Monthly Research Review – February 2021

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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 February 2021.

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

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So, what happened during February 2021?

In world news:

February 4th – More injections than infections – more people have now been vaccinated against Covid-19 than infected worldwide (Source).

February 15th – Ngozi Okonjo-Iweala elected as the seventh Director-General of the World Trade Organisation – a first for women and a first for Africa (Source).

 

February 17th – Researchers reported a high-performance polyethylene plastic made from renewable oils that is chemically recyclable (Source).

February 18th – Nasa’s Perseverance (“Percy”) rover was safely delivered to the surface of Mars (Source).

24 February – Ghana becomes the first country to receive vaccines through the COVAX vaccine-sharing initiative.

 

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

In February 2021, there were 1,228 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (2,463 for all of 2021 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 5 pieces of Parkinson’s news

1.  From enlarged prostates to Parkinson’s:

An analysis of two large medical databases (the Danish nationwide health registries & the Truven Health Analytics MarketScan) indicated that use of prostate treatments terazosin, doxazosin, and alfuzosin was associated with a 12% to 37% decrease in Parkinson’s (vs use of tamsulosin; n=147,248 pairs – Click here to read more about this and click here to read the associated press release). A clinical trial programme exploring the repurposing of terazosin for Parkinson’s is underway in Iowa (USA – click here to read a previous SoPD post about this).

2.  The “BlueRockers” share their recipes

Researchers associated with BlueRock Therapeutics published the preclinical efficacy & safety of their cell transplantation approach for Parkinson’s – a human embryonic stem cell-derived midbrain dopamine progenitor product, MSK-DA01 (Click here to read more about this). A second report from the same researchers (published in the same journal) presented a midbrain dopamine neuron derivation protocol (involving a two-step WNT signaling activation strategy) which minimizes the presence of contaminating hindbrain & diencephalic lineages of cells (Click here to read more about this).

3.  Biogen announces the SPARK study results

Buried deep inside its annual results, biotech company Biogen announced that the phase II study of their alpha synuclein immunotherapy BIIB054 (cinpanemab) in Parkinson’s “did not achieve proof-of-concept”; Biogen has discontinued development of BIIB054 and will apply learnings to future efforts in Parkinson’s (Click here to read more about this).

 

4.  Sanofi announces the MOVES-PD study results

Buried deep inside its annual results, biotech company Sanofi announcesd “the venglustat Phase 2 trial in Parkinson’s with GBA mutations did not meet the primary endpoint (end-January) & the indication was halted” (Click here to read more about this).

5. The genetics of Lewy body dementia

Researchers identified new genetic loci associated with Lewy body dementia & provides insights into its genetic architecture. GWAS analysis identifies 5 independent risk loci, while genome-wide gene-aggregation tests implicate mutations in the GBA gene. The 5 independent genome-wide significant loci that influence risk for developing LBD: GBA, BIN1, TMEM175, SNCA-AS1, & APOE. (Click here to read more about this).

 

Basic biology news

  • Phospholipase iPLA2β is a ferroptosis regulator. Selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation & elevated sensitivity to ferroptosis reported in Parkinson’s cases with associated mutation. Transgenic mice with Pnpla9 R748W/R748W mutation exhibit a “progressive” Parkinson’s-like motor deficits & 15-HpETE-PE accumulation; Elevated 15-HpETE-PE levels also reported in the midbrains of rotenone-infused parkinsonian rats & α-synuclein-mutant SncaA53T mice (Click here to read more about this).
  • Parkinson’s-associated GCase deficiency in flies promotes protein aggregate spread between cells & tissues (via dysregulated extracellular vesicles); EV-mediated trafficking of GCase may partially account for reduction in aggregate spread (Click here to read more about this).

  • G protein alpha subunit o (Gαo) is one of the most abundant proteins in the CNS; Pathogenic mutations in its gene (GNAO1) associated with movement disorder; New research explores mechanistic role it plays in controlling GPCR signaling to cAMP (Click here to read more about this).
  • Could a decrease in the water content in brain cells – as a consequence of increased intracellular protein concentration with advancing age – contribute to the increased incidence of amyloid formation (& therefore, amyloid diseases) in aged populations? New research reports that Parkinson’s-associated α-synuclein “can self-assemble into amyloid aggregates by homogeneous nucleation, without the need of an active surface, & with a preference for an antiparallel β-sheet arrangement” (Click here to read more about this).
  • New biorxiv manuscript suggests actin-binding protein cofilin is a novel player on hippocampal synaptic dysfunction triggered by Parkinson’s-associated alpha-Synuclein in models of Lewy Body dementias (Click here to read more about this).
  • New medrxiv manuscript provides evidence that the Parkinson’s-associated LRRK2 R1441G mutation enhances LRRK2 kinase activity in primary human cells; pRab10-Thr73 phosphorylation is significantly elevated in all R1441G carriers. “LRRK2 dependent pRab10-Thr73 analysis in human peripheral blood neutrophils is a specific & robust biomarker for LRRK2 kinase activation for individuals with mutations such as R1441G that enhance pRab10-Thr73 phosphorylation” (Click here to read more about this).

  • New report finds that preformed fibrils of Parkinson’s-associated α‐synuclein can spread from olfactory bulb, & “causes hyposmia, anxiety, & memory loss” in transgenic BAC‐SNCA mice; No motor, depression, or circadian rhythm disturbances observed (Click here to read more about this).
  • A C. Elegans study, but researchers report glycolate combats oxidative stress by restoring redox potential; A central role for serine/glycine metabolism as a provider of reducing equivalents to maintain cellular antioxidant systems (Click here to read more about this).
  • Extracellular cardiolipin modulates microglial phagocytosis & cytokine secretion (in a TLR4-dependent manner); cardiolipin also inhibits amyloid-β peptide- & Parkinsons-associated α-synuclein-stimulated murine microglia (Click here to read more about this).
  • Researchers use tri-culture systems to model neuroinflammation in Alzheimer’s (hPSCs harboring APPSWE+/+) & report that microglia initiate reciprocal signaling with astrocytes to produce excess levels of inflammatory complement C3 (Click here to read more about this).
  • New study reports Parkinson’s-associated α-synuclein impairs autophagosome maturation via abnormal actin stabilization (Click here to read more about this).

  • “The concentration of Parkinson’s risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms” (Click here to read more about this).
  • New insights into the normal (& abnormal) functions of Parkinson’s-associated protein alpha synuclein; docking of synaptic vesicles on the presynaptic membrane modulated by lipid composition (Click here to read more about this).
  • New study reports that Parkinson’s-associated human α-synuclein forms presynaptic terminal aggregates in zebrafish neurons; This aggregation is not influenced by its phosphorylation at serine-129 (Click here to read more about this).
  • Kinase inhibition of Parkinson’s-associated G2019S-LRRK2 enhances autolysosome formation & function to reduce endogenous alpha-synuclein intracellular inclusions (Click here to read more about this).
  • New report indicates that PREP-mediated phosphorylation, oligomerization, & internalization of DAT is not dependent on PKC or ERK (Click here to read more about this).

  • Neurodevelopmental defects & neurodegenerative phenotypes reported in human brain organoids carrying Parkinson’s-linked DNAJC6 mutations; DNAJC6 may have a role in autolysosomal degradation of α-synuclein in an LMX1A-independent manner (Click here to read more about this).
  • Loss of nigral excitation of cholinergic interneurons contributes to Parkinson’s motor impairments in mice; mGluR1 overexpression in cholinergic interneurons restores circuit function & improves motor deficits (Click here to read more about this).
  • New biorxiv manuscript presents a FRET-based screening in HEK cells that identifies p38 MAPK & PKC inhibition as therapeutic targets for Parkinson’s-associated α-synuclein aggregation (Click here to read more about this).
  • New report investigates whether native alpha-Synuclein interacts with plasma membrane PIP2 & PIP3 in mammalian cells; They report clusters of endogenous alpha-Syn found at the plasma membrane, correlates with PIP2 levels (Click here to read more about this).
  • scRNA-seq identifies age-dependent white matter-associated microglia (WAMs) in mice, which share parts of the disease-associated microglia (DAM) gene signature; In mouse models of Alzheimer’s, the WAM response occurs before DAM (Click here to read more about this).

  • Cell type-specific modulation of TLR2 may be multifaceted therapeutic strategy for synucleinopathies; inhibition of neuronal & astroglial TLR2 decreased α-syn transmission, but activation of microglial TLR2 enhances microglial α-syn extracellular clearance (Click here to read more about this).
  • New data indicating that Parkinson’s-associated α-Synuclein could be a potent regulator of VDAC-facilitated calcium transport (Click here to read more about this).
  • 18F-Labelled pyrrolopyrimidines allows for brain imaging of Parkinson’s-associated leucine-rich repeat kinase 2 (LRRK2) in mice; LRRK2 G2019S mice displayed higher uptakes in the olfactory bulb, striatum, & hippocampus than normal mice (Click here to read more about this).
  • New research reports that astrocytes carrying Parkinson’s-associated LRRK2-G2019S mutation exhibit a decreased internalization & degrading of fibrillar α-synuclein (via the endo-lysosomal pathway); Linked to annexin A2 loss of function (Click here to read more about this).
  • A new research paper describes a causal inference platform for identifying drug repurposing candidates from observational healthcare data; they demonstrate the utility of the framework in a case study of Parkinson’s (Click here to read more about this).
  • New biorxiv Manuscript suggests that SARS-CoV-2 causes neuroinflammation & induces Lewy body formation in the brains of macaques; “We observed Lewy bodies in brains of all rhesus macaques”; Postmortem analysis conducted at 5-6 weeks post infection; Curious distribution of viral RNA; They “report of SARS-CoV-2-related brain involvement in macaques without displaying overt clinical signs”; Bit of a leap between a-syn upregulation/aggregation & “Lewy body” (Click here to read more about this).

  • Monitoring the neurotransmitter release of human midbrain organoids using a redox cycling microsensor as a novel tool for personalized Parkinson’s modelling & drug screening (Click here to read more about this).
  • It has previously been reported that intracellular fatty acid carrier protein, Fabp3 can enhances Parkinson’s-associated α-Synuclein neurotoxicity. Now researchers show deletion of Fabp3 suppresses α-syn accumulation of exogenous α-synuclein (Click here to read more about this).
  • Researchers find Nrf2 activator tBHQ promotes endogenous clearance of Parkinson’s-associated α-synuclein in astrocytes, but NOT neurons; Epigenetic de-repression of neuronal Nrf2 enables response to Nrf2 activators to drive α-syn clearance (Click here to read more about this).
  • Researchers report that AAV-mediated inhibition of autophagic protein ULK1 promotes axonal regeneration in the central nervous system in vitro & in vivo; Optic & spinal cord models; Worth testing in Parkinson’s model? (Click here to read more about this).
  • Brazilin – a natural isoflavonoid – found to specifically bind the aggregation-competent compact monomer conformation of alpha-Synuclein; Also inactivates seeding-competent α-syn isolated from postmortem Parkinson’s brains (Click here to read more about this).

Disease mechanism

  • New report finds the polymethoxyflavonoid GardeninA confers neuroprotection against environmental toxin in a Drosophila model of Parkinson’s, via antioxidant & neuroinflammatory activities (Click here to read more about this).
  • APOE immunotherapy reduces cerebral amyloid angiopathy & amyloid plaques in mouse model of Alzheimer’s; Also improves cerebrovascular function; treatment with APOE antibody HAE-4 in mice removed amyloid & protecting cerebrovasculature (Click here to read more about this).
  • Inhibition of RGMa (repulsive guidance molecule-a) protects dopaminergic neurons in a mouse model of Parkinson’s (MPTP); Increased RGMa expression upregulated pro-inflammatory cytokine expression in microglia (Click here to read more about this).
  • New research explores the role of the adaptive immune system in Parkinson’s-associated α-syn pathology; Find evidence that T cells play a role in pathogenesis of experimental synucleinopathy (Click here to read more about this).

  • Protection of dopamine neurons by CDNF & neurturin variant N4 in in vitro model of Parkinson’s (MPP+ neurotoxin); alone (pre or post toxin) treatment did not significantly increase survival, but combined they successful increased survival (Click here to read more about this).
  • Researchers provide further evidence that inhibition of the L‐tryptophan‐catabolizing enzyme tryptophan 2,3‐dioxygenase (TDO) has beneficial effects in models of Parkinson’s (Click here to read more about this and click here to read the press summary).
  • New report presents an ATF6f-XBP1s fusion protein (“UPRplus”) that behaves as a heterodimer in terms of its selective transcriptional activity; Neuroprotective against Parkinson’s-associated alpha synuclein in vitro & vivo models (Click here to read more about this).
  • Optogenetic stimulation of the parafascicular nucleus-subthalamic nucleus pathway immediately & markedly restores behavior to bilateral 6-OHDA lesioned (completely akinetic) mice; Novel stimulation strategies for the treatment of Parkinson’s? (Click here to read more about this).

 

  • SGLT2 inhibitor Dapagliflozin reported to rescue a rotenone-induced rat model of Parkinson’s (by targeting ROS-dependent AKT/GSK-3β/NF-κB & DJ-1/Nrf2 pathways) without triggering hypoglycemia (Click here to read more about this).
  • New research reports that the neuronal repressor REST protects dopamine neurons from mitochondrial & α-synuclein oligomer pathology in an alpha synuclein overexpressing BAC-transgenic mouse model (Click here to read more about this).
  • Researchers explore c-Abl activation of RIPK3 in the context of Gaucher disease; c-Abl is increased in several GD models; Imatinib decreased RIPK3 signaling; Are c-Abl & RIPK3 attractive therapeutic targets for GBA-associated Parkinson’s? (Click here to read more about this).
  • New biorxiv manuscript suggests alternative splicing of auxiliary β2-subunits stabilizes Cav2.3 Ca2+ channel activity in continuously active midbrain dopamine neurons (Click here to read more about this).
  • New research reports NKAα1 deficiency aggravates PFF-induced pathology in mice; NKA-stabilizing antibody (“DR5-12D”) ameliorates α-syn–induced TH loss & behavioral deficits in mice by accelerating α-synuclein degradation in neurons (Click here to read more about this).
  • Researchers present a blood-brain barrier & plasma membrane-permeable α-synuclein knockdown peptide, called Tat-βsyn-degron, which decreased α-syn aggregates & microglial activation in models of Parkinson’s (Click here to read more about this).
  • New biorxiv manuscript suggests “nicotine exposure initiates neuroprotective mechanisms counteracting the neurodegenerative effects of α-syn accumulation in DA neurons & contributing to Nurr1-mediated therapeutic effects”; Nurr1 was elevated in nigral GABAergic neurons (Click here to read more about this).

  • New research presents a high-throughput behavioral screen in C. elegans that reveals Parkinson’s drug candidates; Highlights enasidenib, ethosuximide, metformin, & nitisinone (Click here to read more about this).
  • New paper reports that total LRRK2 ablation (or in-diet LRRK2 inhibitor MLi-2 treatment) did not significantly modify Parkinson’s-associated α-synuclein–induced motor deficits, dopamine cell loss, or pathology in model of PD (Click here to read more about this).
  • Early low-dose ghrelin intervention (via miniosmotic pumps) exhibits protection against the progressive dopaminergic neuron loss in mouse model of Parkinson’s (Click here to read more about this).
  • More ghrelin research: Acylated ghrelin found to be protective against 6-OHDA-induced neurotoxicity by regulating autophagic flux (Click here to read more about this).
  • Researchers report ambroxol increases glucocerebrosidase (GCase) activity & restores GCase translocation in primary patient-derived macrophages collected from 14 Gaucher disease patients & 6 GBA-associated Parkinson’s (Click here to read more about this).

Clinical research

  • Dysfunction of the nucleus basalis of Meynert has been implicated in the pathogenesis of Parkinson’s dementia. Researchers reveal functional networks of the NBM, likely to subserve important roles in motor control, memory & visual function (Click here to read more about this).
  • Researchers report seeded recombinant alpha synuclein assemblies do not replicate those derived from the multiple systems atrophy (MSA) brain; Additional disease-related molecules/posttranslational modifications required? “The relevance of the structures of amyloids assembled from recombinant protein seeds and the results of self-propagation studies should be interpreted with care”. Has the time for questioning some of the pre-formed fibril model findings in the field has well & truly arrived? (Click here to read more about this).
  • Under-represented communities: There is little data in the literature on Parkinson’s in sub-Saharan populations. Nigeria (pop. 200M) has just 80 neurologists (1:2.5M ratio); New study screens a cohort of early-onset PD cases from Nigeria for PRKN, PINK1, DJ1, SNCA, & LRRK2 variants (Click here to read more about this).

  • Representation of Parkinson’s & atypical Parkinson’s syndromes in the Czech Republic: A nationwide retrospective study (Click here to read more about this).
  • Where are we with body-worn sensors for remote monitoring of Parkinson’s motor symptoms? Researchers review the vision, state of the art, & challenges ahead for the field (Click here to read more about this).
  • So does this mean I should sellotape my appendix back in??? Meta-analysis (4 studies, 6 080 710 patients) finds that appendectomy does not increase the risk of future emergence of Parkinson’s (Click here to read more about this).
  • Researchers report a genetic association study (using Parkinson’s GWAS study data, brain-derived gene regulation data, & various complementary bioinformatic tools) that identifies 11 genes with disease-associated changes. The 11 genes are WDR6, CD38, GPNMB, RAB29, TMEM163, ZRANB3, PCGF3, NEK1, NUPL2, GALC, & CTSB. 5 associated with gene expression regulation, 6 associated with alternative splicing, & 3 with methylation regulation. The authors note CD38 (insulin regulation) & RAB29 (LRRK2) (Click here to read more about this).
  • New report presents converging evidence from observational analyses in UK Biobank & Mendelian randomization that lower lymphocyte count is associated with increased risk of Parkinson’s (Click here to read more about this).

  • New report finds some microbially-derived toxic bile acids are elevated in individuals with Parkinson’s, suggesting biliary abnormalities may play a role in PD pathogenesis – providing further support for the UDCA “UP” study (Click here to read more about this and click here to read the associated press release).
  • New research reports on limb & trunk accelerometer data collected with wearable sensors from 19 individuals with Parkinson’s experiencing motor fluctuations (Click here to read more about this).
  • New research presents a dataset collected using wearable accelerometers with specific focus on individuals with Parkinson’s experiencing motor fluctuations; It is made available via an open data repository (Click here to read more about this).
  • New study explores the effects of Levodopa on quality of sleep & nocturnal movements in Parkinson’s; Results indicate an association between higher Levodopa intake & perception of worse quality of sleep + nocturnal immobility in PD (Click here to read more about this).

  • Big longitudinal study investigating temporal patterns of potential biomarkers; Individuals with ALS (1 year pre- to 2 years post diagnosis) display significantly decreasing level of creatinine; no similar patterns for Parkinson’s or multiple sclerosis (Click here to read more about this).
  • “Synucleinopathy is related to the LRRK2 G2385R genotype & implies a different pathogenesis in G2385R variant carriers & noncarriers. This study also extended the clinical profiles of Parkinson’s patients with the G2385R variant” (Click here to read more about this).
  • New study demonstrates the potential for focused ultrasound to open up the blood brain barrier in Parkinson’s dementia for better drug delivery – question is whether pharmacological approach will eclipse this method? (Click here to read more about this).
  • Nationwide, population-based cohort study from South Korea (n=380,404) finds that lower high-density lipoprotein cholesterol levels (HDL-C) & greater HDL-C variability were associated with a higher incidence of Parkinson’s (Click here to read more about this).
  • Designing & development of a virtual reality-based mobility training game for people with Parkinson’s (Click here to read more about this).

  • Interesting analysis of brain perivascular space burden in early-stage Parkinson’s, suggests potential correlations between PVS burden & both grey + white matter microstructures; possible biomarkers? (Click here to read more about this).
  • The mutation matters: Cross‐sectional & longitudinal analysis of cerebrospinal fluid profiles of GCase, sphingolipids, α‐synuclein in cohorts of Parkinson’s with & without GBA variants highlight GBA‐pathway‐specific biomarker profiles (Click here to read more about this).
  • Poly (ADP-ribose) polymerase 1 (PARP1) analysis of postmortem Parkinson’s brain; “PARP1 positive nuclei in substantia nigra, mainly in dopaminergic neurons but also in astrocytes & oligodendrocytes, were decreased in PD”; PARP1 co-localizes with α-Syn (Click here to read more about this).
  • Researchers have a new biorxiv manuscript presenting a genome-wide omics-based model (called NeuroSCORE) to identify candidate disease genes of the CNS diseases (Click here to read more about this).
  • Small study (based on PPMI data) observes a positive association between skin conditions & Parkinson’s; Also basal cell carcinoma & PD; None of the associations were robust after correction for multiple comparisons (Click here to read more about this).

 

  • The Central European Group on Genetics of Movement Disorders (CEGEMOD) present a case control study on LRRK2 mutations in Parkinson’s from Central Europe; exploring prevalence of 12 LRRK2 pathogenic variants (Click here to read more about this).
  • Researchers explore short-chain fatty acids & inflammation Parkinson’s stool & plasma samples; Intestinal inflammation is “not reflected in plasma inflammatory profiles” (Click here to read more about this).
  • SWEDDs are different – an analysis of the PPMI data, indicates that individuals with “Scans Without Evidence of Dopaminergic Deficit” (or SWEDDs) “may not be early Parkinson’s, but rather a different disease entity” (Click here to read more about this).
  • Differences in MTHFR & LRRK2 variant’s association with sporadic Parkinson’s in Mexican Mestizos correlated to Native American ancestry; “invites further research into the shared risk factors’ role in the pathophysiological mechanisms” (Click here to read more about this).
  • Multiple system atrophy (MSA) in Hokkaido, Japan: a prospective registry study of natural history & symptom assessment scales followed for 5 years (Click here to read more about this).
  • A systematic review of the effect of resistance exercise on body structure & function, plus activity & participation in individuals with Parkinson’s (Click here to read more about this).

  • New report explores genetic variations & neuropathologic features of patients with PRKN mutations (Click here to read more about this).
  • New research reports Gaucher disease plasma biomarkers are “not promising candidates for stratifying the risk for Parkinson’s in carriers of heterozygous GBA pathogenic variants” (Click here to read more about this).
  • Important observation: Pelvic floor dysfunction – more common amongst women with PD – is underreported & undertreated, highlighting a key gap in care of women with Parkinson’s (Click here to read more about this).
  • A longitudinal observational study proposes that detection of α-synuclein in cerebrospinal fluid (by RT-QuIC) in individuals with isolated REM sleep behaviour disorder “represents a potential prodromal marker of Parkinson’s & dementia with Lewy bodies” (Click here to read more about this).
  • New paper presents a two-sample Mendelian randomization study that does not support the hypothesis that TNF-TNFR1 signaling inhibition will prevent or delay Parkinsons onset (Click here to read more about this).
  • New report provides validation for the 27‐item self‐administered Non‐Motor Fluctuation Assessment Questionnaire; 200 individuals with Parkinson’s & their care‐partners participated in the study (Click here to read more about this).
  • New medrxiv manuscript explores autosomal genetic sex differences in Parkinson’s, & finds 19 genome-wide significant regions but no sex-specific effects (Click here to read more about this).

  • Alpha-synuclein has been described as a native antiviral factor within neurons, but new research reports serum or cerebrospinal fluid levels of Parkinson’s-associated alpha-syn do not change in COVID-19 patients with neurological symptoms (Click here to read more about this).
  • Real‐world observational data are needed on the safety & efficacy of ambroxol for patients with Gaucher disease & GBA‐associated Parkinson’s; “these preliminary data may be encouraging to physicians & patients who consider an off‐label use of ambroxol” (Click here to read more about this).
  • Researchers identify CNS-colonizing T cells as potential therapeutic targets to prevent progression of Multiple Sclerosis, using multimodal single-cell profiling of blood & spatial RNA sequencing of brain tissue (Click here to read more about this).
  • Researchers report the first XWAS of Parkinson’s – X‐chromosome‐wide association study – & identify two significant loci, of which the rs28602900 association is replicated in an independent PD dataset; ” X‐chromosome contributes to PD genetic risk” (Click here to read more about this).
  • Coping with COVID-19: The results of a Parkinson’s foundation survey from people with Parkinson’s during the pandemic (Click here to read more about this).

  • Researchers present physical activity profiles in Parkinson’s – accelerometer data from 301 participants (43% women, mean age: 71 yrs) was analysed using latent profile analyses of 15 variables, highlights distinct profiles (Click here to read more about this).
  • Care partners face challenges with clinician communication & learn about psychosis from a variety of informal sources” – new report on knowledge, responsibilities, & peer advice from care partners of individuals with #Parkinsons associated psychosis (Click here to read more about this).
  • A 15-year follow-up of 100 Norwegian LRRK2-G2019S mutation carriers explores the prevalence of inflammatory conditions with the cohort; 1/3 had developed Parkinsons after follow-up (Click here to read more about this).
  • Researchers explore profiling the biochemical signature of GBA‐associated Parkinson’s in peripheral blood mononuclear cells, & find higher α‐synuclein levels, lower GCase activity, higher LIMP‐2, & lower Saposin C levels in GBA‐PD cohort vs non‐mutated PD (Click here to read more about this).
  • Researchers explore profiling the biochemical signature of GBA‐associated Parkinson’s in peripheral blood mononuclear cells, & find higher α‐synuclein levels, lower GCase activity, higher LIMP‐2, & lower Saposin C levels in GBA‐PD cohort vs non‐mutated PD (Click here to read more about this).
  • A systematic review & meta-analysis study reports that helicobacter pylori infection is associated with a poor response to levodopa in Parkinson’s; “emphasizes the importance of considering subsequent eradication of HP infection in patients with PD” (Click here to read more about this).

  • A delphi consensus of psychiatry, neurology, & geriatric experts on depression in Parkinson’s; “PD patients should be systematically screened for depression & anxiety, the diagnostic of which can be aided using clinical scales” (Click here to read more about this).
  • New medrxiv manuscript suggests “no evidence for a causal relationship or genetic correlation between restless legs syndrome & Parkinson’s“; Previous associations may = confounding or non-genetic determinants (Click here to read more about this).
  • New medrxiv manuscript suggests ultrasound may not be a suitable method for detecting vagal axonal loss in individual patients with Parkinson’s; small but significant reduction in sex-adjusted group data (Click here to read more about this).
  • The clinical manifestations of Parkinson’s in 3 Japanese individuals harboring VPS35 retromer complex component p.D620N with long-term follow-up; slow progression of symptoms, with psychosis, but without dementia; good response to Ldopa >10 yrs from onset (Click here to read more about this).
  • New biorxiv manuscript presents assays for the analysis of Parkinson’s-associated LRRK2 activity following inhibition in human PBMCs & whole blood; Potential utility as biomarkers as LRRK2 inhibitors advance in the clinic (Click here to read more about this).
  • Researchers present Class III evidence that a 3-Sniffin’-stick model holds potential utility as a brief screening test in the stratification of individuals with Parkinson’s & isolated REM sleep Behavior Disorder (iRBD – Click here to read more about this).

  • An analysis of anti-geronic protein Klotho using BioFIND study data reports limited associations between this protein & Parkinsons (122 plasma samples analyzed; No diff between PD vs controls: Trend towards higher levels in PD females – Click here to read more about this).
  • Enablers to exercise participation in progressive supranuclear palsy (PSP): Health professional perspectives; “exercise & physical therapies appear beneficial for people living with PSP” (Click here to read more about this).
  • Uric acid and Parkinsons from the PPMI data: No difference in serum uric acid between GBA-PD and sporadic PD; Gradual decrease in uric acid in both PD cohorts; Serum uric acid lower in GBA1-PD patients compared to healthy controls (Click here to read more about this).
  • Under-represented communities: An analysis of the frequency of Parkinsonism & Parkinson’s in African Americans in the Chicago community finds they are less likely to have parkinsonism compared to caucasians, but not significant between groups in terms of frequency of PD (Click here to read more about this).
  • Altered response of innate immune system in PD? New study finds the number of classical & non-classical monocytes in the cerebrospinal fluid of people with Parkinson’s is increased; T-lymphocytes & CD4+ lymphocytes tend to show increased absolute numbers (Click here to read more about this).
  • A “mouse & man” study indicates that oral berberine improves brain (in mice) dopa/dopamine levels by regulating gut microbiota – may aid in ameliorating symptoms of Parkinson’s (Click here to read more about this).

New clinical trials

  • New clinical trial registered: Evaluation of the safety & effectiveness of bilateral ablation of the pallidothalamic tract for the treatment of the motor complications of Parkinson’s is being conducted by InSightec are seeking 50 individuals for this experimental MRgFUS study(Click here to read more about this).
  • New study: University of East Anglia researchers are looking for participants to take part in a research project on how feelings of control & mood in people with Parkinson’s may affect taking medication. Have a look & consider completing their quick survey (Click here to read more about this).
  • New clinical trial registered: Curasen have initiated a Phase II, 14 day, randomized, placebo-controlled, double-blind, crossover PK/PD study of CST-103 co-administered with CST-107 in Parkinson’s-associated cohorts; recruiting 40 participants (Click here to read more about this).

  • “The Levodopameter”! New clinical trial registered: Researchers initiate a study of the “Levodopameter” – a continuous, minimally invasive microneedle device placed on the skin, designed to continuously measure levodopa levels in real time (Click here to read more about this).
  • New clinical trial registered: Eisai has registered an open-label Phase II study to evaluate the pharmacodynamic effects, efficacy, & safety/tolerability of E2027 (PDE9 inhibitor) in individuals with dementia with Lewy bodies or Parkinson’s dementia (Click here to read more about this).

  • New clinical trial registered: Researchers have registered an observational study exploring the treatment burden & capacity of people with Parkinson’s & caregivers; They are seeking 2000 participants (Click here to read more about this).
  • New clinical trial registered: Quantitative imaging of brain glymphatic function in 140 individuals with & without Parkinson’s (Click here to read more about this).
  • New clinical trial registered: Cerevel Therapeutics registers a 58-Week open-label Phase III trial of tavapadon in Parkinson’s (TEMPO-4 Trial); seeking 531 participants (Click here to read more about this).

Clinical trial news

  • Publication of the first‐in‐human studies of Bial Biotech/Lysosomal Therapeutics‘s GCase activator LTI‐291 indicates it was well tolerated when given orally 1x daily for 14 days; Supports continued development of LTI‐291 for GBA1‐associated Parkinsons (Click here to read more about this).
  • Observational open-label, exploratory study of 18 individuals with PD finds that art therapy for Parkinson’s improves overall visual-cognitive skills & visual exploration strategies as well as general motor function (Click here to read more about this).
  • Inhibikase Therapeutics announces 1st patients dosed in Phase I clinical trial of c-Abl inhibitor IkT-148009 for the treatment of Parkinson’s (Click here to read more about this).

  • A randomized placebo-controlled study of multi-strain probiotics treatment (probiotics n = 34, placebo n = 38; 4 weeks study) finds that the treatment was effective for constipation in Parkinson’s (Click here to read more about this).
  • New medrxiv manuscript presents the results of the RESISTA-PD study, suggesting that an 8 week prebiotic treatment with resistant starch is safe & well-tolerated in individuals with Parkinson’s; Calls for long-term studies (Click here to read more about this).
  • Taiwanese probiotic company Bened Biomedical reports consumption of PS128 (a strain of Lactobacillus plantarum) shows benefits on Parkinson’s symptoms in clinical study; Nightly administration of PS128 for 12 weeks improved UPDRS scores (was this a blinded study? Click here to read more about this).

  • Alector announces that the first patient has been dosed with AL002 in their Phase 2 INVOKE-2 study in early Alzheimer’s. AL002 is an investigational, humanized monoclonal antibody that targets TREM2, developed in collaboration with AbbVie (Click here to read more about this).
  • Results of the Phase II clinical trial of tilavonemab (ABBV-8E12; is a monoclonal antibody for the N-terminus of human tau) in progressive supranuclear palsy (PSP) have been published (Click here to read more about this).
  • Results of a prospective, open-label, 2-arm study investigating the efficacy of donepezil for mild cognitive impairment in Parkinson’s have been published; 80 participants; 48 weeks treatment; no improvement in the cognition, but modulatory effect on EEG (Click here to read more about this).
  • A pilot study of the feasibility & effects of table tennis training in Parkinson’s – “safe and feasible, and it may have beneficial effects” (Click here to read more about this).

Conferences/lectures

  • A recording of the Michael J Fox Foundation-supported session exploring “The Promise of Precision Medicine for Parkinsons” is now available to watch (Click here to watch that session).
  • Very much looking forward to the World Parkinson’s Congress virtual meeting on Advancing Science, Care, & Living with Parkinson’s, which will be held Monday-Friday 17 – 21st May. Amazing opportunity to learn more about everything going on (Click here to read more about this).

Other news

  • Voyager Therapeutics provides an update on their NBIb-1817 (VY-AADC) gene therapy program; announces that Neurocrine Biosciences have terminated the Parkinson’s portion of their collaboration agreement (Click here to read more about this).
  • AbFero Pharmaceuticals announces initiation of Phase 1 study for their lead iron chelator, SP-420, in myelodysplastic & myelofibrosis patients with transfusional iron overload; longer term this agent is also being targeted at Parkinson’s (Click here to read more about this).
  • Eli Lilly and Rigel Pharmaceuticals enter a strategic collaboration to develop RIPK1 inhibitors for potential treatment of immunological & neurodegenerative diseases (Click here to read more about this).

  • Iron chelation biotech firm AbFero Pharmaceuticals announces grant funding from Cure Parkinson’s for their next generation brain-penetrant iron chelating agent SP-420 (Click here to read more about this).
  • Newronika announces first participant implanted with the AlphaDBSTM closed-loop adaptive Deep Brain Stimulation System for Parkinson’s (Click here to read more about this).
  • Prothena Corp announces that they will be presenting at the ADPD 2021 meeting some new pre-specified exploratory subgroup analyses from the Parkinson’s immunotherapy Phase II PASADENA study; Plus results from the Roche digital biomarker mobile app (Click here to read more about this).
  • Yumanity Therapeutics provides update on their lead candidate: stearoyl-CoA desaturase inhibitor YTX-7739; Phase 1a results expected by end of Q1 2021; Phase 1b trial in Parkinson’s, preliminary results expected by mid-year 2021 (Click here to read more about this).

  • Imperial College Innovations Fund makes six-figure investment into Charco Neurotech to support development of a new device to manage symptoms of Parkinson’s (Click here to read more about this).
  • AC Immune initiates first-in-human study of its novel diagnostic agent for Parkinson’s; First participant scanned with ACI-12589 – next-gen. PET imaging tracer for detection of deposits of alpha-synuclein protein in the brain (Click here to read more about this).
  • Q-State Biosciences announces achievement of key research milestone with the Silverstein Foundation-backed Chamishi Therapeutics; Generating preclinical antisense oligonucleotide candidates for neurological disorders including GBA-associated Parkinson’s (Click here to read more about this).
  • Nanoform and Herantis Pharma sign Biologics Proof of Concept agreement to enhance nasal drug delivery to the brain of Herantis’ CDNF therapies for Parkinson’s (Click here to read more about this).

  • Alterity Therapeutics announces funding from the Michael J Fox Foundation for dose optimization studies of ATH434 for Parkinson’s clinical trials (Click here to read more about this).
  • Launch of novel gene therapy company, VectorY, to develop vectorized antibody approaches for targeting muscular & neurodegenerative conditions (like Parkinson’s? – Click here to read more about this).
  • The world’s largest contract electronics maker Hon Hai/FoxConn announces a strategic partnership with British medical start-up Gyroglove to help develop the first wearable medical device designed for people with hand tremors (Click here to read more about this).
  • Biotech firm Blackfynn builds its therapeutic pipeline with option to a “Phase 3-ready drug” for Parkinson’s; Also expands its partnership with Clintrex Research Corp (Click here to read more about this).

  • Treg & allogeneic exosome therapeutics biotech company Coya Therapeutics – who recently completed series A funding round to help fund ALS work – mention Parkinson’s among their list of clinical pipeline candidates (Click here to read more about this).
  • Precision life science company Macrogen announces that it will collaborate with US-based Lifex Biolabs on Parkinson’s treatment research, using biomarkers to identify new therapies (Click here to read more about this).
  • Parkinson’s UK announced that they are committing £800,000 to new virtual biotech (“Vivifi Biotech”) to further explore GDNF for Parkinson’s (Click here to read more about this). Director of Research at Parkinsons UK, Dr Arthur Roach provides further information regarding this new project in this blog.

 

Review articles/videos

  • Expanding the role of proteasome homeostasis in Parkinson’s. Also has a useful section on proteasome activation-based approach for potential PD therapies (Click here to read more about this).
  • Researchers at Biogen offer a useful review on mitochondrial dysfunction in astrocytes in the context of Parkinson’s. A lot of areas covered in here (Click here to read more about this).
  • Triggers & alleviating factors for fatigue in Parkinson’s (Click here to read more about this).
  • An important discussion on concerns surrounding COVID-19 vaccines & the Parkinson’s community; The authors “recommend COVID-19 vaccination with approved vaccines to their patients with PD… unless there is a specific contraindication” (Click here to read more about this).

  • New review on mitochondrial dysfunction in neurodegenerative conditions (including Parkinson’s) with a focus on iPSC-derived neuronal models (Click here to read more about this).
  • An overview of animal models of metabolic disorders in the study of neurodegenerative diseases (Click here to read more about this).
  • Useful review on the role of DJ-1 in cellular metabolism & pathophysiological implications for Parkinson’s (Click here to read more about this).
  • Interesting review on how the redox environment affects the ER stress response (& vice versa); Parkinson’s & Alzheimer’s get a few mentions (Click here to read more about this).
  • Interesting discussion on the state of play regarding precision medicine approaches for Parkinson’s (Click here to read more about this).

  • Interesting piece on approaching individuals with early Parkinson’s; from making/delivering the diagnosis to medication & non-medication management, covers a lot of bases (Click here to read more about this).
  • Useful review on the interactions between Parkin & α-synuclein in PARK2-mediated Parkinson’s (Click here to read more about this).
  • Dysregulation of PGC-1α-dependent transcriptional programs in neurological & developmental disorders: Therapeutic challenges & opportunities; Useful section (6.2) on Parkinson’s in this review (Click here to read more about this).
  • A Parkinson’s Foundation survey sought to answer questions about how people with Parkinson’s are coping with COVID-19 (Click here to read more about this).
  • What do we mean when we talk about “reactive astrocytes”? Interesting consensus statement pointing “out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2”. The authors “advocate, instead, that research on reactive astrocytes include assessment of multiple molecular & functional parameters—preferably in vivo—plus multivariate statistics & determination of impact on pathological hallmarks in relevant models” (Click here to read more about this).

  • “Best practice guidelines for dietitians on the nutritional management of Parkinson’s” (Click here to read more about this).
  • A useful introductory review to intercellular mitochondrial transfer as a means of tissue revitalization (Click here to read more about this).
  • Digital progression biomarkers as novel endpoints in clinical trials: A multi-stakeholder perspective – lots of interesting aspects covered, from state of play to future landscape. “One of the unintended consequences of the Coronavirus pandemic is the rapid advancement of remote monitoring technologies. When witnessing the speed that such transformations have taken place in a matter of months, it’s clear that the time is now to apply such innovative strategies to rapidly moving the field of Parkinson’s digital tools forward” (Click here to read more about this).
  • Domotics, Smart Homes, & Parkinson’s” – the authors had me with “Domotics”. Interesting review exploring how technology is being employed to “reshape clinical care & research in PD” (Click here to read more about this).
  • When everything points at mitochondria… “The multi‐faceted role of mitochondria in the pathology of Parkinson’s” (Click here to read more about this).

  • Management, levels of support, quality of life, & social inclusion in Parkinson’s (Click here to read more about this).
  • Cardiolipin, Mitochondria, & Neurological disease“; a thorough overview (including short section on Parkinson’s – Click here to read more about this).
  • An overview on the bile acid TUDCA & it’s therapeutic potential in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • Novel targeted therapies for Parkinson’s – lots of bases covered (Click here to read more about this).

 

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

And there it is, just some of the highlights from February 2021 – 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 March!

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EDITOR’S NOTE: The author of this post is an employee of the Cure Parkinson’s Trust, so he might be a little bit biased in his views on research and clinical trials supported by the trust. That said, the trust has not requested the production of this post, and the author is sharing it simply because it may be of interest to the Parkinson’s community.

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.


4 thoughts on “Monthly Research Review – February 2021

  1. Simon,

    Thanks very much for such a detailed account.

    One thing in particular that caught my attention was the clinical trial for the “Levodopameter”, a device that is placed on the skin and in real-time measures levodopa levels. This would provide the data required for dynamic dosing which, in turn, would reduce fluctuations in levodopa levels, allowing patients to increase their doses without increasing levodopa induced dyskinesia.

    John

    Liked by 1 person

    1. Hi John,
      I hope all is well. I agree completely. The implications for such technology are grand. In combination with a Levodopa delivery system, one assumes that relatively stable levels of dopamine could be maintained. Whether blood levels reflect brain levels needs to be carefully assessed, but it is a step in the right direction.
      Kind regards,
      Simon

      Like

  2. I just have to say that the level of research seems utterly exhausting; I don’t know how you keep up with it! I found so many things in this list that I am very anxious to read, just a fraction of what is there, but I’m sure I will only be able to get to a fraction of *that*. And that is for one month.

    One suggestion would be to put the review articles up front. These are of the greatest value to the lay person trying to gain an understanding of the disease. After going through the entire list, and encountering so many things of interest, I’m planning to start with the review articles, and perhaps that is as far as I will get.

    Like

  3. Hello Simon,
    Thank you for Science of Parkinsons.com, the best resource I have found on the science of Parkinson’s. I am endeavoring to create a list of trials for disease modifying (slowing or halting) treatments or drugs with the intention of then determining what the unmet needs are of these trials. For example, in the past I have spoken with the Director of Development of a hospital about a trial they were prepping for. They had not quite reached their funding goal at the time of our conversation. I will be talking to them again soon about how I, given my background, and other PWP can partner with the hospital to help with advocating for more awareness of the trial and funding.
    I am turning to you Simon in hopes that you can please direct me to the most efficient way of creating the aforementioned trial list.
    May I ask what Cure Parkinson’s is currently trialing? I read that many repurposed drugs are being evaluated but is it correct that at present only Exenatide, Ambroxol, and UDCA are in trial?

    People like myself, people with Parkinson’s, owe so much to you and all of the researcher heroes.
    Thank you Simon,
    Christina

    Like

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