scholarly journals Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

2020 ◽  
Author(s):  
Valerie Joers ◽  
Gunasingh Masilamoni ◽  
Doty Kempf ◽  
Alison R Weiss ◽  
Travis Rotterman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sex Differences ◽  
Microglial Activation ◽  
Motor Deficits ◽  
Sexually Dimorphic ◽  
Motor Symptoms ◽  
Tnf Inhibitor ◽  
Nonmotor Symptoms ◽  
Monkey Model

AbstractInflammation has been linked to the development of nonmotor symptoms in Parkinson’s disease (PD), which greatly impact patients’ quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a “gold standard” model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

scholarly journals Characterization of Nonmotor Symptoms in the MitoPark Mouse Model of Parkinson’s Disease

2020 ◽  
Author(s):  
Monica R. Langley ◽  
Shivani Ghaisas ◽  
Bharathi N. Palanisamy ◽  
Muhammet Ay ◽  
Huajun Jin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Antidepressant Treatment ◽  
Forced Swim Test ◽  
Cognitive Learning ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Nonmotor Symptoms ◽  
Forced Swim ◽  
Non Motor Symptoms

AbstractMitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinson’s disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since non-motor symptoms are now recognized as important features of the prodromal stage of PD, we monitored the clinically relevant motor and nonmotor symptoms from ages 8-24 wks in MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wks and became severe by 16-24 wks. Interestingly, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wks and becoming most severe at 16 wks, as determined by Morris water maze. When compared to age-matched control mice, MitoPark mice exhibited olfactory deficits in novel and social scent tests as early as 10-12 wks. MitoPark mice between 16-24 wks spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in cognitive learning and memory, olfactory discrimination, and anxiety-and depression-like behaviors. Thus, MitoPark mice can serve as an invaluable model for studying motor and non-motor symptoms in addition to studying pathology in PD.

Emerging roles of microglial activation and non-motor symptoms in Parkinson's disease

2012 ◽  
Vol 98 (2) ◽  
pp. 222-238 ◽  
Author(s):  
Karlijn J. Doorn ◽  
Paul J. Lucassen ◽  
Hendrikus W. Boddeke ◽  
Marloes Prins ◽  
Henk W. Berendse ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Microglial Activation ◽  
Motor Symptoms ◽  
Non Motor Symptoms

scholarly journals The Add-On Effect of Lactobacillus plantarum PS128 in Patients With Parkinson's Disease: A Pilot Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Chin-Song Lu ◽  
Hsiu-Chen Chang ◽  
Yi-Hsin Weng ◽  
Chiung-Chu Chen ◽  
Yi-Shan Kuo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lactobacillus Plantarum ◽  
Outcome Measures ◽  
Rating Scale ◽  
Controlled Trial ◽  
Secondary Outcome ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Non Motor Symptoms

Background:Lactobacillus plantarum PS128 (PS128) is a specific probiotic, known as a psychobiotic, which has been demonstrated to alleviate motor deficits and inhibit neurodegenerative processes in Parkinson's disease (PD)-model mice. We hypothesize that it may also be beneficial to patients with PD based on the possible mechanism via the microbiome-gut-brain axis.Methods: This is an open-label, single-arm, baseline-controlled trial. The eligible participants were scheduled to take 60 billion colony-forming units of PS128 once per night for 12 weeks. Clinical assessments were conducted using the Unified Parkinson's Disease Rating Scale (UPDRS), modified Hoehn and Yahr scale, and change in patient “ON-OFF” diary recording as primary outcome measures. The non-motor symptoms questionnaire, Beck depression inventory-II, patient assessment of constipation symptom, 39-item Parkinson's Disease Questionnaire (PDQ-39), and Patient Global Impression of Change (PGI-C) were assessed as secondary outcome measures.Results: Twenty-five eligible patients (32% women) completed the study. The mean age was 61.84 ± 5.74 years (range, 52–72), mean disease duration was 10.12 ± 2.3 years (range, 5–14), and levodopa equivalent daily dosage was 1063.4 ± 209.5 mg/daily (range, 675–1,560). All patients remained on the same dosage of anti-parkinsonian and other drugs throughout the study. After 12 weeks of PS128 supplementation, the UPDRS motor scores improved significantly in both the OFF and ON states (p = 0.004 and p = 0.007, respectively). In addition, PS128 intervention significantly improved the duration of the ON period and OFF period as well as PDQ-39 values. However, no obvious effect of PS128 on non-motor symptoms of patients with PD was observed. Notably, the PGI-C scores improved in 17 patients (68%). PS128 intervention was also found to significantly reduce plasma myeloperoxidase and urine creatinine levels.Conclusion: The present study demonstrated that PS128 supplementation for 12 weeks with constant anti-parkinsonian medication improved the UPDRS motor score and quality of life of PD patients. We suggest that PS128 could serve as a therapeutic adjuvant for the treatment of PD. In the future, placebo-controlled studies are needed to further support the efficacy of PS128 supplementation.Clinical Trial Registration:https://clinicaltrials.gov/, identifier: NCT04389762.

scholarly journals Genetic Impact on Clinical Features in Parkinson’s Disease: A Study on SNCA-rs11931074

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Li Shu ◽  
Dongxiao Liang ◽  
Hongxu Pan ◽  
Qian Xu ◽  
Jifeng Guo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Features ◽  
Rating Scale ◽  
Motor Symptoms ◽  
Nonmotor Symptoms ◽  
Association Analyses ◽  
Comorbidity Burden ◽  
Severe Motor ◽  
Genetic Impact

SNCA-rs11931074 had been demonstrated to be strongly correlated with PD risk. However, there was lack of comprehensive analysis of SNCA-rs11931074-related clinical features which may help explain clinical heterogeneity of PD. In our study, we performed association analyses on the relationship between SNCA-rs11931074 and motor symptoms, nonmotor symptoms, and comorbidities in PD. 611 rs11931074 carriers and 113 rs11931074 noncarriers were enrolled. In the clinical phenotype analyses, the Unified Parkinson’s Disease Rating Scale part II (UPDRS II) and part III (UPDRS III) scores of rs11931074 carriers were lower than those of noncarriers (SC: −0.083, p=0.035; SC: −0.140, p≤0.001). The Charlson Comorbidity Index (CCI) score of carriers was lower than that of noncarriers (SC: −0.097, p=0.009). No significant statistical differences were found between the variant and other clinical features such as motor complications and nonmotor symptoms. The SNCA-rs11931074 carriers may present with more benign clinical profiles than noncarriers with less severe motor symptoms and comorbidity burden.

Development and psychometric evaluation of a scale to measure impaired self-awareness of hyper- and hypokinetic movements in Parkinson’s disease

2015 ◽  
Vol 21 (3) ◽  
pp. 221-230 ◽  
Author(s):  
Franziska Maier ◽  
Anna L. Ellereit ◽  
Carsten Eggers ◽  
Catharine J. Lewis ◽  
Esther A. Pelzer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Psychometric Evaluation ◽  
Principal Component ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Self Awareness ◽  
Left Hand ◽  
Resting Tremor ◽  
Psychosocial Sequelae

AbstractObjective: Patients with Parkinson’s disease (PD) can show impaired self-awareness of motor deficits (ISAm). We developed a new scale that measures ISAm severity of hyper- and hypokinetic movements in PD during medication on state and defined its psychometric criteria. Method: Included were 104 right-handed, non-depressed, non-demented patients. Concerning ISAm, 38 motor symptoms were assessed using seven tasks, which were performed and self-rated concerning presence of deficit (yes/no) by all patients. The whole procedure was videotaped. Motor symptoms were then evaluated by two independent experts, blinded for patient’s ratings, concerning presence, awareness of deficit, and severity. Exploratory principal component analysis (promax rotation) was applied to reduce items. Principal axis factoring was conducted to extract factors. Reliability was examined regarding internal consistency, split-half reliability, and interrater reliability. Validity was verified by applying two additional measures of ISAm. Results: Of the initial 38 symptoms, 15 remained, assessed in five motor tasks and merged to a total severity score. Factor analysis resulted in a four factor solution (dyskinesia, resting tremor right hand, resting tremor left hand, bradykinesia). For all subscales and the total score, measures of reliability (values 0.64–0.89) and validity (effect sizes>0.3) were satisfactory. Descriptive results showed that 66% of patients had signs of ISAm (median 2, range 0–15), with ISAm being most distinct for dyskinesia. Conclusions: We provide the first validation of a test for ISAm in PD. Using this instrument, future studies can further analyze the pathophysiology of ISAm, the psychosocial sequelae, therapeutic strategies and compliance with therapy. (JINS, 2015, 21, 1–10)

scholarly journals CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

2019 ◽  
Author(s):  
Edward N. Wilson ◽  
Michelle S. Swarovski ◽  
Patricia Linortner ◽  
Marian Shahid ◽  
Abigail J. Zuckerman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Microglial Activation ◽  
Soluble Form ◽  
Motor Symptoms ◽  
Cognitively Normal ◽  
Csf Concentration

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by α-synuclein accumulation that frequently associates with amyloid beta (Aβ) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic Aβ and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF Aβ and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not Aβ, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.One sentence summaryCSF sTREM2 correlates with CSF tau in PD

scholarly journals Parkinson’s Disease-Related Motor and Nonmotor Symptoms in the Lancaster Amish

2020 ◽  
Vol 54 (5) ◽  
pp. 392-397
Author(s):  
Michael D.F. Goldenberg ◽  
Xuemei Huang ◽  
Honglei Chen ◽  
Lan Kong ◽  
Teodor T. Postolache ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Daytime Sleepiness ◽  
Bowel Movement ◽  
Motor Symptoms ◽  
Nonmotor Symptoms ◽  
Case Identification ◽  
Movement Frequency ◽  
Bowel Movements ◽  
Bowel Movement Frequency

<b><i>Introduction:</i></b> Previous research has suggested that the Amish may experience a relatively high prevalence of Parkinson’s disease (PD) and/or parkinsonian motor signs. <b><i>Methods:</i></b> In a large sample from the Amish community in Lancaster County, Pennsylvania, age ≥18 years, we assessed the prevalence of self-reported PD diagnosis. For those without self-reported PD diagnosis, we assessed the frequency of PD-related motor symptoms using a 9-item questionnaire that was designed by the PD Epidemiology Research Group. Lastly, we queried study participants for the presence of 2 nonmotor symptoms that have been commonly linked to PD: bowel movement frequency and daytime sleepiness. <b><i>Results:</i></b> Among 2,025 subjects who answered the PD questionnaire, 430 were older than 60 years. Of 430 participants ≥60 years, 5 (1.2%) reported a PD diagnosis. Of those without a PD diagnosis, 10.5% reported ≥1 and 1.2% ≥ 4 motor symptoms for the 9-item PD screening questionnaire. Of the 3,789 subjects who answered the question about bowel movement frequency, 0.7% reported ≤3 bowel movements per week. Among 1,710 subjects who answered the question about daytime sleepiness, 8.1% of the participants reported “always” sleepy during the day. <b><i>Discussion:</i></b> These data neither support a markedly higher PD prevalence in the older Lancaster Amish nor do they show dramatically higher motor and/or selected nonmotor symptoms than the general population. Future studies that employ more rigorous procedures for case identification and PD-specific preclinical symptoms/tests are needed to determine the potential differences and similarities among different Amish populations and between Amish and non-Amish populations.

scholarly journals Memory deficits in Parkinson’s disease are associated with reduced beta power modulation

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Hayley J MacDonald ◽  
John-Stuart Brittain ◽  
Bernhard Spitzer ◽  
Simon Hanslmayr ◽  
Ned Jenkinson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Duration ◽  
Memory Formation ◽  
Motor Deficits ◽  
Beta Activity ◽  
Motor Symptoms ◽  
Memory Encoding ◽  
Beta Power ◽  
Non Motor Symptoms

Abstract There is an increasing recognition of the significant non-motor symptoms that burden people with Parkinson’s disease. As such, there is a pressing need to better understand and investigate the mechanisms underpinning these non-motor deficits. The electrical activity within the brains of people with Parkinson’s disease is known to exhibit excessive power within the beta range (12–30 Hz), compared with healthy controls. The weight of evidence suggests that this abnormally high level of beta power is the cause of bradykinesia and rigidity in Parkinson’s disease. However, less is known about how the abnormal beta rhythms seen in Parkinson’s disease impact on non-motor symptoms. In healthy adults, beta power decreases are necessary for successful episodic memory formation, with greater power decreases during the encoding phase predicting which words will subsequently be remembered. Given the raised levels of beta activity in people with Parkinson’s disease, we hypothesized that the necessary decrease in power during memory encoding would be diminished and that this would interfere with episodic memory formation. Accordingly, we conducted a cross-sectional, laboratory-based experimental study to investigate whether there was a direct relationship between decreased beta modulation and memory formation in Parkinson’s disease. Electroencephalography recordings were made during an established memory-encoding paradigm to examine brain activity in a cohort of adults with Parkinson’s disease (N = 28, 20 males) and age-matched controls (N = 31, 18 males). The participants with Parkinson’s disease were aged 65 ± 6 years, with an average disease duration of 6 ± 4 years, and tested on their normal medications to avoid the confound of exacerbated motor symptoms. Parkinson’s disease participants showed impaired memory strength (P = 0.023) and reduced beta power decreases (P = 0.014) relative to controls. Longer disease duration was correlated with a larger reduction in beta modulation during encoding, and a concomitant reduction in memory performance. The inability to sufficiently decrease beta activity during semantic processing makes it a likely candidate to be the central neural mechanism underlying this type of memory deficit in Parkinson’s disease. These novel results extend the notion that pathological beta activity is causally implicated in the motor and (lesser appreciated) non-motor deficits inherent to Parkinson’s disease. These findings provide important empirical evidence that should be considered in the development of intelligent next-generation therapies.

scholarly journals Neurocognitive Correlates of Apathy and Anxiety in Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yelena Bogdanova ◽  
Alice Cronin-Golomb
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuropsychological Tests ◽  
Rating Scales ◽  
Disease Duration ◽  
Differential Association ◽  
Motor Symptoms ◽  
Healthy Controls ◽  
Nonmotor Symptoms ◽  
Neurocognitive Profiles

Parkinson's disease (PD) is associated with various nonmotor symptoms including neuropsychiatric and cognitive dysfunction. We examined the relation between apathy, anxiety, side of onset of motor symptoms, and cognition in PD. We hypothesized that PD patients would show different neuropsychiatric and neurocognitive profiles depending on the side of onset. 22 nondemented PD patients (11 right-side onset (RPD) with predominant left-hemisphere pathology, and 11 LPD) and 22 matched healthy controls (NC) were administered rating scales assessing apathy and anxiety, and a series of neuropsychological tests. PD patients showed a higher anxiety level than NC. There was a significant association between apathy, anxiety, and disease duration. In LPD, apathy but not anxiety was associated with performance on nonverbally mediated executive function and visuospatial measures, whereas, in RPD, anxiety but not apathy correlated with performance on verbally mediated tasks. Our findings demonstrated a differential association of apathy and anxiety to cognition in PD.

scholarly journals Progression of Nonmotor Symptoms in Parkinson’s Disease by Sex and Motor Laterality

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Zimple Kurlawala ◽  
Paul H. Shadowen ◽  
Joseph D. McMillan ◽  
Levi J Beverly ◽  
Robert P. Friedland
Keyword(s):  
Quality Of Life ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Symptom ◽  
Motor Symptoms ◽  
Healthy Controls ◽  
Nonmotor Symptoms ◽  
Start Up ◽  
Progression Markers

Nonmotor symptoms (NMS) in Parkinson’s disease (PD) can start up to a decade before motor manifestations and strongly correlate with the quality of life. Understanding patterns of NMS can provide clues to the incipient site of PD pathology. Our goal was to systematically characterize the progression of NMS in PD (n = 489), compared to healthy controls, HC (n = 241), based on the sex of the subjects and laterality of motor symptom onset. Additionally, NMS experienced at the onset of PD were also compared to subjects with scans without dopaminergic deficit, SWEDD (n = 81). The Parkinson’s Progression Markers Initiative (PPMI) database was utilized to analyze several NMS scales. NMS experienced by PD and SWEDD cohorts were significantly higher than HC and both sex and laterality influenced several NMS scales at the onset of motor symptoms. Sex Differences. PD males experienced significant worsening of sexual, urinary, sleep, and cognitive functions compared to PD females. PD females reported significantly increased thermoregulatory dysfunction and anxious mood over 7 years and significantly more constipation during the first 4 years after PD onset. Laterality Differences. At onset, PD subjects with right-sided motor predominance reported significantly higher autonomic dysfunction. Subjects with left-sided motor predominance experienced significantly more anxious mood at onset which continued as Parkinson’s progressed. In conclusion, males experienced increased NMS burden in Parkinson’s disease. Laterality of motor symptoms did not significantly influence NMS progression, except anxious mood. We analyzed NMS in a large cohort of PD patients, and these data are valuable to improve PD patients’ quality of life by therapeutically alleviating nonmotor symptoms.

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