Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on Parkinson’s disease.
Title: The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings
Authors: Volha Skrahina, Hanaa Gaber, Eva-Juliane Vollstedt, Toni M. Förster, Tatiana Usnich, Filipa Curado, Norbert Brüggemann, Jefri Paul, Xenia Bogdanovic, Selen Zülbahar, Maria Olmedillas, Snezana Skobalj, Najim Ameziane, Peter Bauer, Ilona Csoti, Natalia Koleva-Alazeh, Ulrike Grittner, Ana Westenberger, Meike Kasten, Christian Beetz, Christine Klein, Arndt Rolfs, the ROPAD Study Group
Type: Brief Report from Movement Disorders
Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants.
Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing.
Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers.
The ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials.
Access this article: https://doi.org/10.1002/mds.28416
Title: Pharmacological validation of TDO as a target for Parkinson’s disease
Authors: Paula Perez‐Pardo, Yvonne Grobben, Nicole Willemsen‐Seegers, Mitch Hartog, Michaela Tutone, Michelle Muller, Youri Adolfs, Ronald Jeroen Pasterkamp, Diep Vu‐Pham, Antoon M. van Doornmalen, Freek van Cauter, Joeri de Wit, Jan Gerard Sterrenburg, Joost C.M. Uitdehaag, Jos de Man, Rogier C. Buijsman, Guido J.R. Zaman, Aletta D. Kraneveld
Type: Original Article of The FEBS Journal
Parkinson’s disease patients suffer from both motor and nonmotor impairments. There is currently no cure for Parkinson’s disease, and the most commonly used treatment, levodopa, only functions as a temporary relief of motor symptoms. Inhibition of the expression of the L‐tryptophan‐catabolizing enzyme tryptophan 2,3‐dioxygenase (TDO) has been shown to inhibit aging‐related α‐synuclein toxicity in Caenorhabditis elegans. To evaluate TDO inhibition as a potential therapeutic strategy for Parkinson’s disease, a brain‐penetrable, small molecule TDO inhibitor was developed, referred to as NTRC 3531‐0. This compound potently inhibits human and mouse TDO in biochemical and cell‐based assays and is selective over IDO1, an evolutionary unrelated enzyme that catalyzes the same reaction. In mice, NTRC 3531‐0 increased plasma and brain L‐tryptophan levels after oral administration, demonstrating inhibition of TDO activity in vivo. The effect on Parkinson’s disease symptoms was evaluated in a rotenone‐induced Parkinson’s disease mouse model. A structurally dissimilar TDO inhibitor, LM10, was evaluated in parallel. Both inhibitors had beneficial effects on rotenone‐induced motor and cognitive dysfunction as well as rotenone‐induced dopaminergic cell loss and neuroinflammation in the substantia nigra. Moreover, both inhibitors improved intestinal transit and enhanced colon length, which indicates a reduction of the rotenone‐induced intestinal dysfunction. Consistent with this, mice treated with TDO inhibitor showed decreased expression of rotenone‐induced glial fibrillary acidic protein, which is a marker of enteric glial cells, and decreased α‐synuclein accumulation in the enteric plexus. Our data support TDO inhibition as a potential therapeutic strategy to decrease motor, cognitive, and gastrointestinal symptoms in Parkinson’s disease.
Access this article: https://doi.org/10.1111/febs.15721
Title: Metabolomics of sebum reveals lipid dysregulation in Parkinson’s disease
Authors: Eleanor Sinclair, Drupad K. Trivedi, Depanjan Sarkar, Caitlin Walton-Doyle, Joy Milne, Tilo Kunath, Anouk M. Rijs, Rob M. A. de Bie, Royston Goodacre, Monty Silverdale, Perdita Barran
Type: Article of Nature Communications
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, which is characterised by degeneration of distinct neuronal populations, including dopaminergic neurons of the substantia nigra. Here, we use a metabolomics profiling approach to identify changes to lipids in PD observed in sebum, a non-invasively available biofluid. We used liquid chromatography-mass spectrometry (LC-MS) to analyse 274 samples from participants (80 drug naïve PD, 138 medicated PD and 56 well matched control subjects) and detected metabolites that could predict PD phenotype. Pathway enrichment analysis shows alterations in lipid metabolism related to the carnitine shuttle, sphingolipid metabolism, arachidonic acid metabolism and fatty acid biosynthesis. This study shows sebum can be used to identify potential biomarkers for PD.
Access this article: https://doi.org/10.1038/s41467-021-21669-4
Title: Biomaterial based strategies to reconstruct the nigrostriatal pathway in organotypic slice co-cultures
Authors: Buket Ucar, Janko Kajtez, Bettina M. Foidl, Dimitri Eigel, Carsten Werner, Katherine R. Long, Jenny Emnéus, Joëlle Bizeau, Mihai Lomora, Abhay Pandit, Ben Newland, Christian Humpel
Type: Article of Acta Biomaterialia
Protection or repair of the nigrostriatal pathway represents a principal disease-modifying therapeutic strategy for Parkinson's disease (PD). Glial cell line-derived neurotrophic factor (GDNF) holds great therapeutic potential for PD, but its efficacious delivery remains difficult. The aim of this study was to evaluate the potential of different biomaterials (hydrogels, microspheres, cryogels and microcontact printed surfaces) for reconstructing the nigrostriatal pathway in organotypic co-culture of ventral mesencephalon and dorsal striatum. The biomaterials (either alone or loaded with GDNF) were locally applied onto the brain co-slices and fiber growth between the co-slices was evaluated after three weeks in culture based on staining for tyrosine hydroxylase (TH). Collagen hydrogels loaded with GDNF slightly promoted the TH+ nerve fiber growth towards the dorsal striatum, while GDNF loaded microspheres embedded within the hydrogels did not provide an improvement. Cryogels alone or loaded with GDNF also enhanced TH+ fiber growth. Lines of GDNF immobilized onto the membrane inserts via microcontact printing also significantly improved TH+ fiber growth. In conclusion, this study shows that various biomaterials and tissue engineering techniques can be employed to regenerate the nigrostriatal pathway in organotypic brain slices. This comparison of techniques highlights the relative merits of different technologies that researchers can use/develop for neuronal regeneration strategies.
Access this article: https://doi.org/10.1016/j.actbio.2020.11.035
Title: Normative vs. patient-specific brain connectivity in deep brain stimulation
Authors: Qiang Wang, Harith Akram, Muthuraman Muthuraman, Gabriel Gonzalez-Escamilla, Sameer A. Sheth, Simón Oxenford, Fang-Cheng Yeh, Sergiu Groppa, NoraVanegas-Arroyave, Ludvic Zrinzo, Ningfei Li, Andrea Kühn, Andreas Horn
Type: Article of NeuroImage
Brain connectivity profiles seeding from deep brain stimulation (DBS) electrodes have emerged as informative tools to estimate outcome variability across DBS patients. Given the limitations of acquiring and processing patient-specific diffusion-weighted imaging data, a number of studies have employed normative atlases of the human connectome. To date, it remains unclear whether patient-specific connectivity information would strengthen the accuracy of such analyses. Here, we compared similarities and differences between patient-specific, disease-matched and normative structural connectivity data and their ability to predict clinical improvement.
Data from 33 patients suffering from Parkinson's Disease who underwent surgery at three different centers were retrospectively collected. Stimulation-dependent connectivity profiles seeding from active contacts were estimated using three modalities, namely patient-specific diffusion-MRI data, age- and disease-matched or normative group connectome data (acquired in healthy young subjects). Based on these profiles, models of optimal connectivity were calculated and used to estimate clinical improvement in out of sample data.
All three modalities resulted in highly similar optimal connectivity profiles that could largely reproduce findings from prior research based on this present novel multi-center cohort. In a data-driven approach that estimated optimal whole-brain connectivity profiles, out-of-sample predictions of clinical improvements were calculated. Using either patient-specific connectivity (R = 0.43 at p = 0.001), an age- and disease-matched group connectome (R = 0.25, p = 0.048) and a normative connectome based on healthy/young subjects (R = 0.31 at p = 0.028), significant predictions could be made.
Our results of patient-specific connectivity and normative connectomes lead to similar main conclusions about which brain areas are associated with clinical improvement. Still, although results were not significantly different, they hint at the fact that patient-specific connectivity may bear the potential of explaining slightly more variance than group connectomes. Furthermore, use of normative connectomes involves datasets with high signal-to-noise acquired on specialized MRI hardware, while clinical datasets as the ones used here may not exactly match their quality. Our findings support the role of DBS electrode connectivity profiles as a promising method to investigate DBS effects and to potentially guide DBS programming.
Access this article: https://doi.org/10.1016/j.neuroimage.2020.117307
Title: Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects
Authors: Borsche, Max; Pereira, Sandro L.; Klein, Christine; Grünewald, Anne
Type: Review Article of Journal of Parkinson's Disease
Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.
Access this article: https://doi.org/10.3233/JPD-201981
Title: Sequence of clinical and neurodegeneration events in Parkinson’s disease progression
Authors: Neil P Oxtoby, Louise-Ann Leyland, Leon M Aksman, George E C Thomas, Emma L Bunting, Peter A Wijeratne, Alexandra L Young, Angelika Zarkali, Manuela M X Tan, Fion D Bremner, Pearse A Keane, Huw R Morris, Anette E Schrag, Daniel C Alexander, Rimona S Weil
Type: Original Articles of Brain
Dementia is one of the most debilitating aspects of Parkinson’s disease. There are no validated biomarkers that can track Parkinson’s disease progression, nor accurately identify patients who will develop dementia and when. Understanding the sequence of observable changes in Parkinson’s disease in people at elevated risk for developing dementia could provide an integrated biomarker for identifying and managing individuals who will develop Parkinson’s dementia. We aimed to estimate the sequence of clinical and neurodegeneration events, and variability in this sequence, using data-driven statistical modelling in two separate Parkinson’s cohorts, focusing on patients at elevated risk for dementia due to their age at symptom onset. We updated a novel version of an event-based model that has only recently been extended to cope naturally with clinical data, enabling its application in Parkinson’s disease for the first time. The observational cohorts included healthy control subjects and patients with Parkinson’s disease, of whom those diagnosed at age 65 or older were classified as having high risk of dementia. The model estimates that Parkinson’s progression in patients at elevated risk for dementia starts with classic prodromal features of Parkinson’s disease (olfaction, sleep), followed by early deficits in visual cognition and increased brain iron content, followed later by a less certain ordering of neurodegeneration in the substantia nigra and cortex, neuropsychological cognitive deficits, retinal thinning in dopamine layers, and further deficits in visual cognition. Importantly, we also characterize variation in the sequence. We found consistent, cross-validated results within cohorts, and agreement between cohorts on the subset of features available in both cohorts. Our sequencing results add powerful support to the increasing body of evidence suggesting that visual processing specifically is affected early in patients with Parkinson’s disease at elevated risk of dementia. This opens a route to earlier and more precise detection, as well as a more detailed understanding of the pathological mechanisms underpinning Parkinson’s dementia.
Access this article: https://doi.org/10.1093/brain/awaa461
Title: Periphery and brain, innate and adaptive immunity in Parkinson’s disease
Authors: Ashley S. Harms, Sara A. Ferreira, Marina Romero-Ramos
Type: Review of Acta Neuropathologica
Parkinson’s disease (PD) is a neurodegenerative disorder where alpha-synuclein plays a central role in the death and dysfunction of neurons, both, in central, as well as in the peripheral nervous system. Besides the neuronal events observed in patients, PD also includes a significant immune component. It is suggested that the PD-associated immune response will have consequences on neuronal health, thus opening immunomodulation as a potential therapeutic strategy in PD. The immune changes during the disease occur in the brain, involving microglia, but also in the periphery with changes in cells of the innate immune system, particularly monocytes, as well as those of adaptive immunity, such as T-cells. This realization arises from multiple patient studies, but also from data in animal models of the disease, providing strong evidence for innate and adaptive immune system crosstalk in the central nervous system and periphery in PD. Here we review the data showing that alpha-synuclein plays a crucial role in the activation of the innate and adaptive immune system. We will also describe the studies suggesting that inflammation in PD includes early changes in innate and adaptive immune cells that develop dynamically through time during disease, contributing to neuronal degeneration and symptomatology in patients. This novel finding has contributed to the definition of PD as a multisystem disease that should be approached in a more integratory manner rather than a brain-focused classical approach.
Access this article: https://doi.org/10.1007/s00401-021-02268-5