Monthly Research Review – September 2021

# # # #

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 September 2021.

The post is divided into 10 parts based on the type of research:

# # # #


So, what happened during September 2021?

In world news:

7th September – El Salvador becomes the first country in the world to accept Bitcoin as an official currency.

16th September – Inspiration4 launched by SpaceX becomes the first all-civilian spaceflight, carrying a four-person crew on a three-day orbit of the Earth.

21st September – A 10-foot wide house in Boston (known as “Skinny House”) sold for US$1.25 Million:

23rd September – Scientists report the discovery of human footprints in the state of New Mexico that are understood to be 23,000 years old, around the time of the last Ice Age – putting humans in North American significantly earlier than previously believed.

27th September – UK traffic was at its lowest for a Monday since England’s pandemic restrictions were lifted in mid-July, according to the data from the Office for National Statistics. Why? Because we do not have enough truck drivers to deliver the petrol. Nothing to do with BREXIT, the Government insisted, but the English were too busy making fun of themselves as they dealt with the crisis:

I particularly liked the way the BBC sent their journalist “Phil McCann” to report on the situation. I also rather liked:

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

In September 2021, there were 1,077 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (9,178for 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 4 pieces of Parkinson’s news

1. Because I’m all about that base:

DNA repair mechanisms – like the “base excision repair” system – can become dysfunctional with age, resulting in an accumulation of single-stranded DNA breaks. And there is some evidence that this problem may contribute to some cases of Parkinson’s pathology. Researchers recently investigated a gene called “NTH-1” (which is involved in the “base excision repair” system), and found that deficiency in NTH-1 promotes neuroprotection in models of PD. Although the researchers expected to see a more severe phenotype, they actually reported a protective effect based on an increase in the activity of protective pathways in cells, indicating that a minor increase in cellular stress could lead to increased neuroprotective activity (Click here to read more about this and click here to read an SoPD post on this topic).

2.The publication of the SURE-PD3 trial results

The results of the SURE-PD3 study were published this month. This was a randomized, placebo controlled clinical trial of a drug called inosine which has the ability to elevate levels of the antioxidant urate in the body. Individuals with high levels of urate were reported to have a reduced risk of developing PD, and inosine had demonstrated protective properties in models of the condition. So researchers tested inosine on the progression of early Parkinson’s. This was a massive, multi-year study involving 300 participants, but the final analysis concluded that “The findings do not support the use of inosine as a treatment for early PD” (Click here to read more about this).

3. When sonic goes dyskinetic:

Researchers recently discovered that pharmacological activation of “Smoothened” – a downstream effector of a protein called “sonic hedgehog” – reduces levodopa-induced dyskinesias in the animal models of Parkinson’s. Dopamine neurons produce sonic hedgehog and release it (along with dopamine) on to target cells in the brain. In Parkinson’s, when the dopamine neurons are lost, we treat the condition with levodopa tablets which replace the lost dopamine, but not the lost sonic hedgehog. The researchers found that the increase in dopamine signaling (via levodopa treatment) + the reduction in sonic signaling = dyskinesias (Click here to read more about this and click here to read a SoPD post on this topic).

4. Dysregulation in a key dysregulation mediator:

Mitochondria are the power stations of cells, providing them with all of their energy needs. Researchers reported this month that mitochondrial dysfunction induces epigenetic problems (specifically, dysregulation by H3K27 hyperacetylation) which affected pathways associated with Parkinson’s. This altered activity subsequently enhances the vulnerability of dopaminergic neurons & eventually activates neuronal cell death – indicating another mechanism that could be involved in PD. They also reported H3K27 hyperacetylation in the substantia nigra of human Parkinson’s brains (Click here to read more about this).

 

Articles of general interest

  • The Cure Parkinson’s Autumn newsletter is out (Click here to read it).
  • Parkinson’s and your diet from Parkinson’s UK (Click here to read more about this).
  • Your questions regarding OFF Episodes (Click here to read more about this).
  • As part of the NECTAR meeting in Edinburgh (see conference section below) there is also a public event exploring clinical trial participation (Click here to learn more about this).
  • Dr. Corinne Jones (The University of Texas at Austin) recently spoke to the “No Silver Bullet Parkinson’s Support Group” about breathing & voice in Parkinson’s:

 

Basic biology news

  • New research reports a previously unknown effect of Parkinson’s-associated α-synuclein on intracellular autophagy-associated SNARE proteins &, as a consequence, a reduced autolysosome fusion (Click here to read more about this).
  • Researchers at Genentech reported knocking out GPNMB in two alpha synuclein-based Parkinson’s models had no impact on any phenotype; PD risk allele was associated with about 30% increase in GPNMB RNA across multiple datasets; GPNMB is elevated in the PD nigra; “We cannot completely exclude the possibility that another gene at this locus might be causal”; “Another possible explanation is that GPNMB could mediate PD risk via a peripheral pathway, such as the gut-brain axis”; “GPNMB’s role in melanosome biology might be relevant to PD” (Click here to read more about this).

  • New research finds IL-17-producing cells (γδ T cells) accumulate in the CNS & the meninges of female (not male) mice, leads to short-term memory issues; IL-17 neutralization into the ventricles blocks memory issues; Early involvement of IL-17 in AD pathology? Opportunity for Secukinumab? (Click here to read more about this).
  • New research proposes a non-invasive diagnostic tool for Parkinson’s based on analysis of sebum RNA profile with machine learning (Click here to read more about this).
  • A wireless magnetothermal neuromodulation approach (via activation of TRPV1 by synthetic magnetic nanoparticles) for deep brain stimulation in two Parkinson’s mouse models; Remote modulation of motor behavior in healthy mice as well (Click here to read more about this).
  • The role of Parkinson’s-associated LRRK2 in mitochondrial metabolism is still not well understood; New research suggests effects on mitochondrial respiratory are indirect & LRRK2/Roco proteins most likely require other cytosolic cofactors to elicit effects (Click here to read more about this).

  • New X-ray, biochemical & cellular studies help to describe the structure of the PPM1H phosphatase that counteracts with Parkinson’s-associated LRRK2 (by dephosphorylating Rab GTPases – click here to read more about this).
  • Researchers tested the ability of α-synuclein to inhibit Snx3-retromer mediated retrograde trafficking of Kex2 & Ste13 between late endosomes & the trans-Golgi in a yeast model of Parkinson’s; Membrane-binding ability of α-synuclein is necessary (Click here to read more about this).
  • New research identifies TAX1BP1 as a central component in the lysophagy pathway & provides a proteomic resource for future studies of the lysophagy process (Click here to read more about this).
  • New research reports mitochondrial dysfunction in adult dopamine (DA) neurons triggers early immune response; Inflammation already present when Mitofusin 2-/- dopamine neurons display first mitochondrial fragmentation (Click here to read more about this).

  • An antioxidant cocktail for space explorers: Researchers propose a workflow for assessing astronaut resistance to ROS damage, infight monitoring of ROS production, and an antioxidant cocktail – with down to Earth implications? (Click here to read more about this).
  • A role for UQCRC1 in regulating cyt-c-induced apoptosis: UQCRC1 regulates dopamine neuronal maintenance & locomotor activity in flies; Parkinson’s-associated UQCRC1 variant fails to bind cytochrome c, triggering apoptosis; Deletion of cytochrome c corrects (Click here to read more about this).
  • Deletion of Parkinson’s-associated LRRK2 causes early developmental abnormalities & age-dependent increase of monoamine catabolism in the zebrafish brain (Click here to read more about this).
  • New research reports that Parkinson’s-associated LRRK2 & WAVE2 are important mediators of cytokine production & cytoskeletal rearrangement necessary for microglial-induced neurotoxicity; MLi2 & inhibition of WAVE2 stunts microglial activation (Click here to read more about this).
  • Often forgotten that Parkinson’s-associated Lewy bodies contain over 70 proteins; Now research explores the selectivity of Lewy body protein interactions along the aggregation pathway of α-synuclein (Click here to read more about this).

  • New research reports the binding of the small heat-shock protein αB-crystallin to Parkinson’s-associated α-synculein fibrils is driven by entropic forces (Click here to read more about this).
  • Characterisation of the Gene-Switch regulable gene therapy system in the primate brain, demonstrates that the clinically approved synthetic steroid Mifepristone can be used to control transgene expression; GDNF is presented as an example (Click here to read more about this).
  • The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons in both mice & humans; These neurons are particularly vulnerable to neurodegeneration & Bcl11a inactivation increases vulnerability (Click here to read more about this).
  • New research highlights quantifiable molecular features of Parkinson’s in patient-derived midbrain dopaminergic neurons that can distinguish healthy individuals from idiopathic PD patients & segregate PD patients with or without rest tremor at onset (Click here to read more about this).

  • New research presents the generation & characterization of iPSC lines from 53 deeply phenotyped aged humans, & reveals sig. assoc. between β-amyloid & tau species, levels of path in the brain, AND the trajectory of cognitive decline (Click here to read more about this and click here for the press release associated with this research).
  • New research report that a reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons (Click here to read more about this).
  • A descriptive & exploratory multiomic analysis of substantia nigra dopaminergic neurons isolated from 10 human postmortem cases of Parkinson’s highlights some of the complexities & difficulties of this research (Click here to read more about this).

  • New research suggests that male cells may rely more on the function of Heat Shock Protein 70 to combat Lewy-related pathology than female counterparts; Implications for Parkinson’s? (Click here to read more about this).
  • New report comprehensively analysed the mitochondrial genome in 146 iPSC & 151 fibroblast lines & found most age-related fibroblast mtDNA mutations are lost during cellular reprogramming; Higher proportion of mtDNA mutations observed in iPSC lines (Click here to read more about this).
  • New research finds inhibition of microglial β-glucocerebrosidase (GCase) hampers the microglia-mediated antioxidant & protective response in neurons; GCase inhibition impairs Nfe2l2 response; Implications for GBA-Parkinson’s (Click here to read more about this).
  • Mortalin down-regulation induced mitochondrial fragmentation & axonal damage, whereas its over-expression conferred protection against axonal degeneration” in rotenone-based Parkinson’s model (Click here to read more about this).
  • New biorxiv manuscript provides new insights into Parkinson’s-associated PINK1 kinase activation based on AlphaFold structure models (by DeepMind). Includes interesting data on decreased stabilisation & activation of endogenous PINK1 in fibroblasts from clinically characterised patient with homozygous PINK1Q126P variant (Click here to read more about this).

  • A biorxiv manuscript explores how microglia might be driving pockets of neuroinflammation in the brain during middle age; Local elevation in inflammation parallel an increase in microglial population; CX3CR1 signaling can shape microglia responses to aging (Click here to read more about this).
  • “GEDI” (Genetically Encoded Death Indicators). Specifically detects & labels an intracellular Ca2+ level that cells achieve early in the cell death process (in vitro & in vivo); Useful new tool (Click here to read more about this).
  • New research finds Parkinson’s-associated alpha synuclein protein aggregation is modulated by patient brain cells’ intracellular milieus at the primary nucleation phase; Clues to the (epi)genetics of idiopathics? (Click here to read more about this).
  • Constrained peptides that are cell-penetrant, bind LRRK2, & inhibit LRRK2 activation by downregulating dimerization; “While many ATP-competitive LRRK2 inhibitors induce toxicity & mislocalization of the protein in cells, these constrained peptides” do not (Click here to read more about this).

  • New research reports that knockdown of PTBP1 fails to convert brain astrocytes into neurons in vivo; Lineage-traced resident astrocytes are not converted into neurons by NEUROD1; NEUROD1-induced, viral-reporter-labeled neurons are just endogenous neurons (Click here to read more about this).
  • Partners in crime? Collusion between Parkinson’s-associated α-Synuclein & Alzheimer’s-related β-amyloid aggravates the co-morbidities in a novel prion-type mouse model (Click here to read more about this).
  • Autosomal, clonally heritable ‘random monoallelically expressed’ genes are estimated to comprise 1 to 10% of genes. In a study of RME genes, Parkinson’s-associated alpha synuclein (SCNA) is investigated (Click here to read more about this).
  • New research finds Parkinson’s-associated α-synuclein (monomers & oligomers) activates the NLRP3 inflammasome (via TLR2), which compromises the α-syn clearance capacity of cells; NLRP3 inhibition helps improve clearance (Click here to read more about this).

  • New research reports heterozygous GBA D490V & ATP13a2 mutations do not exacerbate pathological Parkinson’s-associated α-synuclein spread in the prodromal preformed fibrils model in mice (Click here to read more about this).
  • A missense mutation (D620N) in vacuolar protein sorting 35 (VPS35) is associated with late onset Parkinson’s; Endosomal traffic & glutamate synapse activity are increased in VPS35 D620N mutant knock-in mouse neurons, & resistant to LRRK2 kinase inhibition (Click here to read more about this).
  • PTENα is responsible for protection of brain against oxidative stress during aging; Genetic ablation of Ptenα in mice increased oxidative stress, neuronal cell death, accelerated decline of cognition, & motor coordination as age increases (Click here to read more about this).
  • New research finds that Lewy body disorders (like Parkinson’s) are characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations (but GBA mutations likely accelerate pathological process – click here to read more about this).
  • New biorxiv manuscript suggests neither latent nor lytic herpes simplex virus infection of human neurons in vivo is directly associated with aberrant Alzhiemer’s-associated β-amyloid or pTau expression (Click here to read more about this).

  • Are PARKIN structural genetic variants more common than currently estimated? Israeli researchers report L-dopa-responsive dystonia caused by biallelic PRKN exon inversion which is invisible to exome sequencing (Click here to read more about this).
  • Researchers report longitudinal faecal virome changes from alpha-synuclein (monomeric & PFF) in a gut-initiated rodent model of Parkinson’s; Alterations compounded by the addition of LPS (Click here to read more about this).
  • Researchers report that both lactate & pyruvate in millimolar concentrations can induce a short-term changes in intracellular pH in human fibroblasts with Parkinson’s variants (Pink1, α-syn, etc), which caused activation of mitophagy & autophagy – this treatment protects the cells; The authors note that exercise elevates lactate levels which has been reported to be beneficial to people with Parkinson’s (Click here to read more about this).

 

Disease mechanism

  • Gain Therapeutics announced positive preclinical results in patient derived iPS cells for their two lead Structurally Targeted Allosteric Regulators (STARs) compounds – GT-02287 & GT-02329 – for Gaucher disease & GBA-associated Parkinson’s; Results: Decreased P-alpha-synuclein levels in dopaminergic neurons; Increased GCase enzyme activity; Increased GCase protein levels & transport to lysosomes in dopaminergic & cortical neurons; Decreased GluCer accumulation in cortical neurons; IND-initiating study Q4’21 (Click here to read more about this).

  • New paper finds that c-Abl phosphorylation of parkin interacting substrate (PARIS) is required for PARIS-induced cytotoxicity in models of Parkinson’s; Correlative increases in PARIS phosphorylation, MDM4 repression & p53 activation in postmortem PD brains (Click here to read more about this).
  • A novel, selective c-Abl inhibitor, Compound 5, prevents neurodegeneration in models of Parkinson’s (Click here to read more about this).
  • APOE3-Jacksonville (V236E) variant has been shown to reduce the risk of Alzheimer’s; Now researchers report V236E variant reduces apoE aggregation, elevated lipid association, & in mouse model of AD it reduced brain pathology (Click here to read more about this).
  • Stealth BioTherapeutics presents positive preclinical data at the Movement Disorder Society congress 2021 for their mitochondrial targeting agent SBT-272 in a A53T a-synuclein mouse model of Parkinson’s (Click here to read more about this).

  • The synthetic copper-containing compound, CuATSM, is reported to improve motor function & extend survival in transgenic (SOD1G93A) ALS models, but is not tolerated at a high dose in mice with a C57BL/6 background (Click here to read more about this).
  • The antioxidant Rutin counteracts the pathological impact of A53T α-synuclein on the enteric nervous system in an in vitro model of Parkinson’s (Click here to read more about this).
  • New biorxiv manuscript suggests the activities of LRRK2 & GCase are positively correlated in clinical biospecimens & experimental models of Parkinson’s; Could elevated GCase activity in LRRK2 G2019S cases explain absence of Lewy path? (Click here to read more about this).
  • In vitro genome editing (via adenine base editors) rescues parkinsonism phenotypes in induced pluripotent stem cells-derived dopaminergic neurons carrying Parkinson’s-associated LRRK2 p.G2019S mutation (Click here to read more about this).
  • Herantis Pharma announces positive initial results from their project (with Nanoform) successfully applying the nanoforming process to Herantis’ rhCDNF drug candidate for intranasally administration; Being targeted at Parkinson’s (Click here to read more about this).

  • New research reports a common but regionally selective disruption of pantothenic acid levels across Parkinson’s dementia, Alzheimer’s, & Huntington’s disease (Click here to read more about this).
  • New research finds that the selective PDE4 inhibitor roflupram protects against rotenone-induced neurotoxicity & facilitates α-synuclein degradation in Parkinson’s models (Click here to read more about this).
  • New biorxiv manuscript presents engraftment & biodistribution of genetically engineered HSPC-derivatives in mouse models of GBA-associated Parkinson’s & frontotemporal dementia (Click here to read more about this).
  • Could the neuroprotective effects of statins observed in preclinical models of Parkinson’s be modulated by Nurr1? A new biorxiv manuscript presents evidence suggesting ‘yes’ (Click here to read more about this).

  • Lysine-selective molecular tweezers (like CLR01) are cell penetrant & concentrate in lysosomes (Click here to read more about this).
  • New biorxiv manuscript suggests broader potential for LRRK2 inhibitors than just Parkinson’s; Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency (Click here to read more about this).
  • New research finds that transgenic Parkinson’s-related A53T & α-syn aggregation may affect the intestine microbiota & metabolites of non-human primates; 5 compositional different metabolites identified that are associated with mitochondrial dysfunction (Click here to read more about this).
  • New biorxiv manuscript suggests the internalization & degradation of neuronal mitochondria are significantly increased in astrocytes isolated from aged Alzheimer’s mouse brains; Similar phenomenon in human astrocytes (Click here to read more about this).
  • Zonisamide attenuates the severity of levodopa-induced dyskinesia in a rodent model of Parkinson’s, by activating striatal serotonergic system & inhibiting overactive direct pathway (Click here to read more about this).

  • Quantitative high throughput screen of 155K compounds identifies known AKT inhibitor, A-443654, reduces Parkinson’s-associated α-synuclein expression & normalizes ER stress & autophagy; AKT inhibition as a potential strategy for PD; “A-443654 successfully prevented α-synuclein toxicity & restored cell function in ATXN2-Q58 cells, normalizing the levels of mTOR, LC3-II, p62, STAU1, BiP & CHOP. A-443654 also decreased the expression of DCLK1, an inhibitor of α-synuclein lysosomal degradation” (Click here to read more about this).
  • Mice with 2xfold increase in endogenous GDNF (“GDNF hypermorphic mice”, GDNF wt/hyper) resist an overall age-associated decline in the cholinergic index observed in the brain of GDNF wt/wt animals (Click here to read more about this).
  • IFN-β knockout mice spontaneously develop progressive behavior abnormalities & neuropathology resembling Parkinson’s dementia, notably with α-syn path. Now researchers report absence of α-syn has no impact on phenotype in double knockout mice (Click here to read more about this).
  • “Nico Ribo” rides again: Nicotinamide riboside improves Ataxia scores & immunoglobulin levels in Ataxia Telangiectasia (Click here to read more about this).

  • Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours & parkinsonism in the MPTP-lesioned non-human primates (Click here to read more about this).
  • Could inactivation Complex II or III of the mitochondrial electron transport chain be triggering Parkinson’s pathogenesis (via activating C/EBPβ/AEP pathway)? Constipation & motor defects, associated with “Lewy body-like inclusions” in transgenic mice (Click here to read more about this).
  • New research reports GSK3 inhibitor CHIR99021 administration in Huntington’s disease models suppressed the proteasomal degradation of calpastatin & subsequently inhibited calpain activation; Improved mitochondrial function & cell survival in vitro (Click here to read more about this).
  • Researchers investigated ~45K small molecules using a high-throughput, whole-organism (C. elegan), phenotypic screen identifies 2 compounds that reduced neurodegenerative phenotypes in a Parkinson’s-associated PINK-1-dependent manner (Click here to read more about this).

  • New paper presents a Toll-like receptor2-interaction domain of MyD88 (wtTIDM) peptide that selectively inhibits TLR2, reducing α-syn fibrils-induced microglial inflammation in in vitro & in vivo models of Parkinson’s (Click here to read more about this).
  • Researchers from Merck report the characterization of a novel glucosylceramide synthase inhibitor, called Benzoxazole 1, that rescues lysosomal deficits, α-synuclein pathology & neuron toxicity in a model of Parkinson’s (Click here to read more about this).
  • New research compares Type I (GSK3357679A, MLi-2) & Type II (Ponatinib, GZD-824) LRRK2 kinase inhibitors that bind to the closed or open conformations of LRRK2 kinase domain, respectively (Click here to read more about this).

 

Clinical research

  • Facial expressions can detect Parkinson’s: Evidence from videos collected online; Facial action units (AU) analysis of 1812 videos of 604 individuals (61 with PD & 543 without) achieved 95.6% accuracy; Future digital biomarker for PD? (Click here to read more about this).

  • New research reports frontoparietal network resilience is associated with protection against cognitive decline in Parkinson’s (Click here to read more about this).
  • Researchers highlight reduced cortico-muscular beta coupling as a simple, effective & clinically relevant neural marker of Parkinson’s pathology; Predicts motor impairment; Potential to aid monitoring progression & efficacy of novel treatments for PD (Click here to read more about this).
  • PROPAG-AGEING researchers report heterogeneity of prodromal Parkinson’s symptoms in siblings of Parkinson; 4.4% of siblings presented with subtle signs of motor impairment (Click here to read more about this).
  • An analysis of CSF cholesterol metabolites in Parkinson’s & their association with disease state & clinical features finds a cerebral upregulation of the acidic pathway of bile acid biosynthesis in PD; Some cholesterol metabolites correlate with depression (Click here to read more about this).

  • New research finds that RIC3 variants are not associated with Parkinson’s in large European, Latin American, or East Asian cohorts (Click here to read more about this).
  • New research finds monocyte chemoattractant protein 1 (MCP-1) levels in CSF cannot distinguish between PD, MSA, & controls, BUT correlates with disease progression in Parkinson’s patients (Click here to read more about this).
  • The first postmortem neuropathological findings of a patient with Kufor Rakeb Syndrome (KRS) due to ATP13A2 mutation; Widespread neuronal & glial lipofuscin accumulation with no Lewy-body type inclusions; Absence of 𝛼-synuclein-, tau-, etc pathologies (Click here to read more about this).
  • New report measuring pontine damage using diffusion tensor imaging as a degeneration marker in synucleinopathy finds fair discriminatory power to differentiate controls from cases of Parkinson’s, REM sleep behavior disorder, & multiple system atrophy (MSA – click here to read more about this).
  • New research finds transcriptomic mitochondrial alterations are detectable in Parkinson’s monocytes & distinct from microglia (Click here to read more about this).

  • New study indicates plasma extracellular vesicle tau & Aβ1-42 could be significant markers of cognitive function in Parkinson’s patients (n=116 mild to moderate stage of PD cases & 46 non-PD controls – click here to read more about this).
  • New research finds distinct population code for movement kinematics & changes of ongoing movements in human subthalamic nucleus (Click here to read more about this).
  • Neurofilament light chain protein (NfL): a cognitive impairment biomarker? A new study of N=615 (52PD & 200controls); Plasma & CSF NfL levels correlated; NfL was highest in neurocognitive disorders; PD participants with elevated plasma NfL more likely to develop cognitive impairment (Click here to read more about this).
  • New research does not find sufficient evidence that Parkinson’s is an independent risk factor for severe COVID19. Larger studies with controls are required (Click here to read more about this).

  • New research assessed MRI data from 372 newly diagnosed cases of idiopathic Parkinson’s to evaluate the relationship between individual brain age & clinical characteristics; PD leads to a moderate increase in predicted brain age (Click here to read more about this).
  • New research explores the clinical progression of progressive supranuclear palsy & how Richardson’s syndrome & several other variant phenotypes could potentially impact clinical trial outcomes (Click here to read more about this).
  • New research presents technology-based therapy-response & prognostic biomarkers in a prospective study of a de novo Parkinson’s; N=36 & nearly 30 months of follow up (Click here to read more about this).
  • Subtyping of Parkinson’s patients with similarity fusion (using BioFIND data) finds 3 subtypes: #1 (~58.3%)= mild symptoms (motor & non-motor); #2 (~19.4%)= intermediate severity + high tremor & mild non-motor; #3 (~22.3%) = more severe motor & non-motor (Click here to read more about this).

  • New research extends previously observed impaired processing of emotional facial expressions in people with Parkinson’s to impaired processing of emotions expressed by body language (Click here to read more about this).
  • Radioligand [18F]-AV-1451 exhibits off-target binding to neuromelanin-containing cells; New research suggests that nigral [18F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson’s (Click here to read more about this).
  • New open access topographic atlas of the human brainstem; 45 anatomical plates, each containing a pair of adjacent sections stained with Cresyl Violet & Luxol Fast Blue; Plus 8 plates stained for choline acetyltransferase (Click here to read more about this).
  • Stimulating stuff: A case report on chronic adaptive deep brain stimulation (Percept™ PC; Medtronic) in a 51 year old man with Parkinson’s; Fluctuations of neural oscillations of the local field potential less evident inside the hospital than outside (Click here to read more about this).

  • Longitudinal risk factors for developing depressive symptoms in Parkinson’s assessed in two longitudinal cohorts; Probable REM sleep behavior disorder, hyposmia, UPDRS Part II score were associated with depressive symptoms (Click here to read more about this).
  • New study finds Parkinson’s patients have higher frontoparietal connectivity in cognitive networks (vs controls), irrespective of medication status, but dopaminergic treatment specifically promoted salience/default-mode hyperconnectivity (Click here to read more about this).
  • The GALAXY randomized clinical trial finds general anesthesia vs local anesthesia in microelectrode recording–guided deep-brain stimulation for Parkinson’s finds no difference in the primary outcome of asleep vs awake DBS (Click here to read more about this).
  • Could cerebrospinal fluid iron-ferritin ratio be used as a potential progression marker for Parkinson’s? Longitudinal pilot data of individual patients presents a compelling argument; Larger & longer studies required (Click here to read more about this).
  • A Norwegian Prescription Database study (from 2004 to 2017; N=7580 PD patients) finds no association between NSAID use & incidence of Parkinson’s (Click here to read more about this).

  • 24 hour blood pressure profile in idiopathic REM sleep behaviour disorder suggests control is impaired; Similar to patterns observed in de novo Parkinson’s (Click here to read more about this).
  • A 2-year follow-up of a case controlled study reports a decrease in the levels of naive/central memory CD4 T cells, CD8 T cells, plasma cells, & Lip-AP B cells, along with increased levels of effector & activated CD4 T cells & Tc17 cells in Parkinson’s (Click here to read more about this).
  • New research from BeyoND study researchers presents 1 year data from their open label study of subcutaneous levodopa/carbidopa continuous infusion with two doses of ND0612 in patients with Parkinson’s & motor fluctuations (Click here to read more about this).
  • Pupillometer testing on 132 individuals with Parkinson’s (stratified into two groups according to stage of PD) finds pupillary contraction velocity decreased with the disease progression; No diff. in pupil size, minimum diameter, & dilation velocity (Click here to read more about this).
  • Under-represented communities: A short letter outlining the results of a screening study of GBA variants in Nigerian Parkinson’s patients; Small study, N=92 (vs 51 controls); 10 variants reported (Click here to read more about this).

  • A transcriptome-wide association study (TWAS) identifies susceptibility genes for Parkinson’s; N=480K individuals from the most recent PD GWAS; 18 genes significantly associated with PD; #1 = LRRC37A2 (Click here to read more about this).
  • Researchers report a possible inability in Parkinson’s patients to use reward value of stimuli when automatically allocating their attention; Could this misallocation affect adaptive modulation of other cognitive processes? (Click here to read more about this).
  • A fine-mapping of the HLA region in Parkinson’s, showing that there is likely a single association in this locus; Researchers think it may be driven by specific amino acid alterations in the HLA-DRB1 gene (Click here to read more about this).
  • Intriguing trends in a corneal confocal microscopy study of 65 individuals with Parkinson’s; PD cases show evidence of corneal nerve loss (vs 30 controls) & corneal nerve parameters are associated with the severity of cognitive & motor dysfunction (Click here to read more about this).

 

  • “The choice of compensation strategies for gait impairment in Parkinson’s should be tailored to the individual patient, as well as to the context in which the strategy needs to be applied” (Click here to read more about this).
  • A new report presents that the first Japanese autopsy case of Parkinson’s-associated LRRK2-G2019S mutation with atypical TDP43 proteinopathy; Could TDP43 play a role in the clinical presentation of LRRK2 G2019S mutation carriers? (Click here to read more about this).
  • New research demonstrates that the 5’ LRRK2 non-coding GWAS signal rs76904798 is independently associated with Parkinson’s risk from LRRK2 coding variation (Click here to read more about this).
  • New research explores the optimisation of Parkinson’s classification based on motor, olfactory, neuropsychiatric & sleep features; Prospective studies needed to investigate the value of the PD-prediction models (Click here to read more about this).
  • Low GCase activity does not explain clinical phenotype or risk for prodromal Parkinson’s”; 170 PD cases (102 GBA-PD, 38 LRRK2-PD, & 30 iPD) + 221 non-manifesting carriers; GCase activity is decreased among GBA-PD, GBA-NMC & GBA-LRRK2-NMC; No correlation to phenotype (Click here to read more about this).
  • New biorxiv manuscript explores rapid, real-life wrist-sensor Parkinson’s monitoring; Bradykinesia fluctuations can be classified down to a single minute (Click here to read more about this).

  • Dizziness (not caused by orthostatic hypotension) in Parkinson’s patients is associated with vestibular function (Click here to read more about this).
  • Eight individuals with Parkinson’s were assessed in two 8-h stimulation sessions (1st day: conventional Deep Brain Stimulation; 2nd day: adaptive DBS) with regular levodopa intake & during normal daily activities; Results support safety & effectiveness of aDBS (Click here to read more about this).
  • New report presents a preliminary study with ultra-high field (7T) MRI indicating increased sodium concentrations in the substantia nigra in early Parkinson’s; Further support for bumetanide? (Click here to read more about this).
  • A first look at epigenetic mitotic aging in Parkinson’s; Researchers find accelerated hematopoietic cell mitosis, possibly reflecting immune imbalances in early PD that may also be related to motor & cognitive progression (Click here to read more about this).
  • A nationwide (South Korea) population-based cohort study finds risk of neurodegenerative conditions (including Parkinson’s) was higher in individuals with inflammatory bowel disease (vs non-IBD population – click here to read more about this).
  • Forget air pollution, now it’s NOISE pollution: A nationwide cohort study in Denmark found transportation noise to be associated with a higher risk of all cause dementia & dementia subtypes, especially Alzheimer’s (Click here to read more about this).

New clinical trials

  • New clinical trial registered: CuraSen Therapeutics has registered a Phase I trial of their brain-permeant, selective adrenoceptor modulator CST-2032 in individuals with mild cognitive impairment or Parkinson’s (Click here to read more about this).

Clinical trial news

  • The protocol for the LIPAD (LRRK2/Luebeck International Parkinson’s Disease) study has been published; Deep phenotyping of an international genetic cohort with a future perspective to identify genetic & environmental modifiers of penetrance & expressivity (Click here to read more about this).
  • A study protocol for a randomised controlled trial to study the effect of a Mediterranean diet intervention on gastrointestinal function in Parkinson’s (the MEDI-PD study – click here to read more about this).

  • In a de-novo Parkinson’s cohort, botulinum toxin type A treatment significantly changes cortical excitability, improving tremor severity; “tremor severity in early PD may be related to impaired intracortical inhibition & defective sensorimotor integration” (Click here to read more about this).
  • Secondary analysis of the open-label SAFINONMOTOR study explores the effectiveness of safinamide over mood in Parkinson’s; Results suggest that safinamide improves mood in patients with PD at 6 months (Click here to read more about this).
  • A subanalysis of a 1-year observational study in Japan on the influence of selective adenosine A2A receptor antagonist istradefylline on non-motor symptoms of Parkinson’s (J-FIRST study – click here to read more about this).
  • Interesting write up about the “Study in Parkinson’s of Exercise” (SPARX3) trial (Click here to read more about this).

  • Old drug, new tricks: Small (N=34) randomized trial of antiseizure drug levetiracetam finds it well tolerated in Alzheimer’s; Primary endpoint missed, but in prespecified analysis, it improved performance on spatial memory & executive function tasks; 125 mg twice daily for only 4 weeks; Larger, longer studies required; Effect was in participants with epileptiform activity (Click here to read more about this).
  • Biohaven Pharmaceuticals announced that their myeloperoxidase enzyme inhibitor Verdiperstat did not statistically differ from placebo on the prespecified primary efficacy measure, nor on the key secondary efficacy measures in multiple system atrophy (MSA – click here to read more about this).

 

Conferences/lectures

  • It is not too late to join the virtual “Rallying to the Challenge meeting” which is being held on the 7th & 8th October. This is a meeting designed by and for people with Parkinson’s – with support from Cure Parkinson’s and the Van Andel Institute – to find out how they can accelerate research. This year’s the theme for the meeting is ‘GBA1 and LRRK2 – From Genetic Risk to the Clinic’ mirroring the theme of Van Andel Institute’s ‘Grand Challenges in Parkinson’s Disease’ meeting which will be running in parallel (Click here for more information).

  • On the 7th October at 19:00 (UK), the Edinburgh Parkinson’s Lecture will be given by Prof Roger Barker, entitled “Repairing the brain in Parkinson’s Disease – Is this possible?” (Click here to read more about this).
  • It’s all happening in Edinburgh – I am also really looking forward to the NECTAR 2021 meeting in Edinburgh in November. An extremely impressive line up of speakers/presenters – basically everyone in the field of regenerative therapy for PD (Click here and here to learn more about this). And there are some really interesting podcasts being made to promote this event (Click here to listen to an example).

  • Parkinson’s UK have their 2021 PAR-CON virtual research conference lined up for October – lots of interesting topics (Click here to learn more about this).

 

Other news

  • Biotech firm Emyria recently optioned a library of >100 MDMA-like compounds from University of Western Australia, with the goal of exploring their use in L-DOPA induced dyskinesia with Parkinson’s; Now the company reports MDMA-analogue UWA-101 shown to improve duration and quality of L-DOPA treatment in a parkinsonian animal model (Click here to read more about this).
  • Vanqua Bio launches with $85M Series B financing & a mission to vanquish neurodegenerative conditions; Lead program targets Parkinson’s & all forms of Gaucher disease (Click here to read more about this).

  • Tools4patients presented data at the Movement Disorder Society Congress 2021 that predicted the placebo response in Parkinson’s in a multi-center, multi-national clinical study (Click here to read more about this).
  • TreeFrog Therapeutics secures $75M in Series B financing to advance a pipeline of stem cell-derived cell therapies & deploy proprietary C-Stem™ technology in the USA & Japan; Clinical trial for Parkinson’s in 2024 (Click here to read more about this).

  • Biotech firms Sunovion & BIAL have entered a European licensing agreement for KYNMOBI® (apomorphine hydrochloride) sublingual film for the treatment of Parkinson’s OFF episodes (Click here to read more about this).
  • Clene Nanomedicine presented their Phase II “REPAIR-PD” CNS target engagement data for their experimental gold nanoparticle therapy CNM-Au8 in individuals with Parkinson’s at the Movement Disorder Society Congress 2021 (Click here to read more about this).

  • “A recent survey of 78 neurologists conducted by Morgan Stanley found that half were willing to prescribe Aduhelm, but nearly two-thirds don’t think the FDA should have approved the drug” – Free samples, banker surveys,… Nothing makes any sense anymore (Click here to read more about this).
  • Sinopia Biosciences has been awarded a $3.3 million Fast-Track SBIR grant from NINDS to fund investigational new drug-enabling studies for a small molecule candidate targeting Parkinson’s & levodopa-induced dyskinesias (Click here to read more about this).

 

Review articles/videos

  • New review explores the role of meningeal populations of type II innate lymphoid cells in modulating neuroinflammation in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • Useful review of nanotheranostic approaches targeting Alpha-Synuclein aggregation in Parkinson’s; “Important to consider how they can be metabolized & eliminated”; “Isolating optimal biological samples for PD diagnosis can still pose a challenge” (Click here to read more about this).
  • Retinal inflammation & neurodegenerative conditions (like Parkinson’s) – is there a connection? A new review explores this idea; Includes an interesting discussion on GLP-1 agonists (Click here to read more about this).

  • Interesting book chapter on glycosaminoglycans in neurodegenerative conditions (including Parkinson’s – click here to read more about this).
  • New review explores 16 studies investigating the electromyographic activity of lower limb muscles in people with Parkinson’s during walking activity (Click here to read more about this).
  • The Thermodynamic Consequences of Parkinson’s (Click here to read more about this).
  • A short review on Parkinson’s & the gut microbiota (Click here to read more about this).

  • Post-GWAS knowledge gap: the how, where, & when genetic risk loci contribute to Parkinson’s – a review advocating for more funding towards the exploration of the fundamental biology in post-GWAS studies (Click here to read more about this).
  • New review explores the potential of genome editing in Parkinson’s (Click here to read more about this).
  • An overview of the NRF2/ARE pathway & its role in neurodegenerative conditions (such as Parkinson’s – click here to read more about this).
  • A useful new review exploring the current perspectives on the assessment & management of gait disorders in Parkinson’s; from cholinesterase inhibitors to spinal cord stimulation – it’s all here! (Click here to read more about this).
  • Systematic review explores which exercise/training-based interventions are most effective for freezing of gait in Parkinson’s; Moderate effect size favor various targeted training modes, but no generic exercise (Click here to read more about this).

  • New review explores Src family kinases – critical regulators of microglial homeostatic functions & neurodegeneration in Parkinson’s & Alzheimer’s (Click here to read more about this).
  • New review explores the impact of noncoding variants in neurodegenerative brain conditions, like Parkinson’s; “noncoding elements might also contribute to diagnosis & therapy. Different classes of ncRNAs can act as diagnostic biomarkers” (Click here to read more about this).
  • Amyloid-β & α-synuclein immunotherapy: From experimental studies to clinical trials” – regardless of outcomes, what a resource! A very thorough review of the research in Alzheimer’s & Parkinson’s (Click here to read more about this).

  • New review explores the immunogenicity of midbrain dopaminergic neurons & the implications for neural grafting trials in Parkinson’s; “We have only a very limited understanding of the immunogenicity”- more studies are needed (Click here to read more about this).
  • For me, 14-3-3s proteins have always been like that person at a party on the other side of the room that you’ve never met, but keep meaning to. This review makes a useful introduction, & explores how they could be influencing Parkinson’s (Click here to read more about this).
  • Seeking progress in disease modification in Parkinson’s (Click here to read more about this).
  • The enigma & implications of brain hemispheric asymmetry in neurodegenerative conditions like Parkinson’s (Click here to read more about this).

  • A useful review of novel therapies for Parkinsonian Syndromes (particularly the table on Progressive supranuclear palsy (PSP) trials; Recent progress & future perspectives (Click here to read more about this).
  • A systematic review & meta-analysis on the benefits of cycling for Parkinson’s, particularly for motor performance & improving crucial features of gait (Click here to read more about this).
  • Rather than testing disease modifying therapies on individuals with established Alzheimer’s, are Parkinson’s patients at risk of developing concomitant AD an ideal target population for experimental AD therapeutics? (Click here to read more about this).
  • Four commonsense ways to improve FDA’s accelerated approval pathway (Click here to read more about this).
  • A useful overview of our knowledge of herbal medicines (& their bioactive components) that are being researched in Parkinson’s; Includes summaries of 32 Chinese herbal medicines (Click here to read more about this).

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

And there it is, just some of the highlights from September 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 October!!!

All of the material on this website is licensed under a
Creative Commons Attribution 4.0 International License
You can do whatever you like with it!


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.


3 thoughts on “Monthly Research Review – September 2021

    1. Hi Zebradoodle,
      Thanks for your comment. The next ambroxol trial is still being designed. It has been delayed due to issues like formulation. In the previous study, participants had to take 20+ pills of ambroxol per day (on top of their standard PD medication!). We now have a 3 pills per day reformulation which will hopefully make the next trial easier.
      Kind regards,
      Simon

      Like

  1. Thanks – I thought I read the Canadian Ambroxol trial is due to report at a conference this month. I can’t find the reference so could be wrong though.

    Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.