Premotor Symptoms Research Articles

The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study).

Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.

Anterior Temporal Atrophy and Posterior Progression in Patients with Parkinson's Disease

Background: Parkinson's disease (PD) is characterized by specific motor and nonmotor impairments. This suggests that PD is characterized by disease-specific regional cortical atrophy. Given the change of symptoms over time, a concurrent increase in regional atrophy may further be assumed to reflect the dynamic process of disease progression. Methods: In this study we retrospectively collected T1-weighted MRI scans from previous studies performed in our center, enabling the comparison of gray matter atrophy in 77 PD patients with 87 controls using voxel-based morphometry (VBM). This large VBM analysis provided the opportunity to investigate cortical atrophy in relation with disease progression. Results: We found significant PD-related reductions of gray matter density bilaterally in the anterior temporal cortex, the left inferior frontal and left extrastriate visual cortex, independent from normal aging. The anterior temporal cortex did not show major progression, whereas particularly the posterior parts of the lateral temporal cortex and adjacent extrastriate visual cortex occurred at a later stage of disease. Conclusions: Temporal pole atrophy as an early sign of PD is consistent with the PD pathology classification of Braak. The initial anterior temporal atrophy with spread to occipitotemporal and posterior parietal regions may subserve ‘emotion-based' sensorimotor transformations and deficits in the visual domain, respectively, which may be regarded as premotor symptoms.

History of smoking and olfaction in Parkinson's disease.

Olfactory dysfunction is the most common pre-motor symptom in Parkinson's disease (PD), and smoking is known to be associated with lower risk of PD. This study tested the hypothesis that smoking is associated with better olfaction in PD. Smoking history was obtained from 76 PD subjects (22 with a history of smoking [smokers], 54 who never smoked [nonsmokers]), and 70 controls (17 smokers, 53 nonsmokers). Olfaction was assessed using the 40-item University of Pennsylvania Smell Identification Test (UPSIT). The olfactory scores between groups and subgroups were compared using analysis of covariance with adjustment for age, gender, and monoamine oxidase B (MAO-B) inhibitor usage. Overall the olfactory score was lower in PD compared with controls (olfactory scores: 21.5 vs. 33.5, P < 0.0001). Among controls, there was no significant difference in olfaction between smokers and nonsmokers (olfactory scores, 33.2 vs. 34.2; P = 0.95). Among PD subjects, however, smokers scored significantly better regarding olfaction compared with nonsmokers (olfactory scores: 24.4 vs. 19.9, P = 0.02). These data suggest that a history of smoking is associated with better olfaction among PD patients. The finding may be related to why smoking may be protective against PD. Further studies are needed to confirm this finding and investigate the underlying mechanisms.

Anxiety- and depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson's disease.

CD157, known as bone marrow stromal cell antigen-1, is a glycosylphosphatidylinositol-anchored ADP-ribosyl cyclase that supports the survival and function of B-lymphocytes and hematopoietic or intestinal stem cells. Although CD157/Bst1 is a risk locus in Parkinson's disease (PD), little is known about the function of CD157 in the nervous system and contribution to PD progression. Here, we show that no apparent motor dysfunction was observed in young knockout (CD157−/−) male mice under less aging-related effects on behaviors. CD157−/− mice exhibited anxiety-related and depression-like behaviors compared with wild-type mice. These behaviors were rescued through treatment with anti-psychiatric drugs and oxytocin. CD157 was weakly expressed in the amygdala and c-Fos immunoreactivity in the amygdala was less evident in CD157−/− mice than in wild-type mice. These results demonstrate for the first time that CD157 plays a role as a neuro-regulator and suggest a potential role in pre-motor symptoms in PD.

Nocturnal manifestations of Parkinson's disease and atypical Parkinsonism.

In this Supplement of the Journal of Neural Transmission, we address an important feature of Parkinson’s syndrome, i.e. nocturnal problems. We feel very honoured that so many eminent experts in this field have contributed to a supplement which should be of interest to everyone who deals with Parkinson’s disease (PD). It is accepted by neuroscientists that PD is a progressive disease with an accumulation of a-synuclein (Spillantini et al. 1997). Since these accumulations are also found in the mesencephalon where sleep regulation is located, it follows that impairment of sleep is a natural consequence of this progressive disease (Braak et al. 2003). Even James Parkinson addressed sleep problems in his essay on the shaking palsy when he writes ‘‘...as the malady proceeds, the sleep becomes much disturbed...’’ (Parkinson 1817). REM sleep behaviour disorder (RBD) is associated with hyposmia, constipation and depression as among the most frequent and important pre-motor symptoms in PD (Bhidayasiri and Reichmann 2013; Reichmann 2010). Patients with RBD lack physiological atonia during REM sleep and frequently scream and move violently, often injuring their sleeping partners. More than 60 % of these patients will later develop a second neurodegenerative disorder, very often PD or atypical parkinsonism (Claassen et al. 2010). But there are many more nocturnal disturbances in patients with PD such as nocturia, pollakisuria, problems falling asleep, problems staying asleep, restless legs syndrome, pain during nighttime, early morning akinesia and many more (Grandas and Iranzo 2004). Patients rate nighttime problems rather high when they are asked what impairs their quality of life the most (Barone et al. 2009). Thus, it is obvious that we need scales to quantify these features. Fortunately, such scales have been developed which give a good estimate of sleep problems in PD (Hogl et al. 2010). For others we can use the Parkinson’s disease sleep scale (PDSS) or the scales for outcomes in PD sleep (SCOPA-S) (Chaudhuri et al. 2002; Marinus et al. 2003). Of all nonmotor symptoms in PD, sleep problems belong to the most serious ones since they do not only impair quality of sleep and rest but also impair motor performance in the early morning and give rise to fatigue and somnolence during daytime (Comella 2006). Both nighttime and daytime problems also impair the quality of life of the patients’ caregivers since they do not find enough rest to take care of the patients during the daytime (Martinez-Martin et al. 2007). Thus, treatment of nocturnal problems in PD is extremely important. Most PD specialists use a long-acting dopamine replacement therapy to address a dopaminergic trough during the nighttime (Ray Chaudhuri et al. 2012; Trenkwalder et al. 2011). It is helpful to use extendedrelease preparations of levodopa since there would not be any interference with food at nighttime (Chouza et al. 1990). Long-acting dopamine agonists are extremely helpful to overcome nighttime problems and to increase the possibility of a good start of the next day. In addition, the H. Reichmann Klinik und Poliklinik fur Neurologie, Universitatsklinikum Carl Gustav Carus, Dresden, Germany

Premotor parkinsonism models

Aside from motor symptoms, Parkinson's disease is associated with a number of non-motor symptoms arising many years before motor signs. The most prevalent and predictive premotor symptoms include olfactory dysfunction, REM sleep behaviour disorder (RBD) and constipation. Several studies in toxin- or gene-based models have specifically investigated these non-motor signs in a premotor context. Altered olfactory discrimination has been reproduced both in toxin- and in gene-based models, and genetic models may also reproduce the underlying pathophysiological mechanisms. Sleep alterations have also been demonstrated, mostly in toxin-based models, and RBD-like features can be demonstrated in non-human primates. Gastrointestinal dysfunction and associated enteric pathology are reproduced both in toxin and genetic models displaying reduced colonic motility and enteric α-synuclein accumulation. This review describes the main premotor symptoms that are recapitulated both in toxin- and in gene-based models, their relevance to the human disease, and their potential to understand the underlying mechanisms of early symptoms and disease progression.

Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications

Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967

A pathophysiological link between dystonia, striatal interneurons and neuropeptide Y

The dystonias comprise a heterogeneous group of hyperkinetic movement disorders characterized by involuntary muscle contractions that manifest as twisting, repetitive movements and abnormal postures. They are often misdiagnosed or unrecognized (Muller, 2009). These neurological syndromes are mainly of genetic origin and usually are not associated with gross neuropathological changes. Neurophysiological studies, imaging data and pathological findings support the hypothesis that multiple striatal, cortical, dopaminergic and cholinergic dysfunctions cause the motor alterations in the various forms of dystonias (Phukan et al. , 2011). Among the various primary dystonias, a form of adult-onset X-linked dystonia-parkinsonism (MIM314250), also known as DYT3 dystonia or ‘Lubag’ disease, has been described. It was reported for the first time in Filipino males from Panay Island. X-linked dystonia-parkinsonism appears predominantly as torsion dystonia, later either combined or replaced with parkinsonism. In females it has been reported in a milder clinical form with minor motor symptoms represented by parkinsonism and cervical dystonia and showing either slow or no clinical progression (Lee et al. , 2011). X-linked dystonia-parkinsonism is associated with sequence changes within the TAF1/DYT3 multiple transcript system. It has been postulated that this system might be linked with dopaminergic transmission, potentially explaining the parkinsonism observed in most patients in the late stages of the disease (Herzfeld et al. , 2013). Some clinical observations seem to correlate the pathophysiology of X-linked dystonia-parkinsonism with the dopaminergic basal ganglia circuit dysfunction that characterizes Parkinson’s disease. Hyposmia, a pre-motor symptom frequently reported in patients with Parkinson’s disease has also been demonstrated to occur in X-linked dystonia-parkinsonism (Evidente et al. , 2004). Moreover, bilateral pallidal stimulation, a therapeutic approach successfully utilized in Parkinson’s disease, also ameliorates symptoms in patients with X-linked dystonia-parkinsonism (Fig. 1) (Evidente et al. , 2007). Other findings argue against this view. Indeed, although a selective reduction …

Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease.

Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.

Psychosocial risk factors, pre-motor symptoms and first-time hospitalization with Parkinson's disease: a prospective cohort study.

Experimental studies support a link between stress and development of parkinsonian symptoms, but prospective population studies are lacking. The aim of the current study is to determine the effects of several psychosocial factors on the risk of Parkinson's disease (PD), as well as to identify potential pre-motor symptoms for PD in a large prospective cohort study. In 1991-1993, a total of 9955 women and men free of PD from the Copenhagen City Heart Study were asked about major life events, economic hardship, social network, impaired sleep and vital exhaustion. The participants were followed for first-time hospitalization with PD in nationwide registers until 2011. Vital exhaustion was associated with a higher risk of PD hospitalization in an exposure-dependent manner (P(trend) = 0.001), with high vs. low vital exhaustion being associated with a hazard ratio of 2.50 [95% confidence interval (CI): 1.28-4.89]. A slightly higher risk of PD hospitalization (hazard ratio = 1.49; 95% CI: 0.87-2.56) was suggested in participants with impaired sleep at baseline. No more than weak associations were observed for economic hardship, major life events or inadequate social network in the current study. Overall, the hypothesis that psychosocial risk factors affect the risk of PD is not supported. The results, however, suggest that vital exhaustion may be a pre-motor marker of the neurodegenerative process eventually leading to motor symptoms and clinical PD. Vital exhaustion may be useful for screening aimed at early detection and when considering disease-modifying therapies in people at high risk of clinical PD.

Prevalence of Non-Motor and Pre-Motor Symptoms in Patients with Amyotrophic Lateral Sclerosis (P07.070)

Prevalence of Non-Motor and Pre-Motor Symptoms in Patients with Amyotrophic Lateral Sclerosis (P07.070)

Meta-Analysis on the Prevalence of Selected Premotor Symptoms of Parkinson Disease before and after Diagnosis (P06.097)

Meta-Analysis on the Prevalence of Selected Premotor Symptoms of Parkinson Disease before and after Diagnosis (P06.097)

Meta‐analysis of early nonmotor features and risk factors for Parkinson disease

ObjectiveTo evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population-based screening.MethodsA systematic review and meta-analysis of risk factors for PD.ResultsThe strongest associations with later diagnosis of PD were found for having a first-degree or any relative with PD (odds ratio [OR], 3.23; 95% confidence interval [CI], 2.65–3.93 and OR, 4.45; 95% CI, 3.39–5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10–3.57), constipation (relative risk [RR], 2.34; 95% CI, 1.55–3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39–0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta-blockers, farming occupation, and well-water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results.InterpretationThe strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them. ANN NEUROL 2012

Impaired pain processing in Parkinson's disease and its relative association with the sense of smell

Background and purposeMany non-motor symptoms are associated with Parkinson's disease (PD). Of these, pain and olfactory disturbance tend to be common premotor symptoms. PD has been shown to exhibit abnormal central pain processing, although underlying mechanisms are not yet fully understood. In order to investigate this further, we assessed PD patients by specific Aδ stimulation with intra-epidermal needle electrode and determined olfactory function. MethodsForty-two patients (18 males and 24 females) with PD and 17 healthy control subjects (8 males and 9 females) were studied. A thin needle electrode was used to stimulate epidermal Aδ fibers, and somatosensory evoked potentials (SEPs) recorded at the vertex. Olfactory function was evaluated using the Odor Stick Identification Test for Japanese (OSIT-J) and its relationship with pain-related SEPs was investigated. ResultsThere were no significant differences in N1 latencies or P1 latencies although N1/P1 peak-to-peak amplitudes were significantly lower (p < 0.01) in PD patients than in control subjects. In PD patients, there were significant correlations between N1/P1 amplitudes and disease duration (r = −0.35, p < 0.05), Hoehn-Yahr stage (r = −0.38, p < 0.05) and UPDRS part III (r = −0.42, p < 0.01). Furthermore, the OSIT-J scores correlated with SEP amplitude (r = 0.41, p < 0.01). ConclusionPain processing in PD patients was impaired under specific nociceptive stimulation of Aδ fibers and significant correlation with smell dysfunction was detected. We suggest that this mechanism may involve the limbic system during PD pathology.

Sleep Disturbances in Parkinson's Disease With Emphasis on Rapid Eye Movement Sleep Behavior Disorder

ABSTRACTSleep disturbances are common in patients with Parkinson's disease (PD). These disturbances can primarily affect the patient's quality of life and may worsen the symptoms of PD. Among the multiple sleep disturbances in PD patients, there has been a marked growing interest in rapid eye movement (REM) sleep behavior disorder (RBD). This is likely due to the fact that RBD has been proven to precede the motor symptoms of PD by many years. The aim of this article is to examine the sleep disturbances found in PD, with special attention to RBD as a premotor symptom of PD, as well as to assess its proposed related pathophysiology. MEDLINE (1966–March 2010), American Academy of Sleep Medicine's, The International Classification of Sleep Disorders, and current textbooks of sleep medicine were searched for relevant information. Search terms: RBD, sleep disturbances, Parkinson's disease, and pre-motor were used. Excessive daytime sleepiness (EDS), sleep attack, insomnia, restless leg syndrome (RLS), sleep-disordered breathing (SDB), and RBD are sleep disturbances commonly found in the literature related to PD. Sleep benefit has been proven to lessen PD motor symptoms. RBD has been described as a premotor symptom of PD in several prospective, retrospective, and cross-sectional studies. Sleep disturbances in PD can result secondarily to natural disease progression, as a side effect of the medications used in PD, or in result of pre-clinical pathology. Treatment of sleep disturbances in PD patients is crucial, as what is termed as, “sleep benefit effect” has been shown to improve the symptoms of PD.

Transcranial sonography (TCS) in Parkinson's disease (PD) and essential tremor (ET) in relation with putative premotor symptoms of PD

Background: Hyperechogenicity of substantia nigra (SN+) is a common finding in transcranial ultrasound studies of parkinsonian patients. However, this feature is also found in 13–16% of ET patients. The possible links between ET and PD are of special interest, particularly with the familial aggregated data supporting this association. However, few studies have been conducted regarding the factors associated with the emergence of PD in the ET population. In this study, we investigated the possible association between SN+ and putative premotor symptoms of PD in patients with ET. Methods: A total of 47 patients with PD and 64 patients with ET were enrolled in the study. All patients underwent TCS and completed a structured interview for putative premotor symptoms of PD. Results: As expected, there were significant differences observed in the frequency and size of SN+, and the prevalence of the putative premotor symptoms of PD. More interestingly, in the ET group a significant association between SN+ and each premotor symptom was observed and a trend was also found that ET cases with more putative premotor symptoms of PD had a greater size of SN+. In contrast, in the PD group, SN+ was not influenced by the cumulative effect of premotor symptoms. Conclusion: The results of this study suggest that SN+ in patients with ET is influenced by the putative premotor symptoms of PD.

Premotor Symptoms and Early Diagnosis of Parkinson's Disease

ABSTRACTParkinson's disease is a disorder characterized by the motor findings of bradykinesia, rest tremor, cogwheel rigidity, and postural instability. As the disease progresses, most patients develop numerous nonmotor signs and symptoms, many of which play a major role in reducing quality of life. What is becoming increasingly clear is that nonmotor findings, including hyposmia, sleep disorders, autonomic abnormalities, cognitive changes, and neurobehavioral changes, often precede the motor findings.

REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease.

Sleep problems are a common phenomenon in most neurological and psychiatric diseases. In Parkinson disease (PD), for instance, sleep problems may be the most common and burdensome non-motor symptoms in addition to the well-described classical motor symptoms. Since sleep disturbances generally become apparent in the disease before motor symptoms emerge, they may represent early diagnostic tools and a means to investigate early mechanisms in PD onset. The sleep disturbance, REM sleep behavior disorder (RBD), precedes PD in one-third of patients. We therefore investigated sleep changes in marmoset monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), the non-human primate model for idiopathic PD. Mild parkinsonism was induced in 5 marmoset monkeys (3M/2F) over a 2-week period of subchronic MPTP treatment. Electroencephalograms (EEGs) and electromyograms (EMGs) were recorded weekly. Motor activity and hand-eye coordination were also measured weekly, and any signs of parkinsonism were noted each day. Sleep parameters, motor activity, and performance data before and after MPTP treatment were compared between MPTP-treated marmosets and 4 control marmosets (1M/3F). MPTP increased the number of sleep epochs with high-amplitude EMG bouts during REM sleep relative to control animals (mean ± SEM percentage of REM 58.2 ± 9.3 vs. 29.6 ± 7.7; P < 0.05). Of all sleep parameters measured, RBD-like measures discriminated best between MPTP-treated and control animals. On the other hand, functional motor behavior, as measured by hand-eye coordination, was not affected by MPTP treatment (correct trials MPTP: 23.40 ± 3.56 vs. control: 36.13 ± 5.88 correct trials; P = 0.32). This REM sleep-specific change, in the absence of profound changes in wake motor behaviors, suggests that the MPTP marmoset model of PD could be used for further studies into the mechanisms and treatment of RBD and other sleep disorders in premotor symptom PD.

Progress in defining the premotor phase of Parkinson's disease

Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinson's disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset.Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD.

Parkinson’s disease risk score: moving to a premotor diagnosis

Early pre-motor symptoms (also frequently termed "non-motor" symptoms) in Parkinson's disease (PD), which precede the onset of motor symptoms, are being increasingly recognized by clinicians. Non-motor symptoms in the pre-motor phase of PD include impaired olfaction (hyposmia), sleep disturbances (i.e., radid eye movement sleep behavior disorder, daytime sleepiness), behavioral/emotional dysfunction (i.e., change of personality or change of core personal characteristics), dysautonomia (i.e., constipation, urinary dysfunction, orthostatic hypotension), depressive symptoms (i.e., fatigue, apathy, anxiety), and chronic pain (joint and muscle). The pre-motor phase of PD is based on current pathophysiological concepts that relate these symptoms to early structural changes within lower brainstem nuclei and the peripheral nervous system including the autonomic and enteric ganglia. The perspective to identify these symptoms as early as possible will enable neurologists to make a diagnosis at the pre-motor stage of PD. Thus, the development of a PD risk score will be the first means to identify individuals at risk who are most likely to develop the prototypical motor symptoms of PD later in life. More importantly, these individuals at risk will be the first to benefit from disease-modifying strategies. In this workshop report, the elements of a PD risk score are proposed, including the stepwise sequence of escalating diagnostic measures to diagnose the pre-motor stage in PD.