Prodromal Phase Of Parkinson's Disease Research Articles

Risk of Parkinson's disease in people with New Onset Anxiety over 50 years - Incidence and Associated Features.

Anxiety has been identified as a prodromal feature of Parkinson's disease (PD). The prospective risk of PD in those newly presenting with anxiety and factors that increase the risk of PD in patients with anxiety have not been investigated. To investigate the incidence of PD in people with anxiety above the age 50 years and clinical features associated with later diagnosis of PD in people with anxiety. Retrospective cohort study using UK primary care data of people between 2008 and 2018 who had new onset anxiety over the age of 50 years. We fitted Weibull survival regression models and estimated hazard ratios (HR) for modelling time-to-PD in those with and without anxiety and when determining the risk of developing PD in those with anxiety. Results were adjusted for sociodemographic and lifestyle factors and relevant physical and mental health conditions. The risk of PD was increased 2-fold compared to the non-anxiety group after adjustment for age, sex, social deprivation, lifestyle factors, severe mental illness, head trauma and dementia HR 2.1 (CI: 1.9-2.4). In those with anxiety, the presence of depression, hypotension, tremor, rigidity, balance impairment, constipation, sleep disturbance, fatigue, and cognitive impairment were associated with an increased risk of developing PD. The risk of developing PD was at least doubled in people with anxiety compared to those without. The clinical features of those who developed PD can help identify patients presenting with anxiety who are in the prodromal phase of PD.

Neuromelanin-sensitive magnetic resonance imaging: Possibilities and promises as an imaging biomarker for Parkinson's disease.

Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder characterized by both motor and non-motor symptoms resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus (LC). The current diagnosis of PD primarily relies on motor symptoms, often leading to diagnoses in advanced stages, where a significant portion of SNpc dopamine neurons has already succumbed. Therefore, the identification of imaging biomarkers for early-stage PD diagnosis and disease progression monitoring is imperative. Recent studies propose that neuromelanin-sensitive magnetic resonance imaging (NM-MRI) holds promise as an imaging biomarker. In this review, we summarize the latest findings concerning NM-MRI characteristics at various stages in patients with PD and those with atypical parkinsonism. In conclusion, alterations in neuromelanin within the LC are associated with non-motor symptoms and prove to be a reliable imaging biomarker in the prodromal phase of PD. Furthermore, NM-MRI demonstrates efficacy in differentiating progressive supranuclear palsy (PSP) from PD and multiple system atrophy with predominant parkinsonism. The spatial patterns of changes in the SNpc can be indicative of PD progression and aid in distinguishing between PSP and synucleinopathies. We recommend that patients with PD and individuals at risk for PD undergo regular NM-MRI examinations. This technology holds the potential for widespread use in PD diagnosis.

Experimental Animal Models of Prodromal Parkinson's Disease.

There is an estimated 35-45% loss of striatal dopamine at the time of diagnosis of Parkinson's disease (PD), and cases clinically diagnosed in the early stages may already be pathologically in advanced stages. Recent large-scale clinical trials of disease-modifying therapies (DMT) also suggest the necessity of targeting patients at earlier stages of the disease. From this perspective, the prodromal phase of PD is currently the focus of attention, emphasizing the need for a prodromal mouse model that accurately reflects the pathophysiology, along with early biomarkers. To establish prodromal animal model of PD with high face validity that reflects the disease state, the model must possess high construct validity that accurately incorporates clinical and pathological features in the prodromal phase. Furthermore, as a preclinical model of DMT, the model must possess high predictive validity to accurately evaluate the response to intervention. This review provides an overview of animal models which reflect the characteristics of prodromal PD, including alpha-synuclein (aS) accumulation and associated early non-motor symptoms, with a focus on the aS propagation model and genetic model. In addition, we discuss the challenges associated with these models. The genetic model often fails to induce motor symptoms, while aS propagation models skip the crucial step of initial aS aggregate formation, thereby not fully replicating the entire natural course of the disease. Identifying factors that induce the transition from prodromal to symptomatic phase is important as a preclinical model for DMT to prevent or delay the onset of the disease.

Subjective Cognitive Decline in Women with Features Suggestive of Prodromal Parkinson's Disease.

Cognitive deficits can be present in the prodromal phase of Parkinson's disease (PD). Subjective cognitive decline (SCD) may contribute to identifying individuals with prodromal PD. The objective of this study was to examine whether SCD is more likely to be present in women with features suggestive of prodromal PD compared with women without these features. The study population comprised 12,427 women from the Nurses' Health Study selected to investigate prodromal PD. Prodromal and risk markers of PD were assessed via self-administered questionnaires. We evaluated the association of hyposmia, constipation, and probable rapid eye movement sleep behavior disorder, three major features of prodromal PD, with SCD, adjusting for age, education, body mass index, physical activity, smoking, alcohol, caffeine intake, and depression. We also explored whether SCD was associated with the probability of prodromal PD and conducted additional analyses using data from neurocognitive tests. Women experiencing the three examined nonmotor features had the worst mean SCD score and the highest odds of poor subjective cognition (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.29-2.47). This association persisted when women with objective cognitive deficits were excluded from analyses. SCD was also more common in women with a probability of prodromal PD ≥0.80, particularly among those aged younger than 75 years (OR of poor subjective cognition = 6.57 [95% CI, 2.43-17.77]). These observations were consistent with the results from analyses using neurocognitive tests, where a worse global cognitive performance was observed among women with three features. Our study suggests that self-perceived cognitive decline can be present during the prodromal phase of PD. © 2023 International Parkinson and Movement Disorder Society.

Presence but not the timing of onset of REM sleep behavior disorder distinguishes evolution patterns in Parkinson's disease

BackgroundRapid eye movement (REM) sleep behavior disorder (RBD) could develop preceding or come after motor symptoms during Parkinson's disease (PD). It remains unknown that whether PD with different timing of RBD onset relative to motor symptoms suggests different spatiotemporal sequence of neurodegeneration. This study aimed to explore the sequence of disease progression in crucially involved brain regions in PD with different timing of RBD onset. MethodWe recruited 157 PD, 16 isolated RBD (iRBD), and 78 healthy controls. PD patients were identified as (1) PD with RBD preceding motor symptoms (PD-preRBD, n = 50), (2) PD with RBD posterior to motor symptoms (PD-postRBD, n = 31), (3) PD without RBD (PD-nonRBD, n = 75). The volumes of crucial brain regions, including the basal ganglia and limbic structures in T1-weighted imaging, and the contrast-noise-ratios of locus coeruleus (LC) and substantia nigra (SN) in neuromelanin-sensitive magnetic resonance imaging, were extracted. To simulate the sequence of disease progression for cross-sectional data, an event-based model was introduced to estimate the maximum likelihood sequence of regions' involvement for each group. Then, a statistical parameter, the Bhattacharya coefficient (BC), was used to evaluate the similarity of the sequence. ResultsThe model predicted that SN occupied the highest likelihood in the maximum likelihood sequence of disease progression in the all PD subgroups, while LC was specifically positioned earlier to SN in iRBD, a prodromal phase of PD. Subsequent early involvement of LC was observed in the both PD-preRBD and PD-postRBD. In contrast, atrophy in the para-hippocampal gyrus but relatively intact LC in the early stage was demonstrated in PD-nonRBD. Then, the similarity comparisons indicated higher BC between PD-postRBD and PD-preRBD (BC = 0.76) but lower BC between PD-postRBD and PD-nonRBD group (BC = 0.41). iRBD had higher BC against PD-preRBD (BC = 0.66) and PD-postRBD (BC = 0.63) but lower BC against PD- nonRBD (BC = 0.48). ConclusionThe spatiotemporal sequence of neurodegeneration between PD-pre and PD-post were similar but distinct from PD-nonRBD. The presence of RBD may be the essential factor for differentiating the degeneration patterns of PD, but the timing of RBD onset has currently proved to be not.

Widening the Spectrum of Risk Factors, Comorbidities, and Prodromal Features of Parkinson Disease

The prodromal phase of Parkinson disease (PD) may last for more than 10 years. Recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD can increase understanding of the causes and development of the disease and help identify individuals at risk. To identify the association of a subsequent diagnosis of PD with a range of risk factors and prodromal features, including lifestyle factors, comorbidities, and potential extracerebral manifestations of PD. This was a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2011, and December 31, 2020. Included were patients with incident diagnosis of PD without a previous diagnosis of parkinsonism or dementia and controls matched 1:2 for age, sex, region, and earliest year of outpatient encounter. Exposures were selected based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of PD. Previously postulated risk factors and prodromal features of PD, using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding. A total of 138 345 patients with incident PD (mean [SD] age, 75.1 [9.8] years; 73 720 male [53.3%]) and 276 690 matched controls (mean [SD] age, 75.1 (9.8) years; 147 440 male [53.3%]) were identified. Study participants were followed up for a mean (SD) of 6.0 (2.0) years. Consistent with previous reports, risk factors and prodromal features associated with PD included traumatic brain injury, odds ratio (OR), 1.62; 95% CI, 1.36-1.92; alcohol misuse, OR, 1.32; 95% CI, 1.21-1.44; hypertension, OR, 1.29; 95% CI, 1.26-1.31; anosmia, OR, 2.16; 95% CI, 1.59-2.93; and parasomnias (including RBD), OR, 1.62; 95% CI, 1.42-1.84. In addition, there were associations with restless legs syndrome (OR, 4.19; 95% CI, 3.91-4.50), sleep apnea (OR, 1.45; 95% CI, 1.37-1.54), epilepsy (OR, 2.26; 95% CI, 2.07-2.46), migraine (OR, 1.21; 95% CI, 1.12-1.29), bipolar disorder (OR, 3.81; 95% CI, 3.11-4.67), and schizophrenia (OR, 4.48; 95% CI, 3.82-5.25). The following diagnoses were also found to be associated with PD: sensory impairments beyond anosmia, such as hearing loss (OR, 1.14; 95% CI, 1.09-1.20) and changes of skin sensation (OR, 1.31; 95% CI, 1.21-1.43). There were also positive associations with skin disorders (eg, seborrheic dermatitis, OR, 1.30; 95% CI, 1.15-1.46; psoriasis, OR, 1.13; 95% CI, 1.05-1.21), gastrointestinal disorders (eg, gastroesophageal reflux, OR, 1.29; 95% CI, 1.25-1.33; gastritis, OR, 1.28; 95% CI, 1.24-1.33), conditions with a potential inflammatory component (eg, seronegative osteoarthritis, OR, 1.21; 95% CI, 1.03-1.43), and diabetes types 1 (OR, 1.32; 95% CI, 1.21-1.43) and 2 (OR, 1.24; 95% CI, 1.20-1.27). Associations even 5 to 10 years before diagnosis included tremor (odds ratio [OR], 4.49; 95% CI, 3.98-5.06), restless legs syndrome (OR, 3.73; 95% CI, 3.39-4.09), bipolar disorder (OR, 3.80; 95% CI, 2.82-5.14), and schizophrenia (OR, 4.00; 95% CI, 3.31-4.85). Results of this case-control study suggest that the associations found between PD and certain risk factors, comorbidities, and prodromal symptoms in a representative population may reflect possible early extrastriatal and extracerebral pathology of PD. This may be due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.

Path to Parkinson Disease Prevention: Conclusion and Outlook.

Tremendous progress in our understanding of the pathophysiology and clinical manifestations of the prodromal phase of Parkinson disease (PD) offers a unique opportunity to start therapeutic interventions as early as possible to slow or even stop the progression to clinically manifest motor PD. A Parkinson's Prevention Conference, "Planning for Prevention of Parkinson's: A trial design symposium and workshop" was convened to discuss all issues that need to be addressed before the launch of the first PD prevention study. In this review, we summarize the major opportunities and challenges in designing prevention trials in PD, organized by the following critical trial design questions: Who (should be enrolled)? What (to test)? How (to measure prevention)? and the pivotal question, When during the prodromal disease (should we start these trials)? We outline the implications of these questions and their meaning for a responsible, sustainable, and fruitful further planning for prevention trials. Despite the great progress that has been made, it needs to be acknowledged that several queries remain to be carefully considered and addressed because prevention trials are being planned and become a reality.

Outcome Assessment in Parkinson Disease Prevention Trials: Utility of Clinical and Digital Measures.

The prodromal phase of Parkinson disease (PD) is accompanied by subtle clinical signs that are not sufficient for diagnosis but could potentially be measured in the context of clinical trials of therapies intended to delay or prevent more definitive clinical features. The objective of this study was to review the available literature on the presence and time course of subtle motor features in prodromal PD in the context of planning for possible clinical trials. We reviewed the available literature based on expert opinion. We considered a range of outcomes including measurement of clinical features, patient-reported outcomes, digital markers, and clinical diagnosis. We considered these features and measures in the context of patient stratification, intermediate outcomes, and clinically relevant end points, including phenoconversion. Substantial progress has been made in understanding how motor features evolve in the period immediately before a PD diagnosis. Digital measures hold substantial progress for measurement precision and may be additionally relevant because they can be used in naturalistic environments outside the clinic. Future studies should focus on advancing digital sensor technology and analysis and developing methods to implement available methods, particularly determination of a clinical diagnosis of PD, in a clinical trial context.

Risk of Parkinson disease associated with pesticide exposure and protection by probiotics

Neurodegenerative disease is very harmful to human health. Some common neurodegenerative disease is; Parkinson s disease (PD), Alzheimer disease (AD), Multiple sclerosis (MS). Their cause is associated with various environmental and genetic factors. Several environmental toxins have been involved in the onset of PD. Some of them increase the risk of PD such as agriculture, and handling pesticides and heavy metals, cause death of dopamine producing neurons. Pesticides are primary class of environmental factor associated with PD. These contain various class and subclass of herbicides, insecticides, fungicides, rodenticides, and fumigants. Rotenone, paraquat, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, among the most popular toxicants used to imitate PD. These toxicants have expressed their interaction with different genes associated with PD like alpha-synuclein. In short, a common understanding of genetic and environmental pathways is essential for early diagnosis and successful translation of potential treatments. Other than these, newer classes of pesticides can cause genetic alterations in humans which leads to illness. Environmental factors are important to note in order to detect prodromal phase of Parkinson disease. In order to treat the neurodegenerative disease, the gut microbiota should be healthy. Their present a microbiota gut brain axis (MGBA) which joins the brain to gut via a vagus nerve, which is a bidirectional nerve. Under normal condition the MGBA help in regulating digestive system and also responsible for maintaining homeostasis in metabolic activities. Due to environmental factors constitution of gut microbiome can be disturbed which leads to dysregulation of enteric nervous system. Hence, MGBA function gets disrupt and causes progressive neurodegeneration disease. To reduce the symptoms of neurodegenerative disease the probiotics can be useful as they contain good or healthy microbes such as Lactobacillus, Blautia, Roseburia, Lachnospiraceae, Prevotellaceae, and Akkermansia. In order to treat the neurodegenerative disease various microbes can be used as probiotics. Therefore, this review article gives a detailed description about various pesticides and their association with neurodegeneration and information regarding neuroprotective role of probiotics.

Cognition in prodromal Parkinson's disease.

One characteristic of Parkinson's disease (PD) is a prodromal phase, lasting many years during which both pre-clinical motor and non-motor symptoms occur. Around one-fifth of patients with PD manifest mild cognitive impairment at time of clinical diagnosis. Thus, important challenges are to define the time of onset of cognitive dysfunction in the prodromal phase of PD, and to define its co-occurrence with other specific characteristics. Evidence for cognitive change in prodromal PD comes from various study designs, including both longitudinal and cross-sectional approaches with different target groups. These studies support the concept that changes in global cognitive function and alterations in executive functions occur, and that these changes may be present up to 6 years before clinical PD diagnosis. Notably, this evidence led to including global cognitive impairment as an independent prodromal marker in the recently updated research criteria of the Movement Disorder Society for prodromal PD. Knowledge in this field, however, is still at its beginning, and evidence is sparse about many aspects of this topic. Further longitudinal studies including standardized assessments of global and domain-specific cognitive functions are needed to gain further knowledge about the first appearance, the course, and the interaction of cognitive deficits with other non-motor symptoms in prodromal stage PD. Treatment approaches, including non-pharmacological interventions, in individuals with prodromal PD might help to prevent or delay cognitive dysfunction in early PD.

Trend of recognizing depression symptoms and antidepressants use in newly diagnosed Parkinson's disease: Population-based study.

ObjectivesAlthough depression symptoms are common among patients with Parkinson's disease (PD), the medical literature still reports underrecognition of depression in patients with PD. Our main objective is to examine the trend of depression recognition during the first year of PD diagnosis using large population data.MethodsWe conducted a population‐based study of residents in Wales, using the Secure Anonymized Information Linkage (SAIL) Databank. We included newly diagnosed patients with PD aged 40 years or older with a first PD diagnosis between 2000 and 2015. Depression and antidepressants related data were extracted from SAIL. A series of multilevel logistic regressions were run to determine the factors affecting depression recognition. The results were presented using odds ratios (ORs) with 95% confidence intervals (CI).ResultsThe study included 6596 patients with PD. About 38% of patients had a recorded code of antidepressants, depression diagnosis, or both within the first year of PD diagnosis. There was a significant association of depression diagnosis, antidepressant use, or both with the year of PD diagnosis (OR 0.972, 95% CI 0.962–0.983). We also found that patients who used monoamine oxidase inhibitors (MAO‐B inhibitors) were associated with a lower depression diagnosis, use antidepressants, or both, compared to those who did not use MAO‐B inhibitors (OR 0.769, 95% CI 0.627–0.943).ConclusionThere is a slight decrease in depression recognition in PD patients between 2000 and 2015, which could be due to an increase in depression recognition during the prodromal phase of PD.

Activation-Induced Rigidity in Neurologically and Cognitively Healthy Individuals Aged 18-90 Years: A Cross-Sectional Study.

Rigidity is a key clinical feature of Parkinson's disease (PD), but in a very early phase of the disease it may be absent and can be enhanced through active movements of the arm contralateral to the one being tested. To evaluate in a large cohort of neurologically and cognitively healthy (NCH) subjects aged 18-90 years if activation-induced rigidity (AR) is present in all age classes, and if there are biological differences between subjects showing AR (AR+) and not showing AR (AR-). 2,228 NCH subjects categorized as young adult (18-44 years), adult (45-64 years), elderly (65-74 years), and old/oldest-old (75-90 years) were included in the analysis, and underwent brain MRI. White matter hyperintensities were assessed through two visual rating scales. Lacunes were also rated. Atrophy of the caudate nuclei and ventricular enlargement were assessed through the bicaudate ratio and the lateral ventricles to brain ratio. To elicit AR, the Froment's maneuver (FM) and the instructions of the UPDRS-ME were used. Among the sample, 1,689 (75.81%) subjects showed AR, of which 1,270 (57.00%) subjects showed AR by using FM, and 419 (18.81%) showed AR by using UPDRS-ME instructions. The latter subjects also showed AR by using FM. The number of AR+ subjects significantly increased with increasing age, regardless of the activation maneuver used. In each age class, the number of AR+ subjects was significantly higher by using the FM than the UPDRS-ME instructions. Our findings suggest that AR is likely to be one of the signs of the prodromal phase of PD.

Patients' views on the ethical challenges of early Parkinson disease detection.

To evaluate the point of view of patients with Parkinson disease (PD) on early detection and risk disclosure in the prodromal phase of PD and to derive recommendations for an ethical framework for the recruitment of prodromal PD cohorts. A standardized questionnaire to evaluate the patients' perception on early diagnosis in PD was designed by an interdisciplinary study group. After testing in a preliminary feasibility study (n = 20), the survey was performed retrospectively with patients from our clinic. A total of 101 patients with PD answered the questions. The majority of patients reported that time from onset of motor symptoms to diagnosis was burdensome, including false diagnoses and many consultations of various medical specialists. However, most of the patients evaluated early risk disclosure with skepticism. Freedom of choice and the potential of changes in lifestyle were rated as important. Although patients with PD reported the time to diagnosis retrospectively as burdensome, the majority was skeptical regarding early disclosure of risk, especially with regard to the lack of pharmacologic options. Circumstances under which early detection and disclosure would have been approved by the majority of patients were (1) advice on lifestyle changes (exercise, nutrition) as potentially disease course-modifying therapy; (2) the establishment of an early diagnosis "culture," including early clarification of the patients' wish to know; and (3) regular support and follow-up of individuals after risk disclosure.

Prodromal PD: A new nosological entity.

Recent years have brought a rapid growth in knowledge of the prodromal phase of Parkinson's disease (PD). It is now clear that the clinical phase of PD is preceded by a phase of progressing neurodegeneration lasting many years. This involves not only central nervous system structures outside the substantia nigra and neurotransmitter systems other than the dopaminergic system, but also the peripheral nervous systems. Different ways of alpha-synuclein spreading are presumed, corresponding to typical prodromal non-motor symptoms like constipation, REM sleep behavior disorder (RBD) and hyposmia. Moreover, many risk and prodromal markers have been identified and combined in the prodromal research criteria, which can be used to calculate an individual's probability of being in the prodromal phase of PD. Apart from specific genetic risk markers, including most importantly GBA- and LRRK2 mutations, RBD is currently the most important prodromal marker, predicting PD with a very high likelihood. This makes individuals with RBD a promising cohort for future clinical trials to detect and treat PD in its prodromal phase. New markers, especially those derived from tissue biopsies, quantitative motor assessment and imaging, appear very promising; these are paving the way for a better understanding of the prodromal phase and its potential clinicopathological subtypes, and a more precise probability calculation.

Gait analysis with wearables predicts conversion to Parkinson disease

ObjectiveQuantification of gait with wearable technology is promising; recent cross‐sectional studies showed that gait characteristics are potential prodromal markers for Parkinson disease (PD). The aim of this longitudinal prospective observational study was to establish gait impairments and trajectories in the prodromal phase of PD, identifying which gait characteristics are potentially early diagnostic markers of PD.MethodsThe 696 healthy controls (mean age = 63 ± 7 years) recruited in the Tubingen Evaluation of Risk Factors for Early Detection of Neurodegeneration study were included. Assessments were performed longitudinally 4 times at 2‐year intervals, and people who converted to PD were identified. Participants were asked to walk at different speeds under single and dual tasking, with a wearable device placed on the lower back; 14 validated clinically relevant gait characteristics were quantified. Cox regression was used to examine whether gait at first visit could predict time to PD conversion after controlling for age and sex. Random effects linear mixed models (RELMs) were used to establish longitudinal trajectories of gait and model the latency between impaired gait and PD diagnosis.ResultsSixteen participants were diagnosed with PD on average 4.5 years after first visit (converters; PDC). Higher step time variability and asymmetry of all gait characteristics were associated with a shorter time to PD diagnosis. RELMs indicated that gait (lower pace) deviates from that of non‐PDC approximately 4 years prior to diagnosis.InterpretationTogether with other prodromal markers, quantitative gait characteristics can play an important role in identifying prodromal PD and progression within this phase. ANN NEUROL 2019;86:357–367

The prodromes of Parkinson's disease.

Whilst the diagnosis of Parkinson's disease (PD) relies on the motor triad of bradykinesia, rigidity and tremor, the underlying pathological process starts many years before these signs are overt. In this prodromal phase of PD, a diverse range of non‐motor and motor features can occur. Individually they do not allow a diagnosis of PD, but when considered together, they reflect the gradual development of the clinical syndrome. Different subgroups within the prodromal phase may exist and reflect different underlying pathology. Here, we summarise the evidence on the prodromal phase of PD in patient groups at increased risk of PD with well described prodromal features: patients with idiopathic rapid eye movement sleep behaviour disorder, patients with idiopathic anosmia and families with monogenic mutations that are closely linked to PD pathology. In addition, we discuss the information on prodromal features from ongoing studies aimed at detecting prodromal PD in the general population. It is likely that better delineation of the clinical prodromes of PD and their progression in these high‐risk groups will improve understanding of the underlying pathophysiology.

Mitral cells and the glucagon-like peptide 1 receptor: The sweet smell of success?

The olfactory bulb (OB) is often affected at very early stages of neurodegenerative disorders, in the so-called "prodromal" phase. In Parkinson's disease (PD), olfactory disturbances appear years before motor symptoms arise. Additionally, pathological alpha-synuclein aggregates are found in olfactory regions before spreading to other areas of the brain. Being positioned at the frontier between the brain and a potentially hostile environment, could explain the particular vulnerability of the OB. Mitral cells (MCs), the principal projecting neurons of the olfactory system, are involved in the pathogenesis and in the prion-like progression of PD. They are affected by Lewy pathology and are thought to contribute to the axonal transport of misfolded alpha-synuclein to other regions of the brain. Here, we first describe the main markers reported to distinguish MCs from other olfactory neurons. We focus on the glucagon-like peptide 1 receptor (GLP-1R), a membrane protein specifically expressed in MCs. After summarizing OB pathology, we explore the idea of targeting specifically MCs with GLP-1 or its analogues. Exenatide has shown great promise as a neuroprotective and neurorestorative agent and has been used in a clinical trial for clinical PD. Since GLP-1R activation has the ability to mitigate many facets of prodromal PD pathology, we postulate that once a robust biomarker is in place that is capable of identifying individuals in the prodromal phase of PD, homing in on GLP-1R could assist in deferring, or eradicating to a significant degree, the clinical manifestation of this debilitating human disorder.

Plasma α-synuclein and cognitive impairment in the Parkinson's Associated Risk Syndrome: A pilot study

Plasma total and nervous system derived exosomal (NDE) α-synuclein have been determined as potential biomarkers of Parkinson's disease (PD). To explore the utility of plasma α-synuclein in the prodromal phase of PD, plasma total and NDE α-synuclein were evaluated in baseline and 2-year follow-up samples from 256 individuals recruited as part of the Parkinson's Associated Risk Syndrome (PARS) study. The results demonstrated that baseline and longitudinal increases in total α-synuclein predicted progression of cognitive decline in hyposmic individuals with dopamine transporter (DAT) binding reduction. On the other hand, a longitudinal decrease in NDE α-synuclein predicted worsening cognitive scores in hyposmic individuals with DAT binding reduction. Finally, in individuals with faster DAT progression, decreasing NDE/total α-synuclein ratio was associated with a larger reduction in DAT from baseline to follow-up. These results suggest that, though underlying mechanisms remain to be defined, alterations in plasma total and NDE α-synuclein concentrations are likely associated with PD progression, especially in the aspect of cognitive impairment, at early stages of the disease.

Dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography as imaging markers of prediagnostic Parkinson's disease.

The objective of this study was to examine whether prediagnostic features of Parkinson's disease (PD) were associated with changes in dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography. Prediagnostic features of PD (risk estimates, University of Pennsylvania Smell Identification Test, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire, and finger-tapping scores) were assessed in a large cohort of older U.K. residents. A total of 46 participants were included in analyses of prediagnostic features and MDS-UPDRS scores with the striatal binding ratio on dopamine reuptake transporter-single-photon emission computed tomography and nigral hyperechogenicity on transcranial sonography. The striatal binding ratio was associated with PD risk estimates (P = .040), University of Pennsylvania Smell Identification Test (P = .002), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores (P = .024), tapping speed (P = .024), and MDS-UPDRS motor scores (P = .009). Remotely collected assessments explained 26% of variation in the striatal binding ratio. The inclusion of MDS-UPDRS motor scores did not explain additional variance. The size of the nigral echogenic area on transcranial sonography was associated with risk estimates (P < .001) and MDS-UPDRS scores (P = .03) only. The dopamine reuptake transporter-single-photon emission computed tomography results correlated with motor and nonmotor features of prediagnostic PD, supporting its potential use as a marker in the prodromal phase of PD. Transcranial sonography results also correlated with risk scores and motor signs. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

New concepts in the pathogenesis and presentation of Parkinson’s disease

Parkinson's disease (PD) was first described by James Parkinson in 1817. He noted the complex nature of this condition and that non-motor symptoms (NMS) underpinned the classic motor symptoms of PD. The concept of what PD is has therefore undergone substantial changes and it is now recognised that PD is a combined motor and non-motor syndrome and NMS are present during the prodromal phase of PD, starting up to 20years before the first clinical motor signs emerge. PD may originate from pathology in the gut, olfactory bulb and lower brainstem rather than in the substantia nigra. Complex phenotypes of PD may exist where clinical NMS overshadow motor features. Therapy needs to be adjusted based on motor and non-motor loads, ideally using validated tools. Recently, a multimodal biomarker battery in PD has emerged and might play an important role in the future.