Non-motor Features Of Parkinson's Disease Research Articles

Effect of Dl-3-n-Butylphthalide on olfaction in rotenone-induced Parkinson's rats.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Olfactory dysfunction (OD) is an important nonmotor feature of PD. Dl-3-n-Butylphthalide (NBP) is a synthetic compound isolated from Apium graveolens seeds. The present study was conducted to investigate the effect of NBP on olfaction in rotenone-induced Parkinson's rats to explore the mechanism and pathway of OD in PD. The PD model was established using rotenone-induced SD rats, divided into blank control, model, and treatment groups. A sham group was also established, with 10 rats in each group. The treatment group was given NBP (1 mg/kg, 10 mg/kg, and 100 mg/kg, dissolved in soybean oil) intragastrically for 28 days. Meanwhile, the control group rats were given intra-gastrically soybean oil. After behavioral testing, all rats were executed, and brain tissue was obtained. Proteomics and Proteomic quantification techniques (prm) quantification were used to detect proteomic changes in rat brain tissues. Compared with the control group, the model group showed significant differences in behavioral tests, and this difference was reduced after treatment. Proteomics results showed that after treatment with high-dose NBP, there were 42 differentially expressed proteins compared with the model group. Additionally, the olfactory marker (P08523) showed a significant upregulation difference. We then selected 22 target proteins for PRM quantification and quantified 17 of them. Among them, the olfactory marker protein was at least twofold upregulated in the RTH group compared to the model group.

GLP-1 Receptor Agonists: A New Treatment in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases, including PD and type 2 diabetes mellitus (T2DM), suggesting a crucial interplay between the gut-brain axis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies is also very promising, enhancing the possibility of adding GLP1-R agonists to the current armamentarium of drugs available for PD treatment.

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks.

Cognitive impairment (CI) is a characteristic non-motor feature of Parkinson disease (PD) that poses a severe burden on the patients and caregivers, yet relatively little is known about its pathobiology. Cognitive deficits are evident throughout the course of PD, with around 25% of subtle cognitive decline and mild CI (MCI) at the time of diagnosis and up to 83% of patients developing dementia after 20 years. The heterogeneity of cognitive phenotypes suggests that a common neuropathological process, characterized by progressive degeneration of the dopaminergic striatonigral system and of many other neuronal systems, results not only in structural deficits but also extensive changes of functional neuronal network activities and neurotransmitter dysfunctions. Modern neuroimaging studies revealed multilocular cortical and subcortical atrophies and alterations in intrinsic neuronal connectivities. The decreased functional connectivity (FC) of the default mode network (DMN) in the bilateral prefrontal cortex is affected already before the development of clinical CI and in the absence of structural changes. Longitudinal cognitive decline is associated with frontostriatal and limbic affections, white matter microlesions and changes between multiple functional neuronal networks, including thalamo-insular, frontoparietal and attention networks, the cholinergic forebrain and the noradrenergic system. Superimposed Alzheimer-related (and other concomitant) pathologies due to interactions between α-synuclein, tau-protein and β-amyloid contribute to dementia pathogenesis in both PD and dementia with Lewy bodies (DLB). To further elucidate the interaction of the pathomechanisms responsible for CI in PD, well-designed longitudinal clinico-pathological studies are warranted that are supported by fluid and sophisticated imaging biomarkers as a basis for better early diagnosis and future disease-modifying therapies.

Cajanus cajan (L) Millsp seeds extract prevents rotenone-induced motor- and non-motor features of Parkinson disease in mice: Insight into mechanisms of neuroprotection

Ethnopharmacological relevanceCajanus cajan (L) Millsp (Fabaceae) seed decoction is used by traditional healers in Nigeria as nerve tonic, hence, could be beneficial in the treatment of Parkinson's disease (PD), a progressive and debilitating neurodegenerative disease that imposes great burden on the healthcare system globally. Aim of the studyThis study aimed at investigating the neuroprotective effect of ethanol seed extract of Cajanus cajan (CC) in the treatment of rotenone-induced motor symptoms and non-motor symptoms associated with PD. Materials and methodsTo assess the protective action of CC on rotenone-induced motor- and non-motor symptoms of PD, mice were first pretreated with CC (50, 100 or 200 mg/kg, p.o.) an hour before oral administration of rotenone (1 mg/kg, p.o, 0.5% in carboxyl-methylcellulose) for 28 consecutive days and weekly behavioural tests including motor assessment (open field test (OFT), rotarod, pole and cylinder tests) and non-motor assessment (novel object recognition (NOR), Y-maze test (YM), forced swim and tail suspension, gastric emptying and intestinal fluid accumulation tests) were carried out. The animals were euthanized on day 28 followed by the collection of brain for assessment of oxidative stress, inflammatory markers and immunohistochemical analysis of the striatum (STR) and substantia nigra (SN). Phytochemicals earlier isolated from CC were docked with protein targets linked with PD pathology such as; catechol-O-methyltransferase (COMT), tyrosine hydroxylase (TH) and Leucine rich receptor kinase (LRRK).Results: this study showed that CC significantly reduced rotenone-induced spontaneous motor impairment in OFT, pole, cylinder and rotarod tests in mice as well as significant improvement in non-motor features (significant reversal of rotenone-induced deficits discrimination index and spontaneous alternation behaviour in NORT and YM test, respectively, reduction in immobility time in forced swim/tail suspension test, gastrointestinal disturbance in intestinal transit time in mice. Moreso, rotenone-induced neurodegeneration, oxidative stress and neuroinflammation were significantly attenuated by CC administration. In addition, docking analysis showed significant binding affinity of CC phytochemicals with COMT, TH and LRRK2 receptors. ConclusionCajanus cajan seeds extract prevented both motor and non-motor features of Parkinson disease in mice through its antioxidant and anti-inflammatory effects. Hence, could be a potential phytotherapeutic adjunct in the management of Parkinson disease.

Caffeine alleviates anxiety-like behavior and brainstem lesions in a rotenone-induced rat model of Parkinson's disease

BackgroundParkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. In 2016, approximately 6.1 million individuals were affected by PD, with 211,296 deaths attributed to the disease. The understanding of PD initially came from the observation of dopaminergic system alterations in a specific region of the brainstem, indicating that the core motor and non-motor features of PD are closely associated with brainstem dysfunction. The primary treatment approach for PD revolves around dopamine replacement, as many of the symptoms are responsive to this therapeutic intervention. However, long-term administration of this approach is linked to several complications, and a definitive gold-standard therapy for PD is yet to be identified. The pharmacological management of PD has been challenging and inconsistent, mainly due to the unclear underlying cause of the disease. This study aims to evaluate the effects of caffeine on the brainstem of rats with PD induced by rotenone. MethodologyFifty adult male Wistar rats weighing between 150 and 200 g were used in this study. The rats were randomly divided into five groups of ten rats each: Vehicle Group, Rotenone-only treated Group (rotenone only treated with 3 mg/kg, intraperitoneal administration [IP]), Preventive Group (caffeine 30 mg/kg + rotenone 3 mg/kg, IP), Curative Group (rotenone 3 mg/kg + caffeine 30 mg/kg, IP), and Caffeine only treated Group (caffeine only treated with 30 mg/kg, IP). The animals underwent neurobehavioral assessments, followed by sacrifice. The brains were then excised, weighed, and processed histologically. Appropriate brain sections were taken and processed. Photomicrographs were obtained, morphometric and statistical analysis was performed using an Omax LED digital ResultsThe results demonstrated a significant (p < 0.05) reduction in body weight and relative brain weight, which were increased by caffeine treatments. Rotenone administration led to histological changes similar to those observed in PD, including neuronal structural derangement, degenerated nerve fibers, loss of myelinated neurons, and Nissl substance, as well as downregulation in the expressions of NRF2 and TH in the midbrain. However, these pathological features were counteracted or ameliorated by caffeine treatment. ConclusionOur study contributes additional evidence to the growing body of research supporting the therapeutic potential of caffeine in Parkinson's disease (PD). The results underscore the neuroprotective properties of caffeine and its capacity to mitigate oxidative stress by modulating TH (tyrosine hydroxylase) and cytoplasmic NRF2 (nuclear factor erythroid 2-related factor 2) in the mesencephalon. These findings suggest that caffeine holds promise as a viable treatment option for PD.

Effects of Gut Microbiota Alterations on Motor, Gastrointestinal, and Behavioral Phenotype in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a multi-system disorder consisting of not only classic motor symptoms but also a variety of non-motor symptoms including gastrointestinal (GI) dysfunction and mood disorders. The gut microbiota has been suggested to play a role in modulating PD motor and non-motor features, although the causality and mechanisms behind these proposed interactions remains largely understudied. In this study, we aimed to provide in-depth characterization of an established mouse model of PD (transgenic (TG) SNCA A53T) and experimentally address how changes to the gut microbiota impact the PD-like phenotype. We profiled the PD-like phenotype of transgenic mice through a panel of motor, GI, and behavioral tests. We then investigated how antibiotic treatment or gut microbial community transfer (via cohousing with wild-type mice) impacted the PD-like phenotype. We found that this mouse model demonstrated early (6 weeks of age) motor symptoms when compared to a wild-type control mouse strain. Transgenic mice also exhibited early GI dysfunction, as well as behavioral alterations, including reduced anxiety-like behavior, and increased depression-like and apathy-like behavior. Compared to wild-type mice, the transgenic fecal microbiota was less diverse and compositionally distinct. Interestingly, drastic alterations to the gut microbiota, through antibiotic treatment or cohousing with wild-type mice, had a minimal effect on the motor, GI, and behavioral phenotype of transgenic mice. We concluded that this mouse model effectively recapitulates motor and non-motor features of PD; however, the gut microbiota appears to exhibit a minor impact on the pathophysiology of this PD model.

Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein.

SUMMARYα-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson’s disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.

Olfactory Function and Diffusion Tensor Imaging as Markers of Mild Cognitive Impairment in Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to establish groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

The role of frailty in Parkinson's disease: a cross-sectional study.

Frailty is an age-related state of increased risk for health-related adverse outcomes that reflects multisystem physiological changes and likely influences the clinical expression and disease progression of neurodegenerative disorders. The aim of the present study was to assess the potential relationship between frailty, as assessed by a frailty index (FI), and motor symptom severity, motor subtypes, and non-motor domains in Parkinson's disease (PD). We consecutively enrolled 150 PD patients. We administered an FI specifically designed for PD that included 50 age-related multidimensional biological deficits. Patients underwent a clinical assessment that evaluated motor and non-motor manifestations of PD. Using the FI score, we classified PD patients as relatively fit (FI ≤ 0.10), less fit (0.10 < FI ≤ 0.21), or frail (FI > 0.21). A linear regression model was designed to explore possible associations between frailty level and PD motor and non-motor manifestations. Frail patients showed greater motor symptom severity and motor complications than fitter patients. A trend towards a higher prevalence of the postural instability/gait disorder subtype was also observed in frail versus relatively fit and less fit patients. The global burden of non-motor symptoms was higher in frail patients. Increased frailty was associated with more severe motor and non-motor symptoms, as well as with more pronounced cognitive deficits. These associations remained significant even when "traditional" predictors of PD severity (age, disease duration, and levodopa equivalent daily dose) were considered. The present findings indicate that the FI is associated with both motor and non-motor features of PD.

Recent Progress in Non-motor Features of Parkinson's Disease with a Focus on Circadian Rhythm Dysregulation.

Parkinson's disease (PD) is the second most common neurodegenerative disease, which manifests with both motor and non-motor symptoms. Circadian rhythm dysregulation, as one of the most challenging non-motor features of PD, usually appears long before obvious motor symptoms. Moreover, the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis, and it has emerged as a hot topic in PD research. In this review, we briefly introduce the circadian rhythm and circadian rhythm-related genes, and then summarize recent research progress on the altered circadian rhythm in PD, ranging from clinical features to the possible causes of PD-related circadian disorders. We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD, but also shed light on the better management of PD.

Long-term effect of non-invasive Vagus Nerve in patients with Parkinson's disease: A randomized double blind controlled study

Introduction: Disorders of gait and falls are common in patients with Parkinson's disease (PD). Research efforts have therefore focused on neurostimulation to address the PD gait disorders. Evidence from animal experiments has shown that VNS might treat some of the motor and non-motor features of PD. In our open label pilot study, we found an encouraging result in treatment of freezing of gait in PD patients.

Effects of treadmill training on the balance, functional capacity and quality of life in Parkinson's disease: A randomized clinical trial.

Background There is growing evidence that exercise modalities have considerable effects on Parkinson's disease (PD). This trial aimed to provide a more detailed viewpoint of short-term and long-term treadmill training (TT) effects on some motor and non-motor features of PD. Methods In this prospective, randomized, single-blind clinical trial, 20 mild to moderate PD patients, admitted in Rasoul-e-Akram hospital in Tehran, Iran, were randomly allocated in case (11) and control (9) groups. Treadmill intervention was performed at moderate intensity with 60% of heart rate reserved (HRR) in two 30-min sessions/week for a duration of 10 weeks. Both the groups were evaluated for three times; at the baseline, 2 months later and then 2 months after the second evaluation. We assigned the Timed Up and Go test (TUG), 6-min walk test (6MW), and the SF-8 healthy questionnaire, for assessment of balance, functional capacity, and Quality of life (QoL), respectively. Results Balance and functional capacity were significantly improved in the case group after the intervention (TUG p-value: 0.003, 6MW p-value: 0.003). Moreover, the long-term analysis revealed significant results as well (TUG p-value: 0.001, 6MW p-value: 0.004). Mental condition's scores of SF-8 in cases were not statistically different in short-term follow-up (F/U). However, analysis illustrated p-value: 0.016 for long-term assessment. The intervention induced significant changes in physical condition's scores in both of the F/Us (PC p-value: 0.013). Conclusions This study provides evidence that a TT of mild to moderate intensity has significant and persistent benefits for the balance, functional capacity, and QoL in PD.

Machine Learning Based Classification Using Clinical and DaTSCAN SPECT Imaging Features: A Study on Parkinson’s Disease and SWEDD

DatSCAN single-photon emission computed tomography (SPECT) imaging is a reliable method to assess dopaminergic transporter in degenerative Parkinsonism. Scan without evidence of dopaminergic deficit (SWEDD) subjects are clinically diagnosed as Parkinson's disease (PD) patients although the SPECT imaging does not show any negro-striatal abnormality. In this paper, five models of machine learning were used to carry out binary classification [healthy control (HC)/PD] using clinical assessment and image-derived features applied thereafter on SWEDD group as a potential application of motor and nonmotors features in understanding PD characteristic in this group. The nested cross-validation was an essential component to select reliable models. A high accuracy was achieved for the five models (75.4%-78.4% for motor features and 71%-82.2% for nonmotor features) in binary classification (HCs versus PD). Accordingly, we demonstrate the suitability and usefulness of ML models to carry out binary classification of SPECT data. Cross all models applied on SWEDD group, 17.6% of patients were classified as PD motor disorder lookalikes, 27.4% were classified as having a beginning nonmotor abnormality of PD, and 3.9% were classified as having both motor and nonmotor PD features. However, the interpretability of SWEDD predicted condition must be carefully considered.

A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson's disease: Does age matter?

ObjectivesTo explore if short term, high dose vitamin D supplementation is safe and improves balance in persons with Parkinson's disease (PD).MethodsA pilot randomized, double-blind intervention trial to measure the effects of 16 weeks of high dose vitamin D (10,000 IU/day) on balance as well as other motor and non-motor features of PD. We measured balance, gait, strength, falls, cognition, mood, PD severity, and quality of life before and after 16 weeks of high dose vitamin D supplementation or placebo. All participants also received 1000 mg calcium once daily.ResultsFifty-one randomized participants completed sixteen weeks of high dose vitamin D supplementation or placebo. The intervention resulted in a rise in serum concentrations of vitamin D (25-OH) (30.2 ng/ml to 61.1 ng/ml) and was well tolerated with no serious adverse events. Serum vitamin D (25-OH) levels rose steadily and did not suggest a leveling off at the end of the 16 weeks. There was not an improvement in the primary endpoint, balance as measured by the Sensory Organization Test (p = 0.43). A post hoc analysis examining treatment effects in younger (ages 52–66) versus older (ages 67–86) participants found a significant improvement in the SOT of 10.6 points in the younger half of the cohort (p = 0.012).ConclusionsShort term, high dose vitamin D supplementation appears safe in persons with PD, but did not significantly improve balance as measured with the Sensory Organization Test in this pilot study population. A post hoc analysis suggests that vitamin D may have potential for improving balance in a younger population with PD. High dose vitamin D supplementation in PD needs further study especially in light of new research suggesting that mega doses and even moderate doses (as low as 4000IU a day) may increase falls in an older populations.Trial registrationClinicalTrials.gov: NCT01119131.

Dopaminergic Lesion in the Olfactory Bulb Restores Olfaction and Induces Depressive-Like Behaviors in a 6-OHDA Model of Parkinson's Disease.

Olfactory impairments and depressive behavior are commonly reported by individuals with Parkinson's disease (PD) being observed before motor symptoms. The mechanisms underlying these clinical manifestations are not fully elucidated. However, the imbalance in dopaminergic neurotransmission seems to play an important role in this context. In patients and animal models of PD, an increase in the dopaminergic interneurons of the glomerular layer in olfactory bulb (OB-gl) is observed, which may contribute to the olfactory impairment. In addition, neuronal imbalance in OB is related to depressive symptoms, as demonstrated by chemical olfactory bulbectomy. In view of that, we hypothesized that a reduction in the number or density of dopaminergic neurons present in OB could promote an olfactory improvement and, in contrast, would accentuate the depressive-like behaviors in the 6-hydroxydopamine (6-OHDA) model of PD. Therefore, we performed single or double injections of 6-OHDA within the substantia nigra pars compacta (SNpc) and/or in the OB-gl. We observed that, after 7days, the group with nigral lesion exhibited olfactory impairment, as well as the group with the lesion in the OB-gl. However, the combination of the lesions prevented the occurrence of hyposmia. In relation to depressive-like behaviors, we observed that the SNpc injury promoted depressive-like behavior, being accentuated after a double injury. Our results demonstrated the importance of the dopaminergic neurons of the OB-gl in different non-motor features of PD, since the selective reduction of these periglomerular neurons was able to induce olfactory impairment and depressive-like behaviors.

Chronic MPTP administration regimen in monkeys: a model of dopaminergic and non-dopaminergic cell loss in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically characterized by cardinal motor deficits including bradykinesia, tremor, rigidity and postural instability. Over the past decades, it has become clear that PD symptoms extend far beyond motor signs to include cognitive, autonomic and psychiatric impairments, most likely resulting from cortical and subcortical lesions of non-dopaminergic systems. In addition to nigrostriatal dopaminergic degeneration, pathological examination of PD brains, indeed, reveals widespread distribution of intracytoplasmic inclusions (Lewy bodies) and death of non-dopaminergic neurons in the brainstem and thalamus. For that past three decades, the MPTP-treated monkey has been recognized as the gold standard PD model because it displays some of the key behavioral and pathophysiological changes seen in PD patients. However, a common criticism raised by some authors about this model, and other neurotoxin-based models of PD, is the lack of neuronal loss beyond the nigrostriatal dopaminergic system. In this review, we argue that this assumption is largely incorrect and solely based on data from monkeys intoxicated with acute administration of MPTP. Work achieved in our laboratory and others strongly suggest that long-term chronic administration of MPTP leads to brain pathology beyond the dopaminergic system that displays close similarities to that seen in PD patients. This review critically examines these data and suggests that the chronically MPTP-treated nonhuman primate model may be suitable to study the pathophysiology and therapeutics of some non-motor features of PD.

Near-falls in people with Parkinson's disease: Circumstances, contributing factors and association with falling

ObjectivesTo describe circumstances of near-falls among persons with Parkinson's disease (PD), assess factors associated with near-falling and assess whether near-falls in the first 6 months are associated with falling in the latter 6 months over one year of follow-up. Materials and methodsIn the period August 2011-December 2012, 120 consecutive persons with PD, who denied having fallen in the past 6 months, were recruited at Clinical center of Serbia in Belgrade. Occurrence of falling and near-falls was followed for one year. ResultsA total of 31 persons with PD (25.8%) experienced near-falls, but did not fall. Of 42 fallers, 32 (76.2%) experienced near-falls. Tripping was the most common cause of near-falls among fallers, whereas postural instability was the most common in non-fallers. Regardless of falling experience, the most common manner to avoid fall was holding onto furniture or wall. After adjustment for multiple motor and non-motor PD features, more severe freezing of gait was associated with occurrence of near-falls over one year of follow-up (odds ratio [OR]=1.08, 95% confidence interval [CI] 1.01–1.16; p=0.043). Adjusted regression analysis did not show associations between near-falling in the first 6 months and falling in the latter 6 months of follow-up. ConclusionNear-falls commonly occur in persons with PD. More severe freezing of gait appears to predispose near-falling. Fall prevention programs focusing on balance maintenance when experiencing freezing of gait could potentially be useful in reduction of near-falls.

Olfactory Dysfunction as an Early Biomarker in Parkinson's Disease.

Olfactory dysfunction is common in Parkinson's disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of "pre-motor" PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.

Predictors of anxiety in early-stage Parkinson's disease – Results from the first two years of a prospective cohort study

AimAnxiety has a negative impact on daily functioning and quality of life in patients with Parkinson's disease (PD). This study aims at assessing which sociodemographic and clinical characteristics predict the course of anxiety in early PD. MethodsThe participants of this two-year prospective cohort study were recently diagnosed PD patients not receiving psychiatric medications or dopamine replacement therapy at baseline. Assessments were performed annually after baseline. The primary outcome measure was anxiety, as measured with the State-Trait Anxiety Inventory (STAI). Covariates were age, gender, family history, striatal dopamine transporter binding ratios, and severity of motor and non-motor features of PD at baseline. Data were analyzed using a mixed model analysis. ResultsInclusion criteria were met by 306 subjects. An increase in STAI total score was predicted by older age, lower score on the Montreal Cognitive Assessment, and the presence of a probable REM-sleep behavior disorder (RBD) at baseline. A decrease in STAI total score over time was predicted by a higher baseline score on the 15-item Geriatric Depression Scale, compulsive behavior at baseline and a family history of PD. ConclusionsMore severe baseline anxiety was associated with compulsive behavior and depressive symptoms. These symptoms had a parallel course, showing a decrease over time. An increase in anxiety was predicted by older age, worse cognitive functioning and the presence of RBD. Our findings, when replicated in a sample of PD patients in a more advanced disease stage, could provide starting points for prevention of anxiety in PD patients.

Non-motor features of Parkinson disease.

Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.