Monthly Research Review – October 2021

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At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during October 2021.

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

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So, what happened during October 2021?

In world news:

October 3rd – The International Consortium of Investigative Journalists and assorted media partners publish a set of 11.9 million documents leaked from 14 financial services companies known as the Pandora Papers, revealing offshore financial activities that involve multiple current and former world “leaders”… and nothing happened.

 

October 15th – TV scriptwriters Agustín Martínez, Jorge Díaz and Antonio Mercero shocked guests at the Planeta prize ceremony, when they took to the stage to collect the main €1m prize and reveal that the celebrated crime author, Carmen Mola, does not actually exist.

 

October 16th – The Lucy spacecraft is launched by NASA, the first mission to explore the Trojan asteroids (Click here to learn more about this).

 

October 22nd – The UK Health Security Agency announced the offshoot of COVID19-Delta, known as AY.4.2 (has two mutations in the spike protein) was designated a “variant under investigation”. Preliminary evidence suggests that this subvariant could be 10-15 per cent more transmissible than the original Delta (Click here to read more about this).

(Let’s play a game of “Find the mask”. And yes, I’m picking on West Ham fans)

October 31st – The month started badly for World “leaders”, and it finished much the same way. They began flying into Glasgow for COP26 to talk and… do nothing about rising levels of atmospheric green house gases (What a waste of public morale. Joe really missed a big opportunity, and Boris… was simply Boris)

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

In October 2021, there were 868 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (10,046 for all of 2021 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

1. Making a (G)case for quetiapine:

Many people with Parkinson’s have reduced levels of an enzyme called GCase, which is involved in the waste disposal system of cells. Increasing levels of GCase activity have been shown to rescue models of Parkinson’s, so researchers have been searching for activators of GCase as a therapeutic strategy for PD. A new study screening 1280 cell-permeable FDA-approved drugs and found that the antipsychotic quetiapine binds to GCase and increases its activity. This activation by quetiapine lowered α-synuclein accumulation in mice and partially rescued pathology in dopaminergic neurons with LRRK2 mutations (Click here to read more about this and click here to read a SoPD post on this topic).

 

2. Omega+omega=a mega result?

A small (n=40) randomized, double-blind, placebo-controlled study of a nutritional formula (called Neuroaspis PLP10™, which is made of antioxidant vitamins and omega-3 & omega-6 fatty acids) in early Parkinson’s reports significant improvement in ON state UPDRS (18-30 months – click here to read more about this and click here to read an SoPD post on this topic).

 

3. Further fatty acid research:

Researches also reported that they may have identified the mystery neurotoxic agent that astrocytes release to kill damaged neurons: Saturated lipids contained in lipoparticles. This form of “Lipoapoptosis” (programmed cell death caused by fatty acids) was demonstrated in both cell culture conditions (Click here to read more about this).

4. Novel deep brain stimulation findings

Researchers used optogenetics (a method of stimulating genetically engineered neurons with light) to develop a new deep brain stimulation protocol to drive population-specific neuromodulation in the external globus pallidus. This stimulation corrected a model of Parkinson’s and the benefits were found to last several hours after stimulation was stopped (Click here to read more about this, click here to read the press summary, and click here to read a SoPD post on this topic).

5. Repurposing bumetanide for Alzheimer’s:

A computational drug-repurposing screening experiment seeking to identify molecules that can correct apolipoprotein E4 (APOE4)-related Alzheimer’s phenotypes, identifies the diuretic medication bumetanide. Effect in in vivo & iPSC-derived neurons; Drug exposure associated with a sig. Reduced AD prevalence in >65 years (2 databases – click here to read more about this and click here to read a SoPD post on this topic).

6. The Voyager gene therapy clinical trial results:

The results of the AADC gene therapy (VY-AADC01) for moderately advanced Parkinson’s have been published. This was a Phase 1b, open-label, dose escalation trial of an experimental AAV2 gene therapy encoding AADC enzyme developed by Voyager Therapeutics; 3 cohorts (n=5 per cohort); “All cohorts showed stability or improvement in motor function, global impressions of change, & quality of life”; “No vector-related SAEs were reported & clinical outcomes of motor function & quality of life were stable or improved throughout the 3-year trial”; Requirements for Parkinson’s medications reduced by 21-30% in the 2 highest dose cohorts at 36 months… Sooooo… why have the US FDA got a formal clinical hold on this research? Why have Neurocrine Bio ending their collaboration? And why has VY-AADC clinical development being terminated??? (Click here to read the report and click here to read more about the background of this trial).

 

7. New ASAP research funding: 

Aligning Science Across Parkinson’s announced the awarding of 14 research projects focused on better understanding of the circuitry and brain-body interactions connected to Parkinson’s. These 3 year grants totaled $132 million (Click here to read more about this and click here to read a SoPD post about this topic)

 

Articles of general interest

  • In this Parkinson’s Foundation podcast, Prof. Patrik Brundin explains the approach of the International Linked Clinical Trials program for Parkinson’s. The iLCT – a collaboration between Cure Parkinson’s and the Van Andel Institute has become one of the most comprehensive drug repurposing programs focused on any medical condition (Click here to read more about this).
  • Let’s talk about Parkinson’s Disease – a panel discussion from Bayer:
  • Interesting podcast about brain stimulation and stimulating brains, hosted by Andreas Horn (Click here to learn more about this).
  • Really interesting video of Dr Camille Carroll explaining the Edmond J Safra – Accelerating Clinical Trials in Parkinsons disease initiative (EJS-ACT PD) to the Peninsula Parkinson’s Research Interest Group; MAMS (Multi-Arm, Multi-Stage clinical trials for PD):
  • A useful article providing a practical overview for the general practitioner of the initial diagnosis & management of Parkinson’s (Click here to read more about this).
  • Target or Decoy: Are Drug Developers Chasing the Right Thing? (Click here to read more about this).

 

Basic biology news

  • New research determines cryogenic electron microscopy structure of the Parkinson’s-associated alpha synuclein protein carrying the G51D mutation at 2.96 Å resolution; Shows G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein (Click here to read more about this).
  • HACE1 (HECT domain & Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor; New research finds that HACE1 is a negative regulator of neuroinflammation; Could it be involved in Parkinson’s pathogenesis? (regulating Rac1 activity – click here to read more about this).
  • Researchers from Emulate Inc model Parkinson’s-associated alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption; Reproduces several key aspects of PD path. (accumulation of pSer129-αSyn, mitochondrial impairment, etc – click here to read more about this).

  • LRRK2 G2019S mutation alters astrocyte-to-neuron communication (via extracellular vesicles) & induces neuron atrophy in a human iPSC-derived model of Parkinson’s (Click here to read more about this).
  • New research reports that acetylation rather than H50Q mutation impacts the kinetics of Cu(II) binding to Parkinson’s-associated α-synuclein (Click here to read more about this).
  • Targeting microglial α-synuclein/TLRs/NF-kappaB/NLRP3 inflammasome axis in Parkinson’s: According to emerging studies, the excessive activation of microglia and the subsequent release of pro-inflammatory cytokines may play a role in PD (Click here to read more about this).
  • New research reports the signal peptide of the amyloid precursor protein forms amyloid-like aggregates & enhances Alzheimer’s-associated Aβ42 aggregation (Click here to read more about this).
  • New biorxiv manuscript suggests that LRRK2 kinase activity plays a role in axonal transport, & presynaptic targeting of Parkinson’s-associated alpha-synuclein (Click here to read more about this).

  • LGALS3 (galectin 3) mediates an unconventional secretion of SNCA/α-synuclein in response to lysosomal membrane damage by the autophagic-lysosomal pathway in human dopamine neurons; Implications for Parkinson’s? (Click here to read more about this).
  • A mechanistic explanation for Parkinson’s-associated α-synuclein down-regulation of NURR1; α-syn-induced activation of GSK-3, NURR1 phosphorylation, followed by proteasomal degradation; Mutant analysis IDs a 123-PSSPPTPSTPS-134 domain targeted by GSK-3 (Click here to read more about this).
  • Train mice to perform optogenetic intracranial self-stimulation, & examined how self-initiated goal-directed behavior influences nigrostriatal dopamine transmission; Result: Implications for reinforcement learning & Parkinson’s (Click here to read more about this).
  • New paper finds that Parkinson’s-associated LRRK2 alters responses to critical sonic hedgehog signals in the nigrostriatal pathway; Cilia are reduced in G2019S-LRRK2; PPM1H deficiency phenocopies LRRK2 mutation (Click here to read more about this).

  • Cofilin1 oxidation links oxidative distress to mitochondrial demise & neuronal cell death (Click here to read more about this).
  • New research reports Parkinson’s-associated α-syn oligomers generated from interactions with polyunsaturated fatty acid DHA & DOPAL differentially interact with β-amyloid to enhance neurotoxicity (Click here to read more about this).
  • New paper reports Parkinson’s-associated LRRK2-G2019S downregulates the core regulatory circuit transcription factor NR2F1, accelerating dopaminergic differentiation (Click here to read more about this).
  • Direct and indirect pathway neurons in ventrolateral striatum differentially regulate licking movement & nigral responses in rodents (Click here to read more about this).
  • New research indicates that Parkinson’s-associated α-synuclein negatively regulates immunoproteasome assembly; α-syn perturbs POMP-mediated immunoproteasome β-ring assembly; Enhancement of NRF2-POMP axis ameliorates α-syn neurotoxicity (Click here to read more about this).
  • New research finds that two kinases (GAK+PRKCD) to regulate PARKIN-independent mitophagy; Knockdown of GAK in C. elegans or PRKCD in zebrafish leads to significant inhibition of basal mitophagy (Click here to read more about this).

  • Development of α-synuclein real-time quaking-induced conversion as a diagnostic method for α-synucleinopathies (Click here to read more about this).
  • New biorxiv manuscript suggests a novel role for hemoglobin in α-synuclein post-translational modification & in dopamine neurons homeostasis; Could neuronal hemoglobin be an important modifier for Parkinson’s? (Click here to read more about this).
  • New research provides evidence that neuronal SIRT degradation in Parkinson’s models is executed by autophagy rather than the proteasome; Very conserved process suggests that cells actively remove SIRTs when facing an oxidative imbalance (Click here to read more about this).
  • New report shows that amyloid bodies (reversible amyloid aggregates within the nucleus) are evolutionarily conserved across the eukaryotic domain; Conditions triggering amyloidogenesis varied significantly among the species tested (Click here to read more about this).
  • Researchers report that human midbrain organoids from patients carrying SNCA gene multiplication reliably model key pathological features of Parkinson’s & provide a useful system to study synucleinopathies (Click here to read more about this).
  • TRIP12 ubiquitination of glucocerebrosidase/GCase may contribute to neurodegeneration in Parkinson’s; TRIP12 accumulates in α-syn-mouse & sporadic PD brains; Ubiquitinates GCase at K293; Depletion protects α-synuclein PFFs-induced pathology (Click here to read more about this).

  • Hsp70 family chaperones are good at disaggregating amyloid fibrils. A new report outlines mechanism of action of the Hsc70-DnaJB1-Apg2 chaperone system in disaggregating Parkinson’s-assoc. α-synuclein fibrils (Click here to read more about this).
  • New biorxiv manuscript finds aggregated α-synuclein in the Krabbe disease brain; Brain lysates from KD cases manifest high molecular weight α-synuclein species & are seed-competent (on RT-QuIC – click here to read more about this).
  • New biorxiv manuscript suggests the trans-synaptic cell adhesion molecules neurexins act as key regulators of dopamine neuron connectivity & DA-mediated functions (GABA co-release – click here to read more about this).
  • An investigation of the ability of USP30 inhibition to enhance Parkinson’s-associated PARKIN-mediated mitophagy; PARKIN mutant fibroblasts had reduced p-Ser65-ubiquitin levels (vs WT cells), which could be restored via USP30 inhibition (Click here to read more about this).
  • Could viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer? Implications for Parkinson’s? Vesicular stomatitis virus glycoprotein & SARS-CoV-2 spike S increase aggregate induction (prions & Tau – click here to read more about this).
  • New research finds Zika virus antagonizes mitophagy by inhibiting Ajuba translocation to mitochondria – by doing this it acts as a regulator of Parkinson’s-associated PINK1 signaling; Viral suppression of mitophagy amplifies inflammation (Click here to read more about this).

  • High-throughput chemical screen in DJ-1β mutant flies identifies Zaprinast (experimental phosphodiesterase inhibitor/modulator of PPARy); It also increases mitochondrial viability in DJ-1-deficient human cells (enhancing activity of glycolytic enzymes – click here to read more about this).
  • Ceramide accumulates in Parkinson’s-associated PINK1 deficiency to initiate ceramide-mediated mitophagy; Enhanced ceramide levels negatively correlate with β-oxidation & decrease efficiency of the electron transport chain (Click here to read more about this).
  • New research finds Parkinson’s-associated DJ-1 acts as a scavenger of α-synuclein oligomers & restores monomeric glycated α-synuclein; DJ-1 scavenges glycated N-terminally acetylated-αSyn oligomers without chemical deglycation (Click here to read more about this).
  • New research delves deeper into the role of Wnt signaling inhibitors in the promotion of substantia nigra dopaminergic neuron specification (Click here to read more about this).
  • A new report exploring the role of Pitx3 in maintaining mature mouse dopamine neurons (Pitx3fl/fl; DATCreERT2) finds age-dependent progressive motor deficits, loss of neurons in the nigra but not the VTA, & somatic accumulation of α-synuclein (Click here to read more about this).

 

Disease mechanism

  • New biorxiv manuscript suggests proSAAS – a small secreted chaperone protein – provides neuroprotection & attenuates transsynaptic α-synuclein spread in rodent models of Parkinson’s (Click here to read more about this).
  • New research reports Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein, but not of the aggregated alpha-synuclein; Easy experimental tool for detection of aggregated α-syn (Click here to read more about this).
  • New biorxiv manuscript presents a novel type of stem cells called lineage-restricted undifferentiated stem cells (LR-USCs), which robustly generate mesencephalic dopaminergic neurons (Click here to read more about this).
  • New research exploring the most neuroinductive source of glial cell line‐derived neurotrophic factor (GDNF) finds that recombinant mGDNF produced by E. coli is not as potent as mGDNF produced by human cells; Implications for Parkinson’s? (Click here to read more about this).

  • Neurotrophic factor GDF5 has been shown to increase levels of nucleoside diphosphate kinase A (NME1); Now researchers report NME1 protects against neurotoxin-, α-synuclein- & LRRK2-cell models of Parkinson’s (Click here to read more about this).
  • New research indicates that the neuroprotective effects of celastrol in models of Parkinson’s is mediated by he Nrf2-NLRP3-caspase-1 axis (Click here to read more about this).
  • New biorxiv manuscript uses genetic lineage tracing, scRNA-Seq, & electrophys. analysis to show deletion of Ptbp1 in retinal glia & brain astrocytes does not lead to glia-to-neuron conversion (Click here to read more about this).
  • A newly developed reversible MAO-B inhibitor, KDS2010 (“SeReMABI” – being developed by Neurobiogen) exhibits neuroprotective properties in mouse model of Parkinson’s & good PK/PD in non-human primates (MAO-B IC50= 7.6 nM – Click here to read more about this).

  • New research reports that P2Y6 receptor knockout mice have less inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide; P2Y6 receptor antagonists for Parkinson’s? (Click here to read more about this).
  • A novel multi-target strategy to attenuate the progression of Parkinson’s by diamine hybrid AGE/ALE inhibitor (Click here to read more about this).
  • New research reports 2-Hydroxypropyl-β-Cyclodextrin treatment is sufficient for restoring the impaired dopaminergic differentiation in neuronal cultures & brain organoids from Parkinson’s patients with PINK1 variants (Click here to read more about this).
  • New preclinical research finds vilazodone – novel 5-HT agent with SSRI & 5-HTr1A partial agonist properties – could potentially serve as an adjunct therapeutic for reducing dyskinesia in patients with Parkinson’s (Click here to read more about this).
  • Researchers at Sanofi have published some of the preclinical pharmacology data for their glucosylceramide synthase inhibitor venglustat in a GBA-associated models of Parkinson’s (Click here to read more about this).

  • Researchers demonstrate that optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus can improve locomotion in a mouse model of Parkinson’s (Click here to read more about this).
  • Inhibition of alpha-synuclein aggregation by AM17, a synthetic resveratrol derivative (Click here to read more about this).
  • MicroRNA-7 protects against neurodegeneration induced by Parkinson’s-associated α-synuclein preformed fibrils in the mouse brain; AAV delivered miR-7 prevents the nucleation & propagation of pS129- α-syn in α-syn PFF-inoculated mice (Click here to read more about this).
  • Researchers report that deletion of Parkinson’s-associated VPS35 in neurons induces spinal cord motor neuron degeneration and early post-natal lethality; Loss is preceded by p62-positive protein inclusions & reactive astrogliosis (Click here to read more about this).
  • Researchers from Lundbeck publish their nonclinical safety evaluation, pharmacokinetics, & target engagement results for Lu AF82422 – a monoclonal IgG1 antibody against alpha-synuclein – in development for treatment of synucleinopathies, like Parkinson’s (Click here to read more about this).

  • Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects in in vitro models of Parkinson’s (Click here to read more about this).
  • Microglial activation may drive glucose uptake & FDG-PET alterations in neurodegenerative conditions; Glucose uptake is greater in microglia vs astrocytes & neurons; Microglia activity correlated with FDG-PET in Alzheimer’s cases (Click here to read more about this).
  • New research from vTv Therapeutics & collaborators finds BACH1 derepression is neuroprotective in a mouse model of Parkinson’s; New inhibitor of Bach1 (‘HPPE’) worked better than Tecfidera (Click here to read more about this).

 

Clinical research

  • New medrxiv manuscript explores pre-diagnostic manifestations of Parkinson’s in UK primary care; “Tremor & ‘memory symptoms’ were reported up to 10 years before diagnosis” (Click here to read more about this).
  • New paper uses post-GWAS methods to find evidence for the GRN gene (encoding progranulin) connecting multiple neurodegenerative conditions; Shared mechanisms for Parkinson’s, Alzheimer’s & ALS? (Click here to read more about this).
  • Small (n=22) preliminary study finds Substance P levels in serum are increased in a cohort with Parkinson’s & this correlates with motor impairment; Larger replication studies required (Click here to read more about this).
  • New research deeply characterizes phenogenotypically PLA2G6-related Parkinsonism in the largest cohort yet reported; 54 PLA2G6 mutations have been associated with Parkinsonism (Click here to read more about this).
  • A case-control study (1977-2016) reports influenza was associated with diagnoses of Parkinson’s more than 10 years after infection; The data “do not demonstrate causality” (Click here to read more about this).

  • Longitudinal cerebrospinal fluid samples from the PPMI study (n=252 individuals with Parkinson’s & 115 controls) were analyzed at 6 timepoints (0, 6, 12, 24, 36, & 48 months follow-up) for levels of NfL, sTREM2, YKL40, GFAP, IL-6, S100, & αSyn (Click here to read more about this).
  • Evidence of decreased frontotemporal connectivity in patients with Parkinson’s who experience face pareidolia (seeing faces in everyday objects – “as high as 30% among patients with PD” – click here to read more about this).
  • A novel approach to understanding cognitive decline associated with some cases of Parkinson’s using minimum spanning trees, edge cutting, & magnetoencephalography (Click here to read more about this).
  • New paper explores the feasibility of a polygenic hazard approach in Parkinson’s, integrating the genetic effects on disease risk & age at onset in a single model (Click here to read more about this).
  • Further evidence that the APOE ε4 genotype may be associated with more rapid motor progression in Parkinson’s; Longitudinal PPMI data from 84 APOE ε4 carriers & 299 noncarriers (β=0.283, P=0.026, 95% CI: 0.033–0.532 – click here to read more about this).

  • A new hybrid 18F-fluorodopa (DOPA) PET-diffusion tensor imaging (DTI) for early detection of dopaminergic dysfunction & microstructural degradation involved in Parkinson’s; Early asymmetric disruptions in putaminal dopamine concentrations detected (Click here to read more about this).
  • New research finds an association between another inflammatory disease – Ankylosing Spondylitis – and Parkinson’s in a nationwide study from Korea (Click here to read more about this).
  • New study takes a surgicogenomic approach to investigate axial impairment following deep brain stimulation in Parkinson’s (Click here to read more about this).
  • Measurement of Parkinson’s-associated LRRK2 kinase activity (autophosphorylation levels at serine 1292) by Proximity Ligation Assay in cultured cells & postmortem tissues (Click here to read more about this).
  • New research defines speech subtypes in de novo Parkinson’s & explores their response to long-term Levodopa therapy; Class II evidence indicates speech phenotype is associated with levodopa responsiveness; N=111 de novo PD cases; 12 month follow up (Click here to read more about this).
  • Researchers at Roche have a medrxiv manuscript outlining their version 2.0 mobile application for the remote monitoring of progression in early Parkinson’s; Demonstrating preliminary reliability & validity of remote at-home quantification (Click here to read more about this).

  • A comparative study of asleep & awake deep brain stimulation robot-assisted surgery for Parkinson’s (Click here to read more about this).
  • Researchers performed a hypothesis-free whole-exome sequencing-based screening of time-to-Levodopa-induced dyskineisa onset on 134 Parkinson’s patients (independent replication n=97) & found an association btwn OPRM1 gene (rs1799971) with time-to-LID onset (Click here to read more about this).
  • Trends in mortality from Parkinson’s in the US between 1999–2019 indicate a significant increase; From 5.4 (95% CI, 5.3-5.5) per 100,000 in 1999 to 8.8 (95% CI, 8.7-8.9) per 100,000 in 2019 – an average annual percent change of 2.4%; Higher in men (Click here to read more about this).
  • DaTSCAN (123I-FP-CIT SPECT) imaging of 339 idiopathic Parkinson’s patients & 46 GBA-PD cases in early neurodegenerative processes in PD, with 168 cases available for follow-up analyses (Click here to read more about this).
  • New research analysed the effect of dopaminergic medication on arm swing in Parkinson’s; Arm swing improved with medication, except during dual-tasking (Click here to read more about this).
  • A TSPO PET study ([11C]PBR28) with machine learning analysis reports glia imaging differentiates Multiple System Atrophy (MSA) from Parkinson’s; “Hotspots” in the lentiform nucleus & cerebellar white matter (Click here to read more about this).
  • Underrepresented communities: A Systematic Review of the current state of Parkinsonism in West Africa; “Almost all the prevalence studies were hospital-based & monocentric, making it impossible to accurately estimate the true prevalence of parkinsonism” (Click here to read more about this).

  • New biorxiv manuscript proposes a composite biomarker with a combination of 6 metabolites “exhibiting a high level of predictivity for Parkinson’s diagnosis in its early phase, before motor symptoms appearance”; 6 metabolites: acetoacetate, betaine, BHB, creatine, pyruvate, & valine; Combo biomarker discriminated NIH Parkinson’s cohort from controls (sensitivity=0.95) & an Italian PD cohort (0.83); Dysregulation of betaine, BHB, & pyruvate partially corrected by pramipexole (Click here to read more about this).
  • First delirium episode in Parkinson’s & parkinsonism: New study explores incidence, predictors, & outcomes (Click here to read more about this).
  • A qualitative study provides initial insights relating to the symptom & impact burden of early-stage Parkinson’s patients – development of a patient-centered conceptual model of symptoms & their impact in early PD from Roche researchers & collaborators (Click here to read more about this).
  • New research provides evidence that the beta oscillopathy does not substantially progress following combined subthalamic deep brain stimulation plus medication in moderate to advanced Parkinson’s; Implications for closed-loop DBS? (Click here to read more about this).
  • Neurofilament light chain & α-synuclein RT-QuIC as differential diagnostic biomarkers in Parkinsonisms & related syndromes; Parkinson’s, MSA, PSP/cortico-basal syndrome, dementia with Lewy bodies, iRBD & isolated autonomic failure are assessed (Click here to read more about this).
  • A mendelian randomisation study of smoking, alcohol, & coffee drinking in relation to Parkinson’s reports genetic liability toward PD was positively associated with alcohol drinking (Courage-PD cohort; n=7,369 PD cases – click here to read more about this).

  • Interesting case study: “Braak’s unfinished hypothesis: A clinicopathological case report of α-synuclein peripheral neuropathy preceding Parkinsonism by 20 years” (Click here to read more about this).
  • Remote assessment of parkinsonism supporting ongoing development of interventions in Gaucher disease; Implications for GBA-associated Parkinson’s? (Click here to read more about this).
  • New research reports a mass spec approach to quantify 38 metabolites extracted from the serum of 231 individuals; 6 metabolites significantly altered in idiopathic Parkinson’s (vs controls; AUC of 0.905); Those 6 metabolites were 3-hydroxykynurenine, aspartate, beta-alanine, homoserine, ornithine & tyrosine (Click here to read more about this).
  • The lower the levels of soluble α-synuclein and, to a larger extent, Aβ42 the smaller the brain volume in Parkinson’s. These cross-sectional findings support a loss of protein function, not a gain of protein toxicity (Click here to read more about this).
  • New research reports a reduction in CD8+ T cell replicative senescence which is present at the earliest stages of Parkinson’s; A pre-existing intrinsic adaptive immune system difference in individuals who develop PD? (Click here to read more about this).
  • New research on Parkinson’s & Type 2 Diabetes: New research reports HbA1c is associated with motor & cognitive severity (Click here to read more about this).

  • A Korean nationwide cohort study (n=512,836) with repeated health screening data explores lifestyle factors & Parkinson’s over a 14-year period; Smoking, alcohol use, & physical activity were associated with reduced risk of PD in this Korean population (Click here to read more about this).
  • An epidemiological study of 6500 Slovenian beekeepers indicates that continuous exposure to bee venom does not reduce the risk for Parkinson’s (Click here to read more about this).
  • People with Parkinson’s are at risk of vitamin B12 & B6 deficiencies; Isolated B12 or B6 deficiency may lead to depletion of B6 or B12, respectively; Deficiencies in either should be considered in PD patients with neuropathy (Click here to read more about this).
  • New observations of compensatory mechanisms 9 years before Parkinson’s conversion in a LRRK2 R1441H family (Click here to read more about this).
  • Validation & clinical value of the MANAGE-PD tool: A clinician-reported tool to identify Parkinson’s patients inadequately controlled on oral medications (Click here to read more about this).
  • New pilot experiments on Parkinson’s-associated Parkin biallelic mutation carriers analysing mitochondrial DNA CpG methylation using Nanopore whole-genome sequencing; Significant differences observed (Click here to read more about this).

  • New research suggests a possible role for rare PSAP variants in idiopathic/isolated REM sleep behavior disorder (iRBD) & potential genetic interaction with Parkinson’s-associated GBA (Click here to read more about this).
  • The South African Parkinson’s disease study collection (Click here to read more about this).
  • An interesting report of autopsy cases of Lewy pathology of the submandibular gland in Lewy body disease including Parkinson’s & dementia with Lewy bodies (Click here to read more about this).
  • New PET imaging study finds regional cerebral cholinergic nerve terminal integrity contributes significantly to the postural instability, gait difficulties, tremor & distal limb bradykinesia cardinal motor features of Parkinson’s (Click here to read more about this).
  • New study looks at the feasibility of a continuous, multi-sensor remote health monitoring approach in people living with neurodegenerative conditions like Parkinson’s (Click here to read more about this).
  • Alpha diversity is the mean diversity of species in different sites; New research finds gut microbiome alpha-diversity is NOT a marker of Parkinson’s & Multiple Sclerosis (Click here to read more about this).
  • The oral, nasal, & gut microbiota of Parkinson’s: Samples from 91 PD patients vs 91 controls; The oral & gut microbiota were significantly altered in PD, but no difference in nasal microbiota; Altered microbiota correlated with clinical characteristics (Click here to read more about this).

 

New clinical trials

  • New clinical study registered: Shirley Ryan Ability Lab is initiating an investigation of wearable airbag technology to mitigate falls in individuals at risk, such as Parkinson’s; They are recruiting 200 people (Click here to read more about this).
  • New clinical study registered: AC Immune have registered a study of a morphomer-based alpha-synuclein-specific PET tracer; Recruiting 12 participants (Click here to read more about this).

  • New clinical trial registered: BioVie Inc has initiated a Phase 1/2 study of their ERK-targeting agent NE3107 in 40 people with Parkinson’s; 28 day study, finishing August 2022 (Click here to read more about this).
  • New clinical trial registered: A 6-month study to evaluate sulforaphane effects in 100 people with Parkinson’s; UPDRS & cognitive endpoints; Completes December 2022 (Click here to read more about this).
  • New observational clinical study registered: The Michael J Fox Foundation’s Parkinson’s Progression Markers Initiative Online Study (PPMI Online); 500,000 participants being recruited through till December 2041 (500,000 PD & non-PD volunteers – click here to read more about this).

 

Clinical trial news

  • Annovis Bio announce completion of Phase 2 dose response clinical trial of 4 weeks of ANVS401 (Posiphen) in 54 Parkinson’s patients; Safe/well-tolerated; No adverse effects; Plans for Phase 3 studies in AD & PD; Placebo response in UPDRS Total? (Click here to read more about this).

  • Appello Pharmaceuticals begins Phase 1 clinical testing of their lead drug candidate, AP-472 – a highly selective, small molecule, positive allosteric modulator of the metabotropic glutamate receptor subtype 4 (mGlu4 PAM) – targeting Parkinson’s (Click here to read more about this).
  • Theranexus presents the results of their Phase 2a trial of THN 102 (combination of modafinil & low-dose flecainide) for excessive daytime sleepiness associated with Parkinson’ s (Click here to read more about this).
  • Amgen & Neumora Therapeutics announce a strategic collaboration to develop therapeutics targeting casein kinase 1 delta & glucocerebrosidase in neurodegenerative conditions, like Parkinson’s; Emerging from stealth with US$500M (Click here to read more about this).

  • PharmaTher initiates Phase 2 clinical trial to evaluate ketamine’s safety & efficacy in the treatment of levodopa-induced dyskinesia associated with Parkinson’s (“KET-LID” trial – click here to read more about this).
  • In their latest update Denali Therapeutics announced their eIF2B activator DNL343 achieved safety/biomarker goals in a Phase 1 study in healthy volunteers; A Phase 1b study began in individuals with ALS in Q3 2021 (opportunity for Parkinson’s?); they also announced FDA Fast Track designation had been awarded for SAR443820/DNL788 (a RIPK1 inhibitor) for the treatment of ALS – their partners Sanofi to initiate a Phase 2 “HIMALAYA” study in individuals with ALS in Q1 2022; (again, Parkinson’s? Maybe GBA-PD? Just saying…); A small detail in the summary slide indicates a “late 2021” initiation of late stage clinical development of LRRK2 inhibitors for Parkinson’s, in collaboration with Biogen (Click here to read more about this and their presentation is available on their website).

  • Voyager Therapeutics announces a license option agreement ($630m deal) with pharma Pfizer for their next-generation TRACERᵀᴹ AAV capsids to enable neurologic & cardiovascular gene therapy programs (Click here to read more about this).
  • Digital neurotherapeutics firm MindMaze announces the closure of a US$125 million investment round to further develop its SaaS-based digital neurotherapeutics platform for conditions like Parkinson’s (Click here to read more about this).

  • Supernus Pharma bolsters its Parkinson’s portfolio with $400M purchase of Adamas Pharma (everyone watching the price of Gocovri? – Click here to read more about this).
  • Ionis‘ partner Biogen provided an update on Tofersen Phase 3 VALOR study in SOD1-ALS; Treatment missed primary endpoint, but exhibited signs of reduced disease progression across multiple secondary and exploratory endpoints (Click here to read more about this).

  • The rationale, design, & baseline data for the Roche & Prothena Phase II study evaluating the safety & efficacy of Prasinezumab (an alpha-synuclein targeting immunotherapy) in early Parkinson’s (the PASADENA study) has been published (Click here to read more about this).
  • New Zealand-based Living Cell Technologies secures funding for its 3rd clinical trial of NTCELL in Parkinson’s; Seeking to see if NTCELL can pause/delay PD progression; Starting 2024, with participants being monitored over 3 year follow up (Click here to read more about this).

  • D&D Pharmatech raises $51M in Series C financing to advance potential disease-modifying treatments; Proceeds will support of Phase 2 studies of NLY01 (PEGylated form of exenatide) in Parkinson’s; IPO in Korea in 2022 (Click here to read more about this).
  • TEVA Pharmaceutical Industries Ltd & biotech firm MODAG GmbH announce a strategic collaboration on the exclusive worldwide licensing & development of MODAG’s compound anle138b – inhibitor of alpha synuclein aggregation – & a related compound, sery433. Anle138b is currently being targeted at Parkinson’s & multiple systems atrophy (Click here to read more about this).

  • The results of a randomized controlled trial on the safety & effectiveness of mirabegron in Parkinson’s patients with overactive bladder finds encouraging results (Click here to read more about this).
  • The study protocol for the CHIEF-PD trial has been published; This is a Phase 3 randomised, double-blind placebo-controlled trial to evaluate the potential of rivastigmine to prevent falls in Parkinson’s (Click here to read more about this).

  • New post hoc analysis of Phase 2 & Phase 3 clinical trials finds Zonisamide improves wearing off in Parkinson’s without exacerbating dyskinesia (Click here to read more about this).
  • An update from Herantis pharma highlights results from preclinical animal model of Parkinson’s, HER-096 (xCDNF) shows almost 70% improved neuronal survival compared to controls, reduction of alpha-synuclein levels, & normalization of brain inflammatory changes (Click here to read more about this).

  • Inhibikase Therapeutics announces dosing of first Parkinson’s patient in its Phase 1b clinical trial of IkT-148009 (a selective c-Abl kinase inhibitorclick here to read more about this).
  • Cortexyme reports they missed their overall primary endpoint in their Phase 2/3 GAIN Alzheimer’s Trial,…BUT, pre-specified subgroups (based on P. gingivalis infection level) showed approximately up to 50% slowing of cognitive decline. Their drug – a small-molecule bacterial protease lysine gingipain inhibitor called Atuzaginstat – was safe & well tolerated overall; Placebo, 40mg, & 80mg groups well balanced (n=210+ in each group – Click here to read more about this & a data presentation available on the company’s website).

 

Conferences/lectures

  • On Mon, Nov 15, 11AM ET the World Parkinson’s Congress Research Spotlight will welcome Prof Heidi McBride to discuss the challenges of studying Parkinson’s across scales – join the discussion lead by Prof. Roger Barker (Click here to read more about this).
  • The Michael J Fox Foundation will be holding a two-day event in November that will showcasing the latest advances in Parkinson’s drug development. Day one (Tuesday 9th November from 11 a.m. to 12:30 p.m. ET) will highlight new tools and platforms for drug discovery, while day two (Wednesday 10th November from 11 a.m. to 12:30 p.m. ET) will feature innovative research programs from the Foundation’s funding portfolio (Click here to read more about this).

  • The Michael J Fox Foundation will be holding a 1 hour webinar on “Steps Closer to Stopping Parkinson’s: 2021 Research Review” (Click here to read more about this).
  • 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).
  • There will also be a public event as part of the NECTAR conference, which will be exploring Parkinson’s & Huntington’s disease clinical trials from the perspective of the participant experience (Click here to register for this event).

Other news

  • An international team has received a 5-year US$35 million grant to develop biomarkers that indicate which people with REM sleep behaviour disorder will go on to develop neurodegenerative conditions (Click here to read more about this).
  • What an amazing Parkinson’s resource: PDnexus (Click here to read more about this).

 

Review articles/videos

  • New review explores Tau & MAPT genetics in tauopathies & synucleinopathies (Click here to read more about this).
  • Molecular chaperones & Parkinson’s (Click here to read more about this).
  • Dr Camille Carrol – one of the lead coordinators of the Edmond J Safra – Accelerating Clinical Trials in Parkinson’s disease initiative (EJS-ACT PD), recently explained the project to the Peninsular Parkinson’s Research interest Group (PenPRIG) group. A very interesting talk:
  • The PINK1 repertoire – a useful review of this Parkinson’s-associated protein demonstrating that it is not just a one trick pony (Click here to read more about this).
  • Have been waiting for something like this for a while: New review evaluates strategies for measuring lysosomal glucocerebrosidase activity, highlighting specific strengths & weaknesses of these approaches as well as the gaps that remain (GBA-Parkinson’s – click here to read more about this).
  • Interesting review of squalamine & trodusquemine: Two natural products for neurodegenerative conditions, from physical chemistry to the clinic (squalamine/ENT-01 is currently being targeted at Parkinson’s); ENT-01 does not cross the BBB, but “trodusquemine crosses the blood–brain-barrier following parenteral administration. For these reasons, aminosterols structurally related to trodusquemine are being developed for the treatment of Alzheimer’s” (Click here to read more about this).

  • New review on new therapeutic approaches to Parkinson’s targeting GBA, LRRK2 & Parkin; “Targeted LRRK2 p.G2019S inhibition could be a safer approach”; “GBA & LRRK2 genetic modifiers should be considered in the study design” (Click here to read more about this).
  • A consensus on the treatment of dysphagia in Parkinson’s; Multinational group of experts conducted a systematic evaluation of the literature & reported the results according to PRISMA guidelines (Click here to read more about this).
  • New review provides an overview on the application of fMRI, PET, & SPECT imaging in Parkinson’s, includes a section on new imaging targets for detecting PD-related pathological changes upstream from dopamine cell loss (Click here to read more about this).
  • New review on the function of two Parkinson’s-associated proteins: PTEN-induced kinase 1 (PINK1) & the ubiquitin E3 ligase, Parkin; Addresses the emerging role for aberrant immune activation (Click here to read more about this).

  • New review explores the possible role of transposable elements as new players in neurodegenerative conditions like Parkinson’s (Click here to read more about this).
  • A useful review on the interplay between LRRK2 & GBA1/GCase in Parkinson’s, exploring the links between increased LRRK2 activity & Rab protein function, lysosomal dysfunction, alpha-synuclein accumulation, & GCase activity (Click here to read more about this).
  • New review on biomaterial strategies for restorative therapies in Parkinson’s (Click here to read more about this).
  • A useful review on the development of caspase inhibitors for clinical use – good section on neurodegenerative conditions, including Parkinson’s (Click here to read more about this).
  • A new review maps out existing evidence on clinical utility of digital mobility outcomes, noting commonalities across traditional disciplinary divides; Data from Parkinson’s, multiple sclerosis, COPD & hip fracture (Click here to read more about this).

  • A rather thorough review of gene therapy approaches for neurodegenerative conditions like Parkinson’s with an emphasis on growth factors; Theoretical & clinical outcomes (Click here to read more about this).
  • New review on PINK1 and PARKIN biology, includes cell-autonomous and noncell-autonomous mechanisms (Click here to read more about this).
  • New review explores genome editing in iPSC-based neural systems; From disease models to future therapeutic strategies – a lot of references to Parkinson’s research (Click here to read more about this).
  • New review explores the role of astrocyte dysfunction in Parkinson’s: from the perspectives of transmitted α-synuclein & genetic modulation (Click here to read more about this).

  • A useful new review on novel targets for potential disease modifying therapies for Parkinson’s (Click here to read more about this).
  • New review explores efforts to translate insights from molecular mechanisms to neuroprotection for Parkinson’s (Click here to read more about this).
  • And here is the back story (& future directions) of the woman who can smell Parkinson’s. A wonderful (very personal) presentation from an amazing lady:

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

And there it is, just some of the highlights from October 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 November!!! (Christmas is coming!)

All of the material on this website is licensed under a
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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.


6 thoughts on “Monthly Research Review – October 2021

  1. Regarding the ANVS401(Posiphen) Phase 2 results, Simon wrote: “Placebo response in UPDRS Total?”

    From a more-recent Annovis press release (Nov 2nd) [1]:
    “Annovis Bio … will give both an oral and poster presentation at the 14th Clinical Trials on Alzheimer’s Disease conference (CTAD), November 9-12, 2021.”

    “The poster presentation will highlight the mechanism of action of ANVS401. The oral presentation will elaborate on new biomarker data from the initial Phase 2 clinical trial, as well as expanded safety information from the full range of study participants.”

    Hopefully the biomarker data will give us something more significant to celebrate.

    [1] https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=3da1da04-0352-46b8-93d8-4a56d04ca46a

    Liked by 1 person

  2. I didn’t read much of this post yet, and maybe you mentioned this. But, I thought I would share something I happened to see in a video of Dr. Pagan of Georgetown University Medical School. Georgetown ran a trial of a drug to treat Lewy Body Disease, and he said they would “publish their findings shortly – and you see this big smile on my face based on how the trial went” or something like that. It was in the “Parkinson’s Pointers” lecture put on by PFNCA.

    Hopefully you haven’t already got the scoop – or maybe hopefully you have!

    Liked by 1 person

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