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Prodromal Parkinson's disease

L. Grass, S. Grimaldi, P. Damier

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L. Grass, S. Grimaldi, P. Damier. Prodromal Parkinson's disease. Revue Neurologique, 2025, 181 (9), pp.863-880. 10.1016/j.neurol.2025.06.012. hal-05460817

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# Prodromal Parkinson's disease

Author links open overlay panelL. Grass<sup>a</sup>, S. Grimaldi<sup>b c</sup>, P. Damier<sup>a d</sup>

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## Abstract

The neurodegenerative process responsible for Parkinson's disease (PD) begins years before the level of dopamine denervation of the basal ganglia leads to the characteristic clinical phenotype of the disease. During the past 20 years, numerous symptoms that may occur during the prodromal stage of the disease have been identified: subtle motor symptoms, psychocognitive disorders, sleep disorders, sensorial dysfunction, and dysautonomia. Among them, rapid eye movement sleep behaviour disorder (RBD) is one of the most specific. The follow-up of cohorts of subjects affected by this disorder has provided valuable information about the prodromal stage, including evidence of various biological or imaging biomarkers associated with the pre-clinical stage of the disease. From all the knowledge acquired about this stage of the disease, criteria for diagnosing prodromal PD have been proposed and have progressively improved in sensitivity and specificity. The strong focus on the RBD-associated prodromal stage has, however, tended to conceal other, less florid forms of prodromal PD, such as those beginning with mild cognitive impairment or mild motor symptoms, which affected subjects are less likely to notice. Here, we review the various symptoms observed in the prodromal stage of PD, progress on identifying relevant imaging and biological biomarkers, and recent insights into the pathogenesis of a disease having such a wide spectrum of presentation and progression. Advances in knowledge about prodromal PD will lead to earlier diagnosis and better identification of prognostic factors, and, subsequently, to the capacity to initiate personalized treatment and potentially slow down the degenerative process.

## Keywords

Parkinson's disease

Prodromal stage

Rapid eye movement sleep behaviour disorder

Hyposmia

Dysautonomia

Constipation

Mild cognitive impairment

## Abbreviations
AD

Alzheimer's disease

BMs

bowel movements

BSIT

brief smell identification test

cPD

clinical Parkinson's disease

CCSIT

cross-cultural smell identification test

CSF

cerebrospinal fluid

DAT

dopamine transporter

FDG

fluorodeoxyglucose

GBA

glucocerebrosidase

HAAS

Honolulu Asia Aging study

ICICLE-PD

incidence of cognitive impairment in cohorts with longitudinal evaluation–PD

DLB

dementia with Lewy bodies

LRRK2

leucine-rich repeat kinase 2

MDS

Movement Disorder Society

MIBG

¹²³I-metaiodobenzylguanidine

MSA

multisystem atrophy

NfL

neurofilament light chain

NSD-SS

neuronal synuclein disease integrated staging system

PAF

pure autonomic failure

PARS

Parkinson associated risk syndrome

PET

positron emission tomography

PD

Parkinson's disease

PPMI

Parkinson's progression markers initiative

PRIPS
prospective validation of risk factors for the development of Parkinson syndromes

RBD

REM sleep behaviour disorder

REM

rapid eye movement

SN

substantia nigra

SPECT

single photon emission computed tomography

DTI-ALPS

diffusion tensor image analysis along the perivascular space

TREND

Tübingen evaluation of risk factors for early detection of neurodegeneration

UPSIT

University of Pennsylvania smell identification test

# 1. Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is increasing in both incidence and prevalence, due in part to the aging of the population and increased longevity, and also potentially to increased exposure to some environmental toxic agents such as pesticides and solvents [1]. By 2050, the number of people with PD worldwide is projected to exceed 25 million [2]. Even if PD is driven by age and affects > 1% of people aged over 60 years, it can also affect younger individuals, including those under the age of 50.

To date, the diagnosis of PD has been based on the recognition of a clinical phenotype consisting of movement disturbances, akinesia and bradykinesia, associated with resting tremor, rigidity and/or gait and posture abnormalities. The phenotype is highly specific and is known to be caused by the degeneration of the dopaminergic nigro-striatal pathway associated, in most cases, with a deposition in the brain of abnormal aggregated α-synuclein [3].

Since symptoms progressively worsen over time due to the worsening and the spreading of the lesion, PD has long been considered a slowly progressive neurodegenerative disease. More recently, it has been clearly established that a lesional threshold of more than a 50% loss of striatal dopamine terminals must be reached before the onset of PD motor manifestations [4]. This would indeed suggest that the PD degenerative process begins before the PD clinical phenotype is recognized. This stage of the disease could last for years or perhaps decades.

Over the past 20 years, considerable attention has been given to some clinical, mostly non-motor manifestations, such as hyposmia, constipation, rapid eye movement sleep behaviour disorder (RBD), a parasomnia characterized by the loss of the typical muscle atonia during rapid eye movement (REM) sleep, and depression, that can occur before the PD clinical phenotype appears. This has made it possible to schematically identify three consecutive stages in PD: a pre-clinical stage, in which the neurodegenerative process has started but without any detectable symptoms or signs, a prodromal stage with some subtle and often poorly specific features, and the classic PD phenotype stage
at which the diagnosis is made [5]. In this paper, we make a distinction between the
disease, PD, and its clinical phenotype, which we have designated as cPD.
This review aims to summarize current knowledge about the prodromal stage of PD.
Aside from the clinical symptoms which can be present during that stage, some
biomarkers can also be evidenced that may in the near future help to define a biological
PD. This knowledge led to recently proposed criteria to define prodromal PD, which are
regularly revised and adjusted to keep pace with this fast moving field. As disease-
modifying treatments will hopefully soon be available, it is clearly crucial to be able to
recognize PD at a very early stage so that efforts to slow down the degenerative process
can be initiated even before cPD has become established.

## 2. Growing knowledge about prodromal Parkinson's disease

Initially, our knowledge about the prodromal stage of PD was mainly based on
observations from retrospective data. Available prospective studies were founded either
on large population-based cohorts not specifically designed to assess the prodromal
markers of PD, or on observations in rare families with monogenic PD.
The first large prospective study was the Honolulu Asia Aging study (HAAS), a
population-based study that included 8006 Japanese-American men. While the study
originally focused on heart disease and stroke [6], in 1991, the research focus shifted to
neurodegenerative diseases and included PD [7], [8], [9]. This study identified pre-
motor features associated with PD, but also early pre-clinical neuropathological stages
of α-synuclein deposition, with brain autopsies performed on 20% of the subjects [10].
The Rotterdam Study, created in 1990 and still ongoing (as of February 2024, 17,931
participants aged 40 years and over) [11], [12], [13], and the Bruneck study
(approximatively 900 participants aged 40–79 years at inclusion, with a remarkable
follow-up time extending from 1990 to 2018) [14], are other examples of large,
prospective, population-based studies whose focus was rapidly extended to assess the
incidence, prevalence, and early phases of many age-dependent neurological diseases,
such as cPD.

Due to the low lifetime prevalence of PD, which limited the ability to reach a sufficient
number of cases for analysis, there was a subsequent development in the early 2010s of
purpose-built studies specifically designed to document some already identified
prodromal PD markers and analyse their predictive value. One such study was the
prospective validation of risk factors for the development of Parkinson syndromes
(PRIPS) study, which screened 1847 cPD-free individuals using variables such as age,
male gender, positive family history, hyposmia, subtle motor symptoms, and substantia
nigra (SN) hyperechogenicity. After a 3-year follow-up and the phenoconversion of 11
patients to cPD, they assessed a screening approach for a prediction of incident cPD
based on these markers with a sensitivity of 80.0%, a specificity of 90.6% and a positive
predictive value of 6.1% [15]. Similar approaches was applied in the Tübingen evaluation
of risk factors for early detection of neurodegeneration (TREND) cohort (698 healthy
individuals aged 50–80 years presenting at baseline with at least one of three selected
prodromal features [depression, RBD, and hyposmia] compared to controls with none
of these features [16]) and the Parkinson at-risk syndrome (PARS) study (a cohort of
4999 undiagnosed individuals aged over 50 [17]; with DAT-single photon emission
computed tomography (SPECT) on a subset of the cohort (303 individuals [18]).
More recently, the field of prodromal PD has expanded significantly with the emergence of high-risk population cohorts, enabling direct study of prodromal PD in limited size cohorts. Subjects with RBD appeared among the most relevant populations, as numerous studies provided converging evidence that RBD is a strong predictor of clinical PD, dementia with Lewy bodies (DLB), and multisystem atrophy (MSA), now gathered under the name of synucleopathies [19], [20], [21], [22], [23]. These cohorts of RBD patients, formed worldwide as part of a global initiative by the International RBD Study Group, gave an unprecedented opportunity to learn about the prodromal phase of PD, as the patients were observed from the diagnosis of RBD to phenoconversion to cPD, with approximately a 6-8% per year risk of developing cPD. These cohorts made it possible to validate the predictive value of olfactory loss, abnormal colour vision, subtle motor symptoms, mild cognitive impairment, constipation, and erectile dysfunction. Several other potential markers were assessed in these cohorts but their predictive value still needs to be confirmed.

A specific high-risk population consists of patients presenting pure autonomic failure, a synucleinopathy that can be seen as an early premotor or precognitive phase of numerous diseases, such as PD, DLB, and MSA [24].

In addition to the cohorts of RBD patients, subjects carrying genetic variants linked to PD, such as some variants in the α-synuclein, leucine-rich repeat kinease 2 (LRRK2) and glucocerebrosidase (GBA) genes, are known to be at very high risk for developing cPD, and thus can be followed to investigate the preclinical and prodromal stage of the disease. While the data obtained in such cohorts are less generalizable to the broader population of PD patients, they provide critical insights into the wide phenotypical spectrum of the disease. These populations also represent an ideal group for the development and testing of targeted disease-modifying therapies [25], [26].

Most of these prodromal conditions are included in the Parkinson's progression markers initiative (PPMI) cohort, a global initiative launched in 2010. The study enrolls individuals with sporadic PD, carriers of *LRRK2* and *GBA* variants, healthy controls, prodromal individuals with RBD or hyposmia with a DAT-SPECT deficit, as well as non-manifesting individuals carrying a genetic risk variant (α-synuclein, *LRRK2*, *GBA*). The current expansion phase aims to recruit 2000 prodromal participants across nearly 50 international sites, in order to provide the research community with a comprehensive, standardized, longitudinal dataset and biosample repository [27], [28], [29].

## 3. Prodromal clinical features

From these studies, a large number of clinical features have now been identified. Five main categories can be differentiated: subtle motor symptoms, psycho-cognitive disorders, sleep disorders, sensorial dysfunction, and dysautonomia.

### 3.1. Subtle motor impairment

By definition, all patients with PD will eventually present early motor symptoms, which progress at different rates until meeting the criteria for the motor phase and hence the diagnosis of cPD. Nevertheless, several studies have suggested, and later confirmed, that alterations in the motor pattern may manifest more than 10 years before diagnosis, positioning them as part of the prodromal symptoms. In the Rotterdam study, where
motor assessments were conducted through standardized clinical interviews by trained nurses and supplemented by subjective complaints such as stiffness, slowness, tremor, and loss of balance, it was found that bradykinesia and tremor were usually the first motor signs to appear, occurring respectively approximately 7 years and 6 years before the diagnosis [13]. In "at-risk" groups such those with RBD, mild motor impairment was the strongest predictive marker of future cPD, with a hazard ratio (HR) of 3. Voice changes and facial akinesia were the earliest signs [30]. Using data from the population-based Hellenic Longitudinal Investigations of Aging and Diet cohort (HELIAD) study, which included older adults, subjective and objective motor function in individuals without cPD was evaluated with a 12-item motor symptoms questionnaire, a physical activity questionnaire, and two gait speed tests [31]. The authors observed a 27% increased probability of prodromal PD, as defined by the Movement Disorder Society (MDS) research criteria, for each unit increase in the 12-item motor symptoms questionnaire score. More recently, a case-control study including 138,345 incident cPD subjects compared to 276,690 matched controls was able to identify some prodromal motor features in subjects who went on to develop cPD, with a higher incidence of tremor and restless legs syndrome 5 to 10 years before diagnosis [32].

One of the challenges to detecting subthreshold PD lies in the fact that 30–40% of elderly individuals in the general population exhibit subtle parkinsonism signs on clinical examination, such as slowness, gait alteration, and stiffness, without their having a known neurological condition [33]. These signs can often be attributed to aging, cerebrovascular disease, or musculoskeletal conditions and most of these individuals will not convert to cPD. Certain signs can, however, help differentiate between mild parkinsonism due to normal aging and prodromal PD motor symptoms: hypomimia, alteration in voice modulation, and asymmetry between sides seems indeed to be more specific to PD and can help distinguish between these conditions [34].

## 3.2. Psychological and cognitive disorders

### 3.2.1. Mood disorders

Several studies support mood disorders, such as depression and anxiety, as among the most frequent and early pre-motor symptoms of cPD. These disorders can also emerge at any stage of the disease, with more than 30% of individuals with cPD experiencing depression [35], [36]. In a large case-control study, the initiation of any antidepressant therapy was associated with a higher risk of cPD with an association being the strongest in the first two years of treatment [37]. Similarly, another large case-control study, using data from the NIH-AARP Diet and Health Study Follow-up Survey, showed a positive association between premorbid depression and the risk of developing cPD. This association persisted even when depression onset occurred up to 15 years before cPD diagnosis [38]. Another large, retrospective study found a higher risk for cPD for depressed vs. nondepressed subjects in a multivariable analysis [39]. Additionally, a retrospective cohort analysis of 32,415 individuals in The Netherlands revealed that depressive symptoms emerged 1 to 36 years before the onset of motor symptoms, with an average of 10 years before motor symptom onset. A large case-control study in California found that cPD patients were more likely to have had a diagnosis of
depression in the five years prior to their cPD diagnosis than control subjects during a
similar five-year period [40], [41].

Other studies have also shown a link between anxiety and the development of
cPD [32], [42].

### 3.2.2. Mild cognitive impairment

Mild cognitive impairment is common in early cPD, affecting between 15% and 43% of
newly diagnosed patients [43], [44]. Classically, the onset of dementia before or within a
year of parkinsonism diagnosis has been considered an exclusion criterion of cPD, even
in the absence of core features of DLB, such as visual hallucinations or marked
fluctuations in attention [45]. There is increasing evidence to suggest that poor cognitive
functioning can be part of prodromal PD [46], [47].

In the PARS study, where individuals older than 50 years without cPD were recruited,
individuals with both hyposmia and reduced dopamine transporter binding, which are
strongly associated with PD, had lower mean scores for global cognition, executive
function/working memory, and memory compared to all other participants [18]. In the
ParkWest study in Norway, the 196 de novo, untreated cPD subjects had lower results in
all neuropsychological tests compared to controls, albeit with a small effect size. The
largest effect size was observed for verbal memory. The relative risk of mild cognitive
impairment was 2.1 (95% CI 1.2–3.6) in the cPD group compared to the control
group [48]. The population-based Rotterdam Study also found an association between
poor baseline cognitive functioning and the risk of probable cPD. Notably, nearly half of
the participants diagnosed with incident parkinsonism during follow-up already
exhibited subtle motor symptoms or cognitive dysfunction at baseline, or both.

Participants with both cognitive dysfunction and subtle motor symptoms had a 3.3-fold
increased risk of developing parkinsonism [49]. In a cohort of 219 newly diagnosed
incident cPD cases (incidence of cognitive impairment in cohorts with longitudinal
evaluation-PD [ICICLE-PD]), the frequency of mild cognitive impairment, as defined by
the MDS Task Force proposed diagnostic criteria, was 42.5%, with memory impairment
being the most commonly affected domain [50].

Mild cognitive impairment has therefore become an accepted prodromal marker of PD.
Particular attention must nonetheless be given to the diagnosis of comorbid disease or
to differential diagnoses with predominant cognitive alteration, such as DLB and AD,
but also vascular parkinsonism and MSA.

## 3.3. Sleep disorders

### 3.3.1. REM sleep behaviour disorder

RBD is a parasomnia characterized by the loss of typical muscle atonia during REM
sleep, resulting in sudden body movements and vocalizations as individual experienced
vivid, often unpleasant, dreams. This condition has a reported prevalence of
approximately 0.4–5% in the general population and is more commonly observed in
males over the age of 50. Most patients remain unaware of their parasomnia, with the
diagnosis often suggested by a bed partner or roommate [51], [52]. RBD can also occur
secondary to the use of certain antidepressant drugs or a lesion affecting brain regions involved in sleep/wake regulation, though the majority of cases are still classified as idiopathic RBD [53].

In 1996, Schenck et al. reported that approximately 40% of individuals with idiopathic RBD eventually developed parkinsonism [54]. Since then, this condition has been recognized as one of the most specific predictors of α-synuclein-mediated neurodegenerative disorders, such as PD, DLB, and MSA [55]. In a prospective series reported by Iranzo et al., 174 patients with RBD were followed for a median of 4 years (range: 0.1–15.0). The neurological disease-free survival rates from the time of RBD diagnosis were 65.2% (95% CI 50.9–79.5) at 5 years, 26.6% (95% CI 12.7–40.5) at 10 years, and 7.5% (95% CI 1.9–16.9) at 14 years. In the six patients in whom an autopsy was performed, neuropathological examination confirmed synucleinopathy as the underlying mechanism [56].

These findings have been corroborated by multiple prospective cohorts, which found that over 80% of patients with polysomnographically confirmed RBD converted to a clinically confirmed synucleinopathy, with a phenoc Conversion rate of approximately 6–8% per year. Even patients who remained disease-free for extended periods often displayed early clinical signs and biomarkers indicative of ongoing neurodegeneration [57], [58]. Thus, RBD cohorts were naturally seen by researchers as a privileged way of investigating the pre-motor phase of PD in high-risk populations and of evaluating other clinical prodromal symptoms.

In a large multicentre cohort, Postuma et al. included 1280 patients with polysomnographically confirmed RBD, none of whom had parkinsonism or dementia at baseline. These patients underwent sleep, motor, cognitive, autonomic, and special sensory testing at baseline. After an average follow-up of 4.6 years, with a range of up to 19 years, they observed an overall conversion rate from RBD to another neurodegenerative syndrome of 6.3% per year, with 73.5% converting within 12 years. Importantly, hazard ratios were identified for several prodromal symptoms associated with an increased risk of phenoc oconversion, including olfactory loss (HR = 2.8), abnormal colour vision (HR = 3.1), subtle motor symptoms (HR = 3.9), and non-use of antidepressants (HR = 3.5). Notably, the only baseline difference between the patients converting to primary dementia vs. parkinsonism was related to cognitive variables [59]. Given its robust predictive value for phenoc oconversion, RBD represents an ideal population for neuroprotective trials. Current research is focused on identifying reliable clinical markers and stratification methods to optimize trial design. New cohorts, such as the North American Prodromal Synucleinopathy Cohort, are now being established in preparation for imminent neuroprotective trials [60], [61], [62], [63].

3.3.2. Other sleep disorders

Excessive daytime sleepiness is frequent in cPD, with its prevalence increasing as the disease progresses. In the ONSET PD study, excessive daytime sleepiness could be perceived up to 10 years before the onset of motor symptoms [64]. In the HAAS study, men with excessive daytime sleepiness were found to have a threefold excess risk of developing cPD [7], [10].

In contrast, periodic limb movements in sleep, despite being present in 30–80% of patients with cPD, do not appear to be a prodromal symptom of the disease. Recent
studies have demonstrated no significant differences in the prevalence of periodic limb movements in sleep between individuals with cPD, individuals at high risk for developing the disease, and control groups [65], [66], [67].

### 3.4. Sensorial dysfunction

#### 3.4.1. Olfactory dysfunction

Olfactory dysfunction occurs in over 90% of cPD subjects: it affects odour identification, discrimination, detection thresholds, and recognition memory [68]. Olfactory impairment manifests often years prior to the onset of motor symptoms and therefore was rapidly recognized as a good candidate for a premotor biomarker of cPD [69]. Various tests are available to assess olfactory function. The most commonly used is odour identification using the University of Pennsylvania smell identification test (UPSIT). An abbreviated version of the test is also available [70], [71]. The cross-cultural smell identification test (CCSIT) and the Sniffin' Sticks test in European countries are two other tests frequently employed [72].

Given the simplicity and low cost of the evaluation of smell as well as the high prevalence and early occurrence of olfactory dysfunction, considerable interest has emerged regarding its potential as an early diagnostic marker. Odour identification testing has demonstrated its ability to distinguish cPD patients from controls, with sensitivity and specificity rates exceeding 80% [73].

Several studies have reported an increased risk of developing cPD in individuals with impaired olfaction. In the HAAS study, men in the lowest quartile of olfactory function had a 5.2-fold increased risk of developing cPD within four years [10]. Similarly, in The PRIPS study, the odds of developing cPD were nearly four times higher in subjects with olfactory impairment compared to the others [15]. An extension of the Bruneck study demonstrated a relative risk of 3.60 for incident cPD over a 10-year follow-up period in patients with hyposmia at baseline [74]. In a cohort of 361 non-parkinsonian, non-demented first-degree relatives of cPD subjects, hyposmia at baseline was associated with an increased risk of subsequently developing cPD of at least 10% at 2 years and 12.5% at 5 years of follow-up, along with abnormal striatal DAT binding [75], [76]. Chen et al. evaluated 2462 participants (mean age > 70) in the health, aging, and body composition study with the Brief smell identification test (BSIT), and reported an HR of 4.8 for the lowest BSIT tertile compared to the highest over a 9.8-year follow-up [77]. In the PARS study, individuals with hyposmia (669 adults > 50 years, with hyposmia defined as < 15th percentile by UPSIT) were more likely to develop DAT deficits (¹²³Iβ-CIT SPECT) in follow-up compared to 4330 controls in follow-up reports (11% vs. 1%) [18]. Olfactory abnormalities are not limited to idiopathic PD but can also be found in monogenic PD [78], and in subjects with GBA mutations [28].

Olfactory dysfunction is, however, common in the general population, increasing with aging, and its prevalence could be up to 20% [79]. A large proportion of these individuals may present with idiopathic hyposmia unrelated to any neurodegenerative process. Consequently, hyposmia or anosmia alone cannot predict phenoconversion to synucleinopathies but offer an opportunity to design clinical cohorts for studying the pathological links between idiopathic anosmia and neurodegeneration.
### 3.4.2. Visual dysfunction

Visual disturbances are prevalent in most cPD subjects, with a potentially high impact on quality of life, though they are often underrecognized and overlooked [80]. These disturbances include deficits in visual acuity, spatial contrast sensitivity, convergence, and colour vision. Visual dysfunction has been reported to correlate with disease progression and may already occur in the early and prodromal stages of the disease [81]. A few studies have explored the possibility of prodromal visual dysfunction, and more specifically colour vision, in PD. For example, subjects with RBD were reported to be more likely to exhibit below-average colour vision compared to controls [21]. In a 5-year prospective study concerning subjects with RBD, those who later developed dementia or cPD were more likely to have had lower baseline visual scores, assessed using the Farnsworth-Munsell 100 (FM-100) test, at baseline [82]. However, current data remain insufficient to conclusively support visual dysfunction as a definite prodromal symptom of PD.

## 3.5. Autonomic features

### 3.5.1. Gastrointestinal disorders

Autonomic dysfunction is a frequent non-motor symptom in cPD and often an early manifestation of the disease. Among the various types of autonomic dysfunction, gastrointestinal disturbances are common in PD, affecting the whole of the gastrointestinal tract. Various studies support the notion that gastrointestinal disturbances frequently precede the onset of motor symptoms.

#### 3.5.1.1. Constipation

In the HAAS study, 6790 men were categorized based on their daily bowel movements (BMs) (< 1, 1, 2, and > 2 BMs per day). The study found an increased age-adjusted incidence of cPD with decreasing BMs per day, from 3.9 in men with > 2 BMs per day to 18.9 in men with < 1 BM per day. The average time to diagnosis of cPD was 12 years. Additionally, an association was observed between constipation and incidental Lewy pathology, supporting the argument that constipation may be one of the earliest markers of PD [10]. Similar results were found in a large Danish population cohort study [83]. A 2016 meta-analysis, involving 741,593 participants, those with constipation had a pooled OR of 2.27 (95% CI 2.09–2.46) for subsequently developing cPD compared with those without constipation. The results were consistent even when the assessment was restricted to the period of more than 10 years before cPD diagnosis [84].

### 3.5.2. Orthostatic hypotension

Orthostatic hypotension is the most widely recognized cardiovascular symptom in cPD and may occur years before a formal diagnosis. A recent meta-analysis investigating potential biomarkers for predicting the conversion to α-synucleinopathies in RBD cohorts found that orthostatic hypotension was one of the strongest predictors of
phenoconversion, alongside hyposmia and mild cognitive impairment [85]. A large case-control study of 138,345 patients with incident cPD and 276,690 matched controls found significant associations between dizziness, postural hypotension, and subsequent cPD diagnosis [32]. Orthostatic hypotension, which can have both cardiogenic and neurogenic causes, reflects the broad cardiovascular dysautonomia in PD. In a small study, decreased heart rate variability was noted in electrocardiograms of patients with RBD, suggesting early autonomic dysfunction [86]. Baroreflex sensitivity is also altered in cPD, contributing to cardiovascular instability [87].

# 4. Prodromal non-clinical biomarkers

The identification of prodromal symptoms of PD has opened up a wide field of investigation of the early stages of the disease and has helped to identify prodromal imaging and biological biomarkers. We will, however, mainly focus on the abnormalities observed in patients with RBD, as this is currently the most sensitive and specific prodromal marker of phenoconversion to a clinical α-synuclein-related parkinsonian syndrome.

## 4.1. Prodromal imaging features

### 4.1.1. Structural imaging

#### 4.1.1.1. MRI assessment of atrophy, iron load and neuromelanin

Performing a brain MRI in a patient with RBD but no other neurological symptoms may be useful to rule out secondary causes, such as small vascular lesions, pontine cavernoma, or lymphoma [88]. Since RBD has appeared to have been a prodromal feature in some PD subjects, brain MRI has been largely explored with the aim of identifying early changes associated with the disease [89].

Several structural changes have been observed at the prodromal stage. In short, cortical thinning in frontal regions was related to increasing motor impairment [90].

Neuropsychological scoring showed that RBD subjects with cognitive dysfunction had a wider cortical impairment affecting the frontal cortex, the bilateral insula, the right temporal cortex, and the left posterior temporal cortex [91], whereas those subjects with visuospatial loss had predominant parieto-occipital and orbitofrontal thinning [90]. In subcortical regions, various degrees of volume reduction were reported in the substantia nigra pars compacta, bilateral putamen, caudate nucleus, lentiform nucleus, and right thalamus [89]. Follow-up studies revealed a pattern related to DLB in some RBD subjects who may develop a cognitive decline before the onset of motor symptoms. The DLB pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices [92].

Another study reported atrophy in the basal ganglia, thalamus, amygdala, and fronto-temporal grey and white matter and expansion in the cerebrospinal fluid-filled spaces as a predictable marker of DLB [93].

One of the most interesting findings in recent years regarding structural connectivity was the identification of an impaired relationship between several brainstem nuclei. The
analysis of RBD subjects compared to controls with brain 7 T MRI found the involvement of specific brainstem nuclei in RBD pathophysiology. Notably, an impaired connectivity between areas triggering REM sleep (subcoeruleus nucleus and oral part-pontine reticular nucleus) and areas modulating REM sleep (laterodorsal tegmental nucleus and pedunculo tegmental nucleus), and areas responsible for REM sleep muscle-atonia (mainly the superior and inferior medullary reticular formations) were observed [94]. These findings confirmed experimental studies performed in animals [95].

Recent studies have introduced diffusion tensor image analysis along the perivascular space (DTI-ALPS) as a non-invasive imaging method to assess glymphatic system dysfunction. A lower DTI-ALPS index in individuals with RBD was observed, suggesting decreased perivascular diffusivity and thus an impaired glymphatic clearance function at the prodromal stage of PD [96], [97]. This particularly interesting observation will need to be further evaluated, but it could indicate a new route in the pathogenesis.

In parallel, other investigations focused on iron load and the visualization of neuromelanin in RBD and PD. The disappearance of the dorsolateral hyperintensity of the ventral midbrain in SWI sequences was found in 96% of cPD subjects but solely in 1/4 to 2/3 of RBD subjects (Fig. 1A) [89]. It is considered to reflect iron deposit within nigrosome 1 of the SN. Quantitative analyses of iron load were developed using transverse relaxation rate (R2*) or, more accurately, with quantitative susceptibility mapping (QSM). With the latter parameter, elevated values were reported in the SN [98], [99], and more specifically in nigrosome 2 [100], in RBD subjects, an observation that was however not confirmed in two other studies [101], [102].

Neuromelanin imaging, based on specific T1 imaging parameters, has made it possible to identify the locus coeruleus/subcoeruleus complex without using ultra-high-field imaging such as 7 T MRI. A reduced signal was identified in RBD subjects with 82.5% sensitivity and 81% specificity [103]. Reduced signal intensity was also measured in the SN of RBD subjects in several studies [89] (Figs. 2B, C). Iron burden and a reduced neuromelanin signal were correlated to a loss of dopamine function as measured by DAT-SPECT [101], which raises the possibility of their role in the pathophysiology of neurodegeneration and may lead to the development of potential therapeutic targets. Also, these new biomarkers can be used to monitor potential disease-modifying treatments.
<figure><img src="image_3.png" /><figcaption>Fig. 1. Susceptibility-weighted imaging (SWI) images demonstrating the dorso-nigral hyperintensity in an HC (N means “Normal”), and its absence in PD-RBD and iRBD (A). Axial neuromelanin-sensitive T1-w images of the SN (B) and the locus coeruleus/subcoeruleus area (LC/LSC) (C). The normal SN (arrowheads) and the locus area (arrows) are visible as areas of high signal intensity. There is a decrease in size and signal intensity of the SN and locus area in participants with RBD. HC: healthy control; iRBD: idiopathic REM-sleep behaviour disorder; cPD-RBD: clinical Parkinson's disease with RBD. Modified and printed with permission from Lehericy S, Vaillancourt DE, Seppi K, Monchi O, Rektorova I, Antonini, A, et al. International Parkinson and Movement Disorder Society (IPMDS)-Neuroimaging Study Group. The role of high-field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward. Mov Disord 2017;32(4):510–525.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>Fig. 2. ¹⁸F-ACI-12589 PET in participants with α-synucleinopathies. Transversal images at the level of the middle cerebellar peduncles in a control participant, and patients with dementia with Lewy bodies (DLB), multisystem atrophy with a cerebellar phenotype (MSA-C), and clinical Parkinson's disease (cPD) (A). Transversal images at the level of the basal ganglia in a control participant, and patients with DLB, multisystem atrophy with a parkinsonian phenotype (MSA-P), and cPD (B). Standardized uptake value ratio images (SUVR) for (A, B) have been created using occipital cortex as a reference region. Printed with permission from Smith, R., Capotosti, F., Schain, M. et al. The α-synuclein PET tracer [¹⁸F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases. Nat Commun 2023;14:6750.</figcaption></figure>

#### 4.1.1.2. Ultrasound evaluation of the substantia nigra

SN hyperechogenicity has been observed in cPD and might be used as a tool for diagnosing the disease. In RBD subjects, the proportion of patients with SN hyperechogenicity was higher (around 36%) than in controls (around 11%) [104]. Nevertheless, during a 5-year follow-up study [105], where 11 patients had developed PD, nine had developed DLB, and one had developed MSA among the 55 patients initially diagnosed with RBD, no difference in measures of SN echogenicity was found between the baseline and follow-up ultrasound evaluations, nor between patients who converted compared to those who remained disease-free. These results suggest that SN hyperechogenicity is not a sensitive diagnostic or predictive biomarker in RBD.

### 4.1.2. Functional imaging
#### 4.1.2.1. DAT-SPECT

DAT-SPECT is a method to visualize a radiopharmaceutical marker, ¹²³I- ioflupane, which binds to brain dopamine transporter, and thus helps in particular to observe in vivo dopamine-containing cell terminals in the striatum. A marked decrease in striatal binding reflects the lesion of the dopaminergic nigrostriatal pathway, as observed in cPD with a high sensitivity and a specificity of over 90% to differentiate neurodegenerative parkinsonian syndromes, including PD, from non-dopamine deficiency causes of parkinsonism [106].

A study that specifically looked for an association between REM sleep without atonia metrics (i.e., tonic and phasic electromyographic activities of the musculus mentalis) and DAT-SPECT ratios (i.e., the specific binding ratio for six different striatal regions – right and left caudate, right and left anterior and posterior putamen –, using ioflupane uptake in the occipital lobes as the background reference region) showed that most of the metrics were significantly correlated [107].

Follow-up studies in RBD subjects showed that abnormal DAT-SPECT values indicated a high risk of short-term phenoconversion to clinical synucleinopathies, such as cPD, DLB or MSA [108]. Also, in isolated hyposmia, DAT-SPECT imaging predicted a phenoconversion within a 4-year period, with a sensitivity of 74%, a specificity of 97%, a positive predictive value of 67%, and a negative predictive value of 97% [109]. Today, DAT-SPECT is considered to be the most reliable imaging marker for evidencing the dopamine-containing cell degeneration related to a synucleinopathy.

#### 4.1.2.2. ¹²³I-metaiodobenzylguanidine myocardial scintigraphy and 5-¹¹C-methoxy-donepezil (¹¹C-donepezil) positron emission tomography

Cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy is a method to assess the peripheral postganglionic presynaptic sympathetic noradrenergic innervation of the heart. Based on the results of eight different studies, it was demonstrated that 87 of 95 (92%) RBD patients had abnormal cardiac MIBG binding [110]. Interestingly, one study reported the potential role of identifying neurodegeneration with this technique in RBD patients with negative DAT-SPECT [111], suggesting its greater sensitivity for anticipating phenoconversion to a clinical synucleopathy phenotype. Nevertheless, it should be kept in mind that this paraclinical examination assesses peripheral autonomic dysfunction, which is often normal in prodromal MSA. Indeed, as demonstrated in a recent study, patients with RBD and a normal cardiac MIBG uptake progressed to MSA over time rather than to PD or DLB [112].

On the other branch of the autonomic system, the parasympathetic nervous system can be explored using ¹¹C-donepezil positron emission tomography (PET), a marker of the acetylcholine terminals. Using this technique, the colonic and small intestinal ¹¹C-donepezil signal was found to be significantly lower in RBD subjects compared to healthy subjects [113].

#### 4.1.2.3. Brain ¹⁸F-fluorodeoxyglucose positron emission tomography

Disease-specific patterns of altered brain glucose metabolism on ¹⁸F-fluorodeoxyglucose (FDG) PET imaging can be found in neurodegenerative parkinsonism-related disorders [114]. In RBD subjects, an RBD-related metabolic network was also identified that was characterized by increased activity in the pons, thalamus, medial frontal and sensorimotor areas, hippocampus, supramarginal and inferior temporal gyri, and posterior cerebellum, with decreased activity in occipital and superior temporal regions.
The metabolic expression of this pattern was elevated in RBD subjects as in cPD subjects but tended to decrease with disease progression [115].

#### 4.1.2.4. Towards a new targeted imaging modality: α-synuclein positron emission tomography

Alpha-synuclein imaging may offer the advantage of quantifying changes over time. However, several difficulties need to be addressed. Firstly, due to the low abundance of α-synuclein in the brain, a high-affinity ligand must be developed to detect it effectively. Additionally, the predominantly intracellular localization of α-synuclein depositions limits their accessibility for imaging. Moreover, it is crucial to ensure that the ligand exhibits selectivity over structurally similar amyloids, such as amyloid-beta and tau, which are often found together with α-synuclein pathology. Finally, the abnormal α-synuclein folding differs between the various forms of synucleinopathies (i.e., cPD, MSA), which may make it more difficult to target the right protein [116]. Nevertheless, for the first time in a human study, a team recently revealed promising results [117] using ¹⁸F-ACI-12589. This PET ligand demonstrated clear binding in the middle cerebellar peduncles and the cerebellar white matter of MSA patients but showed reduced binding in these structures in cPD (Fig. 2). Statistically, the binding separated MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies (cPD, DLB, progressive supranuclear palsy [PSP], AD, ataxia). To date, this technique has not been evaluated in RBD subjects. Combined with Tau-PET, these advanced imaging technologies may open up a new era of biological target imaging, which may in turn guide personalized treatment and effective follow-up for patients.

### 4.2. Prodromal biological features

#### 4.2.1. Alpha-synuclein detection and implications for disease staging

In a similar approach to that which has been used for AD for more than 10 years, a biological definition and staging of α-synuclein diseases was proposed in 2024 for cPD and DLB in two publications [118], [119]. This was made possible by the development of a highly sensitive method to detect α-synuclein through a seed amplification assay that leverages the self-replicating properties of the misfolded α-synuclein by fragmentation and elongation cycles. These two closely related models focus on α-synuclein as the central element in the pathophysiology of cPD and DLB, while de-emphasizing other cellular mechanisms such as mitochondrial dysfunction and ferroptosis, which might also be involved in the neurodegenerative process. Additionally, intracellular oligodendroglial synuclein, as observed in MSA, is excluded from such classifications. Briefly, it is proposed that the diagnosis should no longer be based solely on clinical symptoms but should also include the presence of abnormal synuclein and neurodegeneration. In the neuronal synuclein disease integrated staging system (NSD-SS) [119], the classification is based on an “S-D-G” system, and in the SynNeurGe [118], the classification is based on an “S-N-G” system. S indicates the presence (S+) or absence (S−) of abnormal α-synuclein, measured by seed amplification assay in cerebrospinal fluid (CSF) samples or skin biopsies in SynNeurGe or CSF only in NSD-
SS. Synuclein positivity has been found in multiple biological samples, but appears nowadays to have the highest sensitivities only in skin and CSF [120].

D or N indicates the presence (D+ or N+) or absence (D- or N-) of neurodegeneration as measured by quantitative DAT-SPECT biomarker as a single marker in NSD-SS and completed by a cerebral FDG-PET scan and cardiac MIBG scintigraphy in SynNeurGe. G indicates the presence (G+) or absence (G-) of relevant pathogenic variants in genes such as *α-synuclein*, *LRRK2*, *PRKN*, *GBA1*. As an example, a typical non-genetic PD patient will be classified as S+D+G- in NSD-SS, or S+N+G- in SynNeuroGe. cPD patients with an *α-synuclein* or *GBA1* mutation may be classified as S+D+G+ or S+N+G+, whereas those with a *PRKN* mutation may be S-D+G+ or S-N+G+, because abnormal synuclein is absent in most PRKN subjects. Patients at a prodromal stage such as RBD will be S+D-G- or S+N-G- until neurodegeneration is detected (D+ or N+). Atypical parkinsonism subjects such as PSP or CBD are classified as S-D+G- or S-N+G-.

One goal of this biological definition of synuclein disease is to enhance the development of early disease-modifying strategies for cPD and DLB. However, there is a risk of classifying individuals with a condition long before the onset of a disease that may never develop during their lifetime, as pointed out in a recent review [121]. Therefore, detecting the sole biological disease (S+ only) with or without subtle signs of neurodegeneration (D+ or N-) should not justify treating a person if no prodromal symptoms, such as RBD, orthostatic hypotension, or mild cognitive impairment, are present.

### 4.2.2. Neurofilament light chain

Neurofilament light chain (NfL) is a neuron-specific cytoskeletal component that is released in extracellular spaces after neuroaxonal impairment. It has been found to be elevated in several brain diseases such as traumatic brain injury, stroke, multiple sclerosis, or neurodegenerative diseases such as AD, fronto-temporal dementia and cPD [122].

Specifically in cPD, blood NfL levels are associated with a decrease in presynaptic putaminal dopamine transporter binding, reflecting the nigrostriatal degeneration [123]. Besides, NfL levels in CSF and blood are strongly and consistently correlated, allowing its detection in a large number of cPD individuals [123]. The more advanced the cPD, the higher the blood NfL levels, compared to healthy subjects. Indeed, disease duration is important information to obtain, as confirmed in a meta-analysis by Wang et al. [124] which did not find any significant differences in blood NfL levels between cPD subjects and healthy controls when disease duration and severity were not taken into account. In subjects at the prodromal stage, such as RBD subjects, elevated baseline NfL levels were significantly linked to increased risks of cognitive decline, motor and autonomic function progression, and phenocConversion to a clinical synucleinopathy during follow-up [125].

## 5. Towards an early diagnosis of prodromal PD?

In 2015, the International Parkinson and MDS released new standard diagnostic criteria for PD. Although primarily intended for clinical research, these criteria are also
applicable in clinical practice to help systematize diagnostic processes [126]. The
presence of parkinsonism remains central to the diagnosis, with motor symptoms
clearly defined within these guidelines. Notably, the criteria now incorporate nine
absolute exclusion criteria, 10 "red flags", and four supportive criteria. Also, non-motor
manifestations, including hyposmia, autonomic dysfunction, psychiatric symptoms, and
sleep disturbances, and ancillary diagnostic tests, such as olfactory testing, cardiac
MIBG scintigraphy, and presynaptic dopaminergic imaging, have been added. The
presence of dementia at the onset or in the first year of the disease is no longer
considered an exclusion criterion. However, members of the Lewy body dementia
Association Scientific Advisory Council have expressed concerns over this change,
advocating for retention of the "1-year rule" distinguishing PD dementia from DLB until
further data on genetic factors, pathophysiology, and prodromal states of these
disorders become available [127].

In addition to updating the criteria for clinically established and clinically probable PD, the MDS published a second paper in 2015 introducing innovative research criteria and a probabilistic approach for diagnosing prodromal PD [128]. The objective of these criteria is to estimate the likelihood that an individual is in the prodromal stage of PD. They were conceived as a research tool to reliably identify patients in the prodromal phase, enabling recruitment into trials, a critical need as neuroprotective or disease-modifying therapies are under development. Importantly, the MDS did not recommend applying these prodromal criteria outside research settings due to ethical concerns and the current lack of effective neuroprotective or disease-modifying therapies for PD. The MDS prodromal PD criteria rely on calculating the likelihood of prodromal disease based mainly on non-motor markers, with probable prodromal PD defined as > 80% certainty that a neurodegenerative process is present. This threshold, while arbitrarily chosen to represent a high likelihood, may vary depending on specific contexts; a 50% threshold has also been proposed for possible prodromal PD. As the speed of progression from prodromal PD to cPD is variable from one subject to another, the authors stipulated that these criteria should not be used to predict the time to phenoconversion. The individual risk of prodromal PD is assessed using a Bayesian naïve classifier. This method incorporates a baseline probability, determined by age-adjusted prevalence estimates of prodromal PD, and sequentially adds likelihood ratios of designated markers to determine the final post-test probability. The markers include both risk factors (e.g., sex, pesticide exposure, smoking status, caffeine use, genetic markers, and substantia nigra hyperechogenicity) and prodromal indicators (motor and non-motor), identified through a comprehensive literature review. Key prodromal markers include RBD, olfactory dysfunction, excessive daytime sleepiness, constipation, symptomatic hypotension, erectile dysfunction, urinary dysfunction, depression, and subthreshold parkinsonism. For the criteria to be met, risk factors must co-occur with at least one marker of ongoing neurodegeneration (prodromal markers).

The first revision of these criteria occurred in 2019, integrating new evidence on the predictive value of various markers [129]. While likelihood ratios remained largely unchanged, some minor adjustments were made. Notably, four new markers were added, including three risk markers and cognitive deficits as a prodromal marker. Orthostatic hypotension was subdivided into symptomatic (clinically diagnosed with alternative causes excluded) and neurogenic forms (diagnosed via clinical assessment or validated questionnaires without comprehensive diagnostic investigation) based on
emerging evidence. Several promising markers were identified but were excluded due to
insufficient prospective data. Genetic risk markers were also added for intermediate-
strength genetic factors such as mutations in GBA and LRRK2, other common genetic
risk factors, and protective genetic variants of low individual effect strength associated
with a polygenic risk score or a positive family history of PD. Both the original and the
revised MDS prodromal PD criteria have since been tested across multiple cohorts,
including population-based and enriched cohorts using retrospective and prospective
approaches. To test their predictive value in population-based cohorts, the MDS
research criteria for prodromal PD were applied in the Bruneck Study
cohort [130], [131], the HELIAD cohort of community-dwelling individuals aged
$\ge$ 65 years [132], the TREND study, the PRIPS study [133], and the Lifelines cohort, a
large study of 167,000 participants from the general population of the northern
Netherlands [134]. Results across these cohorts demonstrated moderate to high
predictive power and specificity for incident PD, although sensitivity remained
suboptimal, estimated at 14% to 66% [130], with a slight improvement in sensitivity
when using the 2019 updated criteria. However, these population-based cohorts lacked
data on high-LR markers, such as hyposmia, RBD status, and DAT-SPECT results, likely
contributing to the lower post-test probabilities and thus the limited sensitivity
observed.

When applied to enriched cohorts, the MDS prodromal criteria demonstrated their highest performance levels. In a group of patients with idiopathic hyposmia who underwent video-polysomnography and DAT-SPECT to assess RBD and nigrostriatal dysfunction, respectively, the MDS criteria successfully identified a subgroup at high risk of developing cPD. Among individuals meeting the criteria for prodromal PD with a probability exceeding 80%, one out of four converted to cPD within four years, whereas no phenoconversions occurred in the group not meeting the criteria [135]. In a prospective study on patients with RBD, the criteria showed 81% sensitivity and 68% specificity for conversion to PD or DLB after a 4-year follow-up. Remarkably, sensitivity reached 100% one year before conversion [136]. Similarly, in a large cohort of individuals with *LRRK2* mutations, the criteria achieved 92% specificity and 80% sensitivity [137]. Conversely, an exception was observed in a cohort of *GBA1* mutation carriers, where the MDS prodromal criteria failed to identify prodromal PD. This finding suggests that the criteria may lack sensitivity for detecting early prodromal changes in this specific population [138].

The MDS prodromal criteria provide a practical framework and a promising tool for
calculating the risk of prodromal PD [139]. Nonetheless, to address their variable
sensitivity in population-based cohorts and better define target populations for future
neuroprotection trials, additional screening tools and disease risk scores have been
proposed. Several authors have investigated complementary approaches, incorporating
common risk factors and prodromal markers alongside the MDS criteria. These include
the PREDICT-PD algorithm and its revised versions, which are based on a
comprehensive meta-analysis of early non-motor features and risk factors, initially
implemented in an online cohort [140], [141], or sleep-based approaches with the use of
a multistep screening process using RBD screening questionnaires [142] which have
shown promise to effectively identify prodromal PD in the general community.
## 6. What neuronal lesions or dysfunctions underlie the prodromal symptoms?

The core of the PD clinical phenotype is the consequence of a severe lack of dopamine in basal ganglia due to the degeneration of midbrain dopamine-containing cells. Since the degeneration is progressive, a mild to moderate lack of dopamine pre-exists before it reaches a threshold that induces symptoms noticeable by the affected person [4]. The below threshold lack of dopamine likely explains the subtle motor symptoms that can be observed during the prodromal stage.

The lack of dopamine and noradrenaline in the limbic region and the frontal cortex due to the lesion of the medial midbrain (the ventrotegmental area) participates in psychocognitive symptoms such as depression in the cPD phenotype.¹¹C-RTI-32 binding, an in vivo PET scan marker of both dopamine and noradrenaline transporter, was shown to be decreased in depressed vs. non-depressed cPD subjects in the locus coeruleus and in several regions of the limbic system, including the anterior cingulate cortex, the thalamus, the amygdala and the ventral striatum [143]. Another study found a correlation between the severity of depression and dysfunction in mesocorticolimbic dopaminergic transmission [144]. Furthermore, there was a lower dopamine level in the CSF of depressed cPD subjects in comparison to non-depressed cPD subjects [145].

Reduced acetylcholine receptor binding has been observed in the cortex of PD patients with depressive symptoms [146]. There is also growing evidence implicating the serotonergic system in cPD-related depression, with an upregulation of serotonin transporter density in cPD subjects with depression, compared to cPD subjects without, in the raphe nuclei and limbic structures [147]. Reduced concentrations of plasma serotonin were found to be correlated with the severity of depression in PD [148]. Mood disorders observed in prodromal PD have therefore been hypothesized to be linked to the early involvement of the limbic system and seem to result from the alteration of these multiple neurotransmitter pathways, some of which may be affected before significant nigrostriatal degeneration occurs [50], [149], [150].

In most cases, the PD degenerative process is associated with abnormal aggregation of α-synuclein. Such abnormal aggregates are one of the main components of Lewy bodies and neurites, designated as Lewy pathology, and are considered to be hallmarks of the disease [3]. They are found within and in the vicinity of midbrain dopamine-containing cells but also in other brain areas and in extra-cerebral regions, which could account for the motor and non-motor features often observed at the stage of cPD phenotype and most likely at the prodromal stage of the disease as well. Besides symptoms due to the lack of brain dopamine and other neurotransmitters, many prodromal features seem to reflect the development of the neuronal lesion or dysfunction associated with the synucleopathy. Hence abnormal α-synuclein aggregates observed in the locus coeruleus, the anterior olfactory nucleus, and the dorsal X nucleus [151] might be closely associated with prodromal sleep disorders, hyposmia, and constipation. The exact neuronal lesion or dysfunction accounting for these features has not yet been clearly identified.

A complex neuronal network is involved in the genesis of REM sleep [95]. RBD is likely the consequence of some lesion in this network, where abnormal α-synuclein aggregates have been observed [152]. From observations made in animal models, lesions of a pontine-medullary loop are likely to be responsible for RBD [153].
Hyposmia does not seem to be a consequence of direct lesion of the olfactory epithelium [154]. Rather, it might be a consequence of dysfunction or denervation of the cholinergic limbic afferents and of dopaminergic ventral tegmental area afferents [155], [156]. Deposition of misfolded α-synuclein in amacrine and ganglion cells, observed within the inner retina of cPD subjects [157], [158], might be associated with prodromal visual disturbances.

Alpha-synuclein-positive inclusions have been observed in the gastric myenteric and submucosal plexuses in cPD [159]. Constipation and other digestive problems seem however to be mainly a consequence of parasympathetic cholinergic afferents from the X cranial nerve to the gut. This was supported by the direct observation of bowel biopsies in cPD [160] and RBD [161], [162] subjects and reduced acetylcholine PET-scan tracer, ¹¹C-donepezil, signal in both the colon and small intestine in early cPD and RBD subjects [113], [163], [164].

Postganglionic presynaptic cardiac sympathetic innervation, assessed by ¹²³I-MIBG scintigraphy, is reduced in patients with Lewy body disease, such as cPD and clinical DLB. It has also been observed in RBD subjects, highlighting early autonomic involvement in these conditions [165], [166], [167].

## 7. A new view of the pathogenic process

Knowledge of the prodromal symptoms and their underlying lesions provides clues to the very early events in the PD degenerative process. In the early 2000s, the hypothesis of a transmissible proteinopathy was evoked. From series of autopsies of 41 PD subjects at different stages of the disease, 69 non-PD subjects with incidental Lewy bodies or neurites, and 58 normal subjects, Braak et al. [151] observed the distribution of Lewy bodies and neurites (i.e., Lewy pathology) in various parts of the brain. Lewy pathology was mainly observed in the medulla oblongata in the dorsal part of IX and X motor nuclei, frequently in the anterior olfactory nucleus, and sometimes also in the pontine tegmentum in non-PD subjects with incidental brain Lewy bodies. In cases with moderate to severe Lewy pathology, other lesions, in addition to the previously mentioned lesions, were observed at the level of the midbrain and sometimes in the cortex. In these subjects, severe dopamine-containing cell loss was observed in the midbrain and most of them had a clinical PD phenotype. From these observations, Braak inferred that the degenerative process might start at the level of the dorsal IX/X nuclei and sometimes in the anterior olfactory nucleus, before spreading along a rostral course to the pontine nucleus, then the midbrain, and eventually the cortex [151].

Shortly after, Lewy bodies were observed in the dopamine-containing cells grafted more than a decade before the death of some PD patients who underwent foetal mesencephalic dopaminergic neuron transplantation as a means of restoring dopamine to their striatum [168], [169]. These observations suggested host-to-graft disease propagation. Following these observations, numerous experimental in vitro and animal studies have shown that abnormal misfolded α-synuclein can be released and taken up by neurons and can seed misfolding of endogenous α-synuclein, a mechanism similar to what is known in prion diseases [170] (for review see [171], [172]).

Such a seductive hypothesis was however discussed and rapidly appeared unable to be applied to all cases of PD. Braak's hypothesis was based on three main assumptions:
* abnormal brain accumulation of synuclein is a primary phenomenon responsible for the nerve cell death;

* observations made on brains from individuals deceased at different stages of the disease can be extrapolated to obtain a picture of the longitudinal progression of the disease;

* an asymptomatic person with brain Lewy bodies is at a pre-symptomatic stage of the disease.

Abnormal accumulation of synuclein is closely associated with the nerve cell death process in PD. Its primary role, however, is far from being demonstrated. Some other evidence has even suggested that a lack of functional synuclein is the primary phenomenon and that the accumulation of synuclein is only a secondary phenomenon [173]. A gradient of cell vulnerability to an external or internal deleterious factor might be an alternative explanation for the observed distribution of the lesion (e.g., severe lesion at the level of the highly vulnerable dopamine-containing cells in the midbrain and the absence of lesion of the resistant striatal gabaergic cells) [174], [175]. This may lead to an illusion of the lesion spreading from one region to another. The level of bioenergetic demand and the level of free cytosolic calcium are some of the factors that could be associated with a specific cell vulnerability in PD [176]. According to such a hypothesis, the Lewy body pathology might be an epiphenomenon or an aggravating factor of the degenerative process.

As stated above, Braak's hypothesis was based on an extrapolation from individual brain analyses. Without an available in vivo biomarker of the PD degenerative process, such as the α-synuclein PET scan, there is no way of obtaining reliable information about brain disease progression. Several neuropathological studies have also pointed out that 20–50% of cPD patients do not follow the Braak pattern of α-synuclein propagation, with, for example, 7–17% of cases without α-synuclein pathology in the lower brainstem, including the dorsal motor nucleus of the vagus nerve (i.e., Braak stage 1) [177], [178], [179]. Moreover, the level of accumulation of synuclein in the brain is not always associated with the severity of the nerve cell loss [180], [181], [182]. Finally, focusing solely on α-synuclein does not take into consideration the role of the vascular leukopathy and of the other degenerative processes often present in the brain of aged people [183], two factors which likely modify the degenerative process and the clinical phenotype.

In all likelihood there is still a long way to go before the precise pathogenic mechanisms involved in PD can be identified, especially since they are due to multiple interconnected factors, variable from one subject to another [184]. However, general trends might be identified and might already be perceptible at the prodromal stage of the disease. Schematically, three main patterns of PD degeneration seem to have been recognized and may provide some information about the further progression of the disease: a peripheral prodromal PD, a mild cognitive impairment prodromal PD, and a silent prodromal PD. The first one corresponds to the Braak pattern of disease progression. It is also named the “body first PD” [185]. In this form, prodromal symptoms are florid, with constipation, hypotension, and RBD. Even if it is not clinically observed, compared to silent prodromal PD, subjects with this prodromal form are more prone to have parasympathetic denervation of the gut, as assessed by ¹¹C-donepezil PET, and sympathetic denervation of the heart, as assessed by MIBG scintigraphy [186]. In the second form, the lesions seem to be particularly severe in the amygdala and the other
limbic region [185], [186], [187]. The subjects usually rapidly develop cognitive impairment corresponding to DLB cases or early PD dementia [188], [189]. The third form might be the most common although by definition not recognized at the prodromal stage. The disease mainly starts within the central nervous system at the level of the SN. It corresponds to cPD, with a prolonged "pure" dopamine nigrostriatal denervation. Subjects with this form are usually well improved by dopamine replacement treatment but are also prone to develop motor fluctuation and dyskinesia. The peripheral extension of the disease and the cognitive impairment develop later [190], [191].

## 8. Conclusion

There is growing interest in the prodromal stage of PD. Since the classical phenotype of cPD is recognized at a stage where the lesions are already marked, the ability to detect earlier the degenerative process is crucial to enable treatment to be undertaken to slow down the process. Logically, many studies have focused on subjects with detectable prodromal features, such as dysautonomia and RBD. This has led, however, to a biased view, with a degenerative process starting at a peripheral level and then spreading progressively within the brain from the lower brainstem to the cortex. Nowadays, it is clear that the progression of the disease is more complex and variable from one subject to another. In some subjects, a symptomatic prodromal stage exists, with either peripheral symptoms and RBD or mild cognitive symptoms. These cases appear to be at a high risk of a fast evolution. In contrast, very many subjects experience a silent prodromal stage without any clear symptoms before the PD phenotype appears. The development of new biomarkers and the better characterization of the factors associated with different types of disease progression at the prodromal stage of the disease constitute an important challenge in PD.

## Funding

This review did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

## Authors' contributions

Authorship: A. Conception, B. Manuscript draft, C. Manuscript revision, D. Final approval.

L.G.: B, C, D.

S.G.: B, C, D.

P.D.: A, B, C, D.

## Disclosure of interest

The authors declare that they have no competing interest.
# Acknowledgements

We thank Nick Barton for proofreading the manuscript.

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