Monthly Research Review – December 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 December 2020.

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

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Conferences/lectures
  • Other news
  • Review articles/videos

So, what happened during December 2020?

In world news:

December 2nd – The United Kingdom approved the Pfizer/BioNTech BNT162b2 vaccine for COVID-19.

December 8th – Nepal and China officially agree on Mount Everest’s actual height, which is 8,848.86m (0.86m higher than previously officially calculated).

December 9th – The SpaceX Starship prototype SN8 made a first test flight – reaching an altitude of 41,000 feet (12,500 metres) – at the company’s rocket facility in Boca Chica, Texas. The flight was a pretty spectacular feat of engineering (the landing not so much).

December 23rd – Scientists from The Wistar Institute (Philadelphia) reported a new class of compounds that uniquely combine direct antibiotic killing of pan drug-resistant bacterial pathogens with a simultaneous rapid immune response for combating antimicrobial resistance (Click here to read more about this and click here to read the press summary).

December 24th – The UK Government announced that the UK ‘decided not to stay in Erasmus‘ under the Christmas eve Brexit deal. The Erasmus exchange programme, which the UK joined in 1987, has allowed approximately 17,000 young UK citizens each year to study and work at universities across Europe, but more importantly has encouraged 32,000 EU students to come to the UK (approximately 200,000 students across the EU take part each year). In January, Boris Johnson assured MPs there was “no threat to the Erasmus scheme”. A replacement UK scheme named after computing pioneer Alan Turing will be set up (backed by £100 million in its first year), but the new scheme is not expected to fund students coming to the UK, which suggests UK universities will miss out on a source of income (>£200m a year – Click here and here to read more about this. (an absolute disaster for small UK universities).

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

In December 2020, there were 773 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (10,584 for all of 2020). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

1. The NILO-PD clinical trial results were published:

The results of their Phase II clinical study of nilotinib in individuals with moderately advanced Parkinson’s found that the treatment was acceptable safety & tolerability, but data “indicate that nilotinib should not be further tested in PD“. The researchers reported that “the low cerebrospinal fluid exposure & lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in Parkinson’s“. There was no difference in the clinical measures (change of MDS-UPDRS-3 OFF) from baseline to 6 months between the treatment groups. Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3% (Click here to read more about this).

2. Eli Lilly bought gene therapy company Prevail Therapeutics

The large pharmaceutical company Eli Lilly has announced an agreement to acquire Prevail Therapeutics for $1.040 billion. Prevail’s lead gene therapy in clinical development is PR001 – for GBA-associated Parkinson’s (Click here to read more about this and click here to read an SoPD post about this).

3. Bayer buys Brain Neurotherapy Bio

GDNF gene therapy company Brain Neurotherapy Bio has merged with Asklepios Bio Pharmaceutical to jointly advance central nervous system gene therapies, for conditions like Parkinson’s (Note: AskBio is a subsidary of the Pharma company Bayer click here to read more about this and click here to read an SoPD post about this).

4. The genetics of Parkinson’s

By fully sequencing 32 genes in 25 genetic loci previously associated with Parkinson’s (in 2657 patients and 3647 controls from three cohorts), researchers identified rare and common variants that may be driving the associations – highlighting SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB as important players (Click here to read more about this).

5. PARP-kinson’s goes chlorogenic

New research found that activating the kinase Akt1 (with chlorogenic acid, which is found in coffee) prevents neurodegeneration in two mouse models of Parkinson’s. The scientists reported that Akt1 activates the CREB target RNF146 which subsequently inhibits PARP1-dependent cell death in both mouse & human neuronal cultures. “Furthermore, dysregulation of the Akt1-CREB pathway was observed in postmortem brain samples from patients with Parkinson’s” (Click here to read more about this and click here to read a SoPD post about this).

Basic biology news

  • A new biorxiv manuscript suggests the association of Parkinson’s-related LRRK2 to membranous compartments is sufficient for its activation & Rab phosphorylation independent of membrane identity (Click here to read more about this).
  • Altered striatal dopamine levels in Parkinson’s-associated VPS35 D620N mutant transgenic aged mice (Click here to read more about this).
  • New report identifies cellular mechanisms (RNASeq analysis) in the rat frontal cortex that are involved in the response to Parkinson’s-associated L-DOPA treatment; in unilateral model, the changes in gene expression induced by L-DOPA were bilateral (Click here to read more about this).

  • A tale of proteolysis targeting chimeras (PROTACs) for Parkinson’s-associated LRRK2: 2 highly potent, selective & brain‐penetrating kinase inhibitors developed, strong kinase inhibition demonstrated, but degradation of the target protein looks inconclusive (Click here to read more about this).
  • A new medrxiv manuscript analyzes small RNA sequencing profiles of brain tissue of 43 Parkinson’s cases (& 88 controls); identifies 421 miRNA editing sites with significantly different editing levels in prefrontal cortices of PD cases (highlights miR-497-5p – click here to read more about this).
  • A comparison of AAV-vector production methods for gene therapy & preclinical assessment; New protocol enables most standardly equipped laboratories to produce small batches of high quality & high titer AAV vectors for their experimental needs (Click here to read more about this).
  • New report investigates a panel of 12 reported Nurr1 ligands for their Nurr1-dependent & Nurr1-independent transcriptional effects. Amodiaquine & chloroquin directly bind Nurr1 LBD (Click here to read more about this).

  • New report finds that Parkinson’s-associated E3 ligase FBXO7 (& its PD familial mutants) may have chaperon activities, acting as a scaffold protein (together with Bag2) & stabilizing PINK1 (Click here to read more about this).
  • New research identifies Sis1 – an essential Hsp40 co-chaperone of Hsp70 – as a critical sensor of proteotoxic stress; Sis1 functions as a limiting regulator to enable a dynamic stress response & avoid hypersensitivity to environmental changes (Click here to read more about this).
  • New report finds that arkypallidal neurons are part of a novel disynaptic feedback loop differentially recruited by the indirect or hyperdirect pathways; inhibitory control of locomotion when these neurons increase their activity (Click here to read more about this).
  • “PDmethDB” – a curated database of Parkinson’s-associated methylation information – aims to facilitate the understanding of the relationship between PD & methylation; 97K+ PD methylation associated entries among 12K+ molecules, 37K+ CpG sites, & 31 tissues (Click here to read more about this).

  • New report presents a proteomic analysis of a highly penetrant new Drosophila model of α-synucleinopathy; 476 significantly upregulated & 563 significantly downregulated proteins vs controls; highlights GCH1 & folate metabolism (Click here to read more about this).
  • New report demonstrates a compound selection strategy based on the inhibition of Parkinson’s-associated α-synuclein oligomers formation; A useful approach for drug discovery? (Click here to read more about this).
  • MMP13 expression is increased following Parkinson’s-associated mutant α-synuclein exposure & promotes inflammatory responses in microglia (Click here to read more about this).
  • New study reveals impact of Parkin-Mitofilin interaction in Parkinson’s stressor-induced neurotoxicity; Leads to the degradation of Mitofilin, mitochondrial structural damage, & dysfunction + apoptosis (via an AIF-PARP pathway – click here to read more about this).
  • New research explores how directly converted astrocytes retain the ageing features of the donor fibroblasts, & seeks to elucidate the astrocytic contribution to human CNS health & disease (Click here to read more about this).
  • But what happens when you turn them into a pasta sauce? Tomatoes were engineered to synthesise & accumulate L-DOPA; Co-expression of transcription factor, MYB12, doubled the levels of L-DOPA; “exhibited improved shelf life” (Click here to read more about this).

  • Is this a hint about viruses as Parkinson’s triggers? Identification of viral-mediated pathogenic mechanisms in neurodegenerative diseases using network-based approaches (Click here to read more about this).
  • YKL-40 is controlled by the astrocyte circadian clock, regulates neuroinflammation & Alzheimer’s pathogenesis; Deletion of YKL-40 reduces amyloid plaque formation & promoted Aβ phagocytosis; Polymorphism in Chi3l1 (YKL-40 gene) results in slower AD progression (Click here to read more about this and click here to read a summary of the study)
  • New research finds silencing netrin‐1 in the adult mouse substantia nigra induces DCC cleavage & significant loss of dopamine neurons; increasing netrin‐1 is neuroprotective; netrin‐1 significantly reduced in Parkinson’s brains (Click here to read more about this).
  • Parkinson’s-associated cytosolic PINK1 orchestrates protein translation during proteasomal stress by phosphorylating the translation elongation factor eEF1A1 (Click here to read more about this).
  • Towards a PET tracer for Parkinson’s-associated α-synuclein aggregates. Researchers at biotech firm MODAG & collaborators present [11C]MODAG-001; high affinity to pure αSYN fibrils (Kd=0.6nM); moderate affinity to hTau46 (Kd=19nM) & β1–42 fibrils (Kd=20nM – click here to read more about this).

  • Grafts derived from an α-synuclein triplication patient exhibit functional recovery, but develops disease-associated pathology in a preclinical model of Parkinson’s (Click here to read more about this).
  • Researchers report on the development of a multiplexed targeted mass spectrometry assay for Parkinson’s-associated LRRK2-phosphorylated Rabs & Ser910/Ser935 biomarker sites (Click here to read more about this).
  • Experimental investigation in mice into the role of the subthalamic nucleus in motor control using optogenetics (Click here to read more about this).
  • The structure & global distribution of the endoplasmic reticulum (ER) network are actively regulated by lysosomes; lysosomes sense metabolic change in the cell & regulate ER tubule distribution; implications for Parkinson’s? (Click here to read more about this and click here for the press summary).

Disease mechanism

  • Researchers have a biorxiv manuscript suggesting neuroprotective properties for red clover & soy isoflavones in models of Parkinson’s (via Nrf2-mediated antioxidant response – Click here to read more about this).
  • A new biorxiv manuscript presents in vivo evidence that Parkinson’s-related pathogenic LRRK2 impairs basal mitophagy; Pharma company GlaxoSmithKline’s LRRK2 kinase inhibitor, GSK3357679A rescues impaired mitophagy in LRRK2-G2019S mice (Click here to read more about this).

  • BMP5/7 prevents Parkinson’s-associated α-synuclein-indcued loss of dopamine neurons, motor impairment, & gliosis; Also significantly reduces α-synuclein accumulation; Loss of BMP/SMAD resulted in accumulation of α-synuclein; Inhibitory SMAD6 is elevated in the Parkinsonian substantia nigra (Click here to read more about this).
  • Researchers report correction of pathology in mice displaying Gaucher disease type 1 by a clinically-applicable lentiviral vector; No oligoclonal distribution pattern or vector-induced clonal dominance; GBA-assoc Parkinson’s? (Click here to read more about this).
  • The metazoan tripartite motif (TRIM) 11 reported to prevent & reverses alpha synuclein protein aggregation in an ATP-independent manner; Rescued a mouse model of Parkinson’s; Molecular chaperone & disaggregase activities enhance solubility (Click here to read more about this).
  • Neuroprotective & anti-inflammatory effects of a therapy combining agonists of nicotinic α7 & sigma1 receptors in a rodent model of Parkinson’s (Click here to read more about this).
  • Further preclinical evidence supporting TUDCA:  TUDCA pretreatment protected against dopamine neurodegeneration & prevented microglial/astroglial activation. Also prevented protein oxidation & autophagy, & α-SYN aggregation in model (MPTP) of Parkinson’s (Click here to read more about this).

  • Dopamine replacement therapy (L-dopa) is reported to reduce accumulation of α‐synuclein in the MPTP primate model of Parkinson’s. Does this need to be a consideration when assessing response to potential disease‐modifying treatments? (Click here to read more about this).
  • New report finds activating transcription factor-4 (ATF-4) promotes neuronal death induced by Parkinson’s-associated neurotoxins (MPP+ & 6-OHDA) & α-synuclein aggregates (PFFs); eIF2α kinase inhibitor C16 suppresses it (Click here to read more about this).
  • A small proteomic study of molecular processes underlying alterations of synaptic function in Parkinson’s highlights CD9 antigen as overrepresented & 14 proteins as underrepresented, suggesting alteration in mitochondrial translation within synaptosomes (Click here to read more about this).
  • Researchers find that deuterated PUFAs (D-PUFAs) treatment reduces α-synuclein-induced motor deficits, oxidative damage, mitochondrial dysfunction, inflammation & cell neuronal loss in model of Parkinson’s (Click here to read more about this).
  • The rise of nanoscavengers! Researchers present REXO-C/ANP/S – a nanoscavenger for clearing α-synuclein aggregates, reducing their cytotoxicity, suppressing immune activation, & rescuing motor issues in a model of Parkinson’s; REXO-C/ANP/S: “an engineering core-shell hybrid system named rabies virus glycoprotein (RVG) peptide–modified exosome (EXO) curcumin/phenylboronic acid-poly(2-(dimethylamino)ethyl acrylate) nanoparticle/small interfering RNA targeting SNCA” – quite the combo! (Click here to read more about this).

  • Analysis of normal aging & Parkinson’s postmortem human brains (using label-free cryogenic X-ray nanotomography) finds swellings (containing dense granular material) between the myelin sheaths of oligodendrocyte, rather than in the axoplasm (Click here to read more about this).
  • β-sitosterol-β-D-glucoside (BSSG) is a neurotoxin that leads to Parkinson’s features in humans & rodents. Now researchers report that acute administration causes chronic neuroinflammation (via activated microglia & neurotoxic A1 reactive astrocytes – click here to read more about this).
  • Protection from Parkinson’s-associated α-Synuclein-induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20; rescued expression of chaperone protein GRP75/mtHSP70/mortalin (Click here to read more about this).
  • An indazole derivative 6-amino-1-methyl-indazole (AMI) exerts a neuroprotective effect in neurotoxin-induced models of Parkinson’s by inhibiting tau hyperphosphorylation (Click here to read more about this).
  • Curious – New research finds a gender-biased neuroprotective effect of Transferrin Receptor 2 (TfR2) deletion in multiple models of Parkinson’s; The effects were significantly more pronounced in females than males (Click here to read more about this).

Clinical research

  • A new medrxiv manuscript explores their hypothesis-driven “no motor” PREDIGT formula (PR=(E+D+I)xGxT); Uses numerical values for 5 categories known to modulate Parkinson’s risk using data from the DeNoPa & PPMI cohorts (Click here to read more about this).
  • A nationwide (Taiwan) population-based study finds a positive association of Parkinson’s with ankylosing spondylitis (an autoimmune, chronic inflammatory rheumatic disorder – Click here to read more about this).
  • Another case study of an individual with Parkinson’s contracting COVID19 – 58-year-old woman with idiopathic PD; Neurological manifestations, but returned to normal therapy regimen in 3 weeks (Click here to read more about this).
  • Insights from one research institution: Probabilistic Mapping – 15 Years of deep brain stimulation therapy research; 482 patients (Parkinson’s cases=303 – Click here to read more about this).

  • Postmortem characterisation of neuroinflammatory processes – correlating this with protein pathology – in the Parkinson’s brain (with/out dementia); No difference in nigra HLA-DR+ microglia btwn groups. Take home messages: 1. Parkinson’s with Dementia (PDD) is associated with increased neuroinflammation in nigra & amygdala (at postmortem); 2. PDD involves microglial activation & infiltration of T lymphocytes; 3. Upregulation of IL-1β & TLR4 in nigra & extra-nigrostriatal regions in PD (Click here to read more about this).
  • Researchers report that visual hallucinations in Parkinson’s are associated with thinning of the inner retina layers &, possibly, with reduced visual acuity (Click here to read more about this).
  • New report looks at stakeholder perceptions of components of a recent nurse-led proactive care management intervention for Parkinson’s: Care coordination for Health promotion and Activities in Parkinson’s (CHAPSclick here to read more about this).
  • A hallmark – specific of PSP – is midbrain atrophy, measured by midbrain-to-pons ratio. Can it be used for Parkinson’s? Small (n=15 vs 15) 1yr pilot study suggests predictive accuracy between PSP & iPD is good (76.6% – Click here to read more about this).
  • Gut microbiome characterisation study in a large Parkinson’s cohort (n=104 + 96 controls; 16S rRNA gene sequencing + NMR & LCMS) finds low SCFAs in PD is associated with poorer cognition & low BMI, & low butyrate levels = worse postural instability scores (Click here to read more about this).

  • New biorxiv manuscript asks if transcriptional regulation imbalance could explain the late onset phenomenon of some genetically associated neurodegenerative conditions. Huntington’s is the focus but Parkinson’s-associated DJ-1 pops up in the data (Click here to read more about this).
  • A retrospective cohort study (US‐based Humana claims) finds exposure to statins was associated with a lower incidence of Alzheimer’s, dementia, multiple sclerosis, Parkinsons, AND ALS (n=288,515 – Click here to read more about this).
  • Case series finds pedunculopontine nucleus deep brain stimulation for Parkinson’s-associated conditions (PD & PSP) remains investigational treatment for L-dopa-refractory, but bilateral stimulation more effective than unilateral (Click here to read more about this).
  • Novel genetic variants in LRRK2 & GBA genes have been identified in a Latino Parkinson’s cohort enriched based on Caribbean origins; functional analysis required to determine pathogenicity (Click here to read more about this).
  • New report presents the use of “in-the-wild”, multi-modal sensor data to unobtrusively detect Parkinson’s (via deep learning techniques), providing a stepping stone towards the development of an accessible PD screening tool (Click here to read more about this).

  • New report indicates that pattern of neurodegeneration in individuals with Parkinson’s+REM sleep behav disorder is consistent with Braak “brainstem-to-cortex” model, while those without RBD follow a cortex-to-brainstem model (Click here to read more about this).
  • A new study detects microglial activation/neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson’s (using 11C‐(R)‐PK11195 PET imaging); No difference between glucocerebrosidase gene mutation carriers without Parkinson’s & control participants in terms of Fluorodopa imaging (dopamine system appears intact, though greater variance in data observed in the GBA-affected cohort – click here to read more about this).
  • Antisaccade – a predictive marker for freezing of gait in Parkinson’s & gait/gaze network connectivity? New report finds antisaccade latency is a predictive marker of the 5-year onset of freezing of gait (Click here to read more about this).
  • New report presents the “CloudUPDRS smartphone software” in a Parkinson’s study; 16-item-based assessment on 60 participants (990 tests, 2628 blinded video ratings); Predictive value at the subject level on motor (Click here to read more about this).
  • ROPAD Study: Protocol & initial findings. Researchers at the Rostock International Parkinson’s Disease study present initial data based on the first 1360 participants enrolled, revealing “a genetic diagnostic yield of ~14% among a PD cohort” (Click here to read more about this).

  • New medrxiv manuscript provides evidence for GRN (which encodes progranulin) as part of a neuroinflammatory mechanism connecting common neurodegenerative conditions, such as Parkinson’s, Alzheimer’s & ALS (Click here to read more about this).
  • A new report demonstrates microglial activation in the brain of GBA genetic variant carriers (without Parkinson’s) who have normal DAT scans (Click here to read more about this).
  • Mild cognitive impairment found to be associated with mitochondrial dysfunction in PBMCs – as indicated by decreasing mitochondrial ATP production, increasing proton leak, & oxidative stress – in the elderly population (Click here to read more about this).
  • Researchers used publicly available genotype/phenotype data from the Uk Biobank to investigate copy number variants in the Parkinson’s-associated SNCA (alpha synuclein) gene in ~500,000 individuals. 30 carriers of variants of interest identified (including 6 duplications, 6 deletions & 18 large complex likely mosaic events. No known pathogenic missense variants were identified. None of these individuals had Parkinson’s (perhaps later?), while 3 had known prodromal features (Click here to read more about this).

  • New study using Swedish national conscription data suggests a prospective association between high erythrocyte sedimentation rate (measure of inflammation) in early adulthood & reduced risk of Parkinson’s; 659,278 young men; HR=0.94 (95% CI 0.89–0.99, P=0.02 – click here to read more about this).
  • New report suggests that FDG PET imaging provides higher diagnostic accuracy than MIBG scintigraphy for the differentiation between Lewy body dementia & non-LBD as well as between Parkinson’s & MSA (using the blinded follow-up diagnosis as reference – Click here to read more about this).
  • New report finds uptake of beta-amyloid uptake by blood monocytes is reduced in cases of Alzheimer’s (vs unaffected controls); curiously no difference between cases of Parkinson’s & controls (Click here to read more about this).
  • New biorxiv manuscript suggests diversity of virulome in cases of Parkinson’s is the same as healthy controls (across 4 body habitats, including the gut, oral cavity, skin, & vagina; 4000 samples – click here to read more about this).
  • Important research: Outcomes of genetic test disclosure & genetic counseling in a large Parkinson’s-based study; N = 875 responders to a survey; results demonstrate what a tricky business this genetics stuff can be (Click here to read more about this).

  • New research finds that dopamine transporter imaging specific binding ratios analysis in individuals with REM sleep behavior disorder could be useful in determining short‐term risk of an α‐synucleinopathy diagnosis – Parkinson’s (Click here to read more about this).
  • New case–control study confirms the higher risk of Parkinson’s in males & elderly, + the inverse association with smoking. Also highlights “possible etiological role” of familial clustering, dietary habit (meat & carbonated drinks), & certain job tasks (Click here to read more about this).
  • New report looks at Parkinson’s-associated alpha-synuclein accumulation & its phosphorylation in the enteric nervous system of individuals without neurodegeneration (Click here to read more about this).
  • New data presents sCD163 as a potential cognition-related biomarker in Parkinson’s & suggests a role for monocytes in peripheral & CNS immune responses; May be directly related to a‐syn’s proinflammatory capacity & have consequences for a‐syn processing (Click here to read more about this).
  • An exploratory study in 25 de novo Parkinson’s cases found an association between abnormal distribution of specific gut bacterial taxa & the progression of motor & non-motor features over a 3-year period; low baseline Roseburia =worse progression at 3yrs (Click here to read more about this).

  • Delicate topic, but important research & message: Data from Taiwan indicates that Parkinson’s is associated with an increased risk of suicide that is not fully explained by higher rates of mental disorders in individuals with PD; The authors stress “integrating mental health care into primary care & PD specialty care, along with socioenvironmental interventions, may help decrease the risk of suicide in patients with Parkinson’s” (Click here to read more about this).
  • A new medrxiv manuscript on genome-wide association studies of LRRK2 modifiers of Parkinson’s has so many authors that you wonder who is left to review it? Study suggests variants within or near CORO1C may modify the penetrance of LRRK2 mutations (Click here to read more about this).
  • The study protocol for a randomized controlled trial of the effects of virtual reality with motor imagery techniques in patients with Parkinson’s in Pakistan has been published (Click here to read more about this).

  • New research indicates that [18F]PR04-MZ PET tracer provides highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in Parkinson’s (n=19 early PD & 13 moderate-advanced PD – click here to read more about this).
  • New report presents a competing endogenous RNA (ceRNA) network based on the dysregulated mRNAs, lncRNAs & miRNAs in Parkinson’s; The results reveal that dysregulation of MAG, HOXB3, MYRF & PLP1 lead to metabolic disorders of sphingolipid & glutathione (Click here to read more about this).
  • Validation & assessment of preanalytical factors of a fluorometric in vitro assay for Parkinson’s-associated glucocerebrosidase activity in human cerebrospinal fluid
    (Click here to read more about this).
  • New report evaluates oxidative stress biomarkers in 18 individuals with subtype 1 Gaucher disease at 3 time points; results indicate evidence of oxidative stress & lower antioxidant reserves (whether treated or untreated); Implications for GBA-associated Parkinson’s? (Click here to read more about this).
  • New study explores neuron-derived extracellular vesicles from blood samples collected from 94 individuals with Parkinson’s (vs 63 control samples) & finds altered insulin receptor substrate 1 phosphorylation (Click here to read more about this).

  • New data indicate that Dopamine D1R + D3R receptor densities combined (compared to D1R or D3R alone) may correlate with some clinical features Parkinson’s (age of onset, PD stage, dopamine responsiveness, & survival time – click here to read more about this).
  • New data indicates that individuals with idiopathic REM sleep behaviour who are older than 70yrs with constipation & reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy (eg. Parkinsons – click here to read more about this).
  • A new medrxiv manuscript uses X-chromosome-wide association analysis to try & identify genetic variants on the X-chromosome associated with Parkinson’s risk; Results suggest a role for ribosomal proteins in PD pathogenesis (Click here to read more about this).
  • Researchers demonstrate that it is feasible to conduct a large‐scale, international virtual observational study following the completion of participation in brick‐&‐mortar clinical trials in Parkinson’s (SURE-PD & STEADY-PD – click here to read more about this).
  • Geographic variations in neurologic care in the United States; 23.5% patients with a neurologic condition were seen by a neurologist; “The supply of neurologists varies substantially by region, but the prevalence of neurologic conditions does not” (Click here to read more about this).

  • A new medrxiv manuscript explores test retest reliability & longitudinal stability of digital biomarkers for Parkinson’s in the m-Power dataset; indicate the need for further development of more standardized, sensitive & reliable digital biomarkers (Click here to read more about this).
  • Researchers propose a rapid α‐synuclein seed assay of Parkinson’s cerebrospinal fluid panel which shows a high degree of accuracy: BioFIND samples gave positive signals in 105/108 (97%) PD cases vs 11/85 (13%) healthy controls (Click here to read more about this).
  • An expert opinion survey on STAT-ON (wearable that registers ON-OFF fluctuations); Clinical utility of a personalized & long-term monitoring device for Parkinson’s (Click here to read more about this).

New clinical trials

  • New clinical trial registered: A Phase I safety & pharmacokinetics study of UCB7853 in healthy volunteers & participants with Parkinson’s has been initiated (Click here to read more about this – I have asked UCB what exactly UCB7853 is and had no information provided. There is also no information on their website nor on the CT.gov website).

  • New clinical trial registered: 18-month study evaluating efficacy, safety, tolerability & pharmacokinetics of oral UCB0599 (alpha-synuclein misfolding inhibitor from UCB under license from Neuropore Therapies) in individuals with early-stage Parkinson’s. This is a double-blind, placebo-controlled, randomized Phase 2a study of 300 individuals; Primary endpoint=UPDRS Parts I-III; Study finishing in October 2023 (Click here to read more about this).
  • New clinical trial registered: Il-Yang Pharm has registered a Phase II randomised, double-blind, placebo-controlled trial to assess safety, tolerability, PK & efficacy of their c-Abl inhibitor Radotinib in 40 individuals with Parkinson’s (Click here to read more about this and click here to read an old SoPD post about this topic).

  • New clinical study registered: Researchers are seeking 80 participants to examine the role of inflammation, changes in the intestinal epithelial barrier, & the intestinal microbiota in Parkinson’s (Click here to read more about this).
  • New clinical study registered: Researchers are initiating “Learning to PERSEVERE” (PEeR mentor Support and carEgiVER Education); A pilot study to improve Lewy Body Dementia caregiving; 96 participants required (Click here to read more about this).
  • New clinical trial registered: tech firm Remedee Labs SAS are evaluating their millimeter wave emission bracelet for its ability to improving Parkinson’s symptoms (“the BOMP study” – Click here to read more about this).
  • New clinical trial registered: A study to assess the safety, tolerability, PK/PD of multiple ascending oral doses of MODAG‘s alpha synuclein targeting molecule anle138b in Parkinson’s; n=24 volunteers (Click here to read more about this).

  • New clinical study registered: Researchers have initiated the Gait’N’Park study, evaluating disease progression in individuals with Parkinson’s of various severity through regular home-based gait parameters analysis; seeking 150 participants (Click here to read more about this).
  • New clinical study registered: 3yr single site observational study enrolling individuals with Parkinson’s & family members (limited to participants of Ashkenazi Jewish descent with GBA &LRRK2 mutations or with >2 family members with PD – click here to read more about this).
  • New clinical study registered: Use & misuse of domperidone in Parkinson’s in France – an observational study (“DUMP-obs”). Recruiting 3000 participants (Click here to read more about this).

  • New clinical trial registered: Rapid dEvice Testing pROtocol for Parkinsons Disease (RETRO-PD); a 16 wk observational study evaluating feasibility of using remote monitoring technologies in future studies; n=50 volunteers (iPhone, iWatch, Fitbit, etc – click here to read more about this).
  • New clinical trial registered: a pilot study of spinal cord stimulation for gait disorders in Parkinson’s being conducted in Grenoble (France); N=8 (Click here to read more about this).
  • New clinical trial registered: a 10-week randomized, controlled, clinical trial of Mediterranean diet intervention to improve gastrointestinal function in Parkinson’s (MPD); N=52 (Click here to read more about this).

Clinical trial news

  • The results of a Phase 2 randomised trial supports the hypothesis that motor outcomes after asleep subthalamic nucleus-deep brain stimulation in Parkinson’s “may be noninferior to the standard awake procedure” (Click here to read more about this).
  • Anavex Life Science announced ANAVEX®2-73 (Blarcamesine) met primary & secondary endpoints in placebo-controlled U.S. Phase 2 clinical trial in adults with Rett syndrome. Blarcamesine is a sigma-1 receptor agonist, also being tested in Parkinson’s (Click here to read more about this).

  • The protocol for PD SENSORS has been published: An observational feasibility study of multi-modal multi-sensor technology to measure symptoms & activities of daily living in Parkinson’s in a naturalistic setting using SPHERE technology (Click here to read more about this and click here to learn more about SPHERE).
  • REMeDio: a proof‐of‐concept study for prodromal synucleinopathies – a pilot study of selegiline in a iREM sleep behavior disorder (iRBD) cohort (n=30; 30 months) suggests testing is feasible (iRBD=target population, 123I‐FP‐CIT‐SPECT as a biomarker – click here to read more about this).
  • Results of the follow-up assessment of the Living Cell Technologies clinical trial have been published. It reports “no evidence that putaminal NTCELL® administration produces significant clinical benefit in patients with moderately advanced Parkinson’s” (Click here to read more about this).

  • A randomized controlled double-blind study of rotigotine on neuropsychiatric symptoms in de novo Parkinson’s finds low dose rotigotine significantly improved trait anxiety, but not apathy & depression (Click here to read more about this).
  • A recording of TreatER project webcast: World’s first clinical trial with CDNF in Parkinson’s – this highlights the results of the Herantis Pharma study (Click here to read more about this).

  • French biotech firm AB Science announces the results of their Phase 2B/3 clinical trial evaluating tyrosine-kinase inhibitor masitinib in Alzheimer’s; the treatment appears to halt cognitive decline; treatment group had slight improvements on the ADAS-Cog. Masitinib – a veterinary medication used in the treatment of mast cell tumours in animals – is also in trials for other neurodegenerative conditions, such as ALS & progressive multiple sclerosis. In this study, 2 doses of Masitinib were evaluated. 4.5 mg/kg/day (vs its own placebo, n=358, randomization 1:1) & 6.0 mg/kg/day (vs its own placebo, n=277, randomization 2:1). Study met its primary analysis, demonstrating a statistically significant reduction in cognitive impairment based on ADAS-Cog (p=0.0003). The study also demonstrated a statistically significant improvement on daily activity based on ADCS-ADL (p=0.0381); No higher diff btwn 6.0 mg/kg/day & 4.5 mg/kg/day doses, suggesting that masitinib is 4.5 mg/kg/day will be dose used going forward; confirmatory Phase III in 2021 (Click here to read more about this and click here for an interesting review of this announcement).

  • German biotech firm MODAG announces initiation of first-in-patient Phase 1b trial for their alpha-synuclein targetting molecule Anle138b in a cohort of individuals with Parkinson’s (trial supported by the Michael J Fox Foundation – click here to read more about this).
  • The results of a randomised trial of focused ultrasound subthalamotomy for Parkinson’s have been published; N=40; 27=FUS, 13=sham; 10 point reduction in UPDRS at 4 months; Adverse events included speech & gait disturbances, weakness on the treated side, & dyskinesia (Click here to read more about this).
  • Neurocrine Biosciences & Voyager Therapeutics announce that the FDA has put a clinical hold on their gene therapy RESTORE-1 trial (evaluating NBIb-1817/VY-AADC) in Parkinson’s, pending DSMB request for review of additional data in early 2021 (Click here to read more about this).

Other news

  • Pharma company Eisai & biotech firm Wren Therapeutics announce a research collaboration aiming to advance the discovery of novel small molecules targeting α-synuclein for treating synucleinopathies, including Parkinson’s & dementia with Lewy bodies (Click here to read more about this).

  • Biotech firm AbFero has been awarded €2M in Eurostars funding for their iron chelating compound SP-420 which is being developed for Parkinson’s (Click here to read more about this).
  • Biotech firm Gain Therapeutics announces a research collaboration with the University of Maryland School of Medicine to investigate Gain’s structurally targeted allosteric regulators (STARs) in cellular models of neuronopathic Gaucher disease & GBA-associated Parkinson’s (Click here to read more about this).

  • Biotech firm Silo Pharma announces plans for a Phase 2B investigator lead study using micro-dosing of psychedelics Psilocybin & Lysergic acid diethylamide (“LSD”) to explore on cognitive & emotional dysfunctions in Parkinson’s (Click here to read more about this).
  • 4D Pharma announced that they have joined the Michael J Fox Foundation Parkinson’s Progression Markers Initiative (PPMI) as an industry partner; 4D Pharma are focused on the development of live biotherapeutics for conditions like Parkinson’s (Click here to read more about this).

  • A new biotech firm SciNeuro Pharmaceuticals launches with $100 million Series A financing to advance the establishment of a robust & innovative pipeline focused on CNS conditions, including Parkinson’s (Click here to read more about this).
  • Neuron23 launched – by closing $113.5M in series A & B financing – to focus on its AI-enabled drug discovery & biomarker platforms as well as pipeline of therapeutics that includes selective LRRK2 inhibitors for Parkinson’s (Click here to read more about this).

Review articles/videos

  • SARS-CoV-2 & the risk of Parkinson’s: facts & fantasy; “The causal association of SARS-CoV-2 infection with the development of PD is therefore not supported by robust evidence yet”. “Although the potential neurological sequelae of this novel coronavirus should not be underestimated, we are concerned about unjustified claims anticipating a future high incidence of Parkinson’s disease, secondary to the SARS-CoV-2 pandemic” (Click here to read more about this).

  • New review on the role of glial mitochondria in Parkinson’s-associated α-synuclein toxicity (Click here to read more about this).
  • A fantastic quote that has been attributed to Prof John Hardy: “I don’t care if I’m right or if I’m wrong, I simpy want to be certain

  • New review on Parkinson’s & translational research – a discussion of current research on cytoplasmic aggregates of the protein α-synuclein & the degeneration of dopaminergic neurons (Click here to read more about this).
  • Stem cell transplantation for Parkinson’s: Déjà vu all over again? (Click here to read more about this).

  • A systematic review of patient & public perspectives on cell & gene therapies; “Patient & public perceptions could play a vital role in the development of therapies & influence their subsequent uptake” (Click here to read more about this).
  • Interesting musings on disease modification for Parkinson’s from one of the best in the business – recommended viewing (Click here to read more about this).
  • Neuron-astrocyte interactions in Parkinson’s (Click here to read more about this).

  • A useful review of the molecular mechanisms & health implications of ferroptosis – a type of programmed cell death dependent on iron & characterised by the accumulation of lipid peroxides (Click here to read more about this).
  • Delivering dopamine directly into the brain – avoiding the limitations of peripheral drug administration. A useful short overview of the field exploring intrathecal & intracerebroventricular delivery of dopamine for Parkinson’s (Click here to read more about this).
  • Patient advocate Lesley Gosden speaking at “Patients as Partners EU 2020”
    Conference about living with Parkinsons, the GDNF clinical trial, lessons for all stakeholders, & the patient’s point of view. If you do nothing else today, watch this video:
  • Interesting perspective regarding increasing the reproducibility of fluid biomarker studies on neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • New review of the complex mechanisms modulating extracellular vesicles & DAMPS (Damage-Associated Molecular Patterns); could their extracellular trafficking be a Pandora’s box for Parkinson’s? (Click here to read more about this).
  • The Edinburgh Parkinson’s Lecture 2020 – “Genetic Factors of PD: Cause or modifier?” presented by Prof Christine Klein – recommended viewing (Click here to read more about this).

  • Neurons under genetic control: On various new developments in genetically controlling neuronal function & what the next steps are towards using this technology as a treatment for movement disorders, like Parkinson’s (Click here to read more about this).
  • “23 years have passed, data have been collected, hypotheses have been tested, & the causality between Lewy body pathology & [Parkinson’s] disease is still a matter of intense debate” – interesting letter on alpha‐synuclein oligomerization (Click here to read more about this).

  • A useful review of genetic defects in the sphingolipid degradation pathway & their effects on microglia in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • A useful review of current clinical applications of in vivo gene therapy with AAVs, including a section on Parkinson’s (Click here to read more about this).
  • New review critically discusses current knowledge of the role of mitochondrial DNA copy number regulation in ageing & various types of human diseases, including mitochondrial disorders, cancer, & neurodegenerative conditions like Parkinson’s (Click here to read more about this).

  • A useful review summarising current knowledge of the mammalian mitochondrial import machinery & the pathological consequences of mutation of its components; includes section on Parkinson’s (Click here to read more about this).
  • New review discusses the current studies on the molecular mechanisms underlying the release & uptake of Parkinson’s-associated α‐synuclein & their physiological relevance (Click here to read more about this)
  • A video of the UCL Queen Square Institute of Neurology annual address 2020 by 2021 Breakthrough Prize in Life Sciences winner Prof Richard J Youle: “Relationships between Mitophagy, Inflammation, STING & Parkinson’s” – presentation starts at 31 minutes into video:
  • A review of the finely tuned interactions between mitochondria & surrounding intracellular organelles, with focus on the nucleus, endoplasmic reticulum, Golgi apparatus, peroxisomes, & lysosomes in the context of Parkinson’s (Click here to read more about this).
  • A discussion on the ethical challenges of competitive recruitment in disease modifying treatment trials for Parkinson’s; Managing expectations & considering positions of patients, caregivers, physicians & study nurses, as well as industrial partners (Click here to read more about this).
  • New review on mitochondrial dysfunction in Parkinson’s, with a focus on mitochondrial DNA (Click here to read more about this).

  • Researchers provide recommended reading on genetic screening approaches to investigate novel disease mechanisms involving ER-mitochondria contact sites in neurodegenerative conditions like Parkinson’s (Click here to read more about this).
  • New review explores exosomes in Parkinson’s & potential clinical applications (Click here to read more about this).
  • Interesting review on the future of GDNF in Parkinson’s – dependent on significant improvements to preclinical models, clinical striatal delivery methods, less invasive methods, very early PD diagnosis, & PD clinical trial design (Click here to read more about this).

  • A systematic review of the potential use of glutathione as a treatment for Parkinson’s (Click here to read more about this).
  • A short review of nutraceuticals (Niacin & Butyrate) targeting of dysbiosis & intestinal permeability in Parkinson’s (Click here to read more about this).
  • A review of the neuroprotective effects of coffee bioactive compounds in conditions like Parkinson’s (Click here to read more about this).

  • How microbiota & host inflammasome influence brain physiology & pathology; useful section on Parkinson’s (Click here to read more about this).
  • A hot topic for 2020/2021: Infection & risk of Parkinson’s – “Based on multiple avenues of evidence it appears likely that specific bacterial & particularly viral infections may increase vulnerability to PD” (Click here to read more about this).
  • New review exploring interactions of Parkinson’s-associated α-synuclein oligomers with lipid membranes (Click here to read more about this).

  • A useful review on Kv1.3 inhibition & how it attenuates neuroinflammation through disruption of microglial calcium signaling (Click here to read more about this).
  • Interesting review discussing the targeting of mitophagy in Parkinson’s; Assessing the tractability of mitophagy pathways, prospects for drug discovery, & intervention points for mitophagy enhancement; Also explores the “challenges in achieving pre-clinical proof-of-concept, including in vivo mitophagy reporter methodologies & disease models, as well as patient stratification & biomarker” (Click here to read more about this).
  • Interesting video on gene therapy for Parkinson’s:

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

And there it is, just some of the highlights from December 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).

The next SoPD post will be our annual review.

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You can do whatever you like with it!


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.


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