Monthly Research Review – November 2020

 

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

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

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

 


So, what happened during November 2020?

In world news:

November 2nd – While COVID antibodies do not appear to last very long (similar to seasonal flu), a new study suggests that another aspect of the immune response to a COVID infection can last more than 6 months. Analysis of blood samples from a cohort of 2000+ clinical and non-clinical healthcare workers (including 100 who tested seropositive for SARS-CoV-2) found that virus specific T cells were detectable more than six months after infection (Click here to read the study and click here to read a summary).

November 9th – Potential COVID vaccine #1 – Early data from the Pfizer/BioNTech Phase III trial indicates that their COVID vaccine is 90% effective (Click here to read more about this).

10th NovemberBest. Shot. Ever – During the US Masters practice round Jon Rahm hit an impossible hole in one:

 

16th November – Potential COVID vaccine #2 – biotech firm Moderna announced its coronavirus vaccine is 94.5% effective against COVID-19 (Click here to read more about this).

22nd November – New Zealand-based rocket company Rocket lab launched their ‘Return to Sender’ mission – the company’s 16th Electron rocket mission that deployed 30 small satellites into orbit (to date the company has launched 96 satellites), and they managed to recover the first stage of the vehicle. But more importantly, the flight also carried “Gnome Chompski” into space:

23rd November – Potential COVID vaccine #3 – a coronavirus vaccine developed by the University of Oxford (along with AstraZeneca) was reported to be highly effective (providing at least 70% protection – Click here to read more about this).

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

In November 2020, there were 885 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (9811 for all of 2020 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

1. The ANAVEX2-73 Phase II results

The results of a large Phase II clinical trial of ANAVEX®2-73 (also called blarcamesine – being developed by Anavex Life Science) was well tolerated (in oral doses up to 50 mg once daily) and it showed clinically meaningful, dose-dependent, & statistically significant improvements in cognitive tests (Click here to read more about this). The study was a 14 week double-blind, multicenter, placebo-controlled trial involving 132 participants. It will be interesting to see the results of the 48 week extension study (ongoing – Click here to read more about this).

2. Cell painting – a powerful new tool for Parkinson’s research

New biorxiv manuscript presented an unbiased, automated, deep learning phenotypic profiling platform for analysing cells in culture. The investigators applied it to cells collected from 91 people (including 46 cases of Parkinson’s). The trained machine learning models captured individual variations, allowing for the accurate identification of cells from specific people (even across different experiments & different plate layouts). The models also confidently separating LRRK2 & idiopathic Parkinson’s cells from cells collected from control cases. There is serious potential for drug screening applications here (Click here to read more about this and click here to read an SoPD post on this topic).

3.  Accelerating Medicines Partnership Parkinson’s (AMP PD)

A new medrxiv manuscript outlined a new platform: the Accelerating Medicines Partnership Parkinson’s (AMP PD) genetic resource – a solution to democratise data access/analysis for Parkinson’s research. Version 1 is now available and contains Whole Genome Sequencing data derived from 3,941 participants from 4 separate cohorts, including 2,005 idiopathic PD cases, 963 unaffected controls, 64 prodromal cases, 62 SWEDDs & 705 participants with GBA variants or LRRK2 variants, in which 304 were affected. An amazing resource and congrats to all the researchers who made it possible (Click here to read more about this and click here to see the website).

4.  Skin deep: A new biomarker?

Researchers associated with pharmaceutical company Roche have developed an automated bright‐field assay for assessing pathological alpha‐synuclein in patient skin biopsies from cases of iREM sleep behaviour disorder, Parkinson’s, & atypical parkinsonism cases (also unaffected control participants). The investigators found that “Punch biopsies were positive in 23 (82%) subjects with iREM sleep behavior disorder, 14 (70%) subjects with Parkinson’s, 2 (20%) subjects with atypical parkinsonism, & none (0%) of the control subjects“. A 3‐year follow‐up found that 8 of the iREM sleep behavior disorder cases converted to neurodegenerative conditions (Click here to read more about this).

5. The rise of DeepMind

While not specific to Parkinson’s, this achievement will have important implications for the condition: it was announced that the latest version of AlphaFold – an AI deep-learning program from Google’s DeepMind – made a gigantic step forward in solving the “protein folding problem”. More accurately determining the 3D shapes of proteins represents a transformational shift in biology. The accuracy of the software is measured on a range of 0-100. The latest version of AlphaFold has shifted the median score from the mid 60s in the last version to 92.4 across all targets (Click here to read more about this or watch the video below).

Basic biology news

  • RING-finger protein 166 (RNF166) plays a pro-apoptotic role in neurotoxin-models of Parkinson’s (via ubiquitination of XIAP-associated factor-1 (XAF-1)); RNF166 depletion suppressed 6-OHDA–induced caspase activation & apoptotis, reversed by XIAP knockdown (Click here to read more about this).
  • Researchers report that Rab29 knock-out or transgenic overexpression does not impact basal Parkinson’s-associated LRRK2 activity in wildtype & pathogenic mouse & cell line models (Click here to read more about this).
  • Inhibition of Parkinson’s-associated LRRK2 ameliorates dexamethasone-induced glucose intolerance (by preventing impairment in GLUT4 membrane translocation in adipocytes – click here to read more about this).
  • Researchers report that overexpression of α-synuclein by oligodendrocytes in transgenic mice does not recapitulate the fibrillar aggregation seen in Multiple System Atrophy (MSA – click here to read more about this).

  • Researchers present a fully automated high-throughput workflow for 3D-based chemical screening in human midbrain organoids – a useful single-cell drug screening platform for Parkinson’s research (Click here to read more about this).
  • Hsp70 family chaperones are good at disaggregating amyloid fibrils. A new biorxiv manuscript outlines mechanism of action of the Hsc70-DnaJB1-Apg2 chaperone system in disaggregating Parkinson’s-associated α-synuclein fibrils (Click here to read more about this).
  • New biorxiv manuscript presents an ATF6f-XBP1s fusion protein (“UPRplus”) that has stronger aggregation reducing effect on mutant huntingtin & Parkinson’s-associated alpha-synuclein (vs XBP1s or ATF6 alone); gene transfer in vivo as well (Click here to read more about this).
  • New biorxiv manuscript suggests a new regulatory role of α synuclein – regulation of VDAC-facilitated calcium transport – with implications for calcium signaling & Parkinson’s-associated mitochondrial dysfunction (Click here to read more about this).
  • New study reports that Riboflavin (vitamin B2) can attenuate NLRP3, NLRC4, AIM2, & non-canonical inflammasomes, by the inhibition of caspase-1 activity (in vitro & in vivo); vitamin B6 has no effect (Click here to read more about this).

  • New report finds PREP (Prolyl oligopeptidase) inhibition by KYP-2407 increases Parkinson’s-associated alpha-synuclein fibril lysosomal degradation in vitro (SH-SY5Y cells, but no effect on astrocytic αSYN – click here to read more about this).
  • New biorxiv manuscript suggests that Cyclin G-associated kinase (GAK) & Protein Kinase C Delta (PRKCD) are novel regulators of PARKIN independent mitophagy (Click here to read more about this).
  • New biorxiv manuscript presents gene-edited Parkinson’s neurons that show the A30P alpha-synuclein point mutation leads to reduced neuronal branching & function; mutant cells more susceptible to the environmental pesticide Rotenone (Click here to read more about this).
  • Expression, purification & characterisation of Parkinson’s-associated alpha synuclein fibrillar specific scFv from inclusion bodies (Click here to read more about this).
  • New report presents an organelle-interaction network analysis that “opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation” – focused on mitochondria in Parkinson’s (Click here to read more about this).
  • New biorxiv manuscript finds Parkinson’s-associated fibrillar α-synuclein induces neurotoxic astrocyte activation (via RIP kinase signaling & NF-κB); necroptosis-independent RIPK signaling coordinating inflammation (Click here to read more about this).
  • New report presents passive controlled flow for Parkinson’s neuronal cell culture in 3D microfluidic devices; Continuous flow of medium for 24 h culture periods (Click here to read more about this and click here to read the press summary).

  • Researchers present “LYTL” (LYsosomal Tubulation/sorting driven by LRRK2) – a new cellular process for maintaining lysosomes, controlled by Parkinson’s-associated LRRK2 (Click here to read more about this).
  • New biorxiv manuscript suggests that highly conserved, multifunctional 14-3-3s reduces propagation & toxicity of pathologic Parkinson’s-associated alpha-synuclein in the in vivo preformed fibril model (Click here to read more about this).
  • NAB2 rescues α-synuclein trafficking defects associated with early onset Parkinson’s in a Nedd4-dependent manner. Now researchers further characterize the mechanism of action (Click here to read more about this).
  • Researchers propose a novel propagated alpha synucleinopathy-based REM sleep behaviour disorder mouse model, recapitulating some of the features of the phenoconversion from RBD to Parkinson’s in this animal model (Click here to read more about this).
  • Researchers report a novel role for kynurenine 3-monooxygenase in mitochondrial dynamics; interacts with the Parkinson’s-associated genes Pink1 & Parkin, plus the mitochondrial fission gene Drp1 (in flies – click here to read more about this).
  • Using IBM’s Watson for Drug Discovery, researhcers identified several antihypertensive drugs that may reduce Parkinson’s-associated a-Syn oligomerization. Using IBM MarketScan Research Databases, they reveal associations for time to PD diagnosis (Click here to read more about this)

  • A new biorxiv manuscript presents essential structural properties & potential conformations that promote Parkinson’s-associated α-synucleins various functions in membrane interaction or oligomer & fibril formation (Click here to read more about this).
  • New biorxiv manuscript suggests that the lipid profile of fibroblasts derived from cases of GBA-associated Parkinson’s differed significantly from those of control & iPD cases. An indicator of increased risk for α-synuclein pathology? (Click here to read more about this).
  • A new biorxiv manuscript presents a protocol to enrich for Parkinson’s-associated Lewy pathology from formalin fixed human primary tissues, which allows the determination of molecular signatures of Lewy pathology (Click here to read more about this).
  • New research indicates dopamine receptor D3-signalling is a major regulator of regulatory T cells upon gut inflammation; Drd3 deficiency in mice confers a stronger immunosuppressive potency to Treg, attenuating a model of inflammatory colitis (Click here to read more about this).
  • Comparmentalisation of the rodent striatum: A novel giant non-cholinergic striatal interneuron – that is restricted to the ventrolateral striatum + coexpresses Kv3.3 potassium channel, parvalbumin, & the vesicular GABA transporter – has been identified (Click here to read more about this).
  • New research reports that the Japanese Parkinson’s medication Zonisamide can ameliorate the voltage-dependence alteration of the T-type calcium channel CaV3.1 caused by a mutation responsible for spinocerebellar ataxia (Click here to read more about this).

  • New biorxiv manuscript suggests Rab27 GTPases regulates Parkinson’s-associated alpha-synuclein uptake, cell-to-cell transmission, & toxicity (both in vitro & in vivo – click here to read more about this).
  • A new study reports changes in striatal medium spiny neuron morphology resulting from dopamine depletion are reversible (MPTP mouse model of Parkinson’s – click here to read more about this).
  • A new biorxiv manuscript presents genome-wide identification of the genetic basis of Amyotrophic Lateral Sclerosis (ALS); they identified a group of 690 candidate genes which is enriched with previously discovered ALS risk genes (Click here to read more about this).
  • A new biorxiv manuscript presents data shedding light on the amyloidogenic phenomenon of flaviviral protein; The capsid-anchor of Zika forms cytotoxic amyloid-like fibrils in mammalian cells (Click here to read more about this).
  • “A reference study to apprehend glucocerebrosides-related literature at a global level” Researchers use the science citation index expanded database (1956—present) to identify trends in glucocerebrosides research – Parkinson’s gets a mention (Click here to read more about this)
  • Researchers present data revealing a conserved cell protective pathway that counters mitochondrial oxidative stress (via ATP13A2-mediated lysosomal spermine export – click here to read more about this).

  • Interesting patent highlight on a PROTAC approach for degrading LRRK2 as a treatment for Parkinson’s (Click here to read more about this).
  • New report suggests that RPTPβ/ζ plays a role in the neurotrophic phenotype of microglia, neuroinflammation, & in microglia-neuron communication (Click here to read more about this).
  • New report explores the cryopreservation of human midbrain dopaminergic neural progenitor cells poised for neuronal differentiation; comparison of 6 commercial cryopreservation media & different freezing conditions (Click here to read more about this).
  • New report finds that the MHC class II transactivator (Mhc2ta) modulates neuroinflammation, α-synuclein-seeded Lewy-like pathology, dopaminergic neurodegeneration & motor impairment in a rodent model of Parkinson’s (Click here to read more about this).
  • Researchers report that Parkinson’s-associated α-synuclein promotes islet amyloid polypeptide fibril formation in vitro & β-cell amyloid formation in vivo in mice – more data for the association between diabetes & PD (Click here to read more about this).
  • Researchers report an α-Cyanostilbene derivative for the enhanced detection & imaging of amyloid fibril aggregates; a promising alternative to ThT for the in vitro study of amyloid fibrils (Click here to read more about this).
  • Neuraly’s GLP-1R agonist NLY01 (which is being Phase II clinically tested in Parkinson’s) reduces retinal inflammation & neuron death secondary to ocular hypertension in a mouse model of glaucoma (Click here to read more about this).

  • “This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by late-onset Alzheimer’s” – ATP6V1A gets highlighted & pharmacologically targetted (Click here to read more about this).
  • A new report finds that in the absence of Hop/Sti1, eukaryotic cells may be able to shift to a more prokaryote-like mode of operation for the Hsp70-Hsp90 systems; “invention” of Hop shifted us from refolding to proteasomal degradation? (Click here to read more about this).
  • Researchers at Roche identify novel β‐Glucocerebrosidase activators that bind to a new pocket at a dimer interface, induce dimerization, & increase substrate metabolism in the lysosome; interesting development for GBA-associated Parkinson’s (Click here to read more about this).
  • New report identifies EIF2AK2 variants implicated in early‐onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo (Click here to read more about this).
  • More research on direct conversion of skin cells (fibroblasts) to dopamine neurons using a chemical cocktail of small molecules & proteins – without passing through a neural progenitor/stem cell intermediate stage. Useful protocol of Parkinson’s research? (Click here to read more about this).

 

  • A comparison of 170 common & disease-specific post-translational modifications (PTMs) of pathological Tau associated with a wide range of tauopathies indicates that differences in PTMs reflects differences in tau filament core structures across conditions (Click here to read more about this).
  • Wnt signalling again! New research reports that the D620N variant of VPS35 causes the impairment of Wnt/β-catenin signaling cascade & mitochondrial dysfunction in a Parkinson’s-associated PARK17 knockin mouse model (Click here to read more about this).

 

Disease mechanism

  • Human dopaminergic neurons lacking Parkinson’s-associated PINK1 exhibit disrupted dopamine metabolism related to vitamin B6 co-factors; Does a reduction of mitochondrial membrane potential have neurometabolic consequences relevant to PD? (Click here to read more about this).
  • Safety assessment of AAV2-hGDNF administered via intracerebral injection in rats for treatment of Parkinson’s (Click here to read more about this).

  • Researchers report that mitochondrial UQCRC1 mutations “cause autosomal dominant parkinsonism with polyneuropathy”; Whole exome sequencing + in vitro & in vivo studies “support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism (Click here to read more about this).
  • SK609 is a D3R agonist & NET inhibitor that promotes improvement in cognitive task performance in rodent & non-human primate models of Parkinson’s (Click here to read more about this).
  • eIF2α kinase heme-regulated inhibitory (HRI) induced the autophagic clearance of cytosolic protein aggregates; aged HRI-/- mice exhibit accumulation of Parkinson’s-associated misfolded α-synuclein (Click here to read more about this).
  • Novel iron chelator, CN128, reported to mitigate the formation of dopamine oxidation products associated with the progression of Parkinson’s in models of PD; found to be superior to deferiprone; potential for prodromal application? (Click here to read more about this).
  • New biorxiv manuscript suggests the industrial solvent trichloroethylene induces LRRK2 kinase activity & dopaminergic neurodegeneration in a rodent model of Parkinson’s; Moderate, systemic TCE resulted inUpwards arrowLRRK2 kinase activity (Click here to read more about this).

  • An analysis of somatic mutations targeting genes associated with Parkinson’s indicates that coding somatic SNVs in neurodegeneration are rare, but other types of somatic variants may have consequences (Click here to read more about this)
  • Researchers find RNA-binding protein SPEN (an astrocyte-expressed gene) is differentially expressed in the Parkinson’s substantia nigra; in drosophila model it regulates lipid metabolism & storage, contributing to neuroprotection (Click here to read more about this).
  • Orally administered Porphyromonas gingivalis impairs gut permeability & mediates immune responses associated with neurodegeneration in mouse model of LRRK2 (R1441G)-associated Parkinson’s (Click here to read more about this).
  • Chemically modified tetracycline 3 (CMT-3) – a doxycycline derivative with reduced antibiotic activity – targets different Parkinson’s-associated α-synuclein aggregates mitigating their toxic & inflammatory effects (Click here to read more about this).
  • New report asks if pathogenic NUBPL variants can increase the risk for Parkinson’s analogous to variants in the GBA1 gene that increase the risk of developing PD in heterozygous carriers? (Click here to read more about this).
  • Mirtazapine (a noradrenergic & specific serotonergic antidepressant) attenuates loss of dopamine neurons & increases the expression of the antioxidative molecule metallothionein in model of Parkinson’s; highlights astrocytic 5-HT1A receptors as new target (Click here to read more about this).

  • New biorxiv manuscript provides more evidence of the ability of tetracyclic antibiotic doxycycline to inhibit Parkinson’s-associated α-synuclein pathologies in both in vitro & in vivo models (Click here to read more about this).
  • To “rigorously characterize the determinants of spreading”, researchers injected PFF alpha synuclein into the mouse pedunculopontine nucleus. They found “neuronal phenotype governs the somatodendritic uptake” of Parkinson’s-associated α-synuclein (Click here to read more about this).
  • New research suggests that PARKIN substrate AIMP2 may play a critical role in Lewy body formation; it accelerates formation of α-synuclein aggregates, plus knockdown ameliorates aggregation & dopaminergic cell death in models of Parkinson’s (Click here to read more about this).
  • Researchers report the molecular dissection of amyloid disaggregation by human HSP70, finding that DNAJB1 specifically recognizes the oligomeric form of α-synuclein via multivalent interactions, & selectively targets HSP70 to fibrils (Click here to read more about this).
  • New paper reports acquired dysregulation of dopamine homeostasis (via siRNA of VMAT2) reproduces features of Parkinson’s (oxidative damage, activation of LRRK2, & aberrant α-synuclein); rescued by exogenous VMAT2 (Click here to read more about this).
  • Researchers report reduced astrocytic reactivity in human brains & midbrain organoids with Parkinson’s-associated PRKN mutations. Is this evidence of “an astrocyte-related non-autonomous cell death mechanism for dopaminergic neurons”? (Click here to read more about this).
  • Microglial (but not astroglial) activation is associated with Parkinson’s-associated α-synuclein propagation in the mouse striatum (Click here to read more about this).
  • Viral-based rodent & nonhuman primate models of multiple system atrophy (Click here to read more about this).
  • Researchers report that Parkinson’s-associated alpha synuclein aggregates increase the conductance of substantia nigra dopamine neurons; this effect is partly reversed by the diabetes medication KATP channel inhibitor glibenclamide (Click here to read more about this and click here to read the associated press summary).
  • A statin & HDAC inhibitor combo: A dual inhibitor targeting HMG-CoA reductase & histone deacetylase mitigates neurite degeneration in LRRK2-G2019S model of Parkinson’s (in vitro – click here to read more about this).
  • A new biorxiv manuscript reinforces the idea that the LRRK enzymes have evolved as major regulators of Rab biology; Interesting: Widely used LRRK2 inhibitors being developed for Parkinson’s do not inhibit LRRK1 (Click here to read more about this).
  • Desipramine – a commonly used as a noradrenergic neuroprotectant in models of Parkinson’s – leads to local functional changes in the urinary bladder & gastrointestinal tract in healthy rats (Click here to read more about this).

  • A new biorxiv manuscript suggested age-related adjustments to Parkinson’s-associated PARKIN protein in the human midbrain is linked to redox balance & sequestration of reactive dopamine metabolites. The researchers reported that in the normal human brain PARKIN protein is largely insoluble after age 40 years, which is linked to its oxidation. “The loss of these redox effects may augment oxidative stress in dopamine producing neurons of mutant PRKN allele carriers, thereby contributing to neurodegeneration” (Click here to read more about this – an SoPD post is in production).

 

Clinical research

  • The Cincinnati Cohort Biomarker Program (CCBP) – a population-based, phenotype-agnostic longitudinal study; hypothesis-free, reverse biology-to-phenotype direction of biomarker development. Total of 4,000 patients with neurodegenerative conditions & 1,000 healthy age-matched controls with yearly follow-up for at least 5 years, extended to 10; The design is “based on the assumption we do not know which biomarkers have clinical relevance at the individual level”; “Accordingly, the recruitment will be deliberately inclusive of different neurodegenerative phenotypes with the expectation that biological subtypes may not align with clinico-pathological subtypes” (Click here to read more about this).

  • An analysis of nonlinear changes in age-related microRNAs (using whole blood from 1334 healthy individuals & 3059 patients – including 944 Parkinson’s cases) notes how common diseases alter the physiological age-related profile of blood microRNA. Curiously, “With the exception of Parkinson’s, these data show that aged healthy & diseased individuals are more similar than younger healthy & diseased individuals, perhaps suggesting that aged healthy individuals share some phenotypic characteristics of heart & lung disease” (Click here to read more about this).
  • Swallowing assessment in Parkinson’s: Patient & investigator reported outcome measures are not aligned (Click here to read more about this).
  • Pilot of the Agility Boot Camp with Cognitive Challenge (ABC-C) exercise intervention found to improve balance deficits, cognitive-gait interference, & quality of life, especially in participants with more severe Parkinson’s; longer investigation required (Click here to read more about this).
  • New report presents insights into the differential transcript usage (DTU) in Parkinson’s & identifies novel disease-associated genes. They propose that DTU may have important functional consequences in the PD brain (Click here to read more about this)
  • Researchers report that there is no evidence for involvement of UQCRC1 in Europeans Parkinson’s cohorts (Click here to read more about this).
  • Constipation & REM sleep behaviour disorder associate with processing speed & attention more prominently in males with Parkinson’s over a 5-year follow-up (Click here to read more about this).

  • “Following the publication of positive trials, specialized allied healthcare delivery was successfully scaled for patients with Parkinson’s in The Netherlands, potentially serving as a template for other healthcare innovations” (Click here to read more about this).
  • New report proposes that cortical disinhibition is a very early, possibly prodromal feature of Parkinson’s (Click here to read more about this).
  • Cognitive/motivational differences between tremor & non-tremor Parkinson’s. Researchers report that the effects of dopamine medication on reinforcement learning in PD depends on the motor phenotype (Click here to read more about this).
  • REM sleep‐behavior disorder was more likely to develop in dementia with Lewy bodies than Parkinson’s disease or Parkinson’s disease dementia, & in men than women”; Researchers also report RBD “did not increase mortality risk within our cohort” (n=444)
    (Click here to read more about this).
  • A Japanese cohort study of autopsy cases reports that Lewy pathology of the esophagus correlates with the progression of Lewy body disease. 518 autopsy cases involved (includes cases of Parkinson’s); 178 cases (34%) had Lewy pathology, 78 in esophagus (Click here to read more about this).
  • A vision of a completely molecular-based definition of disease. Researchers use ADNI & PPMI data + unsupervised machine learning techniques to identify 4 mixed Alzheimer’s & Parkinson’s patient clusters based on SNP burden scores of common AD/PD mechanisms (Click here to read more about this).

  • New research finds that the width of the 3rd ventricle/internal skull diameter significantly lower in Parkinson’s than progressive supranuclear palsy (PSP). The sensitive and specificity of the measure was assessed across two cohorts (training and testing), and valid in early and advanced disease (Click here to read more about this).
  • Under-represented communities: Researchers report that rare Parkinson’s-associated LRRK2 pathogenic variants reported in Caucasians, Asians, & persons of mixed ancestry are absent in West Africans (Click here to read more about this).
  • Is freezing of gait correlated with postural control in patients with moderate‐to‐severe Parkinson’s disease? (Click here to read more about this).
  • Synchrotron FTIR micro-spectroscopy reveals β-sheet structure in Lewy bodies in patients with Parkinson’s is significantly higher than that in glial cytoplasmic inclusions in patients with multiple system atrophy (MSA – click here to read more about this).
  • New medrxiv manuscript suggests disease-specific differences in COVID-19 susceptibility among individuals affected by neurodegenerative conditions. Parkinson’s patients were found to be at increased risk of infection but NOT mortality from COVID-19. This study of primary health records of 13,338 UK individuals tested for COVID-19 between March & July 2020; low numbers, needs replication; Interesting discussion of potential examplations (“…disruption of the lysosomal machinery needed for viral replication… – click here to read more about this).

  • Pathological case study of a 52 yr old gentleman with alpha-synuclein p.A53T & familial Parkinson’s; severe cell loss in nigra, locus coeruleus, & dorsal nuc. of the vagus; Widespread cortical Lewy bodies, mild tau pathology, & absence of TDP-43 pathology (Click here to read more about this).
  • Opicapone can be an effective additional treatment for wearing off in Parkinson’s; but prior entacapone exposure was associated with higher rates of adverse effects & treatment discontinuation than reported in published trial data (Click here to read more about this).
  • Researchers propose that orthogonal markers for LRRK2 inhibition in urine & CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics that are being developed for Parkinson’s (Click here to read more about this).
  • New medrxiv manuscript presents the most comprehensive characterization of Parkinson’s genetic architecture in Latinos to date; 807 cases vs 690 controls, replication cohort=1,234 cases vs 439,522 controls (Click here to read more about this).
  • You’ve heard of the gut microbiome? What about gut mycobiome? Researchers report signifly lower fungal DNA relative to bacterial DNA among Parkinson’s patients. No fungi differed in abundance (PD vs controls), nor any assoc. with motor, cognitive, etc (Click here to read more about this).

  • A new biorxiv manuscript suggests that vesicular glutamate transporter (VGLUT) mediates vulnerability to age-related dopamine neurodegeneration in a sex-dependent manner; mechanism for sex differences in Parkinson’s? (Click here to read more about this).
  • Could cerebrospinal fluid levels of Kininogen‐1 (KNG1) indicate early cognitive impairment in Parkinson’s? New data from a multicenter study indicates KNG1 is associated with low MoCA total scores, independent of sex, disease duration, & other confounders (Click here to read more about this).
  • Gait progression over 6 years in Parkinson’s: Effects of age, medication, & pathology; “Gait impairment progressed irrespective of dopaminergic medication change” (Click here to read more about this).
  • Both subthalamic & globus pallidus internus deep brain stimulation reduce Parkinson’s-associated action & rest tremor at 12 month follow up (Click here to read more about this).
  • A systematic analysis of essential tremor‐associated genes in early‐onset Parkinson’s finds rare loss‐of‐function & damaging missense variants of TNEM4 are suggestively associated with EOPD (P = 0.026 – Click here to read more about this).
  • A new Medrxix manuscript presents a systematic review and meta-analysis suggesting Type 2 diabetes as a determinant of Parkinson’s risk and progression (Click here to read more about this).

  • New report presents automated analysis of corneal confocal microscopy which detects small fibre neurodegeneration in Parkinson’s; 98 PD vs 26 controls; significant differences observed (Click here to read more about this).
  • New medrxiv manuscript suggests six circRNAs derived from MAPK9, HOMER1, SLAIN1, DOP1B, REPS1, & PSEN1 transcripts are significantly downregulated in peripheral blood of Parkinson’s patients; potential diagnostic biomarkers? (Click here to read more about this).
  • High-throughput & hypothesis-free functional genomic analyses uncover APOE-mediated regulation of brain & cerebrospinal fluid beta-amyloid levels in Parkinson’s – demonstrating a link between PD genetic risk, CSF Aβ42, & APOE locus (Click here to read more about this).
  • The SPID-GBA study“: The results of a large monocentric study of Sex distribution, Penetrance, Incidence, & Dementia in individuals with the for most frequent deleterious variants of GBA-associated Parkinson’s (Click here to read more about this).
  • Researchers report a blinded, controlled trial of objective measurement in Parkinson’s (Click here to read more about this).
  • A pilot study to determine if Google glass technology can improve freezing of gait in Parkinson’s? Preliminary data suggests that some walking tasks may improve with visual-auditory cues (Click here to read more about this).

  • New report exploring current assessment methods & wearable devices for evaluation of motor symptoms in Parkinson’s, taking a patient & healthcare professional perspective – useful points of view (Click here to read more about this).
  • Researchers aimed to identify a brain‐clinical signature that predicts conversion to synucleinopathy/dementia in 48 polysomnography‐confirmed REM sleep behavior disorder (iRBD) cases; new biomarkers for risk reduction strategies, & neuroprotective trials? (Click here to read more about this).
  • A US claims database analysis neuropsychiatric comorbidities in Huntington’s & Parkinson’s (n=587 matched cases) finds dementia, depression & anxiety more common in HD vs PD (Click here to read more about this).
  • “Lewy body synucleinopathies entail cardioselective peripheral noradrenergic deficiency… a better understanding of basis for this selectivity may apply also to the unusual susceptibility of nigrostriatal dopaminergic neurons in Parkinson’s” (Click here to read more about this).
  • New biorxiv manuscript suggests motor sequence learning deficits in idiopathic Parkinson’s are associated with increased substantia nigra activity; no diff btwn PD & controls in task modulation of cortico-striato-cerebellar network (Click here to read more about this).
  • Adopting virtual visits for Parkinson’s patients during the COVID-19 pandemic in Egypt – the challenges & solutions (Click here to read more about this).

  • REM Sleep Behavior Disorder (RBD) occurs in the majority of a cohort carrying the Parkinson’s-associated p.A53T alpha-synuclein gene (SNCA) genetic variant. Hyposmia was also present in almost all of the individuals with RBD (Click here to read more about this).
  • Longitudinal analysis of anthropometric & serological markers indicates that blood pressure, haematocrit & serum cholesterol levels are potential premotor markers of PD Parkinson’s; some changes before PD motor symptoms onset may be sex specific (Click here to read more about this).
  • A new medrxiv manuscript explores using genome-wide homozygosity mapping to identify potential early onset Parkinson’s genes; MIEF1 gets highlighted (Click here to read more about this).
  • Public service announcement: DNAJC13, UCHL1, HTRA2, GIGYF2, & EIF4G1 should NOT be PARK genes. Researchers provide further analysis on determining which genes should be defined as Parkinson’s-associated (Click here to read more about this).
  • A nationwide propensity score-matched longitudinal follow-up study using Taiwan’s National Health Insurance Research Database suggests that osteoporosis is related to an increased risk of Parkinson’s (HR=1.31; p=0.0002), especially among women (HR=1.50 – click here to read more about this).
  • Under-represented communities: Clinical & epidemiological aspects of Parkinson’s in the south of Western Siberia; N=140; “cohort tends to be more prevalent in hyposmia, daytime sleepiness, orthostatic hypotension, depressive, & REM disorders” (Click here to read more about this).

  • New report explores supervised classification of bradykinesia in Parkinson’s disease from smartphone videos of finger-tapping tests (Click here to read more about this).
  • Interesting case study of a 61-year-old woman with bilateral Parkinsonism caused by unilateral infarction; “When patients show bilateral parkinsonism, it is important to consider infarction of the lenticulostriate arteries” (Click here to read more about this).
  • New research paper reports a lack of evidence supporting an association between UQCRC1 genetic variants & Parkinson’s in the European population (Click here to read more about this).
  • New medrxiv manuscript investigates immune & brain cells; they show significant enrichment of Parkinson’s heritability in open chromatin regions of microglia (stronger than neurons) & they highlight P2RY12as (Click here to read more about this).
  • Results of a randomized cross-over pilot study indicate that low-frequency transcranial stimulation of pre-supplementary motor area may help alleviate levodopa-induced dyskinesia in Parkinson’s (Click here to read more about this).
  • Dance like nobody’s watching! New research explores the role of dance-based interventions in perceived well-being & bodily awareness in people with Parkinson’s. A nice quote from one of the participants: “People that have been diagnosed & living with it way longer than me, are still getting up & dancing. In fact, it’s amazingly encouraging, & it keeps you going really” (Click here to read more about this).

  • Pathogenic Huntingtin repeat expansions popping up (VERY rarely; <0.5%) in individuals with Frontotemporal Dementia/Amyotrophic Lateral Sclerosis spectrum diseases; not seen in healthy controls or Lewy body dementia cases. The fascinating part is that in the postmortem analysis, in two of the expansion cases neostriatal atropy – which pathologically defines Huntington’s – was absent in both cases, despite Htt aggregates being present (Click here to read more about this).
  • New research reports a distinct neuromelanin magnetic resonance imaging pattern that allows for the differentiation of the parkinsonian variant of multiple system atrophy from Parkinson’s & unaffected controls (Click here to read more about this).
  • New research from the COPPADIS study in Spain reports that depression is associated with impulse-compulsive behaviors in Parkinson’s (Click here to read more about this).
  • Researchers explore components of the peripheral immune response that are correlated with diagnoses of Alzheimer’s or Parkinson’s. Single-cell peripheral immunoprofiling (n=132) highlights enhanced PLCγ2 as a potential new for AD (Click here to read more about this).

 

New clinical trials

  • Interesting new clinical study registered: The sensitivity & specificity of canine detection of Parkinson’s. A multicenter, double-blind study in China on the sensitivity & specificity of sniffer dogs as a tool for detecting PD; n=300 participants (Click here to read more about this).

  • Interesting new clinical trial registered: Adaptive neurostimulation to restore sleep in Parkinson’s; recruiting 20 participants for this observational study (Click here to read more about this).
  • New clinical trial registered: An 8 week interventional study recruiting 50 individuals with Parkinson’s who will be randomized to either 1) traditional multi-modal training, or 2) augmented reality multi-modal training (Click here to read more about this).
  • New clinical trial registered: Uncovering a novel therapeutic Target to Reduce dementia risk In Parkinson’s (the TRIP study); the researchers will conduct a double-blind, randomised-controlled, within-subject crossover study of Levetiracetam (Click here to read more about this).

 

Clinical trial news

  • A 12-month, dose-level blinded safety/efficacy study of levodopa inhalation powder (CVT-301; Inbrija) in individuals with Parkinson’s reports OFF time improved & no worsening of pulmonary function (Click here to read more about this).

  • Neuraly received US FDA clearance of investigational new drug application to initiate a Phase 2B trial of GLP-1R agonist NLY01 for patients with Alzheimer’s; NLY01 is currently being clinically tested in Parkinson’s (Click here to read more about this).
  • The results of the “PDSAFE” study have been published. This was a multi-dimensional model of falls-rehabilitation for people with Parkinson’s. A mixed methods analysis of therapists’ delivery & experience (Click here to read more about this) – the PD-SAFE team below:

  • The rationale & design of the PAIRED Trial: Partnered dance aerobic exercise as a neuroprotective, motor, & cognitive intervention in Parkinson’s (Click here to read more about this).
  • A protocol for identifying individual response patterns (using a single-subject research design) in high-intensity interval cycle ergometer training in Parkinson’s (Click here to read more about this)
  • The open‐label extension data of the Phase 2 Georgetown study of Nilotinib in Parkinson’s has been published; long‐term nilotinib treatment was safe/tolerated; but study was underpowered, preventing meaningful efficacy analysis (Click here to read more about this).

  • Results of the INFLAPARK study indicate increased microglial activation in nigro-striatal pathway & frontal cortex of individuals with Parkinson’s (using [18F]-DPA714 TSPO PET imaging); not correlated with markers of disease progression, but useful tool (Click here to read more about this).
  • Researchers present the protocol for the randomised double-blind placebo-controlled Phase II clinical trial evaluating azathioprine immunosuppression on disease modification in Parkinson’s (the AZA-PD study – click here to read more about this).

 

Other news

  • Biotech firm AlzeCure Pharma has the green light to start Phase I testing of their lead candidate ACD856, being developed for cognitive impairment (Click here to read more about this).
  • Biogen’s experimental Alzheimer’s disease therapy failed to gain support from an FDA panel (Click here to read more about this).

  • Annovis Bio announced the completion of their toxicology studies for ANVS401 (aka Posiphen). The company can now move forward with longer-term clinical trials for Parkinson’s; also announcing interim data on their Phase 2a trial in Q1 2021 (Click here to read more about this).
  • Biotech firm Escape Bio have published their high-throughput screening study to identify a single selective compound that preferentially inhibits Parkinson’s-associated G2019S-LRRK2 kinase activity (Click here to read more about this).

  • Another pharma supporting another genetic testing initiative: Sanofi announces that they are sponsoring The Parkinson’s Foundation’s genetic study (“PD GENEration”) with $1million for free testing (Click here to read more about this).
  • Biotech firm Caraway Therapeutics has announced that it has received a research grant from the Michael J Fox Foundation to further investigate the function of the lysosomal ion channel TMEM175 & gene variants linked to Parkinson’s (Click here to read more about this).
  • Interesting write up on Clene Nanomedicine’s lead therapy CNM-Au8, a bioenergetic nanocatalyst being developed as an add-on treatment for neurodegenerative conditions like Parkinson’s, multiple sclerosis & ALS (Click here to read more about this).

  • South Korean biotech firm Peptron has signed a licensing agreement with Harvard University to evaluate their sustained-release exenatide treatment, PT320, as a possible treatment candidate for Alzheimer’s (Click here to read more about this).
  • Interesting piece from Axial Theapeutics discussing the harnessing the gut–brain axis to develop CNS therapeutics, particularly for conditions like Parkinson’s & autism (Click here to read more about this).

Review articles/videos

  • A useful review of gene & cell-based therapy approaches for Parkinson’s (Click here to read more about this).
  • A review of the challenges & translational considerations of mesenchymal stem/stromal cell therapy for Parkinson’s (Click here to read more about this).
  • A new reviews asks if Interleukin-17A is the key cytokine in neurodegenerative conditions like Parkinson’s? (Click here to read more about this).
  • Expert review & commentary on globus pallidus internus (GPi) deep brain stimulation for Parkinson’s; everything you need to know (history, anatomy, future areas of research,.. – click here to read more about this).

  • A very useful guide to all things related to nanoparticle technology for drug delivery in Parkinson’s (Click here to read more about this).
  • New perspective discusses the use of multi-organ culture systems to better research Parkinson’s; “brain diseases should be viewed in the context of a similar multi-organ configuration” (Click here to read more about this).
  • Temporal interference is a non-invasive neurostimulation technique that utilizes high-frequency external electric fields to stimulate deep neuronal structures without affecting superficial, off-target structures” (Click here to read more about this).
  • A useful review to brush up on the role of Parkinson’s-associated PINK1/PARKIN signalling in neurodegeneration & neuroinflammation (Click here to read more about this).

  • Aging & neurodegenerative conditions: Is the adaptive immune system a friend or foe? Has a good section of Parkinson’s (Click here to read more about this).
  • Mitochondrial dysfunction & Parkinson’s. “While the link between mitochondrial dysfunction & PD is well-established, the precise sequence of events leading to mitochondrial disruption remains to be fully elucidated” (Click here to read more about this).
  • A review of the current status of stem cell-derived therapies for Parkinson’s: From cell assessment & imaging modalities to clinical trials (Click here to read more about this).
  • Interesting summary on potential pathogenic & protective roles of extracellular vesicles in neurodegenerative conditions, like Parkinson’s (Click here to read more about this)
  • A suggested framework for the treatment of sleep dysfunction in neurodegenerative conditions like Parkinson’s (Click here to read more about this).

  • Modernizing daily function assessment in Parkinson’s: A viewpoint discussing the differences & interdependencies of capacity, perception, & performance assessment types using the example of PD (Click here to read more about this)
  • A useful review on loss of olfactory function: From early indicator for COVID-19 & other viral infections to neurodegenerative conditions (like Parkinson’s); Curious: with aging & loss of sense of smell, “men are stronger afflicted than women” (Click here to read more about this)
  • Could exosomal microRNAs & oxidative stress be playing a role in neurodegenerative conditions? A useful short section on Parkinson’s in this review (Click here to read more about this).
  • Interesting discussion on how the eye could be considered as a complementary experimental model to identify possible novel disease pathways or to test new therapeutic approaches (Click here to read more about this).

  • A review on dissecting the non-neuronal cell contribution to Parkinson’s pathogenesis using induced pluripotent stem cells (Click here to read more about this).
  • “By country, it may have worked in Spain but not Italy, in the Netherlands but not Germany, the U.S. but not Canada”. Fascinating overview on the arguments for & against the potential approval of Biogen’s Alzheimer’s drug aducanumab. Lessons to be learnt, interesting comments section, etc (Click here to read more about this).
  • A useful review of endoplasmic reticulum stress/unfolded protein response & its potential involvement in Parkinson’s physiopathology (Click here to read more about this).
  • Exploring mitochondrial transplantation to resolve mitochondrial dysfunction in neurological disorders – an opportunity for Parkinsons? (Click here to read more about this).
  • The patients’ view of cannabis in Parkinson’s (Click here to read more about this).

  • A useful review of the role of cholesterol in α‐synuclein & Lewy body pathology in GBA-associated Parkinson’s (Click here to read more about this).
  • A useful review on the crucial balancing act that is autophagy & redox homeostasis in Parkinson’s (Click here to read more about this).
  • Keeping Parkinson’s-associated α-synuclein at bay. A review exploring a more active role of molecular chaperones in preventing mitochondrial interactions & transition to pathological states (Click here to read more about this).
  • Interesting short perspective: Genetics provides new individualized therapeutic targets for Parkinson’s – special emphasis on GBA1-associated PD (Click here to read more about this).

  • Useful review of the roles of microglia & astrocytes in neuroinflammation in neurodegenerative conditions, like Parkinson’s, Alzheimer’s, & ALS (Click here to read more about this).
  • A two-phase theory for age-associated neurodegenerative conditions like Alzheimer’s & Parkinson’s; SPOILER ALERT: the transition is triggered by oxidative stress (Click here to read more about this).
  • A useful review of ferroptosis mechanisms involved in neurodegenerative conditions, like Parkinson’s, Alzheimer’s & Huntington’s (Click here to read more about this).
  • New review presents examples of technology-enabled care under development for Parkinson’s & describes the potential challenges to achieving full integration of technology to address complex care needs (Click here to read more about this).
  • An interesting review on the effects of ketone bodies on brain metabolism & function in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).

  • A useful review focusing on extracellular chaperones in neurodegenerative conditions – summarising recent literature for each secreted chaperone (Parkinson’s gets a few mentions – Click here to read more about this).
  • A useful min-review on how intracellular alpha-synuclein & extracellular immune cells interact – implications for Parkinson’s (Click here to read more about this).
  • Researchers propose seven solutions for neuroprotection in Parkinson’s:
    1. Select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement
    2. Combine treatments that target multiple pathways
    3. Establish earliest interventions & develop better prodromal biomarkers
    4. Adopt rigorous methodology & specific disease‐relevant designs for disease‐modifying clinical trials,
    5. Customize drug with better brain biodistribution
    6. Prioritize repurposed drugs as a first line approach
    7. Adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value (Click here to read more about this).

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

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

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

And now: on to December – Christmas is almost here!

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

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


One thought on “Monthly Research Review – November 2020

  1. Hello Simon (hope you don’t mind the first-name basis communication in this post).
    So in the past few months reading this blog and skimming through some PD research I’ve really became interested in one thing. Well actually three main points.

    When it comes to disease modifying treatments in order to considerably slow down or stop PD progression we would need to find the root cause. Current line of thinking is gain of function of alpha synuclein aggregation. However research and recent ones as well are telling us that PD has markers of neuroinflammation, mitochondrial dysfunction, microglial activation. My questions are:

    1. Do we have any idea what is the first thing that starts happening in PD brain? Does it start with endoplasmic reticulum stress (ERS)? Or is ERS started by neuroinflammation? Any research reviewed or undergoing review that is trying to determine that?

    2. If alpha synuclein aggregation is just a secondary effect preceded by the aforementioned thigs then of course therapies that would remove misfolded alpha synuclein would be beneficial but there is still going to be damage because it is not the root cause. Is scientific community moving away from the notion that alpha synuclein aggregation is the major cause of PD?

    3. In my probably wrong understanding of PD, ERS and mitochondria dysfunction precede alpha synuclein aggregation. However we still don’t know what causes ERS and mitochondria dysfunction. But it seems to me that it would be beneficial to tackle ERS and mitochondria dysfunction. Are there any potential preclinical or clinical drug candidates that are trying to do just that?

    To be honest I still have more questions but I don’t want to make this post too long.
    Best regards,
    Romulus

    Like

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