Introduction

Explor Neuroprot Ther

ENT

Exploration of Neuroprotective Therapy

2769-6510

Open Exploration Publishing

10.37349/ent.2023.00049

100449

Review

Rehabilitation for non-motor symptoms for patients with Parkinson’s disease from an α-synuclein perspective: a narrative review

https://orcid.org/0009-0007-8626-4558

Liu

Zhaoyang

Conceptualization Visualization Writing—original draft Writing—review & editing ¹ ² ^* Lemus

Jessica

Writing—original draft Writing—review & editing ¹

https://orcid.org/0000-0002-6075-1223

Smirnova

Irina V.

Conceptualization Visualization Writing—review & editing ¹

https://orcid.org/0000-0002-4762-3104

Liu

Wen

Conceptualization Supervision Writing—original draft Writing—review & editing ¹ ^* Benazzouz

Abdelhamid

Academic Editor Bordeaux University, France

¹Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, Kansas City, KS 66160, USA ²Department of Orthopedic Surgery and Sports Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA

^*Correspondence: Zhaoyang Liu, Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA. zliu2@kumc.edu Wen Liu, Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA. wliu@kumc.edu

2023

27 08 2023

3 4 235 257 28 02 2023 22 06 2023

This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Parkinson’s disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD.

Parkinson’s disease α-synuclein non-motor symptoms rehabilitation

National Institutes of Health

10.13039/100000002

R21HD094003

Introduction

Parkinson’s disease (PD) is an age-related neurodegenerative condition affecting about 3% of people 65 years or older [1, 2]. PD commonly presents with multiple motor and non-motor symptoms [3, 4]. It was estimated in 2020 that more than 930,000 people had a diagnosis of PD in the United States [5]. Current clinical diagnosis of PD primarily relies on the key motor symptoms [6], and dopamine replacement treatments are used to compensate for striatal dopamine deficiency in managing motor symptoms [7]. However, progress in scientific and clinical research has revealed that many brain areas and the peripheral autonomic nervous system are involved in the PD related neuropathology that are not directly involved in motor control [8]. Therefore, most patients with PD present with a variety of non-motor symptoms including neuropsychiatric symptoms, disorders of sleep, autonomic dysfunction, olfactory dysfunction, pain, fatigue, and others [9]. In fact, non-motor signs or symptoms may precede motor symptoms or diagnoses of PD by years and are very prevalent in PD patients [10, 11]. A recent hypothesis has suggested a different theory of neuropathological stages of PD, from which the Lewy body pathology is assumed to affect the lower brainstem areas and olfactory system before the nigrostriatal system [12]. This model has led to many scientific and clinical studies to examine potential risk factors of olfactory dysfunction [13] or rapid eye movement sleep behavior disorder (RBD) [6, 7]. In addition, the non-motor symptoms of PD are a major determinant of quality of life (QOL) and progress over time in people with PD.

Similarly, some past studies examined the effect of rehabilitation approaches on non-motor symptoms with outcomes related to PD pathological progress. Those studies offered promising results and new opportunities for slowing down the progress of the pathological process [14, 15]. This narrative review provides a summary of relevant basic science research findings on α-synuclein pathology in PD; a review of past studies on motor and non-motor symptoms with outcome measurements relevant to α-synuclein pathology; as well as discussion on future directions of rehabilitation research in managing motor and non-motor symptoms in PD and potential impact on α-synuclein pathology.

α-Synuclein pathology in PD α-Synuclein and its aggregation

The protein α-synuclein plays a central role in neurodegenerative diseases, particularly PD, Lewy body dementia, and Lewy body associated diseases [16–20]. Surguchov and Surguchev [21] in their review point out that α-synuclein “exists in a dynamic equilibrium between soluble monomers and a variety of oligomers”. Soluble α-synuclein can form beta sheet-like oligomeric structures, which act as precursors to the signature insoluble fibrils that aggregate forming Lewy bodies [22]. This suggests that α-synuclein is capable of naturally forming aggregates, and that an overaccumulation of α-synuclein could be the cause of pathology leading to PD [21].

Factors modulating α-synuclein aggregation

Formation of insoluble α-synuclein fibrils is influenced by many factors, beginning with the increase in intracellular concentration of soluble monomeric α-synuclein. Molecular crowding is another factor that accelerates fibril formation [23, 24]. External agitation of the α-synuclein solution has also shown a dramatic increase in fibrilization rate [25, 26]. Decreasing the temperature and/or increasing the pH of the protein solution have shown to drastically accelerate fibril formation [27, 28]. Pesticides and herbicides (rotenone, dieldrin and paraquat) have been shown to dramatically increase fibril formation rate of α-synuclein in solution in vitro [29]. Notably, epidemiological studies show an increase in risk of PD among populations exposed to pesticides and herbicides [30, 31]. There are also epidemiological explorations that suggest exposure to heavy metals is associated with a higher risk of developing PD [32–35].

α-Synuclein aggregate uptake, transport, and release

Both in vivo and in vitro studies show rapid uptake of α-synuclein fibrils into neurons [36–39]. Evidence shows that α-synuclein is internalized by neurons via endocytosis [40]. Mouse model studies have shown that microglia, astrocytes and oligodendrocytes also take up α-synuclein from the extracellular space [41, 42]; and that α-synuclein is phagocytosed by microglia, monocytes, and astrocytes [43, 44], but that phagocytic activities seem to be reduced in human monocytes from elderly donors as well as in microglia from adult mice compared to those from young mice [43].

In vivo studies have shown that injecting pre-formed α-synuclein fibrils induces aggregation of α-synuclein both at the site of injection and at distant areas of the brain [45–58]. In vitro studies suggest that axonal transport in both the anterograde and retrograde directions (Figure 1) [37, 40, 59, 60] is responsible for the in vivo observed α-synuclein aggregation in distant areas of the brain.

Figure 1

Axonal transport of α-synuclein (α-syn) fibrils. α-Syn fibrils can be internalized both in the dendrite/cell body compartment and in axons. α-Syn fibrils are actively transported along microtubules both in the anterograde and retrograde direction. It is currently not well understood if internalized α-syn fibrils are being transported directly in the cytoplasm or in transport vesicles following endocytosis. Kinesins and dynein families of proteins are the main types of molecular motors transporting cargos along microtubules in anterograde and retrograde directions. The motor and adapter proteins mediating α-syn fibril transport, both in the cytosol as well as in transport vesicles, are still unknown. Aggregation is thought to initially occur in axons, where α-syn fibrils can encounter and template the misfolding of soluble endogenous α-syn proteins that are transported along axons for delivery to synapses. “??” indicates unknown mechanisms and molecular players. The figure and the legend both borrowed from [40]. PFF: preformed fibrils

Note. Reproduced from “Internalization, axonal transport and release of fibrillar forms of alpha-synuclein,” by Bieri G, Gitler AD, Brahic M. Neurobiol Dis. 2018;109:219–25 (https://www.sciencedirect.com/science/article/pii/S0969996117300554). CC BY-NC-ND.

A few mechanisms have been proposed for how α-synuclein can transfer from cell to cell (Figure 2) [40]. Soluble α-synuclein has been known to be secreted by neurons into cerebrospinal fluid (CSF) and the central nervous system (CNS) interstitial fluid [61, 62]. One study has shown that a chaperone protein can mediate delivery of misfolded proteins to an endosome, which is then released into the extracellular space [63]. Exosomes may also play a role in α-synuclein release into the extracellular space, but the amount of α-synuclein in exosomes appear to be relatively low [64, 65], and though soluble and oligomeric α-synuclein have been found in exosomes, no α-synuclein fibrils have been detected in exosomes [40]. Another possible mechanism of α-synuclein cell-to-cell transfer includes tunneling nanotubes, open-ended channels formed by membrane protrusions connecting distant cells and allowing transfer of different types of cargo between connected cells [66]. An in vitro study has shown that α-synuclein fibrils transfer from donor to acceptor cells via lysosomal vesicles within the tunneling nanotubes [36]. One persistent question in PD is how α-synuclein initially forms aggregates inside the cells. Braak et al.’s [8] hypothesis posits that α-synuclein aggregates are transported from the peripheral nervous system (PNS) into the CNS, but it does not go into details as to how aggregates are formed in the PNS in the first place.

Figure 2

Cellular pathways mediating α-syn release. Following endocytosis, part of the internalized α-syn PFF can be secreted again from the endosomal compartment without being targeted to the lysosome for degradation. Neutralizing antibodies can block the secreted α-syn fibrils and prevent the cell-to-cell transmission. Cytosolic α-syn monomers, oligomers, and possibly fibrils can be targeted to secretory vesicles for release. Two molecular players with chaperone activity, including USP19 and DnaJ/Hsc70, can mediated the secretion of cytosolic α-syn. It is currently unknown if these two pathways can also mediate the secretion of α-syn fibrils as well. Small amounts of soluble and oligomeric α-syn are packaged into endosome-derived membrane vesicles called exosomes and can be secreted into the extracellular space. It is currently unclear if α-syn fibrils are present in exosomes. Tunneling nanotubes can also mediate the direct release and transmission of α-syn between cells, possibly in lysosome-derived transport vesicles. Neutralizing antibodies target α-syn fibrils released into the extracellular space and potentially reduce or prevent transmission to a second cell. “??” indicates unknown mechanisms and molecular players. The figure and the legend both borrowed from [40]. DnaJ/Hsc70: chaperone DnaJ/heat shock cognate 71kDa protein; USP19: ubiquitin specific peptidase 19

α-Synuclein clearance in cells

As referenced above, α-synuclein can be internalized into neuronal cells via endocytosis [40], and several studies have found specific proteases that degrade α-synuclein in the lysosome [67, 68]. An in vivo study found that an over-expression of α-synuclein in a mouse model resulted in an increased α-synuclein concentration in the lysosome [69]. Another study found that oligomeric α-synuclein is also cleared from the cell via the lysosome [70]. Yet another study found that proteasomal inhibitors applied to mouse cortical regions led to an accumulation of α-synuclein [71]. α-Synuclein aggregation itself can lead to lysosomal impairment, due to α-synuclein accumulation in lysosomes, which may result in neurons disposing of aggregates through the tunneling nanotubes [36, 72, 73]. In addition, astrocytes seem to play a role in degrading α-synuclein aggregates via lysosomal digestion [74]. Astrocytes that fail to degrade excess α-synuclein oligomers will develop mitochondrial disturbances and cellular stress. That stress will lead astrocytes to transfer their α-synuclein aggregates to nearby astrocytes as well as to the extracellular space [75]. These findings suggest the lysosome as an important factor in the intracellular regulation of α-synuclein, and that α-synuclein aggregation may be a result of the lysosomal dysfunction.

Staging of α-synuclein aggregation spread in PD—Braak’s hypothesis

Braak et al. [8] (2003) first suggested a staging process for the spread of α-synuclein aggregation. Their original stage hypothesis and later observations of related symptoms by them and other investigators is reflected in Table 1. They hypothesized that the overall progression of PD begins in two places of the PNS: the enteric nervous system (ENS) of the gut, which progresses to the CNS via the vagus nerve and the dorsal motor nucleus of the vagus (DMV) in the medulla oblongata, and the neurons of the nasal cavity (Figure 3) [76–78]. Stages 1–3 are classified as prodromal, non-motor symptom phase of PD, whereas stages 4–6 signify the symptomatic somato-motor phase of PD. In stage 1, α-synuclein is present in the olfactory bulb and the dorsal nucleus of the vagus nerve, coinciding with a loss of smell, which is considered an early sign of PD [79, 80]. In stage 2, nuclei in the lower brainstem are affected, followed by the nuclei that project to the cerebral cortex, correlating with sleep problems, some movement issues, lowered blood pressure, constipation, and possible emotional problems. In stage 3, α-synuclein aggregates reach the midbrain, including the substantia nigra and the amygdala, resulting in the thermoregulation disorder and cognitive impairment. In stage 4, α-synuclein aggregates, composing Lewy bodies, continue to affect the amygdala and the cerebral cortex, leading to bradykinesia, resting tremor, rigidity, and postural instability—the hallmark motor symptoms of PD. In stages 5 and 6, the deep layers of the cerebral cortex are affected, resulting in motion fluctuation, fatigue, visual hallucinations, dementia, and other psychiatric symptoms [81–83].

Table 1

Stages in PD pathology and α-synuclein aggregate locations

PD stages	α-Synuclein aggregate location	Signs/symptoms
Stage 1	Olfactory bulb, dorsal nucleus of vagus nerve, medulla oblongata, ENS, gut	Olfactory dysfunction, constipation, RBD
Stage 2	Lower brainstem, cerebral cortex	Lowered blood pressure, continued stage 1 symptoms
Stage 3	Midbrain, substantia nigra, amygdala	Cognitive impairment, thermoregulation disorder, continued stage 2 and previous symptoms
Stage 4	Amygdala, basal prosencephalon, mesocortex	Bradykinesia, resting tremor, rigidity, postural instability, continued stage 3 and previous symptoms
Stage 5	High order sensory association areas of neocortex, prefrontal neocortex	Motion fluctuation, fatigue, visual hallucinations, dementia, continued stage 4 and previous symptoms
Stage 6	First order sensory association areas of neocortex, premotor areas, primary sensory areas, primary motor field	Continued stage 5 and previous symptoms

Figure 3

A schematic representation of the Braak’s hypothesis of PD. Microbial products come into contact with olfactory and/or enteric neurons, which trigger the aggregation of α-syn (1 and 2). The aggregated α-syn spreads toward the CNS via the olfactory bulb and the vagus nerve (3 and 4). Eventually, the aggregated α-syn arrives at the substantia nigra (5). Genetic factors are likely to contribute to PD, but the exact mechanism remains to be elucidated (6). The figure and the legend both borrowed from [78]. APC: antigen-presenting cell

Note. Reproduced from “Exploring Braak’s hypothesis of Parkinson’s disease,” by Rietdijk CD, Perez-Pardo P, Garssen J, van Wezel RJA, Kraneveld AD. Front Neurol. 2017;8:37 (https://www.frontiersin.org/articles/10.3389/fneur.2017.00037/full). CC BY.

Support for Braak’s hypothesis

Many in vivo studies demonstrated α-synuclein movement and transport [45–58] supporting Braak’s hypothesis for α-synuclein spread from the ENS to the CNS. Braak’s hypothesis states that PD progression begins with inflammation in the gut. PD patients have been found to suffer from increased permeability of the intestinal barrier [84], leading to increased inflammation and oxidative stress, both possibly triggering α-synuclein aggregation [78]. In PD patients, Lewy body pathology has been found in the vagus nerve [85], providing further evidence in support of Braak’s hypothesis that Lewy body pathology begins in the ENS and spreads via the vagus nerve [86]. Epidemiological studies have shown lower risks for PD development in patients who have undergone vagotomies [87, 88], suggesting that the vagus nerve may play an important role in α-synuclein transport to the CNS. Steiner et al. [89] presented the concept of α-synuclein behaving like a prion based on in vivo studies of prion-like movement of α-synuclein. The prion-like hypothesis resulted from an interpretation of findings by Kordower et al. [90] and Li et al. [91] showing Lewy body pathology not only in the host neurons of PD patients, but also in grafted neurons from healthy donors. This hypothesis fits well with Braak’s hypothesis in that if α-synuclein behaves like prions, then misfolded α-synuclein will act as seeds for further misfolding of nearby α-synuclein proteins, leading to widespread pathology. While Braak’s hypothesis is based on the spread of Lewy body pathology via α-synuclein spread, it suggests that the greater the spread of the Lewy bodies the more severe disease ensues [78].

Criticism of Braak’s hypothesis

There is also evidence disputing Braak’s hypothesis [8]. Studies examining autopsies from PD patients have found that 7–11% of PD patients do not exhibit Lewy body pathology in the DMV but they do exhibit Lewy body pathology in higher regions of the brain [92, 93]. Additionally, 27–33% of PD patients do not show Lewy body pathology in the ENS [78]. The Arizona Study of Aging and Neurodegenerative Disorders conducted over 460 autopsies of patients with incidental Lewy body disease [94], believed to be a prodromal stage of PD. While Braak’s hypothesis suggests that the olfactory bulb may be one of the first-affected regions of the body in α-synucleinopathy, the Arizona study found no case where α-synuclein inclusions were present in a peripheral region but not in the brain [94]. The authors believe this result argues against Braak’s [8] contention that PD is a PNS-first disease because one would expect to see prodromal presentations of PD in the PNS in at least some autopsies. There are also studies that do not support gut-to-brain propagation of α-synuclein pathology in vivo. Specifically, injection of α-synuclein fibrils into the colon walls of mice and non-human primates yielded pathology in the ENS, but only transient pathology into upper levels of the PNS, which disappeared after a month [95]. Engelender and Isacson [96] proposed the “threshold theory”, which posits that widespread expression of α-synuclein throughout the body can simultaneously damage many different neurons, and that any dysfunction would come from the inability of reserve neurons to compensate for the damaged neurons. The researchers argue that PNS neurons are less inter-connected than CNS neurons, and therefore have fewer neurons in reserve. Damage to the PNS neuronal network will result in symptoms faster than damage to the CNS neuronal network because a greater percentage of PNS neurons is required to be functional in order to maintain the physiological function [96]. This “threshold” number of neurons required to maintain function is Engelender’s and Isacson’s [96] explanation as to why prodromal non-motor symptoms of PD occur prior to motor symptoms. Engelender and Isacson [96] also argue that somewhat contrary to Braak et al.’s [8] finding, up to 47% of PD cases do not follow an ascending progression of the disease, suggesting that the ascending pathway may not be the only possible direction of the disease progression, and that the Lewy bodies do not travel from the ENS or other peripheral structures to the brain [92, 97]. Horsager et al. [98] argue that there may be two subtypes of PD, the “brain-first” and the “body-first” subtypes, with the “body-first” subtype strongly associated with RBD. RBD is also a non-motor symptom of PD [99]. The two-subtype theory of PD progression may explain why Braak’s hypothesis of the PD progression may be representative of only a subset of PD cases. One review points to Braak’s hypothesis as representing 51–83% of all PD cases and highly representative of a young onset and long duration of the disease, but does not represent disease progression for all PD cases [78].

Inflammation and PD Inflammation and PD—CNS

Neuroinflammation is strongly linked to PD and neurodegeneration [100]. Two possible mechanisms to describe neurodegeneration exist: “cell-autonomous” and “non-cell-autonomous” [101]. Cell-autonomous neuron death refers to accumulated damage within neurons resulting in neuronal death, possibly contributed by aggregated α-synuclein and an inability of the neurons to clear the α-synuclein via lysosomes. The non-cell-autonomous mechanism refers to indirect neuronal degeneration caused by interactions between the neuron and its surrounding cells, such as glial cells. Specifically, activated microglia while releasing cytokines and starting a neuroinflammatory response triggers neurotoxicity [102]. There is ample evidence showing the cytokine production and microglial activation are elevated in PD patients [103–106]. A post-mortem study on excised brains showed higher concentrations of cytokines in the striatum and CSF of PD patients compared to people who did not have PD [107]. Activated microglia have also been detected in transgenic mouse models of PD [108–110]. An in vitro study has shown that activated microglia slows down degradation of α-synuclein and results in α-synuclein accumulation in the microglial cytoplasm [44]. A mouse study showed that both a decreased amount of microglia and an increased amount of activated microglia result in greater cell-to-cell transfer of α-synuclein between neurons, as the microglia are unable to clear α-synuclein from the extracellular space [111].

α-Synuclein behaves like an endogenous agonist for toll-like receptors (TLRs) on microglia membranes [40, 112]. TLRs are cell surface proteins on immune and non-immune cells and are a part of the innate immune response. Agonists to TLRs activate microglia, initiating inflammation, and leading to microglia releasing pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα) and interleukins. Increased amount of a specific TLR, neuronal TLR2 was found postmortem in the brains of patients with PD, and TLR2 activation leads to an increase in the neuronal cytosolic levels of α-synuclein and decreased autophagy of α-synuclein, which would promote α-synuclein accumulation in the cell [113, 114]. TLR2 mainly responds to oligomeric α-synuclein, but not to monomeric α-synuclein [115]. Therefore, the general consensus is that oligomeric α-synuclein inhibits phagocytosis, while monomeric α-synuclein promotes it [116].

In vivo studies have shown that injection of α-synuclein fibrils into the substantia nigra of mice induces recruitment of peripheral innate immune cells to the brain [117]. An in vitro study showed that pathological forms of α-synuclein, such as its fibrillar form, activate human monocytes, and their activation is greatly increased by extracellular vesicles carrying α-synuclein [118]. When mutated forms of α-synuclein that cannot form fibrils were injected into mouse brains, aggregates were still observed [119]. The mice did exhibit heightened neuroinflammation, linking inflammation with α-synuclein aggregation. Drug-induced mouse models of PD have shown that exercise may induce anti-inflammatory effects that can partially protect dopaminergic neurons from α-synuclein aggregation induced toxicity [120–125].

Inflammation and PD—gut

Inflammation in the gut may also contribute to PD risk and progression. Most PD patients exhibit non-motor symptoms such as constipation and gastrointestinal (GI) reflux [86, 126, 127]. There are many factors that could trigger PD pathology in the GI tract: disturbance of the gut microbiota [128], certain gut infections that could lead to inflammation [129–131], or inflammatory bowel disease (IBD) [132]. Increased intestinal permeability or “leaky gut” has also been shown to present in PD patients [133]. One study showed increased levels of endotoxins as well as α-synuclein in the intestinal walls of PD patients compared to healthy patients [84]. Mouse models have shown that gut inflammation can exacerbate neuroinflammation and lead to neuronal loss in the substantia nigra making it a potential risk factor for PD [134]. Furthermore, clinical studies have shown bowel inflammation evidence in PD patients [135–137]. In addition, many cohort studies showed an increased risk for PD in IBD patients [132, 138–141]. Moreover, some of those studies reported that anti-inflammatory medication for IBD lead to decreased risk of developing PD [139, 140]. Of interest, the Lewy body pathology is found in the GI tract in people with PD [142–144]. A study on pediatric patients showed a positive correlation between α-synuclein expression in the enteric neurites of the upper GI tract and inflammation severity in the intestinal wall [130]. However, more research is needed to elucidate possible molecular mechanisms of inflammation in the gut and how it may lead to PD progression.

Physical exercise and α-synuclein aggregation

Past animal studies have explored whether physical exercise could decrease α-synuclein aggregation and lead to halting PD progression since α-synuclein is considered one of the main pathogenic proteins of PD [145]. In a transgenic mouse model of PD, mice that were pre-symptomatic exercised in a running wheel over the span of 3 months and their motor and cognitive functions were assessed using the Rotarod and Morris Water Maze, respectfully. The mice that ran on the wheel had significantly better outcome measures and had significantly less α-synuclein aggregation in the brain when compared to the controls [146]. Similar findings were obtained using a chemically induced mouse model of PD with animals exercised by running on a treadmill. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected mice in the endurance exercise group showed a reduction in α-synuclein in the striatum, leading to restoration of their motor function when compared to control mice, sedentary mice, and MPTP-injected sedentary mice [147]. It was suggested that exercise prevented aggregation of α-synuclein by increasing the level of the neuroprotective protein deglycase DJ-1 known to defend cells from abnormal protein aggregation by upregulating a chaperone protein heat shock protein 70 (Hsp70) [146]. The downregulation of α-synuclein by exercise may add to neuroprotection by decreasing neuroinflammation, due to diminished pro-inflammatory cytokine levels and prevented activation of the TLR2 signaling cascade, and reducing cell death resulting in neuronal cell preservation and restored levels of tyrosine hydroxylase [147]. The precise mechanism of exercise downregulating α-synuclein is not known; three possible pathways have been suggested: inducing antioxidative capacity; enhancing apoptosis of cells containing an excess amount of α-synuclein; and increasing autophagy and ubiquitin-proteasome pathway activity to remove overabundance of α-synuclein [147]. Further clinical studies into exercise and its effects on α-synuclein aggregation may gain valuable insight into possible treatment regimens for PD [146, 147].

Non-pharmacological rehabilitation approaches for motor symptoms in PD

By definition, PD is a progressive neurodegenerative disorder that causes the death of dopaminergic neurons in the basal ganglia [148], resulting in primary motor symptoms including bradykinesia, resting tremor, rigidity of muscles and postural instability [149]. Other major motor symptoms also include various impairments in functional activities such as gait, speech, and daily living [3]. As disease progresses, motor impairments worsen as shown in the increased episodes of freezing of gait, leading to decreased independence and QOL [150, 151].

Without a known cure, treatment of PD has traditionally focused on managing motor symptoms. Pharmacological therapy or surgery can improve some of motor symptoms of PD, but the effect of dopaminergic drugs usually diminishes over time and side effects (e.g., dyskinesias or hallucinations) emerge [152]. Gait and balance impairment make a significant contribution to the decrease of QOL in people with PD [153]; however, current treatment options have limited effects on the progressive deterioration of gait and balance function [152, 154, 155].

Rehabilitation therapies, primarily using various physical exercises, are gaining increased attention in the treatment of PD [156]. Rehabilitation therapies are typically utilized to maximize functional abilities and minimize secondary complications [157, 158]. Randomized controlled trials and systematic reviews have extensively investigated the effects of conventional exercise-based therapies, including aerobic (walking/running) and strength training programs. They have shown evidence in improving cardiovascular fitness, muscle strength and endurance, and motor function in people with PD [158–164]. Specifically, a randomized clinical trial of high-intensity treadmill exercise in individuals with new-onset PD observed significantly less worsening of motor function [164]. These conventional exercises are used primarily to reverse and/or prevent deconditioning (due to lack of physical activity), muscle weakness, or various health conditions [165]. The less common forms of aerobic exercises including cycling [166] and aquatic exercise [167] have also been tried in PD patients. Based on the findings of past animal studies, conventional exercises may stimulate the brain to increase the production of growth factors that can protect dopamine-producing neurons [123, 168] and consequently, slow down the deterioration of the motor function [169–171]. The findings of these promising animal studies need to be confirmed by clinical trials in people with PD.

Motor learning through neuroplastic adaptation is considered the underlying mechanism of many exercise interventions in people with PD. The basal ganglia play an important role in motor learning. The diminished capacity of motor learning in individuals with PD may be due to damage of neurons in the basal ganglia. However, there has been sufficient evidence supporting the remaining motor learning capacity in people with PD when performing upper limb motor tasks [172], or gait and postural control tasks [163]. Recent studies have uncovered promising health benefits following less conventional forms of exercises, including therapeutic dance [173–175], Tai Chi [176], Nordic walking [177, 178], cueing [179, 180], Lee Silverman Voice Treatment (LSVT)-Big [181–183], attention strategies [180, 184] and boxing [185], to counteract the functional deterioration induced by PD. These exercises have been proven with evidence of statistically significant but small short-term benefits in patients with PD. For example, individuals with PD often step or reach at abnormally small amplitude without feedback due to their misperception. The LSVT-Big program, designed to address such deficits by teaching patients to sustain bigger movements in performing daily activities, has been shown to improve the motor function of PD patients at various stages of the disease [181–183].

Non-pharmacological rehabilitation approaches for non-motor symptoms of PD The prevalence of non-motor symptoms and the impact on QOL in patients with PD

On average eight non-motor symptoms were reported in each patient with PD and 98.6% of patients had at least one of the non-motor symptoms [186]. Depression occurs in 10–45% of patients with PD [187, 188]. Psychosis and visual hallucinations are strongly related to the necessity of placement in a nursing home; visual hallucinations have been estimated to affect 40% of patients with PD [189]. People with PD have a six times higher risk of developing dementia than the general population, and about 40% of people with PD are diagnosed with dementia [190]. Autonomic dysfunction includes excessive drooling, orthostatic hypotension, urinary dysfunction, erectile and sexual dysfunctions, constipation and GI dysfunctions [187]. Constipation is one of the most common non-motor symptoms that commonly precedes motor symptoms in people with PD [191, 192]. Disorders of sleep and wakefulness include sleep fragmentation and insomnia, RBD, restless leg syndrome, sleep disordered breathing and excessive daytime sleepiness [187, 193]. It has been speculated that nearly all patients with PD have some sleep disturbances that started early in the disease progression [193–195]. Other non-motor symptoms in people with PD include olfactory dysfunction, pain, fatigue, and voice and speech disorders [187]. Olfactory dysfunction, which has been investigated as a potential preclinical maker of PD, can affect up to 90% of people with PD [187].

The presence of non-motor symptoms significantly diminishes the QOL, and most of these symptoms are resistant to the current therapies aimed at resolving the motor symptoms of PD [196]. Non-motor symptoms can precede the motor symptoms by decades and be present in all stages of the disease, with the severity of non-motor symptoms ranging from mildly debilitating in the early stages to severely debilitating in the later stages [197]. Since non-motor symptoms are correlated to aging, and life expectancy has steadily been increasing, the management of these non-motor symptoms have become increasingly important [187].

Physical exercise interventions

A meta-analysis of by Fang et al. [198] (2018) analyzed eight past studies and found a statistically significant reduction in risk of PD when comparing those who partook in physical activity very frequently versus those who exercised little to none. Furthermore, the risk of PD decreased by 9% with each increase of 10 metabolic equivalents (METs)/h per week; the risk of PD decreased by 17% for men specifically with each increase of 10 METs/h per week in moderate to vigorous physical activity [199]. The results of a cohort study of male veterans exhibited a significant negative relationship between high levels of fitness (greater than 12 METs) and incidence of PD [200]. This cohort study used the maximal exercise testing to objectively measure fitness level, and the onset of PD was taken from the Veterans Affairs computerized program. A possible mechanism behind a reduction in risk of PD caused by physical activity is based on the assumption that long-term, low-to-moderate intensity exercise negatively regulates the inflammatory response [201]. Exercise stimulates skeletal muscle myocytes to release multiple myokines with anti-inflammatory effects including the inhibition of microglial activation. Additional effects of exercise include synthesis and release of neuroprotective heat-shock proteins; increase in leptin sensitivity; upregulation of antioxidants; enhancement of the glymphatic system; downregulation of expression of proinflammatory cytokines such as inteleukin-1β and TNFα; downregulation of the TLR signaling pathway; and changes in the microbiome [201]. These individual pathways and mechanisms are important areas for future research.

Another study examined the effects of a balance training program and found that moderate-intensity balance training could reduce inflammation and increase the level of anti-inflammatory cytokines to promote neuroprotection against inflammation [202]. After 12 weeks of moderate-intensity balance training, the balance-trained PD patients significantly improved their balance control ability, increased the plasma concentration of interleukin 10 and decreased TNFα concentration when compared to a PD control group. Evidence suggests that these changes can lead to improved brain plasticity and reduced neuronal injury [201–203].

Mind-body practice interventions

Some investigators have studied the effect of complementary therapies, especially mind-body practices, in terms of outcomes in cognition, depression and QOL in people with PD. The mind-body practice exercises involve the specifically designed gentle body movements in combination with deep breathing and meditation, including Tai Chi, Qigong, and Yoga. The practice of mind-body exercises has shown to be safe and cost-effective for chronic health conditions [204, 205].

Tai Chi and Qigong have shown the potential in improving cognition, depression, and QOL in people with PD. Tai Chi and Qigong are defined as mind-body exercise interventions with a foundation based in Chinese medicine, martial arts and the Asian lifestyle; both have been practiced for thousands of years for maintaining health and preventing illness [14, 206]. These mind-body interventions are used to train individuals in their abilities to improve body awareness, focus mental attention and enhance planned thought processes [206, 207]. The studies show that QOL scores significantly improved with Tai Chi or Qigong exercise. One review reported that Tai Chi and Qigong improved QOL in patients with PD by 38%, which is comparable to the 4–38% increase in QOL produced by deep brain stimulation [206]. There were slight improvements with cognition (specifically, attention and working memory), warranting further investigation [207, 208]. Significant improvements were reported on the depression scales, i.e., Beck Depression Inventory, Geriatric Depression Scale, and Montgomery-Asperg Depression Rating Scale [207]. Improvements in depression are hypothesized to be due to moderate improvements in cardiovascular system function (lowering heart rate and deepening breaths), improvements in focusing thought processes that lead to decreased rumination and catastrophizing, and secondary improvements in self-confidence and self-efficacy [206].

Qigong has been shown to decrease the levels of pro-inflammatory cytokines, which are closely related to the pathogenesis of PD. Previous studies indicate that TNFα contributes to sleep-wake regulation, and feelings of sleepiness and fatigue [14, 209, 210]. A pilot study assessed TNFα levels after a six-week Qigong intervention [14]. After the intervention, plasma TNFα levels were significantly reduced, and the changes in the TNFα level were associated with the changes in scores of the PD Sleep Scale 2. More research in this direction is needed. There were high levels of adherence and no serious adverse events that occurred in any of the included reviews and studies [14, 206, 207] suggesting that Tai Chi and Qigong are likely safe interventions for people with PD.

Yoga is an ancient Indian mind-body approach combining specific posture, regulated breathing and meditation to improve health and wellbeing [211]. It has been widely used as a complementary therapy for individuals with neurological disorders. A recent systematic review reported that Yoga practices were safe and well-accepted in patients with PD; and that these interventions might benefits patients in ameliorating both motor and non-motor symptoms [212, 213]. Yoga is a cost-effective intervention to reduce anxiety and depression [211, 214, 215]. Studies of Yoga intervention in PD have also reported improvement in executive function and working memory compared to an intensive stretching exercise or passive control [216–218]. A few studies have also indicated that Yoga may reduce stress and inflammation, enhance neuroplastic processes and increase antioxidant levels [219, 220]. A recent study reported an implementation of tele-Yoga as safe, feasible, and enjoyable intervention in people with PD, with preliminary results of improvements in some of the clinically relevant outcome measures [221]. However, the study by Cheung et al. [15] showed improvement in motor function and QOL after a 12-week Yoga training protocol but did not find significant differences in changes of either non-motor symptoms or markers of oxidative stress in people with PD. More studies are needed on non-motor symptoms and biomarkers in PD population.

Limitations of past non-pharmacological rehabilitation studies

In this review, we focus on non-pharmaceutical approaches, such as physical exercise or mind-body movement practices, which have shown promising results in managing non-motor symptoms of PD. However, there were limitations in the past studies. A major limitation is the small sample sizes inherent in those studies and thus, an increased risk of biased results. In addition, in the home or community settings, adherence to physical exercise or mind-body practice programs is often low. Nevertheless, non-pharmaceutical treatments are generally safe for people with PD, and they offer benefits in at least some aspects of general health such as cardiovascular fitness. Future clinical trials with large sample sizes may determine the effect of non-pharmaceutical approaches on non-motor symptoms in people with PD. Furthermore, there has been a lack of mind-body practice trials that examined biomarker changes related to α-synuclein aggregates or neuroinflammation in PD patients, except a few pilot studies [14, 15]. Future research is needed to focus on this area to fully understand the role and underlying biological pathways of mind-body practice intervention on the non-motor symptoms of PD.

Conclusions

This review addressed both the importance of α-synuclein to the pathology of PD, as well as the importance of a renewed focus of rehabilitation therapy on the non-motor symptoms of PD. In addition, this review presented a compelling hypothesis of PD pathogenesis originating in the PNS and spreading to the CNS, as well as research supporting and rebutting that hypothesis. Finally, this review further suggested the connections between inflammation and PD progression, as well as the potential of various rehabilitation therapies, especially the mind-body practices, on inflammation and α-synuclein pathology. If PD pathogenesis is predicated in the PNS as suggested by some, the prodromal non-motor symptoms of PD would take on a greater significance. Any therapies aimed at alleviating these prodromal symptoms may yield a preventative effect on PD pathogenesis, especially if any therapies could be seen to affect α-synuclein aggregation or transport. Future studies are needed to examine the non-motor prodromal symptoms of PD and the connection between inflammation and PD, both from a therapeutic and a biochemical standpoint.

Abbreviations

CNS

central nervous system

ENS

enteric nervous system

gastrointestinal

IBD

inflammatory bowel disease

METs

metabolic equivalents

Parkinson’s disease

PNS

peripheral nervous system

QOL

quality of life

RBD

rapid eye movement sleep behavior disorder

TLRs

toll-like receptors

TNFα

tumor necrosis factor α

Declarations Author contributions

ZL: Conceptualization, Visualization, Writing—original draft, Writing—review & editing. JL: Writing—original draft, Writing—review & editing. IVS: Conceptualization, Visualization, Writing—review & editing. WL: Conceptualization, Supervision, Writing—original draft, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was partially supported by the National Institutes of Health research grant [R21HD094003] (PI - WL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Olanow

Stern

Sethi

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Neurology 2009 72 S1 136

10.1212/WNL.0b013e3181a1d44c

19470958

Strickland

Bertoni

Parkinson’s prevalence estimated by a state registry

Mov Disord 2004 19 318 23

10.1002/mds.10619

15022187

Jankovic

Parkinson’s disease: clinical features and diagnosis

J Neurol Neurosurg Psychiatry 2008 79 368 76

10.1136/jnnp.2007.131045

18344392

Morris

Iansek

Galna

Gait festination and freezing in Parkinson’s disease: pathogenesis and rehabilitation

Mov Disord 2008 23 S451 60

10.1002/mds.21974

18668618

Marras

Beck

Bower

Roberts

Ritz

Ross

et al. Parkinson’s Foundation P4 Group

Prevalence of Parkinson’s disease across North America

NPJ Parkinsons Dis 2018 4

10.1038/s41531-018-0058-0

30003140

PMC6039505

Reichmann

Clinical criteria for the diagnosis of Parkinson’s disease

Neurodegener Dis 2010 7 284 90

10.1159/000314478

20616563

Emamzadeh

Surguchov

Parkinson’s disease: biomarkers, treatment, and risk factors

Front Neurosci 2018 12

612

10.3389/fnins.2018.00612

30214392

PMC6125353

Braak

Del

Tredici K

Rüb

de Vos

RAI

Jansen

Steur ENH

Braak

Staging of brain pathology related to sporadic Parkinson’s disease

Neurobiol Aging 2003 24 197 211

10.1016/s0197-4580(02)00065-9

12498954

Munhoz

Moro

Silveira-Moriyama

Teive

Non-motor signs in Parkinson’s disease: a review

Arq Neuropsiquiatr 2015 73 454 62

10.1590/0004-282X20150029

26017214

Schapira

AHV

Chaudhuri

Jenner

Non-motor features of Parkinson disease

Nat Rev Neurosci 2017 18 435 50 Erratum in: Nat Rev Neurosci. 2017;18:509.

10.1038/nrn.2017.62

28592904

Durcan

Wiblin

Lawson

Khoo

Yarnall

Duncan

et al. ICICLE-PD Study Group

Prevalence and duration of non-motor symptoms in prodromal Parkinson’s disease

Eur J Neurol 2019 26 979 85

10.1111/ene.13919

30706593

PMC6563450

Braak

Ghebremedhin

Rüb

Bratzke

Del

Tredici K

Stages in the development of Parkinson’s disease-related pathology

Cell Tissue Res 2004 318 121 34

10.1007/s00441-004-0956-9

15338272

Ponsen

Stoffers

Booij

van Eck-Smit

BLF

Wolters

ECh

Berendse

Idiopathic hyposmia as a preclinical sign of Parkinson’s disease

Ann Neurol 2004 56 173 81

10.1002/ana.20160

15293269

Moon

Schmidt

Smirnova

Colgrove

Liu

Qigong exercise may reduce serum TNF-α levels and improve sleep in people with Parkinson’s disease: a pilot study

Medicines (Basel) 2017 4

10.3390/medicines4020023

28930237

PMC5590059

Cheung

Bhimani

Wyman

Konczak

Zhang

Mishra

et al.

Effects of yoga on oxidative stress, motor function, and non-motor symptoms in Parkinson’s disease: a pilot randomized controlled trial

Pilot Feasibility Stud 2018 4

162

10.1186/s40814-018-0355-8

30377537

PMC6198358

Arawaka

Saito

Murayama

Mori

Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for α-synuclein

Neurology 1998 51 887 9

10.1212/wnl.51.3.887

9748051

Gai

Power

JHT

Blumbergs

Blessing

Multiple-system atrophy: a new α-synuclein disease?

Lancet 1998 352 547 8

10.1016/s0140-6736(05)79256-4

9716068

Spillantini

Schmidt

Lee

VMY

Trojanowski

Jakes

Goedert

α-Synuclein in Lewy bodies

Nature 1997 388 839 40

10.1038/42166

9278044

Wakabayashi

Matsumoto

Takayama

Yoshimoto

Takahashi

NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson’s disease

Neurosci Lett 1997 239 45 8

10.1016/s0304-3940(97)00891-4

9547168

Woerman

Watts

Aoyagi

Giles

Middleton

Prusiner

α-Synuclein: multiple system atrophy prions

Cold Spring Harb Perspect Med 2018 8

a024588

10.1101/cshperspect.a024588

28213437

PMC5561534

Surguchov

Surguchev

Synucleins: new data on misfolding, aggregation and role in diseases

Biomedicines 2022 10

3241

10.3390/biomedicines10123241

36551997

PMC9775291

Burré

Sharma

Südhof

Definition of a molecular pathway mediating α-synuclein neurotoxicity

J Neurosci 2015 35 5221 32

10.1523/JNEUROSCI.4650-14.2015

25834048

PMC4380997

Munishkina

Cooper

Uversky

Fink

The effect of macromolecular crowding on protein aggregation and amyloid fibril formation

J Mol Recognit 2004 17 456 64

10.1002/jmr.699

15362105

Shtilerman

Ding

Lansbury

PT Jr

Molecular crowding accelerates fibrillization of α-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson’s disease?

Biochemistry 2002 41 3855 60

10.1021/bi0120906

11900526

Conway

Harper

Lansbury

Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease

Nat Med 1998 4 1318 20

10.1038/3311

9809558

Fink

Protein aggregation: folding aggregates, inclusion bodies and amyloid

Fold Des 1998 3 R9 23

10.1016/S1359-0278(98)00002-9

9502314

Baldwin

Temperature dependence of the hydrophobic interaction in protein folding

Proc Natl Acad Sci U S A 1986 83 8069 72

10.1073/pnas.83.21.8069

3464944

PMC386868

Uversky

Fink

Evidence for a partially folded intermediate in α-synuclein fibril formation

J Biol Chem 2001 276 10737 44

10.1074/jbc.M010907200

11152691

Uversky

Fink

Pesticides directly accelerate the rate of α-synuclein fibril formation: a possible factor in Parkinson’s disease

FEBS Lett 2001 500 105 8

10.1016/s0014-5793(01)02597-2

11445065

Betarbet

Sherer

MacKenzie

Garcia-Osuna

Panov

Greenamyre

Chronic systemic pesticide exposure reproduces features of Parkinson’s disease

Nat Neurosci 2000 3 1301 6

10.1038/81834

11100151

Giasson

Lee

A new link between pesticides and Parkinson’s disease

Nat Neurosci 2000 3 1227 8

10.1038/81737

11100135

Gorell

Johnson

Rybicki

Peterson

Kortsha

Brown

et al.

Occupational exposures to metals as risk factors for Parkinson’s disease

Neurology 1997 48 650 8

10.1212/wnl.48.3.650

9065542

Gorell

Johnson

Rybicki

Peterson

Kortsha

Brown

et al.

Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease

Neurotoxicology 1999 20 239 47

10385887

Rybicki

Johnson

Uman

Gorell

Parkinson’s disease mortality and the industrial use of heavy metals in Michigan

Mov Disord 1993 8 87 92

10.1002/mds.870080116

8419812

Zayed

Ducic

Campanella

Panisset

André

Masson

et al.

Environmental factors in the etiology of Parkinson’s disease

Can J Neurol Sci 1990 17 286 91. French

2207882

Abounit

Bousset

Loria

Zhu

de Chaumont

Pieri

et al.

Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes

EMBO J 2016 35 2120 38

10.15252/embj.201593411

27550960

PMC5048354

Brahic

Bousset

Bieri

Melki

Gitler

Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1

Acta Neuropathol 2016 131 539 48

10.1007/s00401-016-1538-0

26820848

PMC4789229

Rey

Petit

Bousset

Melki

Brundin

Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice

Acta Neuropathol 2013 126 555 73

10.1007/s00401-013-1160-3

23925565

PMC3789892

Volpicelli-Daley

Luk

Patel

Tanik

Riddle

Stieber

et al.

Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death

Neuron 2011 72 57 71

10.1016/j.neuron.2011.08.033

21982369

PMC3204802

Bieri

Gitler

Brahic

Internalization, axonal transport and release of fibrillar forms of alpha-synuclein

Neurobiol Dis 2018 109 219 25

10.1016/j.nbd.2017.03.007

28323023

PMC5600643

Reyes

Rey

Bousset

Melki

Brundin

Angot

Alpha-synuclein transfers from neurons to oligodendrocytes

Glia 2014 62 387 98

10.1002/glia.22611

24382629

Thakur

Breger

Lundblad

Wan

Mattsson

Luk

et al.

Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain

Proc Natl Acad Sci U S A 2017 114 E8284 93

10.1073/pnas.1710442114

28900002

PMC5625925

Bliederhaeuser

Grozdanov

Speidel

Zondler

Ruf

Bayer

et al.

Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes

Acta Neuropathol 2016 131 379 91

10.1007/s00401-015-1504-2

26576561

Lee

Suk

Bae

Lee

Clearance and deposition of extracellular α-synuclein aggregates in microglia

Biochem Biophys Res Commun 2008 372 423 8

10.1016/j.bbrc.2008.05.045

18492487

Abdelmotilib

Maltbie

Delic

Liu

Fraser

et al.

α-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic neurodegeneration

Neurobiol Dis 2017 105 84 98 Erratum in: Neurobiol Dis. 2021;159:105506.

10.1016/j.nbd.2017.05.014

28576704

PMC5701756

Desplats

Lee

Bae

Patrick

Rockenstein

Crews

et al.

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

Proc Natl Acad Sci U S A 2009 106 13010 5 Erratum in: Proc Natl Acad Sci U S A. 2009;106:17606.

10.1073/pnas.0903691106

19651612

PMC2722313

Helwig

Klinkenberg

Rusconi

Musgrove

Majbour

El-Agnaf

OMA

et al.

Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice

Brain 2016 139 856 70

10.1093/brain/awv376

26719384

Holmqvist

Chutna

Bousset

Aldrin-Kirk

Björklund

et al.

Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats

Acta Neuropathol 2014 128 805 20

10.1007/s00401-014-1343-6

25296989

Koller

Brooks

MMT

Golde

Giasson

Chakrabarty

Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice

Mol Neurodegener 2017 12

10.1186/s13024-016-0142-z

28049533

PMC5210310

Kordower

Dodiya

Kordower

Terpstra

Paumier

Madhavan

et al.

Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat

Neurobiol Dis 2011 43 552 7

10.1016/j.nbd.2011.05.001

21600984

PMC3430516

Luk

Kehm

Carroll

Zhang

O’Brien

Trojanowski

et al.

Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice

Science 2012 338 949 53

10.1126/science.1227157

23161999

PMC3552321

Luk

Kehm

Zhang

O’Brien

Trojanowski

Lee

VMY

Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice

J Exp Med 2012 209 975 86

10.1084/jem.20112457

22508839

PMC3348112

Mougenot

Nicot

Bencsik

Morignat

Verchère

Lakhdar

et al.

Prion-like acceleration of a synucleinopathy in a transgenic mouse model

Neurobiol Aging 2012 33 2225 8

10.1016/j.neurobiolaging.2011.06.022

21813214

Paumier

Luk

Manfredsson

Kanaan

Lipton

Collier

et al.

Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration

Neurobiol Dis 2015 82 185 99

10.1016/j.nbd.2015.06.003

26093169

PMC4640952

Peelaerts

Bousset

Van

der Perren A

Moskalyuk

Pulizzi

Giugliano

et al.

α-Synuclein strains cause distinct synucleinopathies after local and systemic administration

Nature 2015 522 340 4

10.1038/nature14547

26061766

Recasens

Dehay

Bové

Carballo-Carbajal

Dovero

Pérez-Villalba

et al.

Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys

Ann Neurol 2014 75 351 62

10.1002/ana.24066

24243558

Ulusoy

Phillips

Helwig

Klinkenberg

Powley

Monte DA

Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections

Acta Neuropathol 2017 133 381 93

10.1007/s00401-016-1661-y

28012041

PMC5326583

Ulusoy

Rusconi

Pérez-Revuelta

Musgrove

Helwig

Winzen-Reichert

et al.

Caudo-rostral brain spreading of α-synuclein through vagal connections

EMBO Mol Med 2013 5 1119 27

10.1002/emmm.201302475

23703938

PMC3721477

Danzer

Ruf

Putcha

Joyner

Hashimoto

Glabe

et al.

Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity

FASEB J 2011 25 326 36

10.1096/fj.10-164624

20876215

PMC3005424

Freundt

Maynard

Clancy

Roy

Bousset

Sourigues

et al.

Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport

Ann Neurol 2012 72 517 24

10.1002/ana.23747

23109146

PMC3490229

El-Agnaf

OMA

Salem

Paleologou

Cooper

Fullwood

Gibson

et al.

α-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma

FASEB J 2003 17 1 16

10.1096/fj.03-0098fje

14519670

Emmanouilidou

Elenis

Papasilekas

Stranjalis

Gerozissis

Ioannou

et al.

Assessment of α-synuclein secretion in mouse and human brain parenchyma

PLoS One 2011 6

e22225

10.1371/journal.pone.0022225

21779395

PMC3136497

Lee

Takahama

Zhang

Tomarev

Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells

Nat Cell Biol 2016 18 765 76

10.1038/ncb3372

27295555

Alvarez-Erviti

Seow

Schapira

Gardiner

Sargent

Wood

MJA

et al.

Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission

Neurobiol Dis 2011 42 360 7

10.1016/j.nbd.2011.01.029

21303699

PMC3107939

Emmanouilidou

Melachroinou

Roumeliotis

Garbis

Ntzouni

Margaritis

et al.

Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival

J Neurosci 2010 30 6838 51

10.1523/JNEUROSCI.5699-09.2010

20484626

PMC3842464

Rustom

Saffrich

Markovic

Walther

Gerdes

Nanotubular highways for intercellular organelle transport

Science 2004 303 1007 10

10.1126/science.1093133

14963329

McGlinchey

Lee

Cysteine cathepsins are essential in lysosomal degradation of α-synuclein

Proc Natl Acad Sci U S A 2015 112 9322 7

10.1073/pnas.1500937112

26170293

PMC4522768

Sevlever

Jiang

Yen

SHC

Cathepsin D is the main lysosomal enzyme involved in the degradation of α-synuclein and generation of its carboxy-terminally truncated species

Biochemistry 2008 47 9678 87

10.1021/bi800699v

18702517

PMC2630205

Mak

McCormack

Manning-Bog

Cuervo

Monte DA

Lysosomal degradation of α-synuclein in vivo

J Biol Chem 2010 285 13621 9

10.1074/jbc.M109.074617

20200163

PMC2859524

Lee

Khoshaghideh

Patel

Lee

Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway

J Neurosci 2004 24 1888 96

10.1523/JNEUROSCI.3809-03.2004

14985429

PMC6730405

Ebrahimi-Fakhari

Cantuti-Castelvetri

Fan

Rockenstein

Masliah

Hyman

et al.

Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein

J Neurosci 2011 31 14508 20

10.1523/JNEUROSCI.1560-11.2011

21994367

PMC3587176

Karpowicz

RJ Jr

Trojanowski

Lee

VMY

Transmission of α-synuclein seeds in neurodegenerative disease: recent developments

Lab Invest 2019 99 971 81

10.1038/s41374-019-0195-z

30760864

PMC6609465

Victoria

Zurzolo

The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases

J Cell Biol 2017 216 2633 44

10.1083/jcb.201701047

28724527

PMC5584166

Loria

Vargas

Bousset

Syan

Salles

Melki

et al.

α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading

Acta Neuropathol 2017 134 789 808

10.1007/s00401-017-1746-2

28725967

Rostami

Holmqvist

Lindström

Sigvardson

Westermark

Ingelsson

et al.

Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes

J Neurosci 2017 37 11835 53

10.1523/JNEUROSCI.0983-17.2017

29089438

PMC5719970

Hawkes

Del

Tredici K

Braak

Parkinson’s disease: a dual-hit hypothesis

Neuropathol Appl Neurobiol 2007 33 599 614

10.1111/j.1365-2990.2007.00874.x

17961138

PMC7194308

Hawkes

Del

Tredici K

Braak

Parkinson’s disease: the dual hit theory revisited

Ann N Y Acad Sci 2009 1170 615 22

10.1111/j.1749-6632.2009.04365.x

19686202

Rietdijk

Perez-Pardo

Garssen

van Wezel

RJA

Kraneveld

Exploring Braak’s hypothesis of Parkinson’s disease

Front Neurol 2017 8

10.3389/fneur.2017.00037

28243222

PMC5304413

Chase

Markopoulou

Olfactory dysfunction in familial and sporadic Parkinson’s disease

Front Neurol 2020 11

447

10.3389/fneur.2020.00447

32547477

PMC7273509

Doty

Olfaction in Parkinson’s disease and related disorders

Neurobiol Dis 2012 46 527 52

10.1016/j.nbd.2011.10.026

22192366

PMC3429117

Braak

Del

Tredici K

Potential pathways of abnormal tau and α-synuclein dissemination in sporadic Alzheimer’s and Parkinson’s diseases

Cold Spring Harb Perspect Biol 2016 8

a023630

10.1101/cshperspect.a023630

27580631

PMC5088528

Dunning

CJR

Reyes

Steiner

Brundin

Can Parkinson’s disease pathology be propagated from one neuron to another?

Prog Neurobiol 2012 97 205 19

10.1016/j.pneurobio.2011.11.003

22115849

Goedert

Clavaguera

Tolnay

The propagation of prion-like protein inclusions in neurodegenerative diseases

Trends Neurosci 2010 33 317 25

10.1016/j.tins.2010.04.003

20493564

Forsyth

Shannon

Kordower

Voigt

Shaikh

Jaglin

et al.

Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease

PLoS One 2011 6

e28032

10.1371/journal.pone.0028032

22145021

PMC3228722

Del

Tredici K

Hawkes

Ghebremedhin

Braak

Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease

Acta Neuropathol 2010 119 703 13

10.1007/s00401-010-0665-2

20229352

Braak

de Vos

RAI

Bohl

Del

Tredici K

Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology

Neurosci Lett 2006 396 67 72

10.1016/j.neulet.2005.11.012

16330147

Liu

Fang

Pedersen

Tillander

Ludvigsson

Ekbom

et al.

Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study

Neurology 2017 88 1996 2002

10.1212/WNL.0000000000003961

28446653

PMC5440238

Svensson

Horváth-Puhó

Thomsen

Djurhuus

Pedersen

Borghammer

et al.

Vagotomy and subsequent risk of Parkinson’s disease

Ann Neurol 2015 78 522 9

10.1002/ana.24448

26031848

Steiner

Quansah

Brundin

The concept of alpha-synuclein as a prion-like protein: ten years after

Cell Tissue Res 2018 373 161 73

10.1007/s00441-018-2814-1

29480459

PMC6541204

Kordower

Chu

Hauser

Freeman

Olanow

Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease

Nat Med 2008 14 504 6

10.1038/nm1747

18391962

Englund

Holton

Soulet

Hagell

Lees

et al.

Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation

Nat Med 2008 14 501 3

10.1038/nm1746

18391963

Kalaitzakis

Graeber

Gentleman

Pearce

The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of α-synuclein staging

Neuropathol Appl Neurobiol 2008 34 284 95

10.1111/j.1365-2990.2007.00923.x

18053026

Kalaitzakis

Graeber

Gentleman

Pearce

RKB

Evidence against a reliable staging system of α-synuclein pathology in Parkinson’s disease

Neuropathol Appl Neurobiol 2009 35 125 6

10.1111/j.1365-2990.2008.00998.x

19187066

Adler

Beach

Neuropathological basis of nonmotor manifestations of Parkinson’s disease

Mov Disord 2016 31 1114 9

10.1002/mds.26605

27030013

PMC4981515

Manfredsson

Luk

Benskey

Gezer

Garcia

Kuhn

et al.

Induction of alpha-synuclein pathology in the enteric nervous system of the rat and non-human primate results in gastrointestinal dysmotility and transient CNS pathology

Neurobiol Dis 2018 112 106 18

10.1016/j.nbd.2018.01.008

29341898

PMC5890443

Engelender

Isacson

The threshold theory for Parkinson’s disease

Trends Neurosci 2017 40 4 14

10.1016/j.tins.2016.10.008

27894611

Jellinger

A critical reappraisal of current staging of Lewy-related pathology in human brain

Acta Neuropathol 2008 116 1 16

10.1007/s00401-008-0406-y

18592254

Horsager

Andersen

Knudsen

Skjærbæk

Fedorova

Okkels

et al.

Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study

Brain 2020 143 3077 88

10.1093/brain/awaa238

32830221

Xie

Shen

Zhou

Non-motor symptoms are associated with REM sleep behavior disorder in Parkinson’s disease: a systematic review and meta-analysis

Neurol Sci 2021 42 47 60

10.1007/s10072-020-04769-9

33025325

100

Tansey

Goldberg

Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention

Neurobiol Dis 2010 37 510 8

10.1016/j.nbd.2009.11.004

19913097

PMC2823829

101

Gelders

Baekelandt

Van

der Perren A

Linking neuroinflammation and neurodegeneration in Parkinson’s disease

J Immunol Res 2018 2018

4784268

10.1155/2018/4784268

29850629

PMC5926497

102

Block

Zecca

Hong

Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

Nat Rev Neurosci 2007 8 57 69

10.1038/nrn2038

17180163

103

Caggiu

Paulus

Arru

Piredda

Sechi

Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson’s disease, a triggering role in the disease?

J Neuroimmunol 2016 291 110 4

10.1016/j.jneuroim.2016.01.007

26857504

104

McGeer

Itagaki

McGeer

Expression of the histocompatibility glycoprotein HLA-DR in neurological disease

Acta Neuropathol 1988 76 550 7

10.1007/BF00689592

2974227

105

Mogi

Harada

Kondo

Riederer

Inagaki

Minami

et al.

Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients

Neurosci Lett 1994 180 147 50

10.1016/0304-3940(94)90508-8

7700568

106

Müller

Blum-Degen

Przuntek

Kuhn

Short communication Interleukin-6 levels in cerebrospinal fluid inversely correlate to severity of Parkinson’s disease

Acta Neurol Scand 1998 98 142 4

10.1111/j.1600-0404.1998.tb01736.x

9724016

107

Nagatsu

Mogi

Ichinose

Togari

Cytokines in Parkinson’s disease

J Neural Transm Suppl 2000 143 51

11128604

108

Hoenen

Gustin

Birck

Kirchmeyer

Beaume

Felten

et al.

Alpha-synuclein proteins promote pro-inflammatory cascades in microglia: stronger effects of the A53T mutant

PLoS One 2016 11

e0162717

10.1371/journal.pone.0162717

27622765

PMC5021287

109

McGeer

Kawamata

Yamada

Akiyama

Reactions of the immune system in chronic degenerative neurological diseases

Can J Neurol Sci 1991 18 376 9

10.1017/s0317167100032479

1933684

110

Sanchez-Guajardo

Febbraro

Kirik

Romero-Ramos

Microglia acquire distinct activation profiles depending on the degree of α-synuclein neuropathology in a rAAV based model of Parkinson’s disease

PLoS One 2010 5

e8784

10.1371/journal.pone.0008784

20098715

PMC2808388

111

George

Rey

Tyson

Esquibel

Meyerdirk

Schulz

et al.

Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease

Mol Neurodegener 2019 14

10.1186/s13024-019-0335-3

31419995

PMC6697982

112

Kouli

Horne

Williams-Gray

Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies

Brain Behav Immun 2019 81 41 51

10.1016/j.bbi.2019.06.042

31271873

113

Dzamko

Gysbers

Perera

Bahar

Shankar

Gao

et al.

Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

Acta Neuropathol 2017 133 303 19

10.1007/s00401-016-1648-8

27888296

PMC5250664

114

Kim

Rockenstein

Spencer

Kim

Adame

Trejo

et al.

Antagonizing neuronal toll-like receptor 2 prevents synucleinopathy by activating autophagy

Cell Rep 2015 13 771 82

10.1016/j.celrep.2015.09.044

26489461

PMC4752835

115

Kim

Suk

You

Michael

Kang

et al.

Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia

Nat Commun 2013 4

1562

10.1038/ncomms2534

23463005

PMC4089961

116

Park

Paik

Jou

Park

Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated α-synuclein: implications for Parkinson’s disease

Glia 2008 56 1215 23

10.1002/glia.20691

18449945

117

Harms

Delic

Thome

Bryant

Liu

Chandra

et al.

α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration

Acta Neuropathol Commun 2017 5

10.1186/s40478-017-0494-9

29162163

PMC5698965

118

Grozdanov

Bousset

Hoffmeister

Bliederhaeuser

Meier

Madiona

et al.

Increased immune activation by pathologic α-synuclein in Parkinson’s disease

Ann Neurol 2019 86 593 606

10.1002/ana.25557

31343083

119

Sacino

Brooks

McGarvey

McKinney

Thomas

Levites

et al.

Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein

Acta Neuropathol Commun 2013 1

10.1186/2051-5960-1-38

24252149

PMC3893388

120

Gerecke

Jiao

Pani

Pagala

Smeyne

Exercise protects against MPTP-induced neurotoxicity in mice

Brain Res 2010 1341 72 83

10.1016/j.brainres.2010.01.053

20116369

PMC2884060

121

Goes

ATR

Souza

Filho

Del

Fabbro L

Gomes MG

Boeira

et al.

Neuroprotective effects of swimming training in a mouse model of Parkinson’s disease induced by 6-hydroxydopamine

Neuroscience 2014 256 61 71

10.1016/j.neuroscience.2013.09.042

24090962

122

Shin

Jeong

Lee

Sung

Treadmill exercise facilitates synaptic plasticity on dopaminergic neurons and fibers in the mouse model with Parkinson’s disease

Neurosci Lett 2016 621 28 33

10.1016/j.neulet.2016.04.015

27080424

123

Tajiri

Yasuhara

Shingo

Kondo

Yuan

Kadota

et al.

Exercise exerts neuroprotective effects on Parkinson’s disease model of rats

Brain Res 2010 1310 200 7

10.1016/j.brainres.2009.10.075

19900418

124

Toy

Petzinger

Leyshon

Akopian

Walsh

Hoffman

et al.

Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease

Neurobiol Dis 2014 63 201 9

10.1016/j.nbd.2013.11.017

24316165

PMC3940446

125

Tsou

Shih

Ching

Huang

Jen

et al.

Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP⁺ toxicity

Exp Neurol 2015 263 50 62

10.1016/j.expneurol.2014.09.021

25286336

126

Edwards

Quigley

EMM

Pfeiffer

Gastrointestinal dysfunction in Parkinson’s disease: frequency and pathophysiology

Neurology 1992 42 726 32

10.1212/wnl.42.4.726

1565224

127

Lebouvier

Neunlist

Bruley

des Varannes S

Coron

Drouard

N’Guyen

et al.

Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms

PLoS One 2010 5

e12728

10.1371/journal.pone.0012728

20856865

PMC2939055

128

Hill-Burns

Debelius

Morton

Wissemann

Lewis

Wallen

et al.

Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome

Mov Disord 2017 32 739 49

10.1002/mds.26942

28195358

PMC5469442

129

Chen

Stribinskis

Rane

Demuth

Gozal

Roberts

et al.

Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged fischer 344 rats and Caenorhabditis elegans

Sci Rep 2016 6

34477

10.1038/srep34477

27708338

PMC5052651

130

Stolzenberg

Berry

Yang

Lee

Kroemer

Kaufman

et al.

A role for neuronal alpha-synuclein in gastrointestinal immunity

J Innate Immun 2017 9 456 63 Erratum in: J Innate Immun. 2018;10:82.

10.1159/000477990

28651250

PMC5865636

131

Wang

Chu

Stewart

Ginghina

Wang

Nie

et al.

α-Synuclein, a chemoattractant, directs microglial migration via H₂O₂-dependent Lyn phosphorylation

Proc Natl Acad Sci U S A 2015 112 E1926 35

10.1073/pnas.1417883112

25825709

PMC4403145

132

Villumsen

Aznar

Pakkenberg

Jess

Brudek

Inflammatory bowel disease increases the risk of Parkinson’s disease: a Danish nationwide cohort study 1977–2014

Gut 2019 68 18 24

10.1136/gutjnl-2017-315666

29785965

133

Baizabal-Carvallo

Alonso-Juarez

The link between gut dysbiosis and neuroinflammation in Parkinson’s disease

Neuroscience 2020 432 160 73

10.1016/j.neuroscience.2020.02.030

32112917

134

Villarán

Espinosa-Oliva

Sarmiento

Pablos RM

Argüelles

Delgado-Cortés

et al.

Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson’s disease

J Neurochem 2010 114 1687 700

10.1111/j.1471-4159.2010.06879.x

20584104

135

Devos

Lebouvier

Lardeux

Biraud

Rouaud

Pouclet

et al.

Colonic inflammation in Parkinson’s disease

Neurobiol Dis 2013 50 42 8

10.1016/j.nbd.2012.09.007

23017648

136

Houser

Chang

Factor

Molho

Zabetian

Hill-Burns

et al.

Stool immune profiles evince gastrointestinal inflammation in Parkinson’s disease

Mov Disord 2018 33 793 804

10.1002/mds.27326

29572994

PMC5992021

137

Schwiertz

Spiegel

Dillmann

Grundmann

Bürmann

Faßbender

et al.

Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson’s disease

Parkinsonism Relat Disord 2018 50 104 7

10.1016/j.parkreldis.2018.02.022

29454662

138

Lin

Hsu

Lin

Kao

Association between Parkinson’s disease and inflammatory bowel disease: a nationwide Taiwanese retrospective cohort study

Inflamm Bowel Dis 2016 22 1049 55

10.1097/MIB.0000000000000735

26919462

139

Park

Kim

Chun

Han

Soh

Kang

et al.

Patients with inflammatory bowel disease are at an increased risk of Parkinson’s disease: a South Korean nationwide population-based study

J Clin Med 2019 8

1191

10.3390/jcm8081191

31398905

PMC6723604

140

Peter

Dubinsky

Bressman

Park

Chen

et al.

Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease

JAMA Neurol 2018 75 939 46

10.1001/jamaneurol.2018.0605

29710331

PMC6142934

141

Weimers

Halfvarson

Sachs

Saunders-Pullman

Ludvigsson

Peter

et al.

Inflammatory bowel disease and Parkinson’s disease: a nationwide Swedish cohort study

Inflamm Bowel Dis 2019 25 111 23

10.1093/ibd/izy190

29788069

142

Aldecoa

Navarro-Otano

Stefanova

Sprenger

Seppi

Poewe

et al.

Alpha-synuclein immunoreactivity patterns in the enteric nervous system

Neurosci Lett 2015 602 145 9

10.1016/j.neulet.2015.07.005

26163460

143

Beach

Adler

Sue

Vedders

Lue

White

Iii CL

et al. Arizona Parkinson’s Disease Consortium

Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders

Acta Neuropathol 2010 119 689 702

10.1007/s00401-010-0664-3

20306269

PMC2866090

144

Wakabayashi

Takahashi

Takeda

Ohama

Ikuta

Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses

Acta Neuropathol 1988 76 217 21

10.1007/BF00687767

2850698

145

Fan

Jabeen

Guo

Han

Zhang

et al.

What and how can physical activity prevention function on Parkinson’s disease?

Oxid Med Cell Longev 2020 2020

4293071

10.1155/2020/4293071

32215173

PMC7042542

146

Zhou

Barkow

Freed

Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease

PLoS One 2017 12

e0190160

10.1371/journal.pone.0190160

29272304

PMC5741244

147

Jang

Koo

Kwon

Kang

Soya

et al.

Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson’s disease mice

Brain Res 2017 1655 186 93

10.1016/j.brainres.2016.10.029

27816415

148

Stern

Lang

Poewe

Toward a redefinition of Parkinson’s disease

Mov Disord 2012 27 54 60

10.1002/mds.24051

22252891

149

Bohlhalter

Kaegi

Parkinsonism: heterogeneity of a common neurological syndrome

Swiss Med Wkly 2011 141

w13293

10.4414/smw.2011.13293

22052571

150

Keus

SHJ

Bloem

van Hilten

Ashburn

Munneke

Effectiveness of physiotherapy in Parkinson’s disease: the feasibility of a randomised controlled trial

Parkinsonism Relat Disord 2007 13 115 21

10.1016/j.parkreldis.2006.07.007

17055767

151

Schrag

Jahanshahi

Quinn

How does Parkinson’s disease affect quality of life? A comparison with quality of life in the general population

Mov Disord 2000 15 1112 8

10.1002/1531-8257(200011)15:6<1112::aid-mds1008>3.0.co;2-a

11104193

152

Galna

Lord

Burn

Rochester

Progression of gait dysfunction in incident Parkinson’s disease: impact of medication and phenotype

Mov Disord 2015 30 359 67

10.1002/mds.26110

25546558

153

Muslimovic

Post

Speelman

Schmand

de Haan

Determinants of disability and quality of life in mild to moderate Parkinson disease

Neurology 2008 70 2241 7

10.1212/01.wnl.0000313835.33830.80

18519873

154

Nutt

Holford

NHG

Progression of motor and nonmotor features of Parkinson’s disease and their response to treatment

Br J Clin Pharmacol 2012 74 267 83

10.1111/j.1365-2125.2012.04192.x

22283961

PMC3630747

155

Wright

Gurfinkel

King

Nutt

Cordo

Horak

Axial kinesthesia is impaired in Parkinson’s disease: effects of levodopa

Exp Neurol 2010 225 202 9

10.1016/j.expneurol.2010.06.016

20599976

PMC3052408

156

van der Kolk

King

Effects of exercise on mobility in people with Parkinson’s disease

Mov Disord 2013 28 1587 96

10.1002/mds.25658

24132847

157

Horstink

Tolosa

Bonuccelli

Deuschl

Friedman

Kanovsky

et al. European Federation of Neurological Societies Movement Disorder Society-European Section

Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late (complicated) Parkinson’s disease

Eur J Neurol 2006 13 1186 202

10.1111/j.1468-1331.2006.01548.x

17038032

158

Goodwin

Richards

Taylor

Campbell

The effectiveness of exercise interventions for people with Parkinson’s disease: a systematic review and meta-analysis

Mov Disord 2008 23 631 40

10.1002/mds.21922

18181210

159

Shu

Yang

Huang

Jiang

et al.

Aerobic exercise for Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials

PLoS One 2014 9

e100503

10.1371/journal.pone.0100503

24983753

PMC4077570

160

Mehrholz

Kugler

Storch

Pohl

Hirsch

Elsner

Treadmill training for patients with Parkinson’s disease

Cochrane Database Syst Rev 2015 2015

CD007830

10.1002/14651858.CD007830.pub3

26297797

161

Roeder

Costello

Smith

Stewart

Kerr

Effects of resistance training on measures of muscular strength in people with Parkinson’s disease: a systematic review and meta-analysis

PLoS One 2015 10

e0132135

10.1371/journal.pone.0132135

26146840

PMC4492705

162

Chung

CLH

Thilarajah

Tan

Effectiveness of resistance training on muscle strength and physical function in people with Parkinson’s disease: a systematic review and meta-analysis

Clin Rehabil 2016 30 11 23

10.1177/0269215515570381

25691582

163

Shen

Wong-Yu

ISK

Mak

MKY

Effects of exercise on falls, balance, and gait ability in Parkinson’s disease: a meta-analysis

Neurorehabil Neural Repair 2016 30 512 27

10.1177/1545968315613447

26493731

164

Schenkman

Moore

Kohrt

Hall

Delitto

Comella

et al.

Effect of high-intensity treadmill exercise on motor symptoms in patients with de novo Parkinson disease: a phase 2 randomized clinical trial

JAMA Neurol 2018 75 219 26

10.1001/jamaneurol.2017.3517

29228079

PMC5838616

165

Swanson

Robinson

Geriatric rehabilitation: gait in the elderly, fall prevention and Parkinson disease

Med Clin North Am 2020 104 327 43

10.1016/j.mcna.2019.10.012

32035572

166

Ridgel

Peacock

Fickes

Kim

Active-assisted cycling improves tremor and bradykinesia in Parkinson’s disease

Arch Phys Med Rehabil 2012 93 2049 54

10.1016/j.apmr.2012.05.015

22659536

167

Cugusi

Manca

Bergamin

Blasio A

Monticone

Deriu

et al.

Aquatic exercise improves motor impairments in people with Parkinson’s disease, with similar or greater benefits than land-based exercise: a systematic review

J Physiother 2019 65 65 74

10.1016/j.jphys.2019.02.003

30904467

168

Farley

Fox

Ramig

McFarland

Intensive amplitude-specific therapeutic approaches for Parkinson’s disease: toward a neuroplasticity-principled rehabilitation model

Top Geriatr Rehabil 2008 24 99 114

10.1097/01.TGR.0000318898.87690.0d

169

Kleim

Jones

Schallert

Motor enrichment and the induction of plasticity before or after brain injury

Neurochem Res 2003 28 1757 69

10.1023/a:1026025408742

14584829

170

Shin

Kim

Lee

Lim

Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats

J Exerc Rehabil 2017 13 30 5

10.12965/jer.1734906.453

28349030

PMC5331996

171

Tuon

Valvassori

Lopes-Borges

Luciano

Trom

Silva

et al.

Physical training exerts neuroprotective effects in the regulation of neurochemical factors in an animal model of Parkinson’s disease

Neuroscience 2012 227 305 12

10.1016/j.neuroscience.2012.09.063

23041759

172

Hayes

Hunsaker

Dibble

Implicit motor sequence learning in individuals with Parkinson disease: a meta-analysis

J Parkinsons Dis 2015 5 549 60

10.3233/JPD-140441

26406135

173

Shanahan

Morris

Bhriain

Saunders

Clifford

Dance for people with Parkinson disease: what is the evidence telling us?

Arch Phys Med Rehabil 2015 96 141 53

10.1016/j.apmr.2014.08.017

25223491

174

Blandy

Beevers

Fitzmaurice

Morris

Therapeutic argentine tango dancing for people with mild Parkinson’s disease: a feasibility study

Front Neurol 2015 6

122

10.3389/fneur.2015.00122

26074873

PMC4445309

175

Shanahan

Morris

Bhriain

Volpe

Lynch

Clifford

Dancing for Parkinson disease: a randomized trial of Irish set dancing compared with usual care

Arch Phys Med Rehabil 2017 98 1744 51

10.1016/j.apmr.2017.02.017

28336345

176

Liu

Shi

Guo

Efficacy and safety of Tai Chi for Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials

PLoS One 2014 9

e99377

10.1371/journal.pone.0099377

24927169

PMC4057148

177

Cugusi

Manca

Dragone

Deriu

Solla

Secci

et al.

Nordic walking for the management of people with Parkinson disease: a systematic review

PM R 2017 9 1157 66

10.1016/j.pmrj.2017.06.021

28694221

178

Bombieri

Schena

Pellegrini

Barone

Tinazzi

Erro

Walking on four limbs: a systematic review of Nordic walking in Parkinson disease

Parkinsonism Relat Disord 2017 38 8 12

10.1016/j.parkreldis.2017.02.004

28202374

179

Nieuwboer

Kwakkel

Rochester

Jones

van Wegen

Willems

et al.

Cueing training in the home improves gait-related mobility in Parkinson’s disease: the RESCUE trial

J Neurol Neurosurg Psychiatry 2007 78 134 40 Erratum in: J Neurol Neurosurg Psychiatry. 2010;81:126. Erratum in: J Neurol Neurosurg Psychiatry. 2010;81:1414.

10.1136/jnnp.200X.097923

17229744

PMC2077658

180

Morris

Iansek

Matyas

Summers

Stride length regulation in Parkinson’s disease: normalization strategies and underlying mechanisms

Brain 1996 119 551 68

10.1093/brain/119.2.551

8800948

181

Janssens

Malfroid

Nyffeler

Bohlhalter

Vanbellingen

Application of LSVT BIG intervention to address gait, balance, bed mobility, and dexterity in people with Parkinson disease: a case series

Phys Ther 2014 94 1014 23

10.2522/ptj.20130232

24557655

182

Ebersbach

Edler

Kaufhold

Kusch

Kupsch

et al.

Comparing exercise in Parkinson’s disease—the Berlin BIG study

Mov Disord 2010 25 1902 8 Erratum in: Mov Disord. 2010;25:2478.

10.1002/mds.23212

20669294

183

Farley

Koshland

Training BIG to move faster: the application of the speed-amplitude relation as a rehabilitation strategy for people with Parkinson’s disease

Exp Brain Res 2005 167 462 7

10.1007/s00221-005-0179-7

16283401

184

Morris

Menz

McGinley

Watts

Huxham

Murphy

et al.

A randomized controlled trial to reduce falls in people with Parkinson’s disease

Neurorehabil Neural Repair 2015 29 777 85

10.1177/1545968314565511

25567121

185

Combs

Diehl

Chrzastowski

Didrick

McCoin

Mox

et al.

Community-based group exercise for persons with Parkinson disease: a randomized controlled trial

NeuroRehabilitation 2013 32 117 24

10.3233/NRE-130828

23422464

186

Barone

Antonini

Colosimo

Marconi

Morgante

Avarello

et al. PRIAMO study group

The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease

Mov Disord 2009 24 1641 9

10.1002/mds.22643

19514014

187

Chaudhuri

Healy

Schapira

AHV

National Institute for Clinical Excellence

Non-motor symptoms of Parkinson’s disease: diagnosis and management

Lancet Neurol 2006 5 235 45

10.1016/S1474-4422(06)70373-8

16488379

188

Burn

Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson’s disease

Mov Disord 2002 17 445 54

10.1002/mds.10114

12112190

189

Diederich

Goetz

Stebbins

Repeated visual hallucinations in Parkinson’s disease as disturbed external/internal perceptions: focused review and a new integrative model

Mov Disord 2005 20 130 40

10.1002/mds.20308

15486924

190

Emre

Dementia associated with Parkinson’s disease

Lancet Neurol 2003 2 229 37

10.1016/s1474-4422(03)00351-x

12849211

191

Magerkurth

Schnitzer

Braune

Symptoms of autonomic failure in Parkinson’s disease: prevalence and impact on daily life

Clin Auton Res 2005 15 76 82

10.1007/s10286-005-0253-z

15834763

192

Byrne

Pfeiffer

Quigley

EMM

Gastrointestinal dysfunction in Parkinson’s disease. A report of clinical experience at a single center

J Clin Gastroenterol 1994 19 11 6

10.1097/00004836-199407000-00004

7930424

193

Sauerbier

Cova

Rosa-Grilo

Taddei

Mischley

Chaudhuri

Chapter thirteen - Treatment of nonmotor symptoms in Parkinson’s disease

Bhatia

Chaudhuri

Stamelou

Parkinson’s disease Academic Press; 2017. pp. 361–79.

194

Chaudhuri

Nocturnal symptom complex in PD and its management

Neurology 2003 61 S17 23

10.1212/wnl.61.6_suppl_3.s17

14504376

195

Garcia-Borreguero

Larrosa

Bravo

Parkinson’s disease and sleep

Sleep Med Rev 2003 7 115 29

10.1053/smrv.2002.0229

12628213

196

Naik

Kolikonda

Pittampalli

Lippmann

Looking beyond the obvious: non-motor Parkinsonism

Innov Clin Neurosci 2018 15 11 3

30588361

PMC6292715

197

Kalia

Lang

Parkinson’s disease

Lancet 2015 386 896 912

10.1016/S0140-6736(14)61393-3

25904081

198

Fang

Han

Cheng

Zhang

Zhao

Min

et al.

Association of levels of physical activity with risk of Parkinson disease: a systematic review and meta-analysis

JAMA Netw Open 2018 1

e182421

10.1001/jamanetworkopen.2018.2421

30646166

PMC6324511

199

Nelson

Physical activity and Parkinson disease risk: an intriguing link

JAMA Netw Open 2018 1

e182633

10.1001/jamanetworkopen.2018.2633

30646161

200

Müller

Myers

Association between physical fitness, cardiovascular risk factors, and Parkinson’s disease

Eur J Prev Cardiol 2018 25 1409 15

10.1177/2047487318771168

29667433

201

Mee-Inta

Zhao

Kuo

Physical exercise inhibits inflammation and microglial activation

Cells 2019 8

691

10.3390/cells8070691

31324021

PMC6678635

202

Szymura

Kubica

Wiecek

Pera

The immunomodulary effects of systematic exercise in older adults and people with Parkinson’s disease

J Clin Med 2020 9

184

10.3390/jcm9010184

31936624

PMC7019419

203

van Praag

Exercise and the brain: something to chew on

Trends Neurosci 2009 32 283 90

10.1016/j.tins.2008.12.007

19349082

PMC2680508

204

Kinser

Robins

JLW

Masho

Self-administered mind-body practices for reducing health disparities: an interprofessional opinion and call to action

Evid Based Complement Alternat Med 2016 2016

2156969

10.1155/2016/2156969

27672398

PMC5031847

205

Wang

Zou

Chen

Liu

Traditional Chinese exercise for chronic diseases

Evid Based Complement Alternat Med 2022 2022

9842104

10.1155/2022/9842104

35126607

PMC8813252

206

Song

Grabowska

Park

Osypiuk

Vergara-Diaz

Bonato

et al.

The impact of Tai Chi and Qigong mind-body exercises on motor and non-motor function and quality of life in Parkinson’s disease: a systematic review and meta-analysis

Parkinsonism Relat Disord 2017 41 3 13

10.1016/j.parkreldis.2017.05.019

28602515

PMC5618798

207

Nocera

Amano

Vallabhajosula

Hass

Tai Chi exercise to improve non-motor symptoms of Parkinson’s disease

J Yoga Phys Ther 2013 3

1000137

10.4172/2157-7595.1000137

24278789

PMC3837454

208

Harmer

Fisher

Fitzgerald

Vongjaturapat

Tai Chi-based exercise for older adults with Parkinson’s disease: a pilot-program evaluation

J Aging Phys Act 2007 15 139 51

10.1123/japa.15.2.139

17556781

209

Krueger

Fang

Taishi

Chen

Kushikata

Gardi

Sleep: a physiologic role for IL-1β and TNF-α

Ann N Y Acad Sci 1998 856 148 59

10.1111/j.1749-6632.1998.tb08323.x

9917875

210

Vgontzas

Papanicolaou

Bixler

Kales

Tyson

Chrousos

Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity

J Clin Endocrinol Metab 1997 82 1313 6

10.1210/jcem.82.5.3950

9141509

211

Mooventhan

Nivethitha

Evidence based effects of yoga in neurological disorders

J Clin Neurosci 2017 43 61 7

10.1016/j.jocn.2017.05.012

28599839

212

Suárez-Iglesias

Santos

Sanchez-Lastra

Ayán

Systematic review and meta-analysis of randomised controlled trials on the effects of yoga in people with Parkinson’s disease

Disabil Rehabil 2022 44 6210 29

10.1080/09638288.2021.1966522

34533097

213

Walter

Adams

Van

Puymbroeck M

Crowe

Urrea-Mendoza

Hawkins

et al.

Changes in nonmotor symptoms following an 8-week yoga intervention for people with Parkinson’s disease

Int J Yoga Therap 2019 29 91 9

10.17761/2019-00025

30901529

214

Kwok

JYY

Kwan

JCY

Auyeung

Mok

VCT

Lau

CKY

Choi

et al.

Effects of mindfulness yoga vs stretching and resistance training exercises on anxiety and depression for people with Parkinson disease: a randomized clinical trial

JAMA Neurol 2019 76 755 63

10.1001/jamaneurol.2019.0534

30958514

PMC6583059

215

Cramer

Lauche

Anheyer

Pilkington

de Manincor

Dobos

et al.

Yoga for anxiety: a systematic review and meta-analysis of randomized controlled trials

Depress Anxiety 2018 35 830 43

10.1002/da.22762

29697885

216

Gothe

Kramer

McAuley

The effects of an 8-week Hatha yoga intervention on executive function in older adults

J Gerontol A Biol Sci Med Sci 2014 69 1109 16

10.1093/gerona/glu095

25024234

PMC4202261

217

Eyre

Acevedo

Yang

Siddarth

Van

Dyk K

Ercoli

et al.

Changes in neural connectivity and memory following a yoga intervention for older adults: a pilot study

J Alzheimers Dis 2016 52 673 84

10.3233/JAD-150653

27060939

PMC4927889

218

Eyre

Siddarth

Acevedo

Van

Dyk K

Paholpak

Ercoli

et al.

A randomized controlled trial of Kundalini yoga in mild cognitive impairment

Int Psychogeriatr 2017 29 557 67

10.1017/S1041610216002155

28088925

PMC5540331

219

Eyre

Baune

Assessing for unique immunomodulatory and neuroplastic profiles of physical activity subtypes: a focus on psychiatric disorders

Brain Behav Immun 2014 39 42 55

10.1016/j.bbi.2013.10.026

24269526

220

Black

Cole

Irwin

Breen

Cyr NM

Nazarian

et al.

Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial

Psychoneuroendocrinology 2013 38 348 55

10.1016/j.psyneuen.2012.06.011

22795617

PMC3494746

221

James-Palmer

Daneault

Tele-yoga for the management of Parkinson disease: a safety and feasibility trial

Digit Health 2022 8

20552076221119327

10.1177/20552076221119327

35990111

PMC9386843