Premotor Symptoms Research Articles

Consumption of milk and other dairy products and incidence of Parkinson's disease: a prospective cohort study in French women.

Previous studies showed positive associations between milk intake and Parkinson's disease (PD) in men but not in women, but few studies were available in women. Due to the long prodromal PD phase, reverse causation represents a major threat to investigations of diet in PD; cohort studies with a long follow-up are needed. We investigated associations between intake of milk and other dairy products with PD incidence in women from the E3N cohort study (1993-2018). PD diagnoses were validated using medical records and drug claim databases. Diet was assessed via a dietary questionnaire. Hazard ratios (HR) were estimated using multivariable Cox regression models. Exposures were lagged by 5y in main analyses and longer lags in sensitivity analyses. We examined the impact of adjustment for premotor symptoms (constipation/depression). During a mean follow-up of 18.8y, 845 of 71,542 women developed PD. Main analyses showed a J-shaped association between total milk intake and PD (P-non linearity = 0.045), with a significant linear positive association among drinkers (HR/1-SD = 1.09, 95% CI = 1.01-1.18, P = 0.024), that was explained in secondary analyses by a different pattern of association for plain milk (alone or with cereals) and milk added to drinks (tea/coffee/chicory). PD incidence increased significantly with plain milk consumption (HR/1-SD = 1.08 [1.02-1.14], P = 0.014). A U-shaped relation was observed for milk added to drinks (P-non linearity = 0.038), with lower PD incidence in women with moderate consumption (HR = 0.77 [0.61-0.97], P = 0.030) and no difference between non-drinkers and those with the highest consumption (HR = 0.98 [0.79-1.21], P = 0.848). Findings were similar in analyses using longer lags and adjusted for constipation/depression. Consumption of other dairy products was not associated with PD. A J-shaped association between total milk intake and PD was explained by a different pattern of association for plain milk intake and milk added to drinks. Reverse causation is unlikely to explain a positive association of plain milk with PD incidence in women. The U-shaped relation for milk added to drinks could be explained by an interaction between milk and coffee/tea/chicory. Further studies are warranted to elucidate the underlying mechanisms.

Unveiling the link: hepatitis C virus and Parkinson’s disease

BackgroundParkinson disease (PD) is one of the disabling neurological disorders. The etiology of Parkinson disease is still unknown. Hepatitis C virus is one of the neurotropic viruses which is incriminated in the pathogenesis of Parkinson disease. Hepatitis C virus might affect the dopaminergic neurons, affecting the advancement of PD.MethodsThis study is observational, cross-sectional study done on 2 phases: one phase on PD patients without history of HCV and another phase on HCV patients with no history of PD. 104 PD patient were tested for HCV antibodies and 40 HCV patients with various grades of liver fibrosis were assessed for early pre-motor symptoms of parkinsonism.ResultsAmong patients with parkinsonism, HCV Abs testing was negative in all the studied patients. On the other hand, chronic HCV group included 40 patients, 27.5% were cirrhotic (11/40). Child C patients showed significantly higher percentages of non-motor parkinsonian symptoms, and regarding the HCV group, the majority (85%) of the patients show cognitive impairment, (27.5%) were at stage 1 of anxious mood, while half (50%) of the patients were at stage 1 of fatigue as evaluated by UPDRS Score. Cirrhosis was a significant factor for having non-motor (early) parkinsonism.ConclusionHere we show that advanced cirrhosis is associated with a variety of neurological symptoms including parkinsonian, which needs awareness for better preventive and therapeutic measures for early treatment of hepatitis avoiding the occurrence of cirrhosis, which can lead to parkinsonism.

Revolutionizing our understanding of Parkinson's disease: Dr. Heinz Reichmann's pioneering research and future research direction.

Millions of individuals around the world are afflicted with Parkinson's disease (PD), a prevalent and incapacitating neurodegenerative disorder. Dr. Reichmann, a distinguished professor and neurologist, has made substantial advancements in the domain of PD research, encompassing both fundamental scientific investigations and practical applications. His research has illuminated the etiology and treatment of PD, as well as the function of energy metabolism and premotor symptoms. As a precursor to a number of neurotransmitters and neuromodulators that are implicated in the pathophysiology of PD, he has also investigated the application of tryptophan (Trp) derivatives in the disease. His principal findings and insights are summarized and synthesized in this narrative review article, which also emphasizes the challenges and implications for future PD research. This narrative review aims to identify and analyze the key contributions of Reichmann to the field of PD research, with the ultimate goal of informing future research directions in the domain. By examining Reichmann's work, the study seeks to provide a comprehensive understanding of his major contributions and how they can be applied to advance the diagnosis and treatment of PD. This paper also explores the potential intersection of Reichmann's findings with emerging avenues, such as the investigation of Trp and its metabolites, particularly kynurenines, which could lead to new insights and potential therapeutic strategies for managing neurodegenerative disorders like PD.

A Population-Based Approach to the Argument on Brain-First and Body-First Pathogenesis of Lewy Body Disease.

To explore the clinical progression of the brain-/body-first categories within Lewy body disease (LBD): Parkinson's disease (PD), dementia with Lewy bodies (DLB), and PD dementia. We used of the Rochester Epidemiology Project to establish a population-based cohort of clinically diagnosed LBD. We used two definitions for differentiating between brain- and body-first LBD: a previously hypothesized body-first presentation in patients with rapid eye movement sleep behavior onset before motor symptoms onset; and an expanded definition of body-first LBD when a patient had at least 2 premotor symptoms between constipation, erectile dysfunction, rapid eye movement sleep behavior, anosmia, or neurogenic bladder. Brain-first patients were more likely to be diagnosed with PD (RR = 1.43, p = 0.003), whereas body-first patients were more likely to be diagnosed with DLB (RR = 3.15, p < 0.001). Under the expanded definition, there was no difference in LBD diagnosis between brain-first and body-first patients (PD: RR = 1.03, p = 0.10; DLB: RR = 0.88, p = 0.58) There were no patterns between brain- or body-first presentation, PD dementia under either definition (original: p = 0.09, expanded: p = 0.97), and no significant difference in motor symptoms between brain-first and body-first. Our findings do not support the dichotomous classification of body-first and brain-first LBD with the currently proposed definition. Biological exposures resulting in PD and DLB are unlikely to converge on a binary classification of top-down or bottom-up synuclein pathology. ANN NEUROL 2024;96:551-559.

Dopamine Synthesis in the Nigrostriatal Dopaminergic System in Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

Parkinson’s disease (PD) is diagnosed by the onset of motor symptoms and treated long after its onset. Therefore, the development of the early diagnosis of PD is a priority for neurology. Advanced methodologies for this include (1) searching for patients at risk of developing prodromal PD based on premotor symptoms; (2) searching for changes in the body fluids in these patients as diagnostic biomarkers; (3) verifying the diagnosis of prodromal PD and diagnostic-value biomarkers using positron emission tomography (PET); (4) anticipating the development of motor symptoms. According to our data, the majority of patients (n = 14) at risk of developing PD selected in our previous study show pronounced interhemispheric asymmetry in the incorporation of 18F-DOPA into dopamine synthesis in the striatum. This was assessed for the caudate nucleus and putamen separately using the specific binding coefficient, asymmetry index, and putamen/caudate nucleus ratio. Interhemispheric asymmetry in the incorporation of 18F-DOPA into the striatum provides strong evidence for its dopaminergic denervation and the diagnostic value of previously identified blood biomarkers. Of the 17 patients at risk of developing prodromal PD studied using PET, 3 patients developed motor symptoms within a year. Thus, our study shows the promise of using the described methodology for the development of early diagnosis of PD.

Neuroimmune Connectomes in the Gut and Their Implications in Parkinson's Disease.

The gastrointestinal tract is the largest immune organ and it receives dense innervation from intrinsic (enteric) and extrinsic (sympathetic, parasympathetic, and somatosensory) neurons. The immune and neural systems of the gut communicate with each other and their interactions shape gut defensive mechanisms and neural-controlled gut functions such as motility and secretion. Changes in neuroimmune interactions play central roles in the pathogenesis of diseases such as Parkinson's disease (PD), which is a multicentric disorder that is heterogeneous in its manifestation and pathogenesis. Non-motor and premotor symptoms of PD are common in the gastrointestinal tract and the gut is considered a potential initiation site for PD in some cases. How the enteric nervous system and neuroimmune signaling contribute to PD disease progression is an emerging area of interest. This review focuses on intestinal neuroimmune loops such as the neuroepithelial unit, enteric glial cells and their immunomodulatory effects, anti-inflammatory cholinergic signaling and the relationship between myenteric neurons and muscularis macrophages, and the role of α-synuclein in gut immunity. Special consideration is given to the discussion of intestinal neuroimmune connectomes during PD and their possible implications for various aspects of the disease.

Follow-up of pre-motor symptoms of Parkinson’s disease in adult patients with Gaucher disease type 1 and analysis of their lysosomal enzyme profiles in the CSF

BackgroundParkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Its classic motor symptoms may be preceded by non-motor symptoms (NMS). Population studies have identified GBA variants as risk factors for idiopathic PD. The increased risk of PD has also been suggested in other Lysosomal Storage Disorders (LSDs). Objective: To assess the evolution of the prevalence of NMS compatible with PD in a cohort of South Brazilian adult patients with Gaucher Disease (GD) type 1, already evaluated 3 years ago (2018). Cerebrospinal Fluid (CSF) was collected to assess the levels of LSD enzymes (beta-hexosaminidases, beta-glucuronidase) and biomarker of macrophage activation (chitotriosidase, ChT), compared to controls (metachromatic leukodystrophy, MLD). Cognition was evaluated by the Montreal Cognitive Assessment (MoCA) questionnaire, daytime sleepiness by the Epworth Sleepiness Scale (ESS), depression by Beck´s Inventory, constipation by the Unified Multiple System Atrophy Rating Scale (UMSARS) scale, and REM sleep behavior disorder by the single-question screen. Hyposmia was assessed with Sniffin’ Sticks (SST).ResultsNineteen patients completed the follow-up (mean age of the sample was 44 years; range, 26–71). The patient with the highest number of NMS at the baseline (4 including the lowest SST score) was diagnosed with PD four years later. Apart from an improvement in the ESS score, no other statistical significance was found between the number of NMS between the first and second evaluation, nor between patients with one L444P variant (n = 5) and the rest of the cohort. CSF was collected in five patients (mean age of the sample was 40 years, range 30–53. A significant difference was found in the mean CSF activity levels of beta-hexosaminidases and beta-glucuronidase between GD1 and MLD patients. Mean ChT (CSF) was 62 nmol/h/mL in GD patients and 142 in MLD (n = 6) patients.ConclusionsThe patient with the highest number of NMS in our 2018 cohort was the one that developed PD, corroborating with the importance of this longitudinal follow-up. CSF and plasma analysis might allow a better understanding of the neurodegenerative processes connecting PD and the lysosomal environment. Further analysis is needed to understand this relationship.

Psychosis in Parkinson’s Disease and Current Management Trends- an Updated Review of Literature

As a neurodegenerative disorder, Parkinson’s disease (PD) is characterized by a combination of premotor, motor, and nonmotor symptoms. PD is commonly accompanied by psychosis, which is one of the commonest symptoms in the long run. As a result of Parkinson’s disease psychosis (PDP), symptoms can range from minor consequences of the disease (illusions, passage hallucinations, and presence hallucinations), to visual and nonvisual hallucinations and delusions. PDP is associated with a reduction in function and a reduction in quality of life as well. It is commonly believed that PDP is related to economic burden, and it has a significant impact on the utilization of long-term care services. The main focus should be on diagnosing, classifying, and managing PDP in an appropriate manner. As a first step in the management of PDP patients, the emphasis should be on identifying and treating any contributing medical factors, reducing or discontinuing medications that could cause or worsen psychosis, as well as nonpharmacological strategies and considering acetylcholinesterase inhibitors for treatment when dementia is present. A number of medications are being considered for use in PDP, including pimavanserin, quetiapine, and clozapine. The purpose of the current review is to provide a comprehensive understanding of the disorder in the general population with PD, including epidemiology, psychotic symptoms, risk factors, triggers, neuro-signaling pathways, diagnosis, and treatment of PDP.

Evidence of Sympathetic Overactivity in Subjects with REM Behavior Disorder at Risk for Parkinson’s Disease (P6-13.002)

<h3>Objective:</h3> To evaluate sympathetic nervous system (SNS) activity in subjects with REM sleep behavior disorder (RBD) at risk of Parkinson’s disease, using imaging and autonomic functions markers. <h3>Background:</h3> While the nature of RBD is not completely understood, there is evidence that enhancement of noradrenergic activity may play a causative role, as suggested by evidence of persistent tonic discharge of locus coeruleus (LC) and RBD-triggering action of selective norepinephrine reuptake inhibitors. <h3>Design/Methods:</h3> Subjects &gt;50 years old with RBD with at least one pre-motor PD symptom (hyposmia, constipation, depression) were tested with a battery of autonomic evaluations including SCOPA-AUT questionnaire, cardiac MIBG scintigraphy, Heart Rate Variability (HRV) and neuromelanin sensitive MRI (NSMRI) of LC and substantia nigra (SN). Analyzed variables included: 1) for MIBG, late heart/mediastinum (H/M) ratio and washout ratio (WR); 2) for HRV, time and frequency domain measures; 3) for NSMRI, contrast-to-noise ratio (CNR) between LC and pons and between substantia nigra (SN) and cerebral peduncles. Results were compared with available normative ranges. <h3>Results:</h3> 14 subjects (11M, age 66.2±8.2) were enrolled. Average total SCOPA-AUT score was increased (12.1±6.7 vs 8.8±5.4), with gastrointestinal (2.4±2.1 vs 1.4±1.6), urinary (5.4±2.7 vs 3.9±2.4) and cardiovascular (0.86±1.10 vs 0.3±0.6) scores above normal ranges. MIBG late H/M ratio was reduced (1.45±0.31) with increased WR (33.0±14.8). HRV results showed enhanced sympathetic and low parasympathetic activity both in time (SDNN 106.8±73.2ms; RMSSD 21.9±10.9ms; PNN50% 6.7±8.4%) and frequency domain (LF/HF 3.4±1.8). NMSMRI showed high LC CNR (right 3.26±1.9 vs 2.08±0.5; left 2.95±0.9 vs 2.79±0.5). SN CNR was high (Medial 6.24±1.9 vs 4.57±0.8; Central 6.26±1.6 vs 3.43±0.6; Lateral 3.44±2.1 vs 3.05±0.5) and MDS-UPDRS motor scores were low (2.9±3.3). <h3>Conclusions:</h3> RBD subjects at risk for PD show abnormal autonomic scores, which appears to be driven by SNS overactivity, as suggested by increased MIBG WR, elevated LF/HF HRV ratios and increased LC and SN NSMRI signal. <b>Disclosure:</b> Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbott. Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Boston Scientific. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Supernus. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroDerm. Dr. Tagliati has received publishing royalties from a publication relating to health care. Dr. Gregorio has nothing to disclose. Dr. Maghzi has nothing to disclose. Gloria Obialisi has nothing to disclose. Dr. Hogg has nothing to disclose. Dr. Malatt has nothing to disclose. Dr. Tan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Allergan. Dr. Artal has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharmaceuticals. Dr. Artal has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Private Parties. The institution of Dr. Artal has received research support from Jazz Pharma. The institution of Dr. Artal has received research support from Axsome. The institution of Dr. Artal has received research support from Suven. Dr. Shehata has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Brian Renner has nothing to disclose. The institution of Dr. Sati has received research support from National Multiple Sclerosis Society. The institution of Dr. Sati has received research support from National Institutes of Health. Dr. Sati has received publishing royalties from a publication relating to health care.

DaT Scan Positive Parkinson’s Disease in a Patient with Anti-MuSK Positive Myasthenia Gravis (P5-11.007)

<h3>Objective:</h3> We present a unique clinical case of antibody positive Muscle Specific Kinase (MuSK) Myasthenia Gravis and DaT scan positive Parkinson’s Disease to highlight the overlapping nature of clinical symptoms and challenges seen in clinical diagnosis. <h3>Background:</h3> The concomitant diagnosis of Myasthenia Gravis (MG), an autoimmune condition that affects the neuromuscular junction, and Parkinson’s disease (PD), a neurodegenerative disease that affects the basal ganglia, is remarkably exceptional. Furthermore, there are very few case reports in the literature that have recognized muscle-specific kinase (MuSK), a subtype of MG with overlapping features of PD. We present a unique case of MuSK MG and DaT scan positive Parkinson’s Disease, which to our knowledge has not been previously reported. <h3>Design/Methods:</h3> NA <h3>Results:</h3> 49-year-old male initially presented to neurology clinic with six months of waxing and waning nasal quality dysarthria. After thorough workup with serologic and electrophysiologic studies, patient was diagnosed with seropositive bulbar predominant MuSK Myasthenia Gravis for which steroid sparing immunosuppressive treatment was initiated with mycophenolate mofetil. He subsequently developed clinical exam findings of hypomimia, bilateral bradykinesia, asymmetrical limb rigidity, right arm and jaw tremor that raised concern for the possibility of parkinsonism. Review of systems for premotor symptoms was positive for constipation and dream enactment behavior. There was no previous exposure to anti-dopaminergic therapies and MRI Brain was unrevealing. DaT scan was subsequently obtained, which demonstrated objective evidence of bilateral striatal dopaminergic deficiency, indicative of an inherent basal ganglia disorder. In the absence of any clinical findings of atypical parkinsonism, patient met clinical diagnostic criteria for Idiopathic Parkinson’s Disease. <h3>Conclusions:</h3> This case demonstrates the clinical challenges that present in this overlap of neuromuscular and neurodegenerative disease in a single individual. We highlight the importance of a thorough history and physical examination, supported with objective evidence by a positive DaT scan, to elucidate the appropriate etiology of symptoms. <b>Disclosure:</b> Dr. Andraos has nothing to disclose. Dr. Veerappan has nothing to disclose.

Premotor, nonmotor and motor symptoms of Parkinson's Disease: A new clinical state of the art.

Parkinson's Disease (PD) is a neurodegenerative disorder that affects dopaminergic neurons in the mesencephalic substantia nigra, causing a progressive clinical course characterized by pre-motor, non-motor and motor symptoms, which negatively impact the quality of life of patients and cause high health care costs. Therefore, the present study aims to discuss the clinical manifestations of PD and to make a correlation with the gut-brain (GB) axis, approaching epidemiology and therapeutic perspectives, to better understand its clinical progression and identify symptoms early. A literature review was performed regarding the association between clinical progression, the gut-brain axis, epidemiology, and therapeutic perspectives, in addition to detailing pre-motor, non-motor symptoms (neuropsychiatric, cognitive, autonomic, sleep disorders, sensory abnormalities) and cardinal motor symptoms. Therefore, this article addresses a topic of extreme relevance, since the previously mentioned clinical manifestations (pre-motor and non-motor) can often act as prodromal markers for the early diagnosis of PD and may precede it by up to 20 years.

Approaching the Gut and Nasal Microbiota in Parkinson's Disease in the Era of the Seed Amplification Assays.

Parkinson's disease (PD) is a neurodegenerative disorder often associated with pre-motor symptoms involving both gastrointestinal and olfactory tissues. PD patients frequently suffer from hyposmia, hyposalivation, dysphagia and gastrointestinal dysfunctions. During the last few years it has been speculated that microbial agents could play a crucial role in PD. In particular, alterations of the microbiota composition (dysbiosis) might contribute to the formation of misfolded α-synuclein, which is believed to be the leading cause of PD. However, while several findings confirmed that there might be an important link between intestinal microbiota alterations and PD onset, little is known about the potential contribution of the nasal microbiota. Here, we describe the latest findings on this topic by considering that more than 80% of patients with PD develop remarkable olfactory deficits in their prodromal disease stage. Therefore, the nasal microbiota might contribute to PD, eventually boosting the gut microbiota in promoting disease onset. Finally, we present the applications of the seed amplification assays to the study of the gut and olfactory mucosa of PD patients, and how they could be exploited to investigate whether pathogenic bacteria present in the gut and the nose might promote α-synuclein misfolding and aggregation.

Caracterização Clínica e Polissonográfica do Distúrbio Comportamental do Sono REM: Casuística de um Centro de Medicina do Sono Português

Introduction: REM sleep behavior disorder (RBD) is diagnosed by clinical history of abnormal and complex movements during sleep and by polysomnographic findings. Accordingly, RBD may occur isolated (iRBD) or, frequently, in association with neurodegenerative diseases, namely synucleinopathies generally preceding its onset. Thereby, our aim was to characterize the clinical and video-polysomnography (vPSG) features of patients diagnosed with iRBD and RBD plus Parkinson disease (RBDPD); analyze the symptoms and signs (motor and non-motor) that RBDPD patients presented before the diagnosis of PD, to realize if there is any predictive factor for phenoconversion. Methods: Retrospective, observational and unicentric study. The study included all patients with a clinical diagnosis of RBD (isolated and associated with PD), according to the diagnostic criteria of DSM-5 and ICSD-3 and who underwent polysomnographic recording at the Sleep Medicine Center of a hospital. level III, between January 2008 and May 2021. Results: A total of 48 patients were included and divided in iRBD (27 patients) and RBDPD (21 patients) groups. We proceeded to a clinical, demographic and vPSG characterization and comparison. In both groups, the majority of patients were male and the average age of RBD diagnosis was 64-65 years. In iRBD group, the most reported manifestation was violent sleep movements. In this group, we found five patients with subtle motor signs. In the RBDPD group, the majority had a previous diagnosis of RBD, on average, about six years before. The most common clinical feature was the presence of vivid dreams with violent content. In the iRBD group, the percentage of RSWA was higher in the subgroup of patients with subtle motor signs and other premotor symptoms, namely depression (34.2%), than in patients without any of those features (31.6%). Conclusion: As we found, in the most of RBDDP group, RBD preceded the diagnosis of PD. Although it was not possible to obtain a correlation, as with clinical RBD, the percentage of RSWA should be considered a potential biomarker of phenoconversion in neurodegenerative disease. Early diagnosis of REM sleep anomalies, in a phase of subtil motor symptoms is essential and should be used as a biomarker to an earlier investigation, as DATscan, and therapeutic action.

243 Mood disorder affects age at onset of adult-onset cervical dystonia

IntroductionMood disorder is common in cervical dystonia (CD) and may precede the onset of dystonia. There is controversy as to whether mood disorder is part of the primary process or secondary to the disability.We assessed the characteristics of CD patients in relation to a past history of mood disorder.MethodsWe collected demographic data, medical history of mood disorder, and prospectively measured prevalence of mood disorder using the BAI and BDI.ResultsIn 193 patients (128 women and 65 men) mean age at onset of CD was 43.9 years with mean duration, 17.5 years. Men had earlier age at onset of CD than women(p=0.0037). 53/128 (41%) women with a history of a mood disorder had a significantly earlier median age at onset than 75/128 (59%) women without a history of mood disorder (p=0.005). 33(26%) women with mood disorder prior to CD also had an earlier age at onset than the 75(59%) without such a history (p=0.0154). A history of mood disorder was more common in women(41%) than men(31%). 54/128(42%) women and 21/65(32%) men had current mood disorder symptoms.ConclusionsThe significant differences in the age at onset in women with, and without, a history of mood disorder strongly indicates that anxiety and depression are primary non-motor (and premotor) symptoms of CD.ihedinachindukwe@gmail.com

Pain in atypical parkinsonism, vascular parkinsonism, and Parkinson's disease.

Pain is a common symptom in Parkinson's disease (PD) and is considered a pre-motor symptom suggesting sensory involvement in the pre-motor stage. Pain in other parkinsonian disorders such as atypical parkinsonism and vascular parkinsonism (VP) has been investigated in only a few studies. The characteristics of pain in other parkinsonian disorders, including the temporal relationships between pain and motor symptoms, were investigated in the present study. A total of 236 PD, 42 multiple system atrophy (MSA), 31 progressive supranuclear palsy (PSP), and 38 VP patients were screened for pain. After excluding patients with dementia and pain not related to PD, the presence of pain, severity, onset, type, and location were compared among the four patient groups. Difference was not observed in pain presence (χ2 = 3, p = 0.186), severity (F = 1.534, p = 0.207), or type (χ2 = 6, p = 0.400) among the four groups. However, the temporal relationship between pain and motor symptoms differed (H(3) = 8.764, p = 0.033). Pain predated motor symptoms in PD, MSA, and VP but often followed motor symptoms in PSP. The pain location in the body was different among the four patient groups (χ2 = 21, p = 0.018), and leg involvement was more common in PSP. The present study results suggest that pain can be a pre-motor symptom in PD, MSA, and VP but not in PSP, implying different pain pathogeneses in these disorders. Pain locations were other for each group, which requires further investigation with a more extensive study cohort.

Delusional parasitosis as premotor symptom of parkinson’s disease: A case report

Delusional parasitosis as premotor symptom of parkinson’s disease: A case report

Deep nasal sinus cavity microbiota dysbiosis in Parkinson\u2019s disease

Olfactory dysfunction is a pre-motor symptom of Parkinson’s disease (PD) that appears years prior to diagnosis and can affect quality of life in PD. Changes in microbiota community in deep nasal cavity near the olfactory bulb may trigger the olfactory bulb-mediated neuroinflammatory cascade and eventual dopamine loss in PD. To determine if the deep nasal cavity microbiota of PD is significantly altered in comparison to healthy controls, we characterized the microbiota of the deep nasal cavity using 16S rRNA gene amplicon sequencing in PD subjects and compared it to that of spousal and non-spousal healthy controls. Correlations between microbial taxa and PD symptom severity were also explored. Olfactory microbial communities of PD individuals were more similar to those of their spousal controls than to non-household controls. In direct comparison of PD and spousal controls and of PD and non-spousal controls, significantly differently abundant taxa were identified, and this included increased relative abundance of putative opportunistic-pathobiont species such as Moraxella catarrhalis. M. catarrhalis was also significantly correlated with more severe motor scores in PD subjects. This proof-of-concept study provides evidence that potential pathobionts are detected in the olfactory bulb and that a subset of changes in the PD microbiota community could be a consequence of unique environmental factors associated with PD living. We hypothesize that an altered deep nasal microbiota, characterized by a putative pro-inflammatory microbial community, could trigger neuroinflammation in PD.

\u03b1-Synuclein aggregation in the olfactory bulb induces olfactory deficits by perturbing granule cells and granular\u2013mitral synaptic transmission

Olfactory dysfunction is an early pre-motor symptom of Parkinson’s disease (PD) but the neural mechanisms underlying this dysfunction remain largely unknown. Aggregation of α-synuclein is observed in the olfactory bulb (OB) during the early stages of PD, indicating a relationship between α-synuclein pathology and hyposmia. Here we investigate whether and how α-synuclein aggregates modulate neural activity in the OB at the single-cell and synaptic levels. We induced α-synuclein aggregation specifically in the OB via overexpression of double-mutant human α-synuclein by an adeno-associated viral (AAV) vector. We found that α-synuclein aggregation in the OB decreased the ability of mice to detect odors and to perceive attractive odors. The spontaneous activity and odor-evoked firing rates of single mitral/tufted cells (M/Ts) were increased by α-synuclein aggregates with the amplitude of odor-evoked high-gamma oscillations increased. Furthermore, the decreased activity in granule cells (GCs) and impaired inhibitory synaptic function were responsible for the observed hyperactivity of M/Ts induced by α-synuclein aggregates. These results provide direct evidences of the role of α-synuclein aggregates on PD-related olfactory dysfunction and reveal the neural circuit mechanisms by which olfaction is modulated by α-synuclein pathology.

Prevalence of Advanced Parkinson's Disease in Patients Treated in the Hospitals of the Spanish National Healthcare System: The PARADISE Study.

Background: Advanced Parkinson’s disease (APD) has been recently defined as a stage in which certain symptoms and complications are present, with a detrimental influence on the overall patient’s health conditions and with a poor response to conventional treatments. However, historically, the term APD has been controversial, thus consequently, APD prevalence has not been previously studied. Objectives: The main objective was to determine the prevalence of APD in patients diagnosed with idiopathic PD in hospitals of the Spanish National Healthcare System. Secondary objectives were the prevalence and incidence of PD and the clinical and sociodemographic characteristics and quality of life of patients with APD or non-APD. Methods: This was a non-interventional, cross-sectional, multicenter, national study in the hospital setting. Results: The study population included 929 patients with PD (mean age 71.8 ± 10.1 years; 53.8% male) and a mean time since diagnosis of 6.6 ± 5.4 years. At the time of diagnosis, 613 patients (66.06%) reported having had premotor symptoms. The Hoehn and Yahr stage was 1 in 15.7% of the patients, 2 in 42.8%, 3 in 30.1%, 4 in 9.9%, and 5 in 1.4%; 46.9% of the patients had comorbidities (mean age-adjusted Charlson comorbidity index 3.5 ± 1.7; median 10-year survival 77%) and the mean 8-item Parkinson’s Disease Quality of Life Questionnaire was 27.8 ± 20.5. We found an APD prevalence of 38.21% (95%CI: 35.08–41.42%), a PD prevalence of 118.4 (95%CI: 117.3–119.6), and a PD incidence of 9.4 (95%CI: 5.42–13.4) all per 100,000 population. Among the APD population, a 15.2% were receiving some form of therapy for advanced stages of the disease (deep brain stimulation, levodopa/carbidopa intestinal gel, or apomorphine subcutaneous infusion). Conclusions: The percentage of patients with APD in the hospitals of the Spanish National Healthcare System was 38.2%.

The effect of water-soluble pristine C60 fullerene on 6-OHDA-induced Parkinson’s disease in rats

Oxidative stress is thought to be one of the mechanisms that leads to the dysfunction and degeneration of dopaminergic neurons in Parkinson’s disease pathogenesis and presumed to be underway during the prodromal phase. Therefore, therapy, which is effective against pre-motor symptoms, might be effective in preventing or delaying the development and progression of Parkinson’s disease. The aim of our study was to investigate the therapeutic efficiency of pristine C60 fullerene aqueous solution (C60FAS) during Parkinson’s disease in rats. The unilateral dopamine deficiency was induced in male Wistar rats (220–250 g) by stereotaxic microinjection of neurotoxin 6-hydroxydopamine (6-OHDA, 12 μg). C60FAS was injected to rats intraperitoneally daily for 10 days (0.65 mg/kg per day). The percentage of destroyed dopaminergic neurons was determined by the apomorphine test and by IHC staining of tyrosine hydroxylase-positive neurons in substantia nigra. We evaluated the rat body weight, the water and food intake, Open Field behavioural test, the level of biochemical antioxidant system, the activity of peritoneal macrophages. Levels of spontaneous and carbachol-stimulated colon motility were estimated by ballonographic method in vivo. C60FAS showed a positive tendency to increase the number of tyrosine hydroxylase-positive cells in the midbrain, which was associated with more profound improvement in apomorphine-rotation behaviour and slight relief of the anxiety level in Open Field test. Furthermore, C60FAS treatment increased the index of stimulated distal colon motor activity while it did not have a significant effect on water content in feces and total gastrointestinal transit time. C60FAS treatment did not affect water intake behaviour or body weight changes while it induced an increase of glutathione level and decrease activity of glutathione peroxidase in the brain as well as an increase in activity of peritoneal macrophages in 6-OHDA-Parkinson’s disease rats. These findings confirmed the potential therapeutic effectiveness of water-soluble pristine C60 fullerene in Parkinson’s disease pathogenesis, though there is ground for caution because of its systemic mild toxic effect.