Onset Parkinson's Disease Research Articles

The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson's Disease.

Parkinson's disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.

Sexual Dysfunctions in Females with Parkinson's Disease: A Cross-Sectional Study with a Psycho-Endocrinological Perspective.

Background and Objectives: Normal human sexual functioning is a complex integration of an intact neuroanatomic substrate, vascular supply, a balanced hormonal profile, and a predominance of excitatory over inhibitory psychological mechanisms. However, sexual functioning in Parkinson's disease (PD) is often overlooked in clinical practice, especially in female patients. Materials and Methods: In this cross-sectional study, we have investigated the frequency of sexual dysfunction and the possible correlation with psycho-endocrinological factors in a sample of women with idiopathic PD. Patients were assessed using a semi-structured sexual interview, in addition to psychometric tools, including the Hamilton Rating Scale for Anxiety and for Depression and the Coping Orientation to the Problems Experiences-New Italian Version. Specific blood tests, including testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen E2, prolactin (PRL), and vitamin D3 were also evaluated. Results: Our results reported a statistical difference in sexual intercourse frequency before and after the onset of PD (p < 0.001). The percentage of women who complained about reduced sexual desire increased after diagnosis (52.7%) compared to the period before the onset of the illness (36.8%). The endocrinological profile in females with PD revealed statistically significant differences regarding testosterone (p < 0.0006), estradiol (p < 0.00), vitamin D3 (p < 0.006), and calcium (0.002). Depression (44% characterized by perceived feelings of anger and frustration during sexual intercourse) and anxiety symptoms (29.5% reported feelings of fear and anxiety for not satisfying the partner) with abnormal coping strategies (48.14% experienced feelings of anger and intolerance) were also found to be statistically significant. This study showed a high frequency of sexual dysfunction in female patients with PD, which correlated with sexual hormone abnormalities, mood/anxiety, and coping strategies alterations. This supports the idea that there is a need to better investigate the sexual function of female patients with PD to provide them with an adequate therapeutic approach and potentially improve quality of life.

Characteristics of sagittal spinopelvic alignment in patients with Parkinson’s disease presenting with dropped head syndrome: a case series study

BackgroundDropped head syndrome (DHS) is a rare specific abnormal posture known to develop in Parkinson’s disease (PD). This case series study aimed to characterize DHS by analyzing the characteristics of sagittal spinopelvic alignment in patients with PD/DHS.MethodsThe study included eight patients with PD/DHS (men = 3, women = 5; mean age, 68.1 ± 6.4 years). Sagittal spinopelvic alignment was evaluated using 10 parameters on whole-spine lateral radiographs.ResultsThe time from the onset of PD to that of DHS varied among the patients from 0 to 15.3 years. In three patients, DHS appeared before the diagnosis of PD. The severity of motor symptoms at DHS onset varied from modified Hoehn and Yahr stage 1 to 4 among the patients. Although the spinopelvic parameters differed among PD/DHS individuals, all patients exhibited cervical kyphosis (cervical lordosis < 0˚). In patients with a larger T1 slope and greater thoracic kyphosis, anterocollis tended to be more severe. According to the assessment of the sagittal vertical axis (SVA), half of the patients showed a positive SVA (SVA ≥ 0 mm), whereas the other half showed a negative SVA (SVA < 0 mm).ConclusionDHS appeared regardless of the duration or severity of PD. Although all patients with PD/DHS exhibited cervical kyphosis, the C7 plumb line was shifted anteriorly in half of the patients and posteriorly in the other half.

Sleep Disturbances in Early Onset Parkinsonism (P7-11.010)

<h3>Objective:</h3> To compare the frequencies of sleep disorders between individuals with early onset parkinsonism (age ≤50 at motor symptom onset) and typical onset parkinsonism (age &gt;50 at motor symptom onset). <h3>Background:</h3> Sleep disturbances are common in parkinsonian disorders and have been well-studied in individuals with parkinsonism onset after age 50. Whether sleep disorders affect individuals with early onset parkinsonism and whether they differ from individuals with typical onset parkinsonism is unknown. <h3>Design/Methods:</h3> We used a population-based, 1991 to 2015 incident-cohort study of parkinsonism including 38 patients with early onset and 1001 patients with typical onset parkinsonism. Presence or absence and type of sleep disorder as well as the relationship between motor and sleep symptoms were abstracted. Rates of sleep disorders before and after onset of parkinsonism were compared with logistic regression and Cox proportional hazards models. <h3>Results:</h3> Median (IQR) age of parkinsonism onset was 44.5 (41.0 – 48.7) years for early onset and 75.9 (67.7 – 81.7) years for typical onset patients. Parkinson’s disease (PD) was the most common cause of parkinsonism in each group. The prevalence of sleep disorders prior to the onset of parkinsonism in early vs typical parkinsonism (24% vs 16% p=0.19) and incidence of sleep disorders after parkinsonism onset (5.85 cases per 100 person-years vs 4.11 cases per 100 person-years; HR 1.15 95% CI: 0.74–1.77) were similar between the two groups, with similar latencies of sleep disorders to parkinsonism diagnosis in each group. Early onset parkinsonism had a higher risk for developing insomnia compared with typical onset parkinsonism (HR 1.73, 95% CI: 1.02 – 2.93); the risk for developing all other sleep disorders was similar between groups. <h3>Conclusions:</h3> Sleep disorders are common in individuals with early onset parkinsonism and occur with similar frequency to those with typical onset parkinsonism, except for insomnia, which was more frequent in the early onset group. <b>Disclosure:</b> Dr. McCarter has nothing to disclose. Dr. Camerucci has nothing to disclose. Aidan Mullan has nothing to disclose. Mr. Stang has nothing to disclose. Dr. Turcano has nothing to disclose. Dr. St. Louis has received publishing royalties from a publication relating to health care. Dr. St. Louis has received publishing royalties from a publication relating to health care. Dr. Boeve has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Rainwater Charitable Foundation. The institution of Dr. Boeve has received research support from Alector. The institution of Dr. Boeve has received research support from GE Healthcare. The institution of Dr. Boeve has received research support from Transposon. The institution of Dr. Boeve has received research support from Cognition Therapeutics. Dr. Boeve has received publishing royalties from a publication relating to health care. The institution of Dr. Bower has received research support from Abbvie. The institution of Dr. Savica has received research support from ACADIA Pharmaceuticals, Inc.

Activatable organic upconversion nanoprobe for bioimaging of monoamine oxidase B in Parkinson’s disease

Monoamine oxidase B (MAO-B) activity has been observed abnormally elevated in Parkinson’s disease patients and can be used as a potential biomarker. Herein, we report an activatable frequency upconversion luminescence (FUCL) MAO-B nano-probe (NIR-MNP) capable of highly specific and real-time MAO-B imaging in biological samples. The turn-on FUCL effect is beneficial to obtaining high-quality imaging and penetrating tissue to achieve in vivo imaging, making it stand out from the existing probes. Moreover, we used NIR-MNP to confirm the role of MAO-B inhibitor in delaying Parkinson’s disease (PD) progression in mouse PD models through bio-imaging technique in vivo. Finally, our study may offer a visual way help researchers to gain further insight into the involvement of MAO-B in PD onset and progression in animals.

Small Molecule Inhibitors for Precise Inhibition of Alpha-Synuclein Oligomer Generation in Parkinson’s Disease (S32.002)

<h3>Objective:</h3> To develop small molecules which inhibit the key molecular mechanisms responsible for the generation of toxic alpha-synuclein oligomers in Parkinson’s Disease (PD) and other synucleinopathies with precision, from <i>in vitro</i> to <i>in vivo</i> systems. <h3>Background:</h3> Oligomeric forms of alpha-synuclein have been shown to have wide-ranging neurotoxicity and underlie the onset and progression of PD. They bind to membranes, receptors and organelles, disrupt metabolic and neuronal functional pathways and ultimately cause neuronal death, but are challenging to target with conventional drug discovery approaches. Using the framework of “chemical kinetics”, we mapped the mechanisms of oligomer generation: primary, lipid-induced nucleation (where lipid membranes catalyse the formation of oligomers by several monomers) and secondary nucleation (where oligomer formation is catalysed by larger alpha-synuclein aggregates). <h3>Design/Methods:</h3> Compounds were initially characterized in <i>in vitro</i> protein aggregation assays starting from monomeric recombinant human alphasynuclein. Compounds were then optimised for potency, oral pharmacokinetics and brain penetration. Following this optimisation, compounds were tested in a range of cellular and <i>in vivo</i> systems, including iPSC-derived cortical and dopaminergic neurons, and the Line-61 transgenic mouse model. <h3>Results:</h3> Our compounds were able to inhibit both of the key processes generating alpha-synuclein oligomers by &gt;96% <i>in vitro</i>, and retained potency when reactions were seeded with human PD brain tissue. Efficacy was also demonstrated in iPSC derived cells treated with compound, reducing oligomers and pS129 aggregates and improving functional markers. In the Line 61 mouse model, the same compound substantially reduced pS129 aggregate levels (−44% vs vehicle) with on-target reduction of oligomers (−25% vs. vehicle) after dosing at 15 mg/kg for 10 weeks. <h3>Conclusions:</h3> Our small molecule inhibitors of alpha-synuclein oligomer generation show a robust effect across systems from <i>in vitro</i>, to cellular and <i>in vivo</i> models, demonstrating both target engagement and functional benefit in translational models. <b>Disclosure:</b> Dr. Thomson has received personal compensation for serving as an employee of Wren Therapeutics. Dr. Thomson has stock in Amylyx. Dr. Thomson has received intellectual property interests from a discovery or technology relating to health care. Dr. Thomson has received intellectual property interests from a discovery or technology relating to health care. Mr. Cridland has nothing to disclose. Dr. Ball has received personal compensation for serving as an employee of Wren Therapeutics Ltd. Dr. Staats has received personal compensation for serving as an employee of Wren Therapeutics Ltd. Dr. Staats has stock in Wren Therapeutics Ltd. Dr. Pandey has stock in Wren Therapeutics. Dr. Castellana Cruz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Wren Therapeutics. Dr. Pisani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Wren Therapeutics. Dr. Meisl has received personal compensation for serving as an employee of Wren therapeutics. Dr. Meisl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fluidic Analytics. The institution of Dr. Meisl has received research support from ERC. Dr. Meisl has received intellectual property interests from a discovery or technology relating to health care. Dr. Meisl has received publishing royalties from a publication relating to health care. Dr. Kitchen-Smith has received personal compensation for serving as an employee of Wren Therapeutics. Dr. Yang has nothing to disclose. Dr. Mannini has received personal compensation for serving as an employee of Wren therapeutics. Dr. Pollack has nothing to disclose. Dr. Rajah has received personal compensation for serving as an employee of Wren Therapeutics. Dr. Brewerton has received personal compensation for serving as an employee of Wren Therapeutics. Dr. Habchi has stock in Wren Therapeutics. Dr. Habchi has received intellectual property interests from a discovery or technology relating to health care. Dr. Plowright has received personal compensation for serving as an employee of Wren Therapeutics.

Clinical Characteristics of Early-Onset Parkinson Disease in Mayo Clinic Population (P6-11.004)

<h3>Objective:</h3> To describe the demographic pattern and the clinical characteristics of the patients with Early Onset Parkinson’s Disease (EOPD) at the Mayo Clinic. <h3>Background:</h3> The causes of EOPD remain undefined; the clinical course and phenotypical characteristics of EOPD are different than those of late onset Parkinson disease. Unfortunately, there is still a gap of knowledge on EOPD. <h3>Design/Methods:</h3> We retrieved all the patients with EOPD that have visited the Mayo Clinic from 1990 to 2022 using Mayo Data Explorer (MDE). We included patients with a diagnosis of Parkinson’s disease (PD) at or before the age of 50 years old (according to the current Movement Disorder Society (MDS) recommendation on EOPD). In addition, we assessed the clinical features of those who were included. <h3>Results:</h3> A total of 838 (518 males and 320 females) patients with EOPD were included with a mean age at symptoms onset of 40.6 ± 6.7 years. Overall, 13.6% had a family history of PD, with only 4.5% with genetic testing. Resting tremor was reported in 84.8%, bradykinesia in 85.9%, rigidity in 81.3% and postural instability in 13.1%. Dyskinesias were documented in 44.4% with a mean time from PD diagnosis of 10.5 ± 6.2 years. Cognitive impairment was reported in 19.3% of patients with a mean time from PD diagnosis of 16.8 ± 14.3 years. <h3>Conclusions:</h3> We described the clinical characteristics of the EOPD in a large cohort. EOPD displays distinct clinical patterns regarding symptoms, progression, cognitive decline and response to medications. These differences may reflect multifactorial causes such as pathophysiological backgrounds and genetic, environmental, or age-related factors. <b>Disclosure:</b> Dr. Ghoniem has nothing to disclose. Dr. Jacobson has nothing to disclose. Aidan Mullan has nothing to disclose. Dr. Turcano has nothing to disclose. Dr. Camerucci has nothing to disclose. Mr. Stang has nothing to disclose. The institution of Dr. Bower has received research support from Abbvie. The institution of Dr. Savica has received research support from ACADIA Pharmaceuticals, Inc.

Rare TMEM230 Variants are Potentially Associated With Early Onset Parkinson’s Disease (P3-11.013)

Rare TMEM230 Variants are Potentially Associated With Early Onset Parkinson’s Disease (P3-11.013)

Novel Mutation In The APT13A2 Gene Associated With Ataxia, Cerebellar Tremor, Bipolar Disease and Epilepsy (P9-11.010)

<h3>Objective:</h3> To Report a Novel Mutation In The ATP13A2 Gene Causing Cerebellar Ataxia With Bipolar Disorder And Epilepsy Without Parkinsonism. <h3>Background:</h3> ATP13A2 gene mutations are rare and initially were identified in patients with autosomal recessive (AR) juvenile onset of parkinsonism with supranuclear gaze palsy, and dementia, also known as Kufer-Rakeb disease. Subsequently, recognized phenotypic variability of biallelic mutations in this gene widened and include AR hereditary spastic paraplegia or spastic ataxia. Pure cerebellar ataxia is rarely caused by mutations in this gene. <h3>Design/Methods:</h3> Case report and genetic analysis of the ATP13A2 gene in affected proband and both parents. <h3>Results:</h3> The proband is a 40-year-old male of Iranian descent who developed difficulties walking with multiple falls as a teenager. He transitioned from a walker to a wheelchair dependency in his 20s. He was diagnosed with spinocerebellar ataxia with Holmes tremor in both arms. His examination showed vertical ophthalmoplegia without any signs of Parkinsonism or spasticity. The patient had signs of a mild developmental delay and in his 20s he was also diagnosed with bipolar disorder. He developed seizures in his 40s and they were well-controlled on levetiracetam. Brain MRI showed cerebellar atrophy with no iron deposits in basal ganglia. His parents were first cousins. Family history was noticeable for similar problems in two deceased cousins who were also from consanguineous marriages. Genetic testing showed a novel homozygous mutation in exon 26 of ATP13A2, c.2899G&gt;C (p.Asp967His). We did not find this in 100 controls. Both parents were heterozygous at the same codon. We also confirmed the mutation in the CLIA certified laboratory, which is cataloged as rs772870846. In vitro analysis showed this variant being deleterious. <h3>Conclusions:</h3> We report a novel mutation in the ATP13A2 gene with unique constellation of clinical features, further expanding the phenotypic spectrum of movement disorders associated with this genetic condition. <b>Disclosure:</b> Dr. Yousaf has nothing to disclose. Dr. D’Aguiar Rosa has nothing to disclose. Dr. Ghani has nothing to disclose. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Hedera has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for University of Louisville.

Genetic study of early-onset Parkinson's disease in the Malaysian population

BackgroundAbout 5–10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and globally diverse studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic variants. ObjectivesThis study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort. Methods161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next-generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification (MLPA). ResultsThirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate was even higher in those with familial history (48.5%) or age of diagnosis ≤40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes. ConclusionsThis study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.

Early-onset Parkinson's disease: An assessment of unmet psychosocial needs

BackgroundEarly onset Parkinson's disease (EOPD) affects people in the prime of their lives, typically between 21 and 50 years of age, which results in a variety of challenges that are unique compared to those diagnosed later in life. A better understanding of the unmet needs of this population is critical to delivering bespoke care and improving their quality of life. ObjectivesTo assess the unmet needs of people with early onset Parkinson's disease. MethodsA cross-sectional sample of 198 adults with self-identified early onset Parkinson's disease completed surveys to ascertain the most common unmet needs of this population. Simple descriptive statistics including frequencies, means, and standard deviations were used to quantify the most common unmet needs and were compared between men, women, and Hispanic/Latino with significance determined by chi-square tests. ResultsOverall, the top five unmet needs were (1) need for “a community more like me” (65.2%), (2) more PD information (48%), (3) information about how their PD will progress (47%), (4) help with mental health issues (34.8%), and (5) help with employment issues (33.8%). The top unmet need for men was help with employment issues (50.8%), for women, “a community more like me” (72.3%), and for Hispanic/Latinos, more PD information (47%). ConclusionAlthough the number of people living with EOPD is considerably smaller than those with conventional age at onset, the potential impact to quality of life in this population remains tremendous. We propose a framework to start to address these needs.

Genetic and Epigenetic Study of Monozygotic Twins Affected by Parkinson’s Disease

Background: Genetic and epigenetic modifiers of age at onset of Parkinson’s disease (PD) are largely unknown. It remains unclear whether DNA methylation (DNAm) age acceleration is linked to age at onset in PD patients of different ethnicities with a similar genetic background. We aim to characterize the clinical, genomic and epigenomic features of three pairs of Chinese monozygotic twins discordant for PD onset by up to 10 years. Methods: We conducted whole genome sequencing, multiplex ligation-dependent probe amplification and genome-wide DNAm array to evaluate the three pairs of Chinese monozygotic twins discordant for age at onset of PD (families A–C). Results: We identified two heterozygous PRKN mutations (exon 2–4 deletion and p.Met1Thr) in PD affected members of one family. Somatic mutation analyses of investigated families did not reveal any variants that could explain the phenotypic discordance in the twin pairs. Of note, our epigenetic study revealed that the twins with earlier-onset had a trend of faster DNAm age acceleration than the later-onset/asymptomatic twins, but without statistical significance. Conclusion: The link between DNAm age acceleration and PD onset in Chinese patients should be interpreted with cautious, and need to be further verified in an extended PD cohort with similar genetic background.

Novel SERAC1 Variant Presenting With Adult-Onset Extrapyramidal Dystonia-Parkinsonism Phenotype: A Case Report.

To report a novel likely pathogenic variant in the SERAC1 gene associated with early adult-onset parkinsonism and progressive dystonia. Clinical, biochemical, and imaging assessments were performed on 2 affected adult brothers with a genetically unsolved progressive neurologic disorder followed by whole-genome sequencing. A homozygous likely pathogenic variant in the SERAC1 gene (c.[129-2A > C], p.[(?)];[(?)]) was discovered. We describe a novel homozygous variant in the serine active site-containing protein 1 gene (SERAC1) in 2 brothers with a progressive extrapyramidal movement disorder of early onset parkinsonism and dystonia. Previous variants have been associated with a severe 3-methylglutaconic aciduria with dystonia, deafness, hepatopathy, encephalopathy and Leigh-like syndrome, or juvenile onset complicated spastic paraparesis. Our cases expand the phenotype of SERAC1 variants, with an adult-onset presentation of dystonia-parkinsonism.

Gut Dysbiosis: A Target for Protective Interventions against Parkinson's Disease.

Sub-chronic inflammation, caused by age-related dysbiosis, primes the brain to neuroinflammation and neurodegenerative diseases. Evidence revealed that Parkinson's disease (PD) might originate in the gut, demonstrating gastro-intestinal disturbances, as reported by PD patients long before developing motor symptoms. In this study, we conducted comparative analyses in relatively young and old mice maintained in conventional or gnotobiotic conditions. We aimed to confirm that the effects induced by age-related dysbiosis, rather than aging itself, sensitize to PD onset. This hypothesis was confirmed in germ-free (GF) mice, which proved resistant to the pharmacological induction of PD, regardless of their age. Contrary to conventional animals, old GF mice did not develop an inflammatory phenotype or an accumulation of iron in the brain, two catalysts sensitizing to disease onset. The resistance of GF mice to PD is reverted when colonized with stool collected from conventional old animals, but not if receiving bacterial content from young mice. Hence, changes in gut microbiota composition are a risk factor for PD development and can be targeted preventively by iron chelators, shown to protect the brain from pro-inflammatory intestinal priming that sensitizes to neuroinflammation and the development of severe PD.

Global neurology: It's time to take notice.

Global neurology: It's time to take notice.

Sexual dysfunction precedes motor defects, dopaminergic neuronal degeneration, and impaired dopamine metabolism: Insights from Drosophila model of Parkinson's disease.

Sexual dysfunction (SD) is one of the most common non-motor symptoms of Parkinson's disease (PD) and remains the most neglected, under-reported, and under-recognized aspect of PD. Studies have shown that Dopamine (DA) in the hypothalamus plays a role in regulating sexual behavior. But the detailed mechanism of SD in PD is not known. Drosophila melanogaster shares several genes and signaling pathways with humans which makes it an ideal model for the study of a neurodegenerative disorder such as PD. Courtship behavior of Drosophila is one such behavior that is closely related to human sexual behavior and so plays an important role in understanding sexual behavior in diseased conditions as well. In the present study, a sporadic SD model of PD using Drosophila was developed and SD phenotype was observed based on abnormalities in courtship behavior markers. The Drosophila SD model was developed in such a way that at the window of neurotoxin paraquat (PQ) treatment [PQ is considered a crucial risk factor for PD due to its structural similarity with 1-methyl-4-phenyl pyridinium (MPP+), the active form of PD-inducing agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)], it does not exhibit mobility defects but shows SD. The whole brain tyrosine hydroxylase immunostaining showed no observable dopaminergic (DAergic) degeneration (number of DA neurons and fluorescence intensity of fluorescently labeled secondary antibodies that target anti-TH primary antibody) of the SD model. Similarly, there was no significant depletion of brain DA and its metabolite levels (HVA and DOPAC) as determined using HPLC-ECD (High-Performance Liquid Chromatography using Electrochemical Detector). The present study illustrates that the traits associated with courtship and sexual activity provide sensitive markers at the earlier stage of PD onset. This PQ-induced SD fly model throws an opportunity to decipher the molecular basis of SD under PD conditions and to screen nutraceuticals/potential therapeutic molecules to rescue SD phenotype and further to DAergic neuroprotection.

Nanoscale imaging of individual amyloid aggregates extracted from brains of Alzheimer and Parkinson patients reveals presence of lipids in α-synuclein but not in amyloid β1-42 fibrils.

Abrupt aggregation of misfolded proteins is the underlying molecular cause of Alzheimer disease (AD) and Parkinson disease (PD). Both AD and PD are severe pathologies that affect millions of people around the world. A small 42 amino acid long peptide, known as amyloid β (Aβ), aggregates in the frontal cortex of AD patients forming oligomers and fibrils, highly toxic protein aggregates that cause progressive neuron death. Similar aggregates of α-synuclein (α-Syn), a small protein that facilitates neurotransmitter release, are observed in the midbrain, hypothalamus, and thalamus of people with PD. In this study, we utilized the innovative nano-Infrared imaging technique to investigate the structural organization of individual Aβ and α-syn fibrils postmortem extracted from brains of AD and PD patients, respectively. We observed two morphologically different Aβ and α-Syn fibril polymorphs in each patient's brain. One had twisted topology, whereas another exhibited flat tape-like morphology. We found that both polymorphs shared the same parallel β-sheet-dominated secondary structure. These findings suggested that both fibril polymorphs were built from structurally similar if not identical filaments that coiled forming twisted fibrils or associated side-by-side in the case of straight Aβ and α-Syn fibrils. Nano-Infrared analysis of individual protein aggregates also revealed the presence of lipids in the structure of both twisted and tape-like α-Syn fibrils that were not observed in any of the Aβ fibril polymorphs. These findings demonstrate that lipid membranes can play a critically important role in the onset and progression of PD.

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.

Reliability and validity of visual analysis of [ 18 F]FE-PE2I PET/CT in early Parkinsonian disease.

[ 18 F]FE-PE2I (FE-PE2I) is a new radiotracer for dopamine transporter (DAT) imaging with PET. The aim of this study was to evaluate the visual interpretation of FE-PE2I images for the diagnosis of idiopathic Parkinsonian syndrome (IPS). The inter-rater variability, sensitivity, specificity, and diagnostic accuracy for visual interpretation of striatal FE-PE2I compared to [ 123 I]FP-CIT (FP-CIT) single-photon emission computed tomography (SPECT) was evaluated. Thirty patients with newly onset parkinsonism and 32 healthy controls with both an FE-PE2I and FP-CIT were included in the study. Four patients had normal DAT imaging, of which three did not fulfil the IPS criteria at the clinical reassessment after 2 years. Six raters evaluated the DAT images blinded to the clinical diagnosis, interpreting the image as being 'normal' or 'pathological', and assessed the degree of DAT-reduction in the caudate and putamen. The inter-rater agreement was assessed with intra-class correlation and Cronbach's α . For calculation of sensitivity and specificity, DAT images were defined as correctly classified if categorized as normal or pathological by ≥4/6 raters. The overall agreement in visual evaluation of the FE-PE2I- and FP-CIT images was high for the IPS patients ( α = 0.960 and 0.898, respectively), but lower in healthy controls (FE-PE2I: α = 0.693, FP-CIT: α = 0.657). Visual interpretation gave high sensitivity (both 0.96) but lower specificity (FE-PE2I: 0.86, FP-CIT: 0.63) with an accuracy of 90% for FE-PE2I and 77% for FP-CIT. Visual evaluation of FE-PE2I PET imaging demonstrates high reliability and diagnostic accuracy for IPS.

Time Taken for and Causes of a Decline to Hoehn and Yahr Stage 5 in Patients with Parkinson's Disease.

Objective Prediction of time until and causes of becoming bedridden may help patients with Parkinson's disease (PD) plan their productive lives. This study assessed the relationship between the age at the PD onset and time taken to reach Hoehn and Yahr stage (HY) 5 as well as the causes of motor decline to HY5 in Japanese patients with PD. Patients and Methods We enrolled patients with PD who visited our institute between April 2015 and December 2020, met the UK brain bank criteria, had medical records from the early PD stage, and had had HY5 for over three months. The relationship between the age at the PD onset and the disease duration was evaluated. Data on the possible causes of motor decline to HY5 were obtained from patients, caregivers or medical records. Results In total, 123 patients with PD (mean age at the PD onset was 69.3 years old; 80 women and 43 men) were included. The age at the PD onset was significantly and negatively correlated with the time until the decline to HY5. Among the 123 patients, 49 reported that the natural course of PD caused the decline to HY5. Possible events that accelerated the motor decline to HY5 included traumatic injury, pneumonia, and other medical or social conditions that might have resulted in reduced daily activities. Conclusions The time until the decline to HY5 can be estimated based on the age at the PD onset. In addition to natural PD progression, medical or social conditions that reduce physical activity may accelerate motor decline to HY5.