Research Progress On Non-motor Symptoms in The Prodromal Phase Of Parkinson's Disease

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Parkinson's disease is a common neurodegenerative disease, and early diagnosis and intervention can effectively improve the prognosis of patients with Parkinson's disease. The International Society of Movement Disorders in 2015 emphasized the importance of the prodromal stage of Parkinson's disease, in which patients have developed central or peripheral neuropathological changes, and patients may present with varying degrees of non-motor symptoms and signs, but the limited movement. Symptoms are still not enough to make a diagnosis of Parkinson's disease. Understanding the current characteristics of non-motor symptoms and possible biomarkers in the prodromal stage of Parkinson's disease will help clinicians to identify suspected Parkinson's disease patients earlier. The characteristics and possible mechanisms of motor symptoms (hyposmia, sleep disturbance, cognitive decline, neuropsychiatric symptoms, and autonomic dysfunction) and related articles are classified and described, in order to improve clinicians' understanding of non-motor symptoms in prodromal Parkinson's disease. Pay attention to and strengthen relevant clinical retrospective or prospective studies.

Background

Parkinson's disease (PD) is one of the most common slowly progressive neurodegenerative diseases in the elderly. Abnormal deposition in the body is the main pathological change [1]. The typical motor symptoms of PD(Parkinson's disease) are tremor, rigidity, bradykinesia, and postural gait abnormalities. Recent studies have shown that characteristic neurological pathological changes occur years or more than a decade before the onset of typical motor symptoms in PD(Parkinson's disease) patients. In addition to environmental and genetic factors, many non-motor symptoms are also found in the prodromal phase of PD(Parkinson's disease) patients, such as hyposmia, sleep disturbance, cognitive decline, affective disturbance, and autonomic dysfunction [2]. Early diagnosis of PD is critical for timely and effective intervention in disease progression [1]. In 2015, the International Parkinson's and Movement Disorders Association revised the diagnostic criteria for prodromal PD(Parkinson's disease), which particularly emphasized the importance of clinical non-motor symptoms as early markers of PD(Parkinson's disease) [3]. The following will mainly describe the correlation between common PD(Parkinson's disease) prodromal non-motor symptoms and PD(Parkinson's disease).

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Parkinson's disease prodromal non-motor symptoms

2.1 hyposmia

Olfactory dysfunction is one of the non-exercise manifestations of PD(Parkinson's disease). A domestic cross-sectional study report showed that 88． 43% of PD(Parkinson's disease) patients will have hyposmia [4]. The olfactory information mainly enters the primary olfactory cortex directly from the olfactory bulb through the olfactory tract, including the anterior olfactory nucleus, piriform cortex, olfactory tubercle, entorhinal area, periamyg dala cortex, and medial amygdala, and further projects to the secondary olfactory cortex, such as Hippocampus, amygdala complex [5]. At the same time, the transmission of smell involves the regulation of multiple transmitters such as dopamine, acetylcholine, norepinephrine, and serotonin. According to the classic Braak staging, some studies speculate that the prodromal olfactory dysfunction in PD(Parkinson's disease) patients is mainly due to the appearance of a synapse in the primary and secondary olfactory centers and other olfactory-related areas before the peripheral nerves, midbrain, cerebral cortex and other parts are involved. Pathological deposition of nuclear proteins [6]. At the same time, studies have shown that olfactory dysfunction may not be completely related to the pathology of olfactory structure. Neurodegeneration of the amygdala and functional changes of disease-related neurotransmitters may also lead to the emergence of olfactory dysfunction in PD(Parkinson's disease) [6,7].

Olfactory dysfunction can be divided into odor recognition disorder, olfactory discrimination disorder, and olfactory memory disorder, and related manifestations can even appear decades before PD(Parkinson's disease) is diagnosed. A prospective study reported that olfactory dysfunction was the earliest prodromal non-motor manifestation in a population with sporadic rapid eye movement sleep disorder (iRBD), dating back to 22 years before the onset of typical motor symptoms in PD(Parkinson's disease) and the diagnostic accuracy was high (0.889, 95% CI 0.825-0.954) [8]. Olfactory dysfunction is more specific in PD(Parkinson's disease) compared to other non-motor manifestations of the PD(Parkinson's disease) prodromal phase. A prospective study of 1847 50-year-old people without PD(Parkinson's disease) showed that 60% of patients diagnosed with PD(Parkinson's disease) after 5 years of follow-up had hyposmia at baseline, compared with only 29% of those without a diagnosis of PD(Parkinson's disease). There is hyposmia at the baseline level [9]. Another retrospective study showed that anosmia was 75% sensitive and 86% specific for differentiating patients >50 years of age with a diagnosis of PD(Parkinson's disease) 5 years, and anosmia in PD(Parkinson's disease) and dementia with Lewy bodies (Dementia with Lewy Bodies, DLB) seems to be a specific manifestation in the prodromal phase, and there is currently no evidence that there is anosmia in the prodromal phase of Huntington's disease, spinocerebellar ataxia or progressive supranuclear palsy [10]. At the same time, some studies have shown that there is a partial overlap between the pathophysiological changes of olfactory dysfunction in the prodromal stage of PD(Parkinson's disease) and other non-motor symptoms, such as cognitive impairment and sleep disturbance [11].

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2.2 Sleep disorders

80% of PD(Parkinson's disease) patients have sleep problems [12]. In addition to the motor symptoms and non-motor symptoms of PD(Parkinson's disease), which can cause sleep disorders in patients, some PD(Parkinson's disease) patients can also have sleep disorders as the main clinical manifestations in the prodromal phase. The common symptoms are related to PD(Parkinson's disease). Sleep disorders mainly include: insomnia, restless legs syndrome, RBD, excessive daytime sleepiness, obstructive sleep apnea and sleep rhythm disturbance [13]. Among them, fast RBD has the highest sensitivity in predicting the occurrence of PD(Parkinson's disease), and sleep rhythm disturbance, sleep apnea, and insomnia are also possible risk factors for PD(Parkinson's disease).

RBD is manifested as parasomnia related to bad dreams in the rapid eye movement (rem) phase during sleep [14]. The pathogenesis of RBD mainly focuses on the on/off of the rem sleep phase in the brainstem and medulla oblongata. The locus coeruleus, dorsolateral tegmental nucleus, pontine peduncle nucleus, raphe nucleus, medulla oblongata giant cell reticulum, and ventrolateral reticulospinal tract, which are involved in the regulation of rem sleep, can all cause RBD. The occurrence of the disease is mainly diagnosed clinically by polysomnography [15, 16]. Current studies suggest that iRBD is the early stage of α-synucleinopathy, and most iRBD patients have abnormal deposition of α-synuclein mainly located in the brainstem (sublocus coeruleus and giant cell nucleus), diencephalon, amygdala and extensive brain. Neocortex [17]. Not only that, iRBD patients also have abnormal pathological changes of α-synuclein in peripheral nerves, which can involve the paravertebral sympathetic chain, the ganglia in the epicardial adipose tissue, and the myenteric plexus [17]. With the prolongation of RBD symptoms, the probability of patients with cognitive impairment, autonomic disorder, and hyposmia also gradually increases, which may be related to the deposition site of α-synuclein [18]. Schenck et al. conducted prospective studies in 1996 and 2013, respectively, and found that the proportion of iRBD patients who developed PD(Parkinson's disease) was 38% after 4 years of follow-up, and the proportion of PD(Parkinson's disease) developed after 16 years of follow-up increased to 44.5%. 8% [19]. A recent prospective study of 174 iRBD patients with an average follow-up of 4 years showed that 65 patients developed α-synuclein-related neurodegenerative diseases, of which 24 were PD(Parkinson's disease) [18]. Although RBD, as an important clinical manifestation of PD(Parkinson's disease) prodromal stage, how to initiate or accelerate PD(Parkinson's disease) progression is still unclear, clinically, it is possible to improve the prediction of future PD(Parkinson's disease) through the case characteristics of iRBD patients, such as advanced age, male sex, daytime sleepiness, and clinical comorbidities. The patients suffer from hyposmia, color discrimination disorder, depression, autonomic dysfunction and cognitive impairment, or the imaging features of abnormal deposition of α-synuclein in the central nervous system [15, 20].

In addition to RBD, nocturnal sleep apnea is an independent risk factor for PD(Parkinson's disease). A study involving 1944 patients with sleep apnea showed that 0.0% of patients developed PD(Parkinson's disease) after 3 years compared with normal controls. Among them, men and sleep apnea patients over 60 years old are more likely to suffer from PD(Parkinson's disease) [21]. This may be related to the fact that chronic hypoxia-induced oxidative stress and inflammatory response caused by nocturnal sleep apnea accelerate the damage of substantia nigra dopamine neurons [15]. Some scholars believe that the decline of sleep quality and sleep rhythm disorder accompanying aging is also the pathogenic factor of PD(Parkinson's disease). Studies have shown that the decreased activity of slow-wave sleep in the elderly is usually associated with atrophy of the medial prefrontal gray matter, while slow-wave sleep activity reflects synaptic density or the strength of cortical synapses [15]. Another study showed that the sleep rhythm imbalance caused by aging directly affects the glutamatergic system of the central nervous system to clear abnormal proteins in the cerebrospinal fluid, including α-synuclein, β amyloid (amyloid-beta protein, Aβ), TDP-43 and phosphorylated tau protein, etc., and the excessive deposition of these proteins are related to the occurrence and development of PD(Parkinson's disease) disease [22]. Not only that, sleep rhythm disturbances or chronic insomnia caused by work or lifestyle are also risk factors for prodromal PD(Parkinson's disease). A prospective study showed that nurses who often work night shifts have an increased risk of PD(Parkinson's disease) compared with nurses who do not work night shifts. [23], chronic insomnia patients over 3 m have a higher risk of developing PD(Parkinson's disease) than normal people, which may be related to abnormal melatonin concentration caused by changes in circadian rhythm, while serum melatonin and cortisol concentrations in PD(Parkinson's disease) patients are higher than those in normal people. The occurrence of daytime sleepiness in the prodromal phase of PD(Parkinson's disease) may also be correlated with changes in circadian rhythm [15], but the specific mechanism still needs to be explored in large sample studies.

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2.3 Cognitive decline

Research shows that 32. 9% of newly diagnosed PD(Parkinson's disease) patients have mild cognitive impairment (Mild cognitive impairment, MCI) [24], and 83% of PD-MCI patients will progress to PD(Parkinson's disease) dementia in a follow-up study of up to 20 years ( Parkinson's disease dementia, PDD) [25]. Cognitive impairments related to PD(Parkinson's disease) are mainly manifested in cognitive domains such as attention, executive power, language, and visuospatial orientation [26]. Studies have shown that PD-MCI patients with more severe posterior cortex-related functional damage are compared with frontal lobe damage. Severe PDMCI patients are more likely to progress to PDD [27]. Compared with other degenerative diseases, the phenomenon of memory impairment in PD(Parkinson's disease) patients in the early stage is not prominent, and in the PDD stage, on the basis of the above-mentioned cognitive domain damage, it further develops into visual and word memory, work and learning and memory. The damage [28] ]. The cognitive impairment associated with PD(Parkinson's disease) is mainly related to the degeneration of subcortical neurons and the atrophy of corresponding nuclei or cortex caused by abnormal deposition of synuclein, which does not usually involve the hippocampus [28, 29]. The degeneration of subcortical neurons can cause abnormal secretion of a variety of neurotransmitters, among which the decreased ability of cholinergic neurons to transmit acetylcholine is prominently manifested in the nucleus basalis of Meynert (nbM), while the small Lewis Abnormal deposition of the body is also very common in nbM, and the neuronal degeneration of nbM is currently considered to be one of the important indicators to distinguish PD(Parkinson's disease) from Alzheimer's disease (AD) [30].

Characteristic cognitive domain impairment is an important clinical manifestation of the prodromal stage of PD(Parkinson's disease). A recent prospective study confirmed that the average pre-diagnosis of PD(Parkinson's disease) patients was 5. Within 6 years, the Mini-Mental State Examination (MMSE) scores had already shown a downward trend; 7. Within 1 year, patients had significantly impaired letter-Digit-Substitution Test (LDST); and Stroop test tasks were also diagnosed in PD(Parkinson's disease) patients compared to normal controls. The former average 3. 8 to 6. Differences occurred within 2 y; and memory decline occurred before PD(Parkinson's disease) diagnosis 1. 5 y is gradually manifested [31]. If the prodromal phase is accompanied by postural balance disturbances, daytime somnolence, autonomic disturbances or RBD in MCI patients, the risk of progression to PDD is significantly increased [28, 32]. In addition to the characteristic cognitive domain damage characteristics, carriers of apolipoprotein E (ApoE) ε4 allele, tau (microtubule-associated protein tau, MAPT) gene mutation, H1/H2 haplotype and glucose brain Mutations in the glucocerebrosidase (GBA) gene are all risk factors for cognitive impairment associated with prodromal PD(Parkinson's disease) [28]. In addition, with the development of medical imaging technology in patients with prodromal PD(Parkinson's disease) and patients with PD-MCI and PDD with a clear diagnosis, it also provides some enlightenment for patients with MCI in the prodromal stage. Studies have shown that functional magnetic resonance imaging (fMRI) ) and metabolic-related positron emission tomography (positron emission tomography, PET) in PD patients with cognitive impairment more prone to the bilateral frontal lobe, occipital lobe, parietal lobe and caudate nucleus atrophy and hypometabolism [33,34], Diffusion tensor imaging (DTI) showed that patients who developed PDD were more likely to have increased mean diffusivity (MD) in the central white matter [35], and cholinergic PET suggested that patients who developed PDD were more likely to develop PDD. The cholinergic activity of the frontal and temporal cortices is prone to decrease [36]. Similarly, some biomarkers in the cerebrospinal fluid can also play a role in predicting the direction of cognitive impairment in PD(Parkinson's disease), and studies have shown that low levels of Aβ42, high levels of cardiac fatty acid-binding protein, and high levels of α-synucleus. All proteins can play a role in predicting the declining trend of cognitive function associated with the prodromal period of PD(Parkinson's disease) [28].

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2.4 Neuropsychiatric symptoms

30% of PD(Parkinson's disease) patients have different degrees of anxiety and depression symptoms, of which depressive symptoms are the main manifestations [37]. In addition to secondary factors, PD-related psychiatric symptoms are mainly related to the imbalance of neurotransmitters in the central nervous system. Clinical statistics have found that the time window from the first onset of depressive symptoms to the diagnosis of PD(Parkinson's disease) can range from 1 m to 36 years, with an average prodromal period of 10 years [38]. Because of the lack of specificity in the incidence of depression in the population [39], mere depressive symptoms are of little significance for the diagnosis of prodromal PD(Parkinson's disease) [40]. Prospective studies have shown that patients with anxiety and depression symptoms in the prodromal stage of PD(Parkinson's disease), compared with the normal control group, have no obvious specificity in the prodromal stage except for a slight decrease in scores, only in the prodromal stage 2. Affective disturbances in PD(Parkinson's disease) patients only become significant after about 3 years [31]. However, cross-symptom studies also suggest that if depressed patients have a family history of PD(Parkinson's disease), hyposmia, constipation, mild dyskinesia, or hyperechoic substantia nigra, they are also potential clinical markers for progression to PD [40-43]. Recent studies have shown that patients with major depression disorder (MDD) and the above concomitant symptoms have a significantly higher tendency to develop PD(Parkinson's disease) [44].

2.5 Autonomic dysfunction

Autonomic dysfunction is considered one of the non-motor manifestations of PD(Parkinson's disease), even 10–20 years before PD(Parkinson's disease) diagnosis [45]. At the same time, autonomic dysfunction combined with other non-motor symptoms, especially RBD and hyposmia, is of great significance for the differential diagnosis of α-synucleinopathies [8]. A cross-sectional study showed that about 84% of PD(Parkinson's disease) patients had autonomic dysfunction [46], and dysfunctions of the cardiovascular system, digestive system, genitourinary system, and pupillary movement were more common. These manifestations may be caused by early neurodegenerative disease involving the dorsal motor nucleus of the vagus nerve and degeneration of alpha-synuclein in Lewy neurites and Lewy bodies of sympathetic ganglia along with the heart, periadrenal tissue, bladder, skin, colon, and sympathetic ganglia caused by deposition [10]. Cardiovascular symptoms are the most commonly discovered and studied manifestations of autonomic dysfunction, which are almost universal in PD(Parkinson's disease) patients and may precede motor symptoms, including orthostatic hypotension, hypotension, and supine hypertension. , but it is greatly affected by factors such as drugs, age, environment, blood pressure measurement time, and sample characteristics. It has been reported that resting heart rate < 70 bpm in supine position and heart rate response < 10 bpm after postural changes are closely related to PD/DLB phenotype transformation after excluding blood pressure lowering [47, 48]. Gastrointestinal symptoms mainly include constipation, salivation, and difficulty swallowing. Among them, constipation is a common complaint in all stages of idiopathic PD(Parkinson's disease), and the incidence rate can reach 70% to 80% before PD(Parkinson's disease) diagnosis, and it can appear 10 to 16 years before typical motor symptoms of PD(Parkinson's disease) appear [8, 9]. Some studies have shown that erectile dysfunction can appear in the first 10 to 16 years of the prodromal period of PD(Parkinson's disease), and it appears successively with orthostatic hypotension. Urinary tract symptoms mainly appear 7 to 9 years before the PD(Parkinson's disease) phenotype transformation, relatively late and mild symptoms [8].

Summary and Outlook

To sum up, non-motor symptoms in the prodromal phase of PD patients play a very important role in the pathophysiological development of PD(Parkinson's disease). The pathological basis of various non-motor symptoms and the corresponding neuronal degeneration, α-synaptic nucleus Abnormal protein deposition is related, but clinically, the order of prodromal non-motor symptoms in PD(Parkinson's disease) patients is still irregular. In addition, a large number of studies have confirmed that the occurrence and development of non-motor symptoms in the prodromal stage of PD(Parkinson's disease) overlap and interact with each other. The specific pathogenesis of the damage of each system in the prodromal stage of PD(Parkinson's disease) is still unclear, and a large-scale prospective study is still needed in clinical practice. Observe the characteristics of the occurrence and development of various non-motor symptoms, use serum, cerebrospinal fluid, imaging and other biomarkers for comprehensive analysis, and find a combination of biomarkers with extremely high sensitivity and specificity to facilitate the screening of specific PD(Parkinson's disease) precursors. To better predict the development trend of long-term PD(Parkinson's disease), it is conducive to early diagnosis and early intervention of clinicians, and ultimately achieves the purpose of benefiting patients.

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