unconscious drowsy. Our data showed 24.1% of PD patients experienced excessive daytime sleepiness, indicating this might be a symbolic subclinical symptom of PD.[17,18] About one third of PD patients reportedly underwent RBD. The damages of nuclei pontis, locus ceruleus, and corpora rubrum may be the pathological basis of RBD. Occurrence of RBD could provide a significant clue for screening in high risk population and early diagnosis of PD.
Almost 90% of the PD patients are concomitant with hyposmia to different degrees; it is considered a marked warning of PD before MS. We discovered a significant smell decline in PD patients, which was due to the early involvement of olfactory related brain regions by α-synuclein according to Braak staging and has a good clinical predictive value for PD.
The causes of restless leg syndrome remain elusive currently. Clinical and functional MRI studies link the possibility to DA metabolism in central nervous system. Numerous studies held that restless leg syndrome was more common in patients with PD than healthy people, but the reported prevalence in PD patients were inconsistent, ranging from 7.90% to 20.80%.[22,23] The prevalence of restless leg syndrome in PD patients in this investigation was about 21.6%, similar to the foreign and domestic reports.
Autonomic disorders include the deregulations of sweat gland, body temperature, cardiovascular, gastrointestinal, and genitourinary systems, mainly relevant to appearance of Lewy bodies in sympathetic or parasympathetic cholinergic ganglion, and sympathetic adrenergic nerve ganglion. Our data suggested that the major problems were constipation, frequent urination at night, orthostatic hypotension, polyhidrosis, and sexual dysfunction.
Fatigue is one of important NMS of PD; the affliction it brings along for patients is no less than MS does. According to the foreign study, 42% of patients with PD feel fatigue and one third of them deem fatigue as the most disabling factor. The significance of fatigue for PD patients has not been fully realized and only14% of the PD patients with fatigue is diagnosed. The mechanism of the fatigue is as yet undetermined and its risk factors are still disputed. Fatigue is a quite common complaint of PD patients, which exerts great influences on the activity and life quality of the patients. There may be other factors that contributes to the occurrence of fatigue in PD, such as depression and daytime somnolence, which needs to be further explored.
Next, we specifically focused on the cardinal NMS through further group comparison. We observed that the PD patients with olfactory dysfunction group were older, exhibited lower Argentina hyposmia rating scale scores, more severe depression, sleep and autonomic nerve disturbances, and worse quality of life. These potential connections could be explained because these mentioned NMS are all likely to occur before onset of MS, and are all pathologically involved in similar locations according to Braak staging, such as peripheral nerves, medulla oblongata, and brainstem. Besides, we discovered that the patients who already had olfactory problems before MS, displayed older age of onset, more common onset from right side, and more severe olfactory symptoms, meanwhile, the patients who developed olfactory problems after MS presented earlier age of onset, longer disease duration, and more common left-side onset, demonstrating that pathological progression is heterogeneous in individual patient. It is consistent with the typical Braak stage that the patients with right onset are more likely involved in olfactory bulb and olfactory tract at early stage have more serious smell dysfunction but develop MS much later. However, in left-onset patients, substantia nigra is involved earlier and accordingly MS appears earlier, dysosmia is milder due to later involvement of olfactory bulb and olfactory tract.
Compared to the patients without RBD, the patients accompanied by RBD showed more male, more right-side onset, older age, longer course of disease, and older age of onset, displayed higher H-Y staging, more prominent in cognitive impairment, depression, sleep disorders, autonomic nerve dysfunction, fatigue, and worse quality of life. It is suggested that right onset, older male are more susceptible to RBD. Compared to the patients who develop RBD after MS, the patients who presented RBD before MS featured older onset age, more serious anxiety, and daytime sleepiness, suggesting heterogeneity in pathological progression among individual patient. The patients who have RBD earlier often develop MS later (older age of onset), consistent with the typical Braak staging, while the patients who have RBD later often develop MS earlier (younger onset age), which means younger patients are more likely to present MS rather than NMS.
In summary, we collected the clinical information of 1119 cases of primary PD patients, conducted up to 19 scales, covering all of the MS and NMS of PD patients. The patients recruited at Beijing Tiantan hospital are from all parts of the country, therefore this sample has a good representative. It found that PD patients in our hospital present quite a number of NMS (including cognitive impairment, emotion disorder, mental and behavioral disorders, sleep disorders, autonomic dysfunctions, fatigue, and sensory abnormalities); NMS may occur before MS, PD pathology may be heterogeneous, MS always appear earlier than NMS in young patients and NMS always appear earlier than MS in older patients, and the latter is more conform to the classic Braak pathological stage.
The authors thank Run-hua Zhang for her guidance and assistance in statistics.
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Keywords:Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
clinical heterogeneity; olfactory dysfunction; rapid eye movement sleep behavior disorder