Monthy research review – August 2020

 

 

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during August 2020.

The post is divided into seven parts based on the type of research:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials (Oooh, new section for 2019!)
  • Clinical trial news
  • Other news
  • Review articles/videos

 


So, what happened during August 2020?

In world news:

August 4th – Two explosions caused by unsafely stored ammonium nitrate killed over 220 people, injure thousands, and severely damage the port in Beirut, Lebanon.

August 16th – In Death Valley (California), the appropriately named Furnace Creek (population of 24) logged a day time high temperature of 130° Fahrenheit (54.4° Celsius).

Augst 20th – The US FDA holds on Emergency Use Authorization for convalescent plasma the treatment of COVID–19, with health regulators stating the “importance of robust data through randomized control trials” and “that a pandemic does not change that”. Apparently the emerging data on the treatment was “too weak”

August 23rd – The US FDA issued “Emergency Use Authorization for convalescent plasma as potential promising COVID–19 treatment, Another Achievement in Administration’s Fight Against Pandemic” (Source). What a difference 3 days and no data makes….

August 24th – A 33 year old man in Hong Kong became the first confirmed case of coronavirus reinfection (additional cases have been confirmed). Humans appear to have a short immunity to COVID-19 (2-3 months, similar to influenza).

In the world of Parkinson’s research, a great deal of new research and news was reported:

In August 2020, there were 890 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (6,948 for all of 2020 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 6 pieces of Parkinson’s news

1.  Alpha synuclein: Not an ideal biomarker

Alpha synuclein is a protein that aggregates in the brain of many people with Parkinson’s, and it can be detected in blood, leading to suggestions that it could be a biomarker in PD. Researchers from the Systemic Synuclein Sampling Study, however, have provided class III evidence that total cerebrospinal fluid alpha synuclein does not accurately distinguish Parkinson’s from healthy controls. They found lower total alpha synuclein levels in the CSF in PD, but the specificity of this result was low. Plus alpha synuclein monoclonal antibody staining on skin & submandibular gland samples is specific for PD, but (again) sensitivity is low. The researchers also pointed out that “relationships within subjects across different tissues & biofluids could not be demonstrated“. Thus, alpha synuclein does not appear to be an ideal biomarker ( to read more about this).

2. Neurofilament light chain: A better biomarker?

Using biological samples from two independent Parkinson’s biorepositories (the Michael J Fox supported “Parkinson’s Progression Marker Initiative” and the “De Novo Parkinson’s disease (DeNoPa) study“), researchers analysed levels of a protein called ‘neurofilament light chain‘ and suggested it could be “the first blood‐based biomarker candidate that could support disease stratification of PD vs other cognate/neurodegenerative disorders( to read more about this).

3. Lots of Denali Therapeutics news this month:

The San Francisco-based biotech firm Denali Therapeutics is leading the development of LRRK2 inhibitors for Parkinson’s, firstly announced that they have signed an agreement to co-develop & co-commercialise their small molecule LRRK2 inhibitors with the pharmaceutical company Biogen ( to read more about this). In addition, Denali announced that their LRRK2 inhibitor DNL151 has been selected to progress to late stage studies in Parkinson’s patients with a LRRK2 kinase activating genetic mutations & in sporadic PD cases. Denali & Biogen are finalizing plans for the LRRK2 program & intend to commence two separate Parkinson’s clinical trials in 2021 (Click here to read more about this and click here to read an SoPD post on the topic).

4. PARKIN in PARIS

Researchers reported that a CRISPR-induced reduction in PARIS completely restores the mitochondrial biogenesis & function (without affecting the deficits in mitophagy) in dopamine neurons without Parkinson’s-associated PARKIN. “Although there are defects in mitophagy in human dopamine neurons lacking PARKIN, the mitochondrial deficits are primarily due to defects in mitochondrial biogenesis that are driven by the upregulation of PARIS & the subsequent downregulation of PGC-1α“. So what we really need now is a PARIS inhibitor ( to read more about this).
5. The epigenetics of TET2

Epigenetics is the study of how non-genetic factors affect the genetics of an organism. It explores how lifestyle or environmental factors can influence the activity surrounding our DNA. Researchers at the Van Andel Institute (Michigan) reported that epigenomic analysis of Parkinson’s neurons identifies the loss of TET2 – a master-regulator of cytosine modification status – as neuroprotective. Widespread epigenetic dysregulation of enhancers due to TET2? ( to read more about this and click here to read the press summary).

6.  Subtypes of Parkinson’s

New data was published that supported the existence of “brain-first” and “body-first” subtypes of Parkinson’s. Individuals with de novo Parkinson’s with & without REM sleep behaviour disorer were found to be very similar clinically, but they displayed strikingly different profiles when assessed on a set of multimodal imaging techniques ( to read more about this). In addition, in another study (using data-driven approach to cluster Parkinson’s patients from the Michael J Fox Foundation PPMI database), researchers identified two neuroanatomical subtypes of Parkinson’s based on subcortical brain volumes: (1) smaller & (2) larger. Subtype 1 was characterised by more severe motor impairment, autonomic dysfunction, & worse RBD. While disease duration at initial visit & follow-up were similar between the two biotypes, PD patients with smaller subcortical brain volume had poorer prognosis ( to read more about this).

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Before we start: A special thanks to those readers who provided some thoughts on how this monthly research review could be improved. Very much appreciated. I will try to apply some of the ideas proposed over the next few months. If anyone would like to add their thoughts, please contact me directly.

And an apology for the lack of content over the month of August. We have been busy in the workshop (the research dept of The Cure Parkinson’s Trust) getting ready for the international Linked Clinical Trials meeting in September (Click here to read more about this and click here for a SoPD post on the topic).

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Basic biology news

  • Parkinson’s-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure (revealed by cryo-EM). Illuminates the mechanism of pY39 pathology & highlights importance of posttranslational modifications in defining the structure/pathology ( to read more about this).
  • New bioRxiv manuscript suggests Parkinson’s-asasociated α-synuclein localization at the plasma membrane correlates with cellular phosphatidylinositol polyphosphate levels ( to read more about this).
  • There is already a connection between LRRK2 and tuberculosis, but now researchers report a role for Parkinson’s-associated PARK7/DJ-1 interactome in regulating the epigenetics of PBMC lifecycle & “tuberculosis symbiosis” (Click here to read more about this).

  • Identification of differentially expressed genes profiles in a combined mouse model of Parkinson’s & colitis ( to read more about this).
  • Garciesculenxanthone B, a new xanthone compound from Garcinia esculenta, reported to induces Parkinson’s-associated PINK1-Parkin-mediated mitophagy & prevent ischemia-reperfusion brain injury in mice ( to read more about this).
  • Interesting exploration of GLP-1 agonists ability to access the brain (in mice). Could have implications for Parkinson’s & Alzheimer’s research? ( to read more about this).
  • New biorxiv manuscript suggests (in mouse PFF model) Parkinson’s-associated α-synuclein inclusion formation is not a major driver of early phases of neurodegeneration, but diffusible oligomeric alpha-synuclein species may play a key role in this process ( to read more about this).
  • New bioRxiv manuscript presents optogenetic-activation of neurotrophic receptor can ameliorate disease hallmarks in a genetic model of Parkinson’s (PINK1 drosophila & human cells –  to read more about this).
  • A new report on the genetic architecture of human brainstem structures & their involvement in common brain disorders. Implications for Parkinson’s? ( to read more about this).

  • What you see is not what you get – researchers  present data providing new insightes into the monitoring of alpha‐synuclein oligomerization & aggregation using bimolecular fluorescence complementation assays (Click here to read more about this).
  • Researchers report deletion of Parkinson’s-associated DJ-1 in rats affects protein abundance & mitochondrial function at the synapse ( to read more about this).
  • New report explores polypeptides derived from α-synuclein binding partners for the prevention of Parkinson’s-associated α-synuclein fibrils interacting & aggregating ( to read more about this).
  • New tools generated from the identification of peptides interfering with the LRRK2/PP1 interaction ( to read more about this).
  • A new medRxiv manuscript describes the pooling together multiple genomic datasets based on Parkinson’s cases & controls, and creation of an exonic summary data user-friendly browser ( to read more about this, and click here to view the brower).
  • A new medRxiv manuscript explores the usefulness of real-world data in identifying drug repurposing candidates for disease-modifying effects in Parkinson’s (rasagiline & zolpidem get highlighted – to read more about this).
  • Researchers investigated the ultrastructure and prevalence of mitochondrial membranous protrusions (and, by extension, vesicles) in neurons. Mitochondria in neurons under mild stress produce more protrusions & vesicles ( to read more about this).

  • You’ve heard of optogenetics? Well now there’s sonogenetics. Researchers report targeted neurostimulation in the mouse brain with non-invasive ultrasound – implications for Parkinson’s & deep brain stimulation? ( to read more about this).
  • ‘Ribbons’, ‘waves’, ‘helices’…  Researchers report on a series of macromolecular assemblies of Parkinson’s-associated α-synuclein that have not been previously described. They form in the presence of lipid vesicles ( to read more about this).
  • A new bioRxiv manuscript proposes a novel acetylated-α-synuclein seeding mechanism that is driven by the recruitment of intrinsically disordered monomers by the fibril intrinsically disordered regions. Implications for Parkinson’s & other synucleinopathies? ( to read more about this).
  • New observations predict enhanced inhibition of dopaminergic signaling by A1R-G279S7.44 (in vivo) consistent with a pathogenic role in Parkinson’s ( to read more about this).
  • Cysteine cathepsins (Cts) has previously been reported as the main class of lysosomal proteases that degrade Parkinson’s-associated α-syn. Now researchers find CtsK is a more potent protease for degrading α-syn amyloids. Time to start drug screening… ( to read more about this).
  • Optogenetics is a hot area of Parkinson’s research & could have implications for future deep brain stimulation. Now researchers report on the development of a wireless, implantable optoelectrochemical probe for optogenetic stimulation & dopamine detection ( to read more about this).
  • New research presents a novel molecular mechanism of Fas-associated factor 1 (FAF1) in neurodegeneration (Spoiler alert: it’s cell-to-cell transmission). Implications for Parkinson’s? (Click here to read more about this).
  • Ribosome profiling of Parkinson’s-asssociated G2019S-LRRK2 dopamine neurons (ips cell-derived) finds mRNAs with complex secondary structures in the 5′ UTR are translated more efficiently in G2019S LRRK2 neurons, resulting in increased calcium influx. This study “reveals a link between dysregulated translation control & calcium homeostasis in G2019S-LRRK2 human dopamine neurons, which potentially contributes to the progressive & selective dopaminergic neurotoxicity in PD” ( to read more about this).

  • A new bioRxiv manuscript finds clinically used lysosomotropic drugs activate Parkinson’s-associated LRRK2 phosphorylation of Rab10 & the LRRK2-mediated exocytic release of lysosomal content ( to read more about this).
  • At the risk of sounding controversial: Females are different! New study reports female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters ( to read more about this).
  • A study on the link between neuronal death, glial response, & the MAPK pathway in an (importantly) aged mouse model of Parkinson’s ( to read more about this).
  • A new research report outlines a novel interaction between BAG5 & p62. BAG5 promotes Parkinson’s-associated alpha-synuclein oligomer formation & functionally interacts with p62 ( to read more about this).
  • New word for me: Macropinocytosis. It is a specialized form of endocytosis in macrophages. New research reports Rab10 is a primary effector of macropinocytosis, & Parkinson’s-associated LRRK2 is involved (Click here to read more about this).
  • Division of amyloid protein fibrils is required for the propagation theory of the amyloid state. Researchers compared the intrinsic stabilities of amyloid fibrils, & found that Parkinson’s-associated α-synuclein fibrils exhibited low stability to division ( to read more about this).

  • New study describing a human single-nuclei transcriptomic atlas for the substantia nigra (~ 17,000 nuclei), identifing a cell type association between Parkinson’s risk & oligodendrocytes (Click here to read more about this, click here to read an associated press summary, and click here to read a recent SoPD post on this topic).
  • Researchers reported on the structure of Parkinson’s-linked LRRK2 ( to read more about that) and that the conformation of Parkinson’s-associated LRRK2’s kinase domain regulates its microtubule interaction; closed conformation favoring binding. This has implications for the design of LRRK2 inhibitors ( to read more about this and click here to read the press summary).
  • A map of ∼30K connections of ∼5,000 human proteins relevant to neurodegeneration (ND), revealing interconnectivity across diseases & links ‘known knowns’, such as Parkinson’s-associated α-synuclein, to a host of proteins previously unrelated to neurodegeneration. Interesting that the map enables the prediction of neurodegeneration-specific subnetworks & the identification of proteins (eg ATXN1 & MKL1), that are abnormally aggregated in postmortem Alzheimer’s brains, suggesting widespread protein aggregation in neurodegenerative conditions ( to read more about this).
  • Using CRISPR to generate a comprehensive metabolic map of genes & pathways that regulate cellular ATP – “the ATPome” – reveals cross-optimization of metabolic pathways & identifies therapeutic targets to correct energy failure ( to read more about this).

 

Disease mechanism

  • Researchers report that splice-switching antisense oligonucleotides reduce Parkinson’s-associated LRRK2 kinase activity in humanised-LRRK2 transgenic mice ( to read more about this).
  • Researchers report iron chelator deferiprone improves the phenotype in a mouse model of tauopathy (via downregulation GSK3β & CDK5, & increase in the methylation of the catalytic subunit of protein phosphatase 2A – to read more about this).
  • Cysteine string protein α (CSPα) is a member of the DNAJ/HSP40 family of co-chaperones. A new bioRxiv manuscript suggests it could be a potential therapeutic target for treatment of early-stage Parkinson’s ( to read more about this).
  • Equol – a blood–brain barrier permeable gut microbial metabolite of dietary isoflavone daidzein – exhibits neuroprotective properties in in vitro & in vivo (C. elegans) neurotoxin models of Parkinson’s ( to read more about this).

  • Researchers report that upregulating enzyme β-hexosaminidase (responsible 4 turnover GM2) activity in rodents prevents α-synuclein lipid associations & protects dopamine neurons from Parkinson’s-associated α-synuclein neurotoxicity ( to read more about this).
  • New bioRxiv manuscript suggests that Parkinson’s-associated “neuronal α-synuclein inclusions contain α-synuclein fibrils intermixed with cellular membranes, & illuminate the mechanism of aggregate nucleation” ( to read more about this).
  • Researchers report that activation of p62-Keap1-Nrf2 pathway protects 6-OHDA-induced ferroptosis in models of Parkinson’s. Targeting this pathway in combination with a pharmacological inhibitor of ferroptosis warrants further investigation ( to read more about this).
  • Vasodilator papaverine reported to inhibit α-synuclein aggregation (by modulating neuroinflammation & matrix metalloproteinase-3 expression) in the subacute MPTP mouse model of Parkinson’s ( to read more about this).
  • IL‐1β/IL‐1R1 signaling (induced by intranasal lipopolysaccharide infusion) regulates Parkinson’s-associated alpha‐synuclein pathology in the olfactory bulb, substantia nigra & striatum in mice ( to read more about this and click here to read the press summary).
  • So nilotinib is now a DDR1 inhibitor? Researchers report data suggesting Discoidin Domain Receptor 1 (DDR1) could be a therapeutic target for neurodegenerative conditions like Parkinson’s (Click here to read more about this).

  • New bioRxiv manuscript suggests biotech firm Khondrion‘s Sonlicromanol (formerly KH176; a mPGES-1 inhibitor) improves neuronal network dysfunction & transcriptome changes linked to MELAS in iPSC-derived neurons ( to read more about this).
  • New bioRxiv manuscript explores whole genome CRISPR screens to identify genes/pathways required for uptake of monomeric/aggregated tau. Parkinson’s-associated LRRK2 noted as a key player. Further evidence of viral role too ( to read more about this).
  • Further evidence of the beneficial effects of kaempferol – a polyphenol antioxidant found in fruits & vegetables – on a transgenic drosophila model of Parkinson’s ( to read more about this).
  • Researchers report prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions ( to read more about this).
  • Researchers report a systems biology analysis that reveals reprogramming of the S-nitroso-proteome in the cortical & striatal regions of mice during aging process ( to read more about this).
  • Cysteamine improves motor performance in Thy-1-α-Syn Parkinson’s mouse model at both early & late disease stages; also protects iPS cells with a SNCA gene triplication ( to read more about this).
  • Trodusquemine, a naturally-occurring aminosterol, displaces protein misfolded oligomers (like Parkinson’s-associated alpha synuclien) from cell membranes & abrogates their cytotoxicity through a generic mechanism ( to read more about this).

  • Researchers report T cell infiltration & upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s ( to read more about this).
  • LRRK2 inhibitors reduced alpha-synuclein in multiple iPSC-derived cell lines from individuals with Parkinson’s (via autophagy/lysosomal systems). Prolonged inhibitor treatment was not toxic to neurons ( to read more about this).
  • “We here show that the presumed astrocytes-converted neurons are essentially endogenous neurons in the adult mouse brain”. A new bioRxiv manuscript suggests caution in interpretation of the “in vivo reprogramming phenomena” – implications for Parkinson’s? ( to read more about this).
  • Researchers present an anti-α-synuclein antisense oligonucleotide, which when delivered (intranasal or ICV) prevents α-synuclein accumulation in monoamine neurons in mouse & primate models of Parkinson’s. This indatraline-conjugated ASO molecule (IND-1233-ASO) is being developed by nLife Therapeutics. “highlights that the conjugated ASO used offers an early intervention strategy to delay PD progression, something that might be attractive in conjunction with current immunotherapy” ( to read more about this).
  • Researchers report Fyn kinase is a key regulator of Tau pathology (independent of Aβ-induced toxicity) & representing a potential therapeutic target for not only Alzheimer’s but tauopathies more generally (LRRK2-associated Parkinson’s? to read more about this).
  • Parkinson’s genetic risk evaluation in microglia highlights autophagy and lysosomal genes ( to read more about this).

  • Could Parkinson’s be accompanied by an abnormality in the mechanisms that control synapse growth & maturity? Researchers report developmental changes in dendritic spine morphology in the striatum & their alteration in the A53T α-synuclein transgenic mouse ( to read more about this).
  • New research reports that Parkinson’s-associated L444P GBA1 mutation increases formation & spread of α-synuclein deposits in mice (mouse pre-formed fibrils model –  to read more about this).
  • Widely used insecticide fenpropathrin reported to induce cellular death of dopaminergic neurons in vivo (via increased generation of ROS & disrupting mitochondrial function). Implications for Parkinson’s? ( to read more about this).
  • New paper uses mendelian randomization to evaluate lipid‐lowering drug targets in the prevention of Parkinson’s, highlighting Apolipoprotein‐A5 or ‐C3 inhibition ( to read more about this).
  • New report presents Neurolixis‘s selective 5-HT1A receptor agonist, NLX-112, demonstrating anti-dyskinetic effects in Parkinson’s primate model (MPTP-treated macaques – to read more about this).
  • Preclinical data from the biotech firm Peptron (& collaborators) reports that the GLP-1 receptor agonist PT320 attenuates L-DOPA/benserazide-induced dyskinesia in a 6-OHDA rodent model of Parkinson’s ( to read more about this).

 

Clinical research

  • A research consortium investigating frequency of GBA mutations in Parkinson’s cohort (n=314) in Ireland, 8.3% of their cohort had a GBA variant (vs 3.1% in controls). Curiously, LRRK2 mutations were rare (n=1 – to read more about this).
  • An analysis of disease trajectory in 2 large Parkinson’s patient cohorts (n=700+ across 5 countries) using identical clinical measures, finds that over 13 year period 2 trajectories appear: one benign, the other more severe ( to read more about this).
  • “These data neither support a markedly higher Parkinson’s prevalence in the older Lancaster Amish nor do they show dramatically higher motor &/or selected nonmotor symptoms than the general population” ( to read more about this).

  • A medRxiv manuscript outlines the “Ontario Neurodegenerative Disease Research Initiative” (ONDRI) -multi-site, longitudinal, observational cohort study that recruited participants across multiple neurodegenerative (Parkinson’s) & cerebrovascular conditions ( to read more about this).
  • New study investigated changes in inflammatory cytokines levels in individuals with Parkinson’s who underwent general anesthesia with inhalational anesthetics or total intravenous anaesthesia. Authors suggest serum IL-17 may be a PD progression biomarker ( to read more about this).
  • Researchers analyzed co-pathology (Alzheimer’s amyloid-β-containing plaques, Parkinson’s α-synuclein inclusions, tau neurofibrillary tangles, etc) across 18 brain regions in 1389 autopsies & found transdiagnostic “disease clusters” ( to read more about this).
  • Researchers analyse 30 post-mortem Dementia with Lewy bodies (DLB) cases (& 29 controls) & report DLB to be characterised by a lack of neuroinflammation & neuropil degeneration, despite presence of increased neuropathology. Increased recruitment of T lymphocytes in DLB (supports a role for adaptive immunity); microglial activation not a major feature of DLB (in contrast with Alzheimer’s); preservation of cortical structures “suggests the dementia could be more amenable to potential therapies” ( to read more about this).
  • A systematic review & meta-analysis of the efficacy of dance for improving motor impairments, non-motor symptoms, & quality of life in Parkinson’s ( to read more about this).

  • Assessment of initial clinical symptoms in large Dementia with Lewy bodies cohort (n=234) finds gender differences. Higher incidence of REM sleep behav. disorder in men, whereas women had a higher incidence of psychotic symptoms (Click here to read more about this).
  • The PPP2R5D p.E200K mutation may be a possible new cause of early‐onset parkinsonism. A new study describes 3 cases; Neuropathological examination indicates severe dopamine neuronal loss & gliosis in the substantia nigra, without Lewy bodies (Click here to read more about this).
  • Screening for hallucinations may be useful for assessing risk of dementia in participants with Parkinson’s ( to read more about this).
  • Differential protein expression in diverse brain areas of postmortem Parkinson’s & Alzheimer’s cases (proteins involved in microtubule assembly, autophagic-lysosomal pathway & unfolded protein response – click here to read more about this).
  • A two-cohort case-controlled study reports deleterious variants & non-coding variants of GCH1 can influence the Parkinson’s phenotype in the Chinese mainland ( to read more about this).
  • Researchers report distinctive clusters of Parkinsonism based on brain imaging (FP-CIT PET)-derived heterogeneous neurodegeneration patterns (2 cohorts; n=94 & 813), which were associated with different clinical features ( to read more about this).

  • Patients’ experiences of Parkinson’s: a qualitative study in glucocerebrosidase-associated & idiopathic PD (n=15 & 5, respectively –  to read more about this).
  • RAB39B is redistributed in dementia with lewy bodies & is sequestered within Aβ plaques & lewy bodies (Click here to read more about this).
  • Results from the HELIAD study have been published. This project investigated the association between frailty, Parkinson’s & the probability of prodromal PD in Greek community of 1765 elderly individuals ( to read more about this).
  • 30 recently diagnosed cases of Parkinson’s exhibit significant reduction in presynaptic terminal integrity in the substantia nigra (based on 11C‐UCB‐J/SV2A & 18F‐FE‐PE2I/DAT imaging – click here to read more about this).
  • A novel mutation (c.368C>G (p.S123*)) in Parkinson’s-related FBXO7 is associated with impaired proteasome activity that overlaps with brain iron accumulation ( to read more about this).
  • Researchers report four MAPT H1 subhaplotypes (but not H2 haplotypes) were significantly associated with specific clinical features of Parkinson’s. MAPT haplotypic structure may explain some of the phenotypic variability in disease ( to read more about this).
  • Researchers conduct an exploratory machine learning study investigating hand resting tremor assessment of healthy & individuals with Parkinson’s ( to read more about this).

  • Researchers point to the importance of reward rather than punishment avoidance in driving impulsive behaviors. Providing insights into the pathophysiological of impulsivity & with implications for Parkinson’s ( to read more about this).
  • New data finds serum urate concentration is not a monitoring biomarker of Parkinson’s progression in early stages ( to read more about this).
  • New bioRxiv manuscript suggests urinary proteomics as a valuable strategy for biomarker discovery & patient stratification in Parkinson’s. Interestingly, the data revealed lysosomal dysregulation in LRRK2-G2019S cases ( to read more about this).
  • The same but different – a new bioRxiv manuscript suggests that REM sleep behaviour disorder exhibits similar but distinct gut dysbiosis compared to Parkinson’s ( to read more about this).
  • CHAPS: Care coordination for Health promotion & Activities in Parkinson’s. Researchers discuss quality & extent of implementation of a nurse-led, telephone-administered 18-month care management intervention ( to read more about this).
  • A new medRxiv manuscript validates a measure of rigidity in Parkinson’s using alternating finger tapping on an engineered keyboard ( to read more about this).
  • Comparative transcriptome analysis of Parkinson’s & progeria syndrome reveals shared susceptible cellular network processes. Of interest: CDC5L. Need to extend analyses to longitudinal expression ( to read more about this).

  • Penetrance of Glucocerebrosidase (GBA1) genetic variants in Parkinson’s (Click here to read more about this).
  • 2 for 1: an economic evaluation & a randomised controlled trial. Researchers report the results & cost-effectiveness of the PDSAFE personalised physiotherapy intervention for fall prevention in Parkinson’s ( to read more about this).
  • New paper reports the majority of people with Parkinson’s observed in their study had an inadequate intake of vitamin D & iron (respectively, 55.9 and 76.5% of all participants – to read more about this).
  • A new report on a novel SNCA mutation, E83Q, found in a patient with dementia, parkinsonism and frontotemporal lobar degeneration. Extensive Lewy pathology all over. The patient’s father, who carried the same mutation, was diagnosed with Pick’s disease ( to read more about this).
  • “Cellists’ sound quality is shaped by their primary postural behavior” – implications for music-based rehabilitation for Parkinson’s? ( to read more about this).
  • The PRIAMO study group report age- & sex-related relationships between prodromal constipation & disease phenotype in early Parkinson’s ( to read more about this).
  • Interesting brain imaging (MRI) cohort profile: the Discovery Cohort MRI substudy (OPDC-MRI) has baseline images from 290 participants (including 68 controls & 87 RBD prodromal cases), includes images from 15 Parkinson’scases with LRRK2 or GBA pathogenic mutations. Overall findings to date: Differences in brain structure in early PD were found to be subtle ( to read more about this).

  • A new medRxiv manuscript suggests clinic-based quantitative mobility assessments using a wearable sensor better capture features of motor performance in Parkinson’s (beyond those obtained using the motor MDS-UPDRS – to read more about this).
  • New brain autopsy of PINK1-associated Parkinson’s case: female patient, L-dopa responsive, followed 35+ years since diagnosis, positive response to bilateral GPi DBS. Pathology in the brain involved gliosis, large loss of melanin+ neurons in substantia nigra, & Lewy body pathology. This is only the 4th case of brain autopsy of PINK1-associated Parkinson’s – previous reports describe 2 patients with Lewy-related pathologies (albeit with differential distribution) & 1 patient with no Lewy-related pathology (Click here to read more about this).
  • “Immune profiling of plasma-derived extracellular vesicle represents a crucial step toward the identification of biomarkers of disease for Parkinson’s & atypical Parkinsonisms”. Could there be potential for a minimally invasive blood test for PD? CD146 & MCSP get highlighted ( to read more about this).
  • First cryo-EM images of plasma derived-exosomes from Gaucher disease patients. Larger exosomes, enriched with CD9, СD63, CD81 &HSP70; proteomic profiling did not reveal any proteins associated with Parkinson’s pathogenesis (Click here to read more about this).
  • A systematic review adding further confirmation of the benefits of aerobic exercise for people with Parkinson’s (Click here to read more about this).

  • Using medical records of 150 individuals who were diagnosed with de novo Parkinson’s & treated with levodopa until onset of LID, researchers report rapid drug increase is associated with early onset of levodopa-induced dyskinesia ( to read more about this).
  • New research reports akinetic rigid symptoms are associated with decline in a cortical motor network in Parkinson’s ( to read more about this).
  • Researchers evaluate patterns of cognitive progression in a large PD cohort. Age, disease duration, sex, & GBA status were the primary biological factors associated with cognitive progression ( to read more about this).
  • Is there a typical progression of Alzheimer’s pathology? In a new medRxiv manuscript researchers characterise the spatiotemporal spread of tau from over 1500 tau-PET images and do not find one predominant pattern, but rather four separate patterns ( to read more about this).
  • New study identifies a set of 25 genes from the gut microbiome that may be a potential diagnostic biomarker of PD; discriminated 78 PD cases from 75 controls, 40 MSA, & 25 Alzheimer’s cases ( to read more about this).
  • A new study presents a case study (along with postmortem examination findings) of Twinkle-associated (C10orf2 gene) familial parkinsonism with Lewy pathology ( to read more about this).
  • “Healthy diet may reduce the occurrence of non-motor symptoms that often precede Parkinson’s diagnosis”. Analysis of Nurses’ Health Study database (n=47K) indicates inverse association between these diet patterns & prodromal PD features (Click here to read more about this).

  • “What happens when I watch a ballet & I am dyskinetic?”. A brain imaging (fMRI) sheds light on a possible use of complex action observation to improve or slow the deterioration of motor abilities and levodopa-induced dyskinesias in Parkinson’s ( to read more about this).
  • An analysis of the prevalence of LRRK2, SNCA, & VPS35 mutations & associated clinical features in a large French multi-center cohort of Parkinson’s (n=1,805 – to read more about this).
  • A genetic screen of NOTCH2NLC GGC repeat expansion in 1000 individuals with sporadic PD & 1076 controls finds 13 PD cases with expansions >40 units, but no repeat expansions in healthy control participants (P < .001 – click here to read more about this).
  • New study reports the clinical, metabolomic, & multimodal neuroimaging phenotypes of GBA variants in 56 patients with mid‐stage Parkinson’s -13 GBA variant carriers identified & characterised ( to read more about this).
  • Assessing individuals with Parkinson’s from sub-Saharan Africa, researchers uncovered a key, previously unknown features of the long-duration response of levodopa: it is robust from the outset, does not decay over time, and appears to be independent of disease duration ( to read more about this).
  • “After diagnosis of COVID-19, this Parkinson’s patient had worsening of motor symptoms, complicated with acute hypoxemic respiratory failure, urinary tract infection, & acute encephalopathy” The management of a Wuhan PD case with severe COVID-19 pneumonia ( to read more about this).

New clinical trials

  • New clinical trial registered: Citalopram as a posterior cortical protective therapy in Parkinson’s. Being conducted at the University of Michigan, the study is recruiting 60 participants to take citalopram (20mg) or placebo daily over 26 months (Click here to read more about this).
  • New clinical trial registered: Annovis Bio has registered a dose-finding, biomarker study for their agent ANVS-401/”Posiphen” in early Alzheimer’s & Parkinson’s. The study will involve 28 participants across 15 sites across the US followed by a dose response study in 40 PD patients (Click here to read more about this and click here to read more about this).

  • New clinical trial registered: researchers are initiating a pilot open-label study exploring short chain fatty acid enhancing prebiotics & normalization of the Parkinson’s microbiome (10 participants, 10 days, prebiotic dietary bars – click here to read more about this).
  • New clinical trial registered: Misfolded proteins in the skin of people with Parkinson’s & other Parkinsonisms. Recruiting 250 people to determine whether misfolded proteins in the skin can help to determine what sort of parkinsonism someone has (Click here to read more about this).

 

Clinical trial news

  • MODAG announced that they have successfully completed Phase 1 study of their lead candidate Anle138b in healthy volunteers, and receives an additional US$1.4M from the Michael J Fox Foundation to further their Parkinson’s programme ( to read more about this).

  • PD Working Group Innsbruck report the results of the NMS-Nab study: synthetic tetrahydrocannabinol analogue, nabilone, has positive effects on anxiety & night‐time sleep issues (Click here to read more about this).
  • Prof Jeanne Loring – a co-founder of Parkinson’s cell transplantation biotech venture Aspen Neuroscience – is stepping down from her role as its chief scientific officer. Staying on as special advisor to the company ( to read more about this).

  • The “Parkin’Play” Study: Home-based gamified cognitive training shows acceptable feasibility in patients with Parkinson’s, according to new study. Larger trial needed to establish efficacy ( to read more about this).
  • Prothena announced that the Part 1 of the Phase 2 PASADENA (a-syn immunotherapy) clinical trial results will be presented at the International Congress of Parkinson’s Disease & Movement Disorders Society on Sept 14th ( to read more about this).

  • A multicenter, double‐blind, placebo‐controlled, Phase 4 trial of DA 9701 – a gastroprokinetic agent formulated with pharbitis seed & corydalis tuber – finds improved gastrointestinal symptoms & related quality of life in 144 individuals with Parkinson’s ( to read more about this).
  • Prevail Therapeutics’second quarter financial reports reveal two participants enrolled in the Phase 1/2 PROPEL gene therapy trial of PR001 for GBA-associated Parkinson’s. Preliminary data: PR001 normalized GCase enzyme activity in CSF 3-4 months after administration ( to read more about this).

  • Another study protocol was published: this time it’s the TRACK-PD study: a longitudinal ultra-high field imaging study in a cohort of 130 individuals recently diagnosed with Parkinson’s (+ 60 controls –  to read more about this).
  • Axovant Gene Therapies announces that they have completed enrollment of the 2nd dose cohort for Phase 1 Parkinson’s gene therapy trial & remain on-track to deliver 6-month safety & efficacy data in Q4 2020. Enrollment of Phase 2 study=2021 ( to read more about this).

  • The protocol for the ‘UP’ (Ursodeoxycholic acid in Parkinson’s) study has been published. This is a two-centre, randomised, double-blind, placebo-controlled trial of 30 individuals with early PD, assessing safety/tolerability. Also confirming target engagement of UDCA, applying a novel motion sensor-based approach to quantify disease progression in Parkinson’s objectively, & estimating the mean effect size/variance on the change in motor severity (Click here to read more about this).
  • The Phase I pharmacokinetics, pharmacodynamics, safety, & tolerability results of Sanofi‘s oral inhibitor of glucosylceramide synthase, Venglustat, in healthy volunteers has been published. This therapeutic is being targeted at GBA-associated Parkinson’s ( to read more about this).

  • Shake it up Australia and Anavex Life Science announced a commitment for financial investment into an appropriately powered 48 week placebo-controlled clinical study of once-daily oral sigma-1 agonist ANAVEX®2-73 (blarcamesine) in Parkinson’s. The new trial will attempt to confirm the previously reported potentially disease modifying features of ANAVEX2-73 in animal models of Parkinson’s. Safety and efficacy will be investigated as well as some “ANAVEX®2-73-specific precision medicine biomarkers” ( to read more about this and click here to read a SoPD post on this topic).

Other news

  • The European Physiotherapy Guideline for Parkinson’s: translation for non-English speaking countries (Click here to read more about this).
  • Interesting perspective from the research team at the Michael J Fox Foundation providing a holistic description & model of how their foundation supports Parkinson’s-associated LRRK2 research – targeting important barriers to help move the field forward ( to read more about this).

  • Everyday there is yet another viewpoint or perspective on COVID & potential links with Parkinson’s. This one is the best one yet & certainly worth reading. Outlining what we know & what we need to learn more about. They provide an interesting overview of COVID19, historical research on viruses in the context of PD, and highlight the need for detailed autopsy studies and “consensus-led guideline for management of PD with varying grades of COVID-19” ( to read more about this).
  • Denali Therapeutics & MedGenome announce a strategic collaboration on Parkinson’s – focusing on under-represented population groups, in particular those from South Asia ( to read more about this).

  • The Michael J Fox Foundation has relaunched their Parkinson’s podcast, with the living legend Larry Gifford hosting monthly conversations on the latest advances in PD research & care (Click here to read more about this).
  • Biotech firm Athira Pharma – who are developing NDX-1017 (small molecule enhancer of activity of Hepatocyte Growth Factor (HGF) & its receptor, MET) for Alzheimer’s & Parkinson’s – are filing for initial public offering ( to read more about this).

 

Review articles/videos

  • “If your patients were too embarrassed to go out in public, what would you do? Public education to break the stigma of Parkinson’s using integrated media, an interesting report from Thailand ( to read more about this).
  • A useful review of microglia & astrocyte dysfunction in Parkinson’s – a lot of areas covered ( to read more about this).
  • Ever wanted to learn about midbrain dopaminergic neuron development at the single cell level (in mice & humans, in vitro & in vivo)? This review is your starting point (to read more about this).
  • “A holistic approach for better understand multisystemic interactions & perturbations of neurodegenerative diseases focused on the role of the microbiome is possible, which might potentially reveal novel effective solutions” ( to read more about this).
  • An interesting review of the data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s ( to read more about this).

  • “Parkinson’s is more than meets the eye” – an interesting perspective on the current pitfalls in the search for future treatments & prevention of PD (latency between actual onset & diagnosis, sensitivity & specificity of outcome measures, classic PD=late stage, etc – to read more about this).
  • The role of alpha-synuclein & other Parkinson’s genes in neurodevelopmental & neurodegenerative conditions ( to read more about this).
  • Researchers explore insights from animal models of Parkinson’s regarding LRRK2 & protein aggregation (Click here to read more about this).
  • Useful review of infusion therapies for Parkinson’s – covering methods like L-dopa-carbidopa intestinal gel infusion which can have meaningful improvements in motor fluctuations with a positive impact on the quality of life in advanced PD ( to read more about this).
  • Ambroxol is being repurposed for Parkinson’s by The Cure Parkinson’s Trust and the Van Andel Institute, but a new review suggests other areas of neurodegenerative research are investigating this old drug as well ( to read more about this).

  • A very thorough review of the genetics of synucleins (like Parkinson’s-associated alpha synuclein) in the context of neurodegenerative conditions ( to read more about this).
  • Mapping clinical trials in Parkinson’s with a bit of a personal perspective (Click here to read more about this).
  • Where & how alpha‐synuclein pathology spreads in Parkinson’s – “it cannot be ruled out that alpha‐synuclein pathology in PD is multicentric in origin” (Click here to read more about this).
  • “The next frontier for subtypes research as it applies to personalized medicine in PD is the development of genotype-specific therapies” – a review of the current approaches being explored for treating Parkinson’s subtypes ( to read more about this).
  • Telomere attrition in neurodegenerative disorders” – there is conflicting data in Parkinson’s. A useful section of this review tries to make sense of the differences (Click here to read more about this).
  • Interesting review of key mechanisms & potential targets of the NLRP3 inflammasome in neurodegenerative, with good sections on Parkinson’s, Alzheimer’s & ALS ( to read more about this).

  • Researchers discuss progress in the use of antisense oligonucleotides, small interfering RNAs, short hairpin RNAs, aptamers, & microRNA‐based therapeutics to target critical elements in the pathogenesis of Parkinson’s ( to read more about this).
  • The complete guide to Parkinson’s-associated LRRK2 animals models (Click here to read more about this).
  • Interesting short section on Parkinson’s in this review of blood neurofilament light chain protein in neurodegenerative conditions ( to read more about this).
  • Useful review of recent developments in the treatment of Parkinson’s (
    to read more about this).
  • Moving towards early disease modification for Parkinson’s: A review the lessons learnt in the Alzheimer’s field (suboptimal participant selection, insensitive outcomes, narrow target focus, & trial design flaws – click here to read more about this).
  • Two experts debate the past and future roles of animal models for Parkinson’s ( to read more about this).
  • Helicobacter pylori infection: Beyond gastric manifestations (with small section on Parkinson’s – to read more about this).

  • “Placebos make good medicine better” – a reexamination of the GDNF clinical trials in Parkinson’s & discussion of a unique human dimension not predicted by the animal models ( to read more about this).
  • Interesting review on glia cell crosstalk in neuroinflammatory conditions (including Parkinson’s – to read more about this).
  • A useful overview on trophic activities of endoplasmic reticulum proteins CDNF & MANF, which are both being targeted at Parkinson’s ( to read more about this).
  • From synaptic dysfunction to neuroprotective strategies in genetic Parkinson’s: Lessons from transgenic LRRK2 experimental models ( to read more about this).
  • Interesting section on Parkinson’s in this review of Transient receptor potential (TRP) channels in pain associated with neurodegenerative conditions (to read more about this).
  • Researchers present a current literature review exploring diabetes mellitus & Parkinson’s, discussing “shared pathophysiological links & possible therapeutic implications” (Click here to read more about this).

* * * * * * * * * * * *

And there it is, just some of the highlights from August 2020 – another very busy month of Parkinson’s research. Hopefully there will be bits and pieces of interest for everyone in the list. Much of the material used here was collected from the Science of Parkinson’s Twitter feed (and there is a lot more posted there each day).

Any thoughts/feedback would be greatly appreciated (either in the comments below, or contact me directly).

And now: on to September!!!

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EDITOR’S NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.

In addition, many of the companies mentioned in this post are publicly traded companies. That said, the material presented on this page should under no circumstances be considered financial advice. Any actions taken by the reader based on reading this material is the sole responsibility of the reader. None of the companies have requested that this material be produced, nor has the author had any contact with any of the companies or associated parties. This post has been produced for educational purposes only.


One thought on “Monthy research review – August 2020

  1. Thanks as always Simon. I’m looking forward finding what’s shared on the Pasadena study, which has now been pushed off a day to the 15th BTW. The participants have been left in the dark except for the April financial call shenanigans and knowing that it’s been extended for five years in part 3. (That must be good for something)

    Hopefully there is a press release to accompany it. Seems like it will be a big day for the field…

    Like

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