scholarly journals Adaptive and pathological connectivity responses in Parkinson’s disease brain networks

2021 ◽  
Author(s):  
An Vo ◽  
Katharina Schindlbeck ◽  
Nha Nguyen ◽  
Andrea Rommal ◽  
Phoebe Spetsieris ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Disease Modifying Therapies ◽  
Sham Surgery ◽  
Slow Progression ◽  
Connectivity Patterns ◽  
Flow Through ◽  
Disease Specific ◽  
Over Time

Abstract Functional imaging has been used extensively to identify and validate disease-specific networks as biomarkers in neurodegenerative disorders. It is not known, however, if connectivity patterns in these networks differ with disease progression compared to the beneficial adaptations that may also occur over time. To distinguish the two responses, we focused on assortativity, the tendency for network connections to link nodes with similar properties. High assortativity is associated with unstable, inefficient flow through the network. Low assortativity, by contrast, involves more diverse connections that are also more robust and efficient. We found that in Parkinson’s disease (PD), network assortativity increased with over time. Assoratitivty was high in clinically aggressive genetic variants, but low for genes associated with slow progression. Dopaminergic treatment increased assortativity despite improving motor symptoms, but subthalamic gene therapy, which remodels PD networks, reduced this measure compared to sham surgery. Assortativity may therefore be useful in evaluating disease-modifying therapies.

scholarly journals Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Muhammad Aslam ◽  
Nirosiya Kandasamy ◽  
Anwar Ullah ◽  
Nagarajan Paramasivam ◽  
Mehmet Ali Öztürk ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Rare Variants ◽  
Alpha Synuclein ◽  
Younger Age ◽  
Targeted Treatments ◽  
Genes Encoding ◽  
Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

Development of standardized regression-based formulas to assess meaningful cognitive change in early Parkinson’s disease

2020 ◽  
Author(s):  
Hannah L Combs ◽  
Kate A Wyman-Chick ◽  
Lauren O Erickson ◽  
Michele K York
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Test Scores ◽  
Prediction Models ◽  
Early Stage ◽  
Cognitive Change ◽  
Cognitive Test ◽  
Healthy Controls ◽  
Change Over Time ◽  
Over Time

Abstract Objective Longitudinal assessment of cognitive and emotional functioning in patients with Parkinson’s disease (PD) is helpful in tracking progression of the disease, developing treatment plans, evaluating outcomes, and educating patients and families. Determining whether change over time is meaningful in neurodegenerative conditions, such as PD, can be difficult as repeat assessment of neuropsychological functioning is impacted by factors outside of cognitive change. Regression-based prediction formulas are one method by which clinicians and researchers can determine whether an observed change is meaningful. The purpose of the current study was to develop and validate regression-based prediction models of cognitive and emotional test scores for participants with early-stage idiopathic PD and healthy controls (HC) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). Methods Participants with de novo PD and HC were identified retrospectively from the PPMI archival database. Data from baseline testing and 12-month follow-up were utilized in this study. In total, 688 total participants were included in the present study (NPD = 508; NHC = 185). Subjects from both groups were randomly divided into development (70%) and validation (30%) subsets. Results Early-stage idiopathic PD patients and healthy controls were similar at baseline. Regression-based models were developed for all cognitive and self-report mood measures within both populations. Within the validation subset, the predicted and observed cognitive test scores did not significantly differ, except for semantic fluency. Conclusions The prediction models can serve as useful tools for researchers and clinicians to study clinically meaningful cognitive and mood change over time in PD.

scholarly journals Rehabilitation Therapy Utilization in Patients with Parkinson’s Disease in Korea

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Han Gil Seo ◽  
Sang Jun Park ◽  
Jiah Seo ◽  
Seong Jun Byun ◽  
Byung-Mo Oh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Health Insurance ◽  
Clinical Practice ◽  
Patient Characteristics ◽  
National Sample ◽  
Present Evidence ◽  
Rehabilitation Therapy ◽  
Swallowing Therapy ◽  
Over Time

Objective. Although evidence and guidelines recommend appropriate rehabilitation from the beginning of diagnosis in patients with Parkinson’s disease (PD), there is a lack of data addressing the utilization of rehabilitation therapies for these patients in practice. The aim of this study is to investigate the rate of rehabilitation therapy utilization over time in patients with PD using a nationwide cohort in Korea. Methods. Patients were identified using the registration code for PD in the program for rare, intractable disease from the National Health Insurance Service-National Sample Cohort database, which consists of 979,390 Korean residents. Data were divided into four periods: 2004–2006, 2007–2009, 2010–2012, and 2013–2015. We assessed the utilization of rehabilitation therapies and the associated patient characteristics. Results. The numbers of patients with PD were 384 in 2004, 855 in 2007, 1,023 in 2010, and 1,222 in 2013. The numbers of physiatrist visits per person were 0.58, 0.96, 1.97, and 2.91, in the respective periods. Among the patients, 35–40% had claims for physical therapy, 16–19% for occupational therapy, and 4–6% for swallowing therapy. There were no remarkable differences between these rates between the study periods. Sex, age, income, disability, and levodopa-equivalent dose were significantly associated with the utilization of rehabilitation therapy. Conclusion. This study demonstrated that the rate of rehabilitation therapy utilization did not change remarkably in patients with PD from 2004 to 2015 in Korea although the number of physiatrist visits increased dramatically. The present evidence and guidelines may have not been adequately integrated into clinical practice during the period of study. Additional efforts may be warranted to provide adequate rehabilitation therapies in clinical practice for patients with PD.

scholarly journals Accelerating diagnosis of Parkinson’s disease through risk prediction

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
William Yuan ◽  
Brett Beaulieu-Jones ◽  
Richard Krolewski ◽  
Nathan Palmer ◽  
Christine Veyrat-Follet ◽  
...  
Keyword(s):  
Machine Learning ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Subsequent Development ◽  
Time Compression ◽  
Disease Modifying Therapies ◽  
Machine Learning Approach ◽  
Diagnostic Window

Abstract Background Characterization of prediagnostic Parkinson’s Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. Methods We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. Results We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. Conclusions Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.

Genetic variants of PARK genes in Korean patients with early-onset Parkinson's disease

2019 ◽  
Vol 75 ◽  
pp. 224.e9-224.e15 ◽  
Author(s):  
Jinyoung Youn ◽  
Chung Lee ◽  
Eungseok Oh ◽  
Jinse Park ◽  
Ji Sun Kim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Early Onset ◽  
Korean Patients ◽  
Park Genes ◽  
Early Onset Parkinson’S Disease

scholarly journals Strain- and age-dependent features of the nigro-striatal circuit in three common laboratory mouse strains, C57BL/6J, A/J, and DBA/2J - Implications for Parkinson’s disease modeling

2020 ◽  
Author(s):  
Mélanie H. Thomas ◽  
Mona Karout ◽  
Beatriz Pardo Rodriguez ◽  
Yujuan Gui ◽  
Christian Jaeger ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Brain ◽  
Dopaminergic Neurons ◽  
Mouse Strains ◽  
List Type ◽  
Background Strain ◽  
Age Related ◽  
Health And Disease ◽  
Over Time

AbstractMouse models have been instrumental in understanding genetic determinants of aging and its crucial role in neurodegenerative diseases. However, few studies have analyzed the evolution of the mouse brain over time at baseline. Furthermore, mouse brain studies are commonly conducted on the C57BL/6 strain, limiting the analysis to a specific genetic background. In Parkinson’s disease, the gradual demise of nigral dopaminergic neurons mainly contributes to the motor symptoms. Interestingly, a decline of the dopaminergic neuron function and integrity is also a characteristic of physiological aging in some species. Age-related nigro-striatal features have never been studied in mice of different genetic backgrounds. In this study, we analyze the morphological features in the striatum of three common mouse strains, C57BL/6J, A/J, and DBA/2J at 3-, 9- and 15 months of age. By measuring dopaminergic markers, we uncover age-related changes that differ between strains and evolve dynamically over time. Overall, our results highlight the importance of considering background strain and age when studying the murine nigro-striatal circuit in health and disease.HighlightsStudy of the integrity of the nigro-striatal circuit in C57BL/6J, A/J, and DBA/2J at different agesAge related evolution of essential features of nigral dopaminergic neurons differ between strainsConsider background strain and age is crutial to study the nigrostriatal circuit in health and disease

Parkinson's Disease Genetics and Pathophysiology

2021 ◽  
Vol 44 (1) ◽  
pp. 87-108
Author(s):  
Gabriel E. Vázquez-Vélez ◽  
Huda Y. Zoghbi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Disease Modifying ◽  
Common Neurodegenerative Disorder

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.

scholarly journals Evolution of impulsive–compulsive behaviors and cognition in Parkinson’s disease

2019 ◽  
Vol 267 (1) ◽  
pp. 259-266
Author(s):  
Aleksander H. Erga ◽  
Guido Alves ◽  
Ole Bjørn Tysnes ◽  
Kenn Freddy Pedersen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Short Form ◽  
Population Based ◽  
Self Report ◽  
Cognitive Changes ◽  
Compulsive Behaviors ◽  
Changes Over Time ◽  
Over Time

Abstract The longitudinal course of ICBs in patients with Parkinson’s disease (PwP) relative to controls has not been explored as of yet. The aim of this study is to determine the frequency, evolution and associated cognitive and clinical features of impulsive and compulsive behaviors (ICBs) over 4 years of prospective follow-up in a population-based cohort with early Parkinson’s disease (PD). We recruited 124 cognitively intact participants with early PD and 156 matched controls from the Norwegian ParkWest study. ICBs were assessed using the self-report short form version of the Questionnaire for Impulsive–Compulsive Disorders in PD. Cognitive changes were examined in PwP with and without ICBs who completed the 4-year follow-up. Generalized linear mixed modelling and mixed linear regression were used to analyze clinical factors and cognitive changes associated with ICBs in PwP over time. ICBs were more common in PwP than controls at all visits, with an age-adjusted odds ratio (OR) varying between 2.5 (95% CI 1.1–5.6; p = 0.022) and 5.1 (95% CI 2.4–11.0; p < 0.001). The 4-year cumulative frequency of ICBs in PwP was 46.8% and 23.3% developed incident ICBs during the study period, but the presence of ICBs was non-persistent in nearly 30%. ICBs were independently associated with younger age (OR 0.95, 95% CI 0.91–0.99: p = 0.008) and use of dopamine agonist (OR 4.1, 95% CI 1.56–10.69). Cognitive changes over time did not differ between patients with and without ICBs. In conclusion, ICBs are common in PwP, but are often non-persistent and not associated with greater cognitive impairment over time.

Intranigral Grafts of Fetal Ventral Mesencephalic Tissue in Adult 6-Hydroxydopamine-Lesioned Rats can Induce Behavioral Recovery

1997 ◽  
Vol 6 (3) ◽  
pp. 267-276 ◽  
Author(s):  
R.E. Johnston ◽  
Jill B. Becker
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cyclosporine A ◽  
Ventral Mesencephalon ◽  
Behavioral Recovery ◽  
Treatment Conditions ◽  
Movement Sequence ◽  
Ventral Mesencephalic ◽  
6 Hydroxydopamine ◽  
Disease Specific

Intrastriatal grafts of fetal ventral mesencephalon in rats with unilateral 6-hydroxydopamine lesions can reduce and even reverse rotational behavior in response to direct and indirect dopamine agonists. These grafts can ameliorate deficits on simple spontaneous behaviors, but do not improve complex behaviors that require the skilled integration of the use of both paws. We report here that rats with grafts into the DA-depleted substantia nigra, that receive cyclosporine A, can experience recovery on spontaneous behaviors that mimic those observed in Parkinson's disease. Specific cyclosporine A treatment conditions can differentially affect whether intranigral grafts normalize paw use during initiation or termination of a movement sequence. These findings may have important implications for the treatment of Parkinson's disease.

Sign in / Sign up

Export Citation Format

Share Document