Parkinson's Disease Parkinsonism Research Articles

Uncovering the Molecular Link Between Lead Toxicity and Parkinson's Disease.

Significance: Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects millions around the world. The etiology of PD remains unknown, but environmental and occupational exposures to heavy metals are likely at play, and may impact the severity of the disease. Lead is a toxin known to affect many organs in the body throughout life, particularly the central nervous system. Recent Advances: In this study, we summarize and examine the evidence for such environmental and/or occupational exposures, with a focus on the molecular mechanisms associated with lead exposure and its potential contribution to the onset of parkinsonism in PD. In particular, populational studies suggest higher bone and blood lead levels are associated with increased risk of PD. Interestingly, low levels of lead exposure in the very early stages of life cause increase the production of alpha-synuclein protein in animal models. Critical Issues: Although the specific mechanisms underlying this association have not been fully assessed, oxidative stress and mitochondrial dysfunction are likely implicated and may explain the toxic effects that connect lead exposure to parkinsonism. Future Directions: Additional pre-clinical and clinical studies should be performed in order to further document the molecular link between lead toxicity and PD, as this may open novel perspectives in terms of disease prevention. Antioxid. Redox Signal. 39, 321-335.

Passing the sniff test

Parkinson's Disease Parkinson's disease (PD) is a chronic progressive neurological disorder that largely affects movement. There is currently no diagnostic test. Trivedi et al. collected sebum samples from PD patients and unaffected volunteers to identify volatile metabolites that may serve as PD biomarkers. The research team included a woman with a sensitive sense of smell who reported to be able to detect PD by odor. In blinded studies, she identified the “musky” samples that belonged to the PD patients with high accuracy, which guided mass spectrometry to identify the volatile compounds that constituted a signature PD scent. These studies may pave the way for development of the first PD-specific diagnostic test. ACS Cent. Sci. 10.1021/acscentsci.8b00879 (2019).

Effects of Progressive Resistance Exercise Training on the Motor and Nonmotor Features of Parkinson's Disease: A Review

Objective:This paper reviews the therapeutically beneficial effects of progressive resistance exercise training (PRET) on motor and nonmotor symptoms in Parkinson's disease (PD).Methods:First, we perform a systematic review of the literature on the effects of PRET on motor signs of PD, functional outcomes, quality of life, and patient perceived improvement, strength, and cognition in PD. Second, we perform a meta-analysis on the motor section of the UPDRS. Finally, we discuss the results of our review and we identify current knowledge gaps regarding PRET in PD.Conclusion:This systematic review synthesizes evidence that PRET can improve strength and motor signs of Parkinsonism in PD and may also be beneficial for physical function in individuals with PD. Further research is needed to explore the effects of PRET on nonmotor symptoms such as depression, cognitive impairment, autonomic nervous system dysfunction, and quality of life in individuals with PD.

Genetics of Parkinson disease.

PD : Parkinson disease Parkinson disease (PD) is a degenerative disorder of the nervous system. It is characterized by loss of dopamine-producing cells which, in time, develops into motor system dysfunction. A small portion of PD cases are purely genetic. Currently, diagnosis is based on clinical

Punding as a Transient Symptom in a Patient With an Early-Onset Form of Dementia

Punding as a Transient Symptom in a Patient With an Early-Onset Form of Dementia

Adenosine A2A Receptors Measured with [11C]TMSX PET in the Striata of Parkinson's Disease Patients

Adenosine A2A receptors (A2ARs) are thought to interact negatively with the dopamine D2 receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinson's disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD.

PATH52 Parkinsonism incidence in north-east Scotland: the PINE study

BackgroundThere have been few high-quality incidence studies of parkinsonism/Parkinson's disease (PD) worldwide and none from Scotland.MethodsWe performed a population-based prospective incidence study of degenerative or vascular parkinsonian disorders from 37...

Baicalein reduces E46K α‐synuclein aggregation in vitro and protects cells against E46K α‐synuclein toxicity in cell models of familiar Parkinsonism

The E46K is a point mutation in alpha-synuclein (alpha-syn) that causes familial Parkinsonism with Lewy body dementia. We have now generated a cell model of Parkinsonism/Parkinson's disease (PD) and demonstrated cell toxicity after expression of E46K in the differentiated PC12 cells. E46K alpha-syn inhibited proteasome activity and induced mitochondrial depolarization in the cell model. Baicalein has been reported to inhibit fibrillation of wild type alpha-syn in vitro, and to protect neurons against several chemical-induced models of PD. We now report that baicalein significantly attenuated E46K-induced mitochondrial depolarization and proteasome inhibition, and protected cells against E46K-induced toxicity in a cell model of PD. Baicalein also reduced E46K fibrilization in vitro, with a concentration-dependent decrease in beta sheet conformation, though it increased some oligomeric species, and decreased formation of E46K alpha-syn-induced aggregates and rescued toxicity in N2A cells. Taken together, these data indicate that mitochondrial dysfunction, proteasome inhibition and specific aspects of abnormal E46K aggregation accompany E46K alpha-syn-induced cell toxicity, and baicalein can protect as well as altering aggregation properties. Baicalein has potential as a tool to understand the relation between different aggregation species and toxicity, and might be a candidate compound for further validation by using in vivo alpha-syn genetic PD models.

Depression in Parkinson's Disease

To examine predictive factors associated with onset of depression among individuals diagnosed with Parkinson's disease (PD). Depression may precede or follow symptomatic parkinsonism in PD. It is frequently treatable but often overlooked. The clinical series comprised 685 individuals who were diagnosed with PD and followed by one neurologist (RJU) from 1994 to 2007. The primary outcome was time to depression following the onset of PD. Diagnosis of depression was based on clinical assessment of depressive symptoms from patients (and spouse/family/caregiver) and antidepressant usage. A number of demographic, historical and clinical predictive factors were examined, including gender, age at symptomatic onset, disease duration, onset characteristics, clinical ratings, antiparkinsonian medications, cognitive status, depression history, and familial history of PD and other neurodegenerative disorders. Seventy-two percent of patients developed depression within ten years of symptomatic PD onset, and the mean time to depression was 7.9 years (median: 5.7 years). Factors associated with depression included longer PD duration, greater impairment in activities of daily living, and positive family history of motor neuron disease (MND). A high rate of individuals with PD develop depressive symptoms during the course of the disease. Based on first clinic visit characteristics, most factors examined were not helpful in identifying individuals with an increased risk of depression. However, disease duration, functional limitations and family history of MND should lead clinicians to an increased vigilance for identifying depression.

Homocysteine is not associated with global motor or cognitive measures in nondemented older Parkinson's disease patients

Levodopa (L-dopa) treatment of Parkinson's disease (PD) is associated with elevated homocysteine (Hcy). To examine the relationship between Hcy, methylenetetrahydrofolate reductase polymorphisms (MTHFR: 677C/T; 1298A/C), and B-vitamins in older PD patients and whether Hcy or MTHFR polymorphisms were associated with clinical measures. MTHFR polymorphisms, B-vitamin intake, and blood concentrations of Hcy, vitamin B12 and folate, and creatinine were determined and compared between groups (PD and controls). The relationship of Hcy to clinical measures was examined in PD. Among 51 patients [30M/21F, mean age (SD): 71.5 (4.7)] and 50 controls [29M/21F, 71.5 (4.8)], Hcy was higher in PD [13.6 (3.8); controls: 10.5 (2.5), P < 0.0005]. Hcy was associated with B-vitamin intake [F = 21.7, P < 0.0005], folate level (R = 0.31, P = 0.035), and the interaction of intake with MTHFR 677T (F = 5.2, P = 0.007), but not MTHFR 1298C genotype. Hcy did not correlate with global measures of cognition, mood, or parkinsonism in PD or with dyskinesias, fluctuations, or freezing. Higher vitamin B12 levels were associated with lower dyskinesia risk. Hcy was influenced by PD, MTHFR 677 genotype, and vitamin use, but not by the MTHFR 1298 genotype. There was no clear association with motor or cognitive measures, but dyskinesias were less likely with higher B12.

Usefulness of rCBF analysis in diagnosing Parkinson’s disease: supplemental role with MIBG myocardial scintigraphy

(123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is a useful tool for differentiating idiopathic Parkinson's disease (PD) from parkinsonism (PS) caused by other disorders. However, cardiac MIBG uptake is affected by various causes. Alternatively, hypoperfusion in the occipital lobe of PD is reported recently. The objective is to clarify the correlation between regional cerebral blood flow (rCBF) alteration and cardiac MIBG uptake in PD. In addition, we examined whether additional brain perfusion analysis improved the differential diagnostic ability for PD from PS when compared with MIBG scintigraphy alone. Forty-nine patients with PD (27 mild groups: Hoehn and Yahr stages I, II; 22 severe groups: Hoehn and Yahr stages III, IV) and 28 patients with PS participated. We compared absolute rCBF values between PD and PS. In addition, we determined correlation between MIBG parameters and each rCBF value. Finally, we compared the diagnostic ability for the differentiation of PD from PS between two diagnostic criteria, each MIBG index abnormality alone [heart-to-mediastinum ratio, H/M (E) < 1.9, H/E (D) < 1.7, washout rate > 40%] and each MIBG index abnormality or occipital lobe hypoperfusion (<36 ml/100 g per min). Absolute rCBF value of occipital lobe was significantly lower in severe PD as compared with PS or mild PD. In the correlation analysis, rCBF of occipital lobe correlated positively with MIBG parameters (H/M). Regarding the diagnostic ability, sensitivity improved by accounting for occipital hypoperfusion as compared with MIBG indices alone. In contrast, neither specificity nor accuracy improved by adding occipital lobe analysis. MIBG parameters (H/M) correlated positively with occipital hypoperfusion in PD. In the differential diagnosis between PD and PS, although its usefulness might be limited, analysis of rCBF in the occipital lobe added to (123)I-MIBG myocardial imaging can be recommended.

Comorbidity was associated with neurologic and psychiatric diseases: A general practice-based controlled study

Background and Objective To comprehensively examine comorbidity in unselected cohorts of patients with depression, stroke, multiple sclerosis (MS), Parkinson's disease/parkinsonism (PD/PKM), dementia, migraine, and epilepsy. Methods This cross-sectional study used morbidity data recorded by Dutch general practitioners. Index disease cohort sizes ranged from 241 patients with MS to 6,641 patients with lifetime depression. Thirty somatic and seven psychiatric disease categories were examined to determine whether they were comorbid with the index diseases by performing comparisons with age- and gender-matched control cohorts. Identified comorbidities were classified as either “possible” or “highly probable” comorbidity. Results An extensive range of 26 disease categories was found to be comorbid with lifetime depression. The comorbidity profile of stroke was also wide, including 21 disease categories. The comorbidity patterns of migraine and epilepsy comprised each 11 disease categories. Those concerning MS, PD/PKM, and dementia included a small number of disease categories. Conclusion This study provides comprehensive knowledge of the occurrence of somatic and psychiatric comorbidity in general populations of patients with depression, stroke, MS, PD/PKM, dementia, migraine, and epilepsy. The implications of the findings for clinical practice and research are discussed.

The Effects of Intensive Voice Treatment on Facial Expressiveness in Parkinson Disease

The purpose of the present retrospective study was to examine the effects of intensive voice therapy on facial expression in Parkinson disease. Parkinson disease (PD) often presents with symptoms that reduce communicative effectiveness on multiple levels, including decreased vocal loudness and reduced facial mobility. Recent advances in voice treatment have provided the first short- and long-term efficacy data indicating improvements in voice and speech following intensive voice therapy (Lee Silverman Voice Treatment [LSVT]). Anecdotal reports from both clinicians and patients indicate that the LSVT also has a positive impact on facial expression. These observations suggest a need to investigate more directly the effects of voice therapy on facial movement and expressiveness in PD. Forty-four individuals with idiopathic PD participated in this study. Video data were taken from recordings of individuals with PD who had received either one month of phonation-based treatment (LSVT) or respiratory treatment (RT) as part of a large treatment efficacy study designed to examine the effects of different types of therapy on speech and voice in PD. Twenty-second video samples of all subjects taken before and after treatment were paired and played at random without sound to trained raters, who judged each pair of video clips for facial mobility and engagement. All recordings were made while subjects were engaged in conversational speech. Inter-rater reliability was extremely high (0.90) for both the rating of facial mobility and engagement. Overall, members of the LSVT group received more ratings of increased facial mobility (P = 0.036) and engagement (P = 0.056) following treatment relative to members of the RT group. In addition, the extent of change for facial mobility after treatment was perceived as greater (P = 0.05) for the LSVT group than for the RT group. These results indicate that intensive voice therapy may have a positive effect on facial expressivity in PD. Such findings lend support to contemporary theories relating multiple expressive modalities (e.g., voice, face, and gesture) and suggest that targeting voice may be an effective and efficient way to influence expressive output in general.

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects

This study was undertaken to measure serotonergic modulation of dopamine in vivo by using positron emission tomography (PET), a radiotracer for the striatal dopamine D2 receptor ([11C]raclopride), and a pharmacologic challenge of the serotonin system (d,l-fenfluramine). Two PET studies using [11C]raclopride were performed in 11 normal male subjects before administration of the serotonin-releasing agent and reuptake inhibitor fenfluramine (60 mg p.o.) and 3 hours afterward. A graphical analysis method was used with the [11C]raclopride data to derive the distribution volume of D2 receptors. Plasma levels of fenfluramine, norfenfluramine, homovanillic acid (HVA), cortisol, and prolactin were determined. Levels of fenfluramine and prolactin were elevated 2 hours after fenfluramine administration and remained significantly elevated during the second scan, while levels of HVA and cortisol were not altered significantly during the time of scanning. A significant decrease in the specific binding (striatum) and the nonspecific binding subtracted from the specific binding (striatum minus cerebellum) of [11C]raclopride was observed. The rate of metabolism of [11C]raclopride and the nonspecific binding (cerebellum) were not significantly altered by the fenfluramine intervention. The observed decrease in [11C]raclopride binding is consistent with an increase in dopamine concentrations and with the ability of serotonin to stimulate dopamine activity. The ability to measure serotonergic modulation of dopamine in vivo may have implications for the study of etiologic and therapeutic mechanisms in schizophrenia, major depressive disorder, obsessive-compulsive disorder, and substance abuse.