Journal of Parkinson's Disease - Volume 12, issue 4

Authors: Bloem, Bastiaan R. | Kordower, Jeffrey H.

Article Type: Editorial

Keywords: Parkinson’s disease, Linked Clinical Trials, neurodegeneration

DOI: 10.3233/JPD-229003

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1069-1072, 2022

Authors: McFarthing, Kevin | Rafaloff, Gary | Baptista, Marco | Mursaleen, Leah | Fuest, Rosie | Wyse, Richard K. | Stott, Simon R.W.

Article Type: Review Article

Abstract: Background: As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) in 2021. This progress included both “symptomatic treatments” (ST – improves/reduces symptoms of the condition) and “disease modifying treatments” (DMT - attempts to delay/slow progression by addressing the underlying biology of PD), which can be categorised further based on their mechanisms of action and class of drug. Objective: This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT …- in clinical trials for PD during 2021– 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community. Methods: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. Results: There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%). Conclusion: Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute. Show more

Keywords: Clinical trials, studies, Parkinson’s, disease modification, neuroprotection, immunotherapy, inflammation, gene therapy

DOI: 10.3233/JPD-229002

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1073-1082, 2022

Authors: Fasano, Alessio | Mazzoni, Alberto | Falotico, Egidio

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is known to affect the brain motor circuits involving the basal ganglia (BG) and to induce, among other signs, general slowness and paucity of movements. In upper limb movements, PD patients show a systematic prolongation of movement duration while maintaining a sufficient level of endpoint accuracy. PD appears to cause impairments not only in movement execution, but also in movement initiation and planning, as revealed by abnormal preparatory activity of motor-related brain areas. Grasping movement is affected as well, particularly in the coordination of the hand aperture with the transport phase. In the last fifty years, numerous …behavioral studies attempted to clarify the mechanisms underlying these anomalies, speculating on the plausible role that the BG-thalamo-cortical circuitry may play in normal and pathological motor control. Still, many questions remain open, especially concerning the management of the speed-accuracy tradeoff and the online feedback control. In this review, we summarize the literature results on reaching and grasping in parkinsonian patients. We analyze the relevant hypotheses on the origins of dysfunction, by focusing on the motor control aspects involved in the different movement phases and the corresponding role played by the BG. We conclude with an insight into the innovative stimulation techniques and computational models recently proposed, which might be helpful in further clarifying the mechanisms through which PD affects reaching and grasping movements. Show more

Keywords: Reach and grasp, Parkinson’s disease, motor control, upper limb aiming movements, bradykinesia, hypokinesia, akinesia, basal ganglia, computational modelling, brain stimulation

DOI: 10.3233/JPD-213082

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1083-1113, 2022

Authors: Heim, Beatrice | Peball, Marina | Hammermeister, Johannes | Djamshidian, Atbin | Krismer, Florian | Seppi, Klaus

Article Type: Systematic Review

Abstract: Background: Essential tremor (ET) and the tremor of Parkinson’s disease (PD) are the most common tremors encountered in clinical practice. Especially in early disease stages, discrimination between the tremors of ET and PD can be challenging. Objective: The aim of this study was to evaluate the diagnostic accuracy of transcranial sonography (TCS) of the substantia nigra echogenicity for differential diagnosis of PD versus ET. Methods: A systematic PubMed search identified 512 studies. Sensitivity and specificity of substantia nigra hyperechogenicity was estimated. Data synthesis was carried applying a random effects bivariate binomial model. To assess study quality …and risk of bias, the QUADAS-2 tool was used. Results: Eighteen studies were suitable for analysis including 1,264 PD and 824 ET patients. The meta analysis showed a pooled sensitivity and specificity for TCS in the differential diagnosis of PD versus ET of 84.6% (95% CI, 79.4–88.6%) and 83.9% (95% CI, 78.4–88.2%), respectively. Furthermore, we found nearly similar results in sensitivity and specificity comparing TCS and DaTSCAN in a subgroup-analysis of three studies using both diagnostic tools including 107 patients with PD and 62 patients with ET. The QUADAS-2 toolbox revealed a high risk of bias regarding the methodological quality of patient selection. Conclusion: Substantia nigra hyperechogenicity yield high diagnostic accuracy for the discrimination of PD from ET. TCS is a low cost, widely available, non-invasive marker without radiation Therefore, a diagnostic algorithm based on presence or absence of substantia nigra hyperechogenicity is highly warranted. Show more

Keywords: Transcranial sonography, essential tremor, substantia nigra, hyperechogenicity, Parkinson’s disease

DOI: 10.3233/JPD-213012

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1115-1123, 2022

Authors: Javanshiri, Keivan | Drakenberg, Tove | Haglund, Mattias | Englund, Elisabet

Article Type: Research Article

Abstract: Background: Alpha-synucleinopathies (AS) are characterized by pathologic aggregations of alpha-synuclein (α -syn) in the central nervous system, and comprise dementia with Lewy bodies, Parkinson’s disease, and multiple system atrophy. Previous studies on AS have reported findings of α -syn pathology in the peripheral nervous system of multiple organs, including the heart. Objective: The aim of this study was to further investigate and confirm the presence of cardiac α -syn in AS compared to other major neurocognitive disorders in a neuropathologically confirmed cohort. Methods: All deceased patients with performed autopsy and with neuropathologically confirmed AS at the …Clinical Department of Pathology in Lund 2010–May 2021 were evaluated for inclusion. Cases with insufficiently sampled cardiac tissue or only limited neuropathological investigation were excluded. An age-matched group of individuals with other neurodegenerative diseases, having no α -syn in the CNS, served as controls. In total, 68 AS and 32 control cases were included in the study. Immunohistochemistry for detection of cardiac α -syn aggregates was performed. Results: The AS group had a significantly higher prevalence of cardiac α -syn pathology (p ≤0.001) than the control group, 82% and 0%, respectively. Conclusion: This study confirms the association between AS and the presence of cardiac α -syn in a neuropathologically confirmed cohort. This motivates further research on potential pathophysiological effects on cardiac function in AS patients. Show more

Keywords: Alpha-synuclein, cardiac nerve fibers, Lewy body disease, multiple system atrophy, Parkinson’s disease, synucleinopathies

DOI: 10.3233/JPD-223161

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1125-1131, 2022

Authors: Negrini, Matilde | Tomasello, Giuseppe | Davidsson, Marcus | Fenyi, Alexis | Adant, Cécile | Hauser, Swantje | Espa, Elena | Gubinelli, Francesco | Manfredsson, Fredric P. | Melki, Ronald | Heuer, Andreas

Article Type: Research Article

Abstract: Background: Preclinical rodent models for Parkinson’s disease (PD) based on viral human alpha-synuclein (h-αSyn) overexpression recapitulate some of the pathological hallmarks as it presents in humans, such as progressive cell loss and additional synucleinopathy in cortical and subcortical structures. Recent studies have combined viral vector-based overexpression of human wild-type αSyn with the sequential or simultaneous inoculation of preformed fibrils (PFFs) derived from human αSyn. Objective: The goal of the study was to investigate whether sequential or combined delivery of the AAV vector and the PFFs are equipotent in inducing stable neurodegeneration and behavioral deficits. Methods: Here …we compare between four experimental paradigms (PFFs only, AAV-h-αSyn only, AAV-h-αSyn with simultaneous PFFs, and AAV-h-αSyn with sequential PFFs) and their respective GFP control groups. Results: We observed reduction of TH expression and loss of neurons in the midbrain in all AAV (h-αSyn or GFP) injected groups, with or without additional PFFs inoculation. The overexpression of either h-αSyn or GFP alone induced motor deficits and dysfunctional dopamine release/reuptake in electrochemical recordings in the ipsilateral striatum. However, we observed a substantial formation of insoluble h-αSyn aggregates and inflammatory response only when h-αSyn and PFFs were combined. Moreover, the presence of h-αSyn induced higher axonal pathology compared to control groups. Conclusion: Simultaneous AAV and PFFs injections are equipotent in the presented experimental setup in inducing histopathological and behavioral changes. This model provides new and interesting possibilities for characterizing PD pathology in preclinical models and means to assess future therapeutic interventions. Show more

Keywords: AAV, alpha synuclein, behavioral deficits, dopamine, inflammation, motor deficits, Parkinson’s disease, phosphorylated synuclein, preclinical rodent model, preformed fibrils

DOI: 10.3233/JPD-212555

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1133-1153, 2022

Authors: Weinshel, Sarah | Irwin, David J. | Zhang, Panpan | Weintraub, Daniel | Shaw, Leslie M. | Siderowf, Andrew | Xie, Sharon X.

Article Type: Research Article

Abstract: Background: While cutoffs for abnormal levels of the cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ142 ), total tau (t-tau), phosphorylated tau (p-tau), and the ratios of t-tau/Aβ142 and p-tau/Aβ142 , have been established in Alzheimer’s disease (AD), biologically relevant cutoffs have not been studied extensively in Parkinson’s disease (PD). Objective: Assess the suitability and diagnostic accuracy of established AD-derived CSF biomarker cutoffs in the PD population. Methods: Baseline and longitudinal data on CSF biomarkers, cognitive diagnoses, and PET amyloid imaging in 423 newly diagnosed patients with PD from the Parkinson’s Progression Markers Initiative (PPMI) cohort …were used to evaluate established AD biomarker cutoffs compared with optimal cutoffs derived from the PPMI cohort. Results: Using PET amyloid imaging as the gold standard for AD pathology, the optimal cutoff of Aβ142 was higher than the AD cutoff, the optimal cutoffs of t-tau/Aβ142 and p-tau/Aβ142 were lower than the AD cutoffs, and their confidence intervals (CIs) did not overlap with the AD cutoffs. Optimal cutoffs for t-tau and p-tau to predict cognitive impairment were significantly lower than the AD cutoffs, and their CIs did not overlap with the AD cutoffs. Conclusion: Optimal cutoffs for the PPMI cohort for Aβ142 , t-tau/Aβ142 , and p-tau/Aβ142 to predict amyloid-PET positivity and for t-tau and p-tau to predict cognitive impairment differ significantly from cutoffs derived from AD populations. The presence of additional pathologies such as alpha-synuclein in PD may lead to disease-specific CSF biomarker characteristics. Show more

Keywords: Parkinson’s disease, Alzheimer’s disease, cerebrospinal fluid, cutoff, PET

DOI: 10.3233/JPD-212989

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1155-1167, 2022

Authors: Zhu, Shaochun | Bäckström, David | Forsgren, Lars | Trupp, Miles

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) present with similar movement disorder symptoms but distinct protein aggregates upon pathological examination. Objective: Discovery and validation of candidate biomarkers in parkinsonian disorders for differential diagnosis of subgroup molecular etiologies. Methods: Untargeted liquid chromatography (LC)-mass spectrometry (MS) proteomics was used for discovery profiling in cerebral spinal fluid (CSF) followed by LC-MS/MS based multiple reaction monitoring for validation of candidates. We compared clinical variation within the parkinsonian cohort including PD subgroups exhibiting tremor dominance (TD) or postural instability gait disturbance and those with detectable …leukocytes in CSF. Results: We have identified candidate peptide biomarkers and validated related proteins with targeted quantitative multiplexed assays. Dopamine-drug naïve patients at first diagnosis exhibit reduced levels of signaling neuropeptides, chaperones, and processing proteases for packaging of self-aggregating peptides into dense core vesicles. Distinct patterns of biomarkers were detected in the parkinsonian disorders but were not robust enough to offer a differential diagnosis. Different biomarker changes were detected in male and female patients with PD. Subgroup specific candidate biomarkers were identified for TD PD and PD patients with leukocytes detected in CSF. Conclusion: PD, MSA, and PSP exhibit overlapping as well as distinct protein biomarkers that suggest specific molecular etiologies. This indicates common sensitivity of certain populations of selectively vulnerable neurons in the brain, and distinct therapeutic targets for PD subgroups. Our report validates a decrease in CSF levels of self-aggregating neuropeptides in parkinsonian disorders and supports the role of native amyloidogenic proteins in etiologies of neurodegenerative diseases. Show more

Keywords: Neurodegeneration, parkinsonism, proteomics, mass-spectrometry, cerebrospinal fluid, biomarkers

DOI: 10.3233/JPD-213031

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1169-1189, 2022

Authors: Prasuhn, Jannik | Strautz, Robert | Lemmer, Felicitas | Dreischmeier, Shalida | Kasten, Meike | Hanssen, Henrike | Heldmann, Marcus | Brüggemann, Norbert

Article Type: Research Article

Abstract: Background: Degeneration of dopaminergic neurons within the brainstem substantia nigra (SN) is both a pathological hallmark of Parkinson’s disease (PD) and a major contributor to symptom expression. Therefore, non-invasive evaluation of the SN is critical for diagnosis and evaluation of disease progression. Hyperechogenicity (HE+) on midbrain transcranial sonography (TCS) supports the clinically established diagnosis of PD. Further, postmortem studies suggest involvement of neuromelanin (NM) loss and iron deposition in nigral neurodegeneration and HE+ emergence. However, the associations between HE+ and signs of nigral NM loss and iron deposition revealed by magnetic resonance imaging (MRI) have not been examined. …Objective: To elucidate the magnetic resonance- (MR-) morphological representation of the HE+ by NM-weighted (NMI) and susceptibility-weighted MRI (SWI). Methods: Thirty-four PD patients and 29 healthy controls (HCs) received TCS followed by NMI and SWI. From MR images, two independent raters manually identified the SN, placed seeds in non-SN midbrain areas, and performed semi-automated SN segmentation with different thresholds based on seed mean values and standard deviations. Masks of the SN were then used to extract mean area, mean signal intensity, maximal signal area, maximum signal (for NMI), and minimum signal (for SWI). Results: There were no significant differences in NMI- and SWI-based parameters between patients and HCs, and no significant associations between HE+ extent and NMI- or SWI-based parameters. Conclusion: HE+ on TCS appears unrelated to PD pathology revealed by NMI and SWI. Thus, TCS and MRI parameters should be considered complementary, and the pathophysiological correlates of the HE+ require further study. Show more

Keywords: Disease progression, dopaminergic neurons, hyperechogenicity, magnetic resonance imaging, melanins, neuromelanin, neuromelanin-weighted imaging, Parkinson’s disease, substantia nigra, susceptibility-weighted imaging, transcranial sonography, ultrasonography

DOI: 10.3233/JPD-213000

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1191-1200, 2022

Authors: Nguyen, Tinh Thi | Kim, Yun Joong | Lai, Thuy Thi | Nguyen, Phuong Thi | Koh, Young Ho | Nguyen, Linh Thi Nhat | Ma, Hyeo-il | Kim, Young Eun

Article Type: Research Article

Abstract: Background: Mutations in PTEN-induced putative kinase 1 (PINK1 ) cause autosomal recessive Parkinson’s disease (PD) and contribute to the risk of sporadic PD. However, the relationship between PD-related PINK1 mutations and alpha-synuclein (α-syn) aggregation—a main pathological component of PD—remains unexplored. Objective: To investigate whether α-syn pathology is exacerbated in the absence of PINK1 after α-syn preformed fibril (PFF) injection in a PD mouse model and its effects on neurodegeneration. Methods: In this study, 10-week-old Pink1 knockout (KO) and wildtype (WT) mice received stereotaxic unilateral striatal injection of recombinant mouse α-syn PFF. Then, α-syn pathology …progression, inflammatory responses, and neurodegeneration were analyzed via immunohistochemistry, western blot analysis, and behavioral testing. Results: After PFF injection, the total α-syn levels significantly increased, and pathological α-syn was markedly aggregated in Pink1 KO mice compared with Pink1 WT mice. Then, earlier and more severe neuronal loss and motor deficits occurred. Moreover, compared with WT mice, Pink1 KO mice had evident microglial/astrocytic immunoreactivity and prolonged astrocytic activation, and a higher rate of protein phosphatase 2A phosphorylation, which might explain the greater α-syn aggravation and neuronal death. Conclusion: The loss of Pink1 function accelerated α-syn aggregation, accumulation and glial activation, thereby leading to early and significant neurodegeneration and behavioral impairment in the PD mouse model. Therefore, our findings support the notion that PINK1 dysfunction increases the risk of synucleinopathy. Show more

Keywords: Alpha-synuclein, PTEN-induced putative kinase 1, Protein phosphatase 2A, Inflammation, Parkinson’s disease

DOI: 10.3233/JPD-213065

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1201-1217, 2022