Monthly Research Review – September 2020

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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 September 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
  • Other news
  • Upcoming conferences/lectures
  • Review articles/videos

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So, what happened during September 2020?

In world news:

September 2nd – Researchers found a way of floating toy boats under a levitating liquid (Click here to read more about this and click here to read a press summary)

September 3rd – The skeletons of 200 mammoths and 30 other animals are unearthed at a construction site for the Mexico City Santa Lucía Airport. It is the largest find of mammoth bones to date, surpassing the Mammoth Site in the U.S. which had 61 skeletons (Click here to read more about this).

September 14th – The Royal Astronomical Society announces the detection of phosphine in Venus’ atmosphere, which is suggested to be a strong predictor for the presence of microbial life (Click here to read more about this).

September 19th – A 1634 edition of The Two Noble Kinsmen, the last play by English playwright William Shakespeare, is discovered at the Royal Scots College’s library in Salamanca, Spain. It is believed to be one of the oldest copies of any of his works.

September 25th – Researchers report the development of rectangular, magnetically controlled robots (300 micrometers long) that can coax nerve cells to grow new connections (Click here to read more about this and click here to read a press summary)

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

In September 2020, there were 1,021 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (7,969 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 PASADENA study results (again):

Roche and Prothena Corp announced that their alpha synuclein immunotherapy treatment Prasinezumab slows motor progression on measures of Parkinson’s in their Phase 2 PASADENA Study. “As previously reported, the study did not meet the primary objective, but signals of efficacy showing a reduction in disease progression were observed in both of the prasinezumab arms when compared to placebo”. Prasinezumab “significantly reduced decline in motor function by 35% (pooled dose levels) vs. placebo after one year of treatment” on MDS-UPDRS Part III, & “delayed time to clinically meaningful worsening of motor progression over one year”. The company says the “results support further clinical development of prasinezumab” (Click here to read more about this and click here to read a SoPD post on this topic).

2. Topline result of the PD-STAT clinical trial:

The initial results from the Phase II PD-STAT clinical trial assessing the cholesterol-lowering Simvastatin in Parkinson’s were announced. The study coordinators indicated that the drug “does not slow progression of PD” (Click here to read more about this).
3. COVID and Parkinson’s:

A case of probable Parkinson’s following SARS-CoV-2 infection was announced in September, and 3 additional cases were since been reported. In the first case, the 45 year old gentleman in Israel was hospitalised due to COVID-19. He lost his sense of smell a few days before admission. Over the next few weeks, his handwriting changed (becoming smaller and less readable) and he had episodes of tremor in his right hand. Three months after being infected, his gait slowed and he displayed mild bradykinesia. Brain imaging (18F-fluorodopa PET) indicated reduced dopamine activity.  “A genetic analysis for these mutations [GBA & LRRK2] and 62 other mutations associated with the disease was negative & our patient had no previous family history of PD”. While extremely rare events (considering the 34 million cases of COVID to date), researchers worry that this could be the start of a new problem associated with the pandemic (Click here to read more about this).

4.  Results of the Helicobacter pylori eradication clinical trial:

A double‐blind, randomised placebo‐controlled trial of Helicobacter pylori eradication therapy finds no improvement in clinical outcomes in Parkinson’s; “there is no justification for routine HP screening or eradication with the goal of improving PD”. N=80 randomised; 67 included in the full‐analysis set (32 treatment group patients, 35 placebo patients); assessment at weeks 6, 12, 24, & 52; no significant improvement in any motor, nonmotor, or quality‐of‐life outcome (Click here to read more about this). This was a follow up study to previous research (Click here to read that study report).

5. Roche & Inflazome:

Inflammasome-focused biotech company Inflazome announced that it was being acquired by the pharmaceutical company Roche. “Roche intends to further develop NLRP3 inhibitors across a wide variety of indications” including Parkinsons (Click here to read more about this,  click here for the press summary and click here to read an old SoPD post on this topic).

6. Which came first? The brain or the body?

New report provides data supporting the existence of brain-first and body-first subtypes of Parkinson’s. Individuals with de novo PD with & without REM sleep behaviour disorder are very similar clinically, but they display strikingly different profiles on a multimodal imaging battery (Click here to read more about this and click here to read the press summary).

In other Parkinson’s research news:

Basic biology news

  • Combined lipid & transcriptomic profiling of substantia nigra & putamen in Parkinson’s highlights gender-related differences & also β-synuclein (Click here to read more about this).
  • Researchers have a biorxiv manuscript outlining a CRISPR/Cas9-based gene editing approach for deleting Parkinson’s-associated A53T-SNCA both in vitro & in vivo (in rats). Deletion of A53T-SNCA prevented dopaminergic neurodegeneration & associated motor issues (Click here to read more about this).

  • From the folks that brought us mannitol: Researchers report tryptophan-galactosylamine conjugates inhibit & disaggregate amyloid fibrils of Aβ42 & hIAPP peptides while reducing their toxicity (Click here to read more about this).
  • Researchers report that naphthoquinone‐dopamine hybrids inhibit Parkinson’s-associated α‐synuclein aggregation, disrupt preformed fibrils & attenuate aggregate‐induced toxicity (Click here to read more about this).
  • Aggresomes/Lewy bodies & the centrosome sit side-by-side in the cells. Now researchers report Parkinson’s-associated alpha synuclein aggresomes inhibit ciliogenesis & multiple functions of the centrosome (Click here to read more about this).
  • A new biorxiv manuscript presents comparative analysis of human brain organoids of brainstem & midbrain at single-cell resolution. Interesting differences in cell types (Click here to read more about this).
  • NatB is a N-terminal acetyltransferase complex that acetylate N-term. Now researchers report that NatB-specific elements are responsible for Parkinson’s-associated alpha synuclein recognition & N-terminal acetylation (Click here to read more about this).
  • Researchers reports that cholesterol inhibits Parkinson’s-associated α-synuclein interactions with lipid bilayers, but significantly promotes α-synuclein fibrillation (>20x lag-time reduction before fibrillation – Click here to read more about this).

  • New biorxiv manuscript proposes a robust paradigm to generate enriched iPS cell-derived dopamine neurons “which can be used to faithfully model key aspects of Parkinson’s” (Click here to read more about this).
  • A new report highlight the importance of membrane-induced self-assembly in alpha-synuclein neurotoxicity & suggests that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in Parkinson’s (Click here to read more about this).
  • Researchers report that protein synthesis is suppressed in familial & idiopathic Parkinson’s by LRRK2; Translation is 40% reduced in PD patient (G2019S & sporadic) fibroblasts (unchanged in ALS cells). In a rotenone model of Parkinson’s they find that LRRK2 activity increases, which leads to repression of translation & dopaminergic neuron atrophy both of which are prevented by LRRK2 inhibition (Click here to read more about this).
  • Increased prevalence of EKG/cardiac abnormalities in found across all ATP1A3-related syndromes, including ATP1A3-associated Parkinson’s (Click here to read more about this).
  • Things are heating up in inflammasome research: Scientists at NodThera report the discovery of a series of ester-substituted NLRP3 inflammasome inhibitors. New experimental agents for Parkinson’s? (Click here to read more about this).

  • A new medrxiv manuscript suggests that somatic mutations in Parkinson’s are enriched in synaptic & neuronal processes; exome seq of 5 different tissues from 10 sporadic PD cases (x60 coverage) highlighted 59 candidate SNVs, deep seq confirmed 27 of them (Click here to read more about this).
  • Somatic mutations in Parkinson’s-associated LRRK2 identify a subset of invasive mammary carcinomas associated with high mutation burden (Click here to read more about this).
  • Researchers report functional dissection of basal ganglia inhibitory inputs onto substantia nigra dopaminergic neurons; Striosomes powerfully inhibit SNc dopamine neurons through GABA-B receptors on SNr dendrite (Click here to read more about this).
  • A lot of HOTAIR in Parkinson’s research at the moment! Researchers report that overexpression of HOTAIR (a gene, for those out of the loop) accelerates development of dyskinesia in a mouse model of Parkinson’s (via SSTR1 methylation-mediated ERK1/2 axis – Click here to read more about this).
  • New research reports that one of the functions of vesicular-glutamate transporter 2 (Vglut2) in adult dopamine neurons is to promote post-lesional recovery of meso-striatal axons (Click here to read more about this).
  • New study reports the optimal combo of fate determinants for efficient conversion of human astrocytes directly to dopaminergic neurons, displaying subtype-specific phenotypic maturation & functional properties (Click here to read more about this).

  • Maybe you can teach an old DUB new tricks: Researchers report UCH-L1 regulates mitofusin-2 levels, altering mitochondrial morphology, function & calcium uptake (Click here to read more about this).
  • Researchers report tristetraprolin (TTP) destabilizes NOX2 mRNA & protects dopaminergic neurons from oxidative damage in neurotoxic model of Parkinson’s; interesting that antioxidant N‐acetyl cysteine (NAC) reversed siRNA‐TTP‐induced cell apoptosis (Click here to read more about this).
  • Researchers investigated the role of Parkinson’s-associated SNCA in the nucleus, using human-iPS cells-derived neurons with autosomal dominant mutations (A53T & SNCA-x3) & propose defects in nucleocytoplasmic transport may be a pathomechanistic driver (Click here to read more about this).
  • A new biorxiv manusript suggests a novel mechanism of IRE1α regulation during ER stress. Also demonstrates an intracellular mode of action of MANF as a modulator of UPR & neuronal cell survival (via direct interaction with IRE1α & regulation of its activity – Click here to read more about this).
  • A new biorxiv manuscript provides “a spectrally diverse & spatially specific understanding of transient network connectivity in Parkinson’s on a whole-brain level, disambiguating temporal & spatial changes of the underlying networks” (Click here to read more about this).

  • New report finds LncRNA MALAT1 facilitates inflammasome activation (via epigenetic suppression of Nrf2) in models of Parkinson’s (Click here to read more about this).
  • We need more of this: Pathogenic LRRK2 requires secondary factors to induce cellular toxicity – a cautionary tale about conclusions made using different types of Parkinson’s-associated LRRK2-based assays. “Our findings stress the importance of technical & biological factors in LRRK2-induced cellular phenotypes & hence imply that conclusions based on these types of LRRK2-based assays should be interpreted with caution” (Click here to read more about this).
  • A new paper reports that Parkinson’s-associated DJ-1 (Park7) affects the gut microbiome, metabolites & the development of innate lymphoid cells; Plus increased inflammatory genes related to PD in DJ-1−/− mice midbrain (Click here to read more about this).

  • Researchers report that selective impairment of RIPK1 ubiquitination can lower the threshold for RIPK1 activation by TNF resulting in cell death (Click here to read more about this).
  • A new biorxiv manuscript suggests that in fly dopamine neurons, Rab10 is involved differentially in Parkinson’s-associated LRRK2-induced behavioral deficits; Rab10 loss of function rescues bradykinesia in aged flies with LRRK2-G2019S in DA neurons (Click here to read more about this).

 

Disease mechanism

  • Researchers report trans-synaptic & retrograde axonal spread of Parkinson’s-like Lewy pathology following pre-formed fibril injection in an A53T alpha-synuclein mouse model of synucleinopathy (Click here to read more about this).
  • Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology & non-motor features of Parkinson’s (Click here to read more about this).

  • A new biorxiv manuscript suggests a gut-secreted peptide (CCHa1) that controls arousability through modulation of dopaminergic neurons in the brain of flies (Click here to read more about this).
  • Further preclinical support for GLP-1 agonists in treating age-associated changes connected with neurodegenerative conditions, like Parkinson’s. Zonation-dependent transcriptomic changes in aged mouse brain endothelial cells reversed by exenatide (Click here to read more about this).
  • High levels of SUMOylation mediated by Ubc9 overexpression protects dopaminergic cells in both MPTP- & PFF-models of Parkinson’s; Protection=inhibition of ROS generation & protein aggregation; Interesting: SUMOylated α-syn avoided lysosomal degradation (Click here to read more about this).
  • Multiple dystonia-associated genes interact & contribute to pathogenesis, likely via dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons & frontal cortical neurons (Click here to read more about this).
  • New report explores metabolic alterations in astrocytes derived from iPS cells from cases of LRRK2(G2019S)-associated Parkinson’s. Polyamines & polyamine precursors up; lysophosphatidylethanolamine levels down (Click here to read more about this and click here to read the press summary).

  • Do we need to reduce the Yin Yang in our lives? Astrocyte-specific deletion of the transcription factor Yin Yang 1 in the substantia nigra mitigates a mouse model of neurodegeneration. Implications for Parkinson’s? (Click here to read more about this).
  • Norepinephrine depleting toxin DSP-4 & LPS alter gut microbiota & induce neurotoxicity in a transgenic mouse model of Parkinson’s (A53T α-synuclein – Click here to read more about this).
  • Mutations in PARK7/DJ-1 are associated with early-onset Parkinson’s. Researchers explored an exonic splicing mutation in PARK7 patient-derived cellular models & found that kinetin analog RECTAS in combo with phenylbutyric acid provide neuroprotection (Click here to read more about this and click here to read the press summary about this).
  • Squalamine restores the function of the enteric nervous system in mouse models of Parkinson’s (further preclinical support for Enterin‘s ENT01 clinical trial program – click here to read more about this).
  • Graphene & quantum dots again! Researchers report graphene oxide sheets & quantum dots inhibit Parkinson’s-associated α-synuclein amyloid formation by different mechanisms (Click here to read more about this).

  • Netrin1 is involved in dopaminergic neuronal survival & axon guidance. Reductions in Netrin1 levels triggers Hippo/MST1/YAP pathway activation, leading to dopaminergic neuronal loss in mice. Netrin1 reported to be reduced in Parkinson’s brains (Click here to read more about this).
  • Changes in the cellular fatty acid profile drive the proteasomal degradation of α‐synuclein & enhance neuronal survival; α‐syn‐fatty acid interaction=determinant of conformation & fate of α‐syn in cells, cPLA2 inhibitors may reduce α‐syn burden Parkinson’s (Click here to read more about this).
  • A new biorxiv manuscript suggests that alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson’s; LD accumulation also increased the resistance of alpha-Syn to proteolytic digestion (Click here to read more about this).
  • HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation (Click here to read more about this).
  • New paper reports that the Parkinson’s-associated pesticide rotenone causes astrocyte senescence, & that the senescent secretome exaggerates neurodegeneration in patient iPS cell derived midbrain neurons (SNCA duplication – Click here to read more about this).

  • A new biorxiv manuscript presents AAV-mediated CRISPR editing of both PINK1 & DJ-1 in the substantia nigra of 4 adult primates. Two of the monkeys exhibited Parkinson’s symptoms (bradykinesia, tremor etc), dopamine neuron loss (60%+), & α-synuclein pathology (Click here to read more about this).
  • Researchers report that the loss of “Major intrinsically disordered NOTCH2-associated receptor 2” (MINAR2; aka KIAA1024L) impairs motor function & results in Parkinson’s-like features in mice (Click here to read more about this).
  • Researchers report that an oxidative switch drives mitophagy defects in dopaminergic neurons carrying Parkinsons-associated PARKIN genetic variants. Specifically, during early differentiation ‘pre-neurons’ are glycolytic & mitophagy is unimpaired, but as neurons become oxidative phosphorylation-dependent, mitophagy becomes severely impaired. Mitophagy status is highly dependent on the metabolic status of the cell. Redox-modulating compounds KH176 & KH176m from Khondrion BV were evaluated in this study & they dramatically reduce mitochondrial ROS production (with no significant effect on MMP or cellular ATP levels – Click here to read more about this).

  • Researchers transplanted hESC-derived midbrain dopamine or cortical glutamate neurons into the substantia nigra or striatum & found that functional synaptic inputs depend on the neuronal type & not graft site in a mouse model of Parkinson’s (Click here to read more about this).
  • GDNF reduces accumulation of α-synuclein aggregates in cultured dopamine neurons & in a mouse model of Parkinson’s (AAV-hGDNF & α-syn pre-formed fibrils). The effect of GDNF on accumulation of α-syn is mediated by RET (Click here to read more about this).
  • “Largest postmortem study to date investigating α-Syn in gastrointestinal samples of Parkinson’s” – “GI samples of healthy controls were frequently positive” – “Both α-Syn & p-α-Syn immunoreactivity were significantly reduced in GI samples of PD” – Huh? (Click here to read more about this).
  • Dual therapy: An analyze the therapeutic efficacy of AFFiRiS‘s PD03 (a new AFFITOPE® immunotherapy approach) either alone or in combination with MODAG‘s Anle138b in a α-synucleinopathy PLP-α-syn mouse model (Click here to read more about this).

  • Researchers report that the molecular tweezer CLR01 decreased aggregation & toxicity in iPS cell-derived dopaminergic cultures treated with PD brain protein extracts & improved mouse models of Parkinson’s (Click here to read more about this).
  • Researchers explore the molecular effects of chronic LRRK2 inhibition in mouse models of Parkinson’s (Click here to read more about this).

 

Clinical research

  • PINK1 p.Leu347Pro genetic variant – associated with early onset Parkinson’s – was previously thought to be restricted to Filipinos, but now there is a new report of a malaysian case (MRI abnormalities in the corticospinal tract & hypothalamus – Click here to read more about this).
  • Under-represented communities: Rare & novel variants of PRKN & PINK1 genes identified in Vietnamese patients with early‐onset Parkinson’s (Click here to read more about this).

  • Researchers use neuromelanin-sensitive MRI to investigate the spatiotemporal changes in the substantia nigra in prodromal & clinical Parkinson’s. Two cohorts: ‘early’ (38 control, 42 iRBD & 99 early PD) & ‘progressing’ (27 controls & 30 advanced PD). Results=volume of nigra progressively reduced with increasing disease severity. Neuromelanin signal changes start in posterolateral motor areas of nigra & progress more medial. Model suggests pre-symptomatic phase of the disease started ~5.3 years before disease diagnosis, & 23.1% of the substantia nigra volume was lost at the time of diagnosis. Getting closer to a better means of tracking Parkinson’s progression? Implications for clinical trials? (Click here to read more about this).
  • New research suggests GBA mutations are associated with early cognitive decline (independent of age) after bilateral subthalamic deep brain stimulation in Parkinson’s (study=208 patients, including 25 GBA, 18 LRRK2 & 22 PRKN carriers, plus 143 iPD). Larger replication obviously required, but “genetic screening may be recommended to advise of future risk of cognitive decline” (Click here to read more about this).
  • There has always been a strong link between Parkinson’s & melanoma. Now a brief communication suggests that α-synuclein modulates the aggregation of the premelanosomal protein Pmel17 in the melanosome – providing a molecular link between the two conditions (Click here to read more about this).

  • Analysis of DNM3 does not show an effect on age at onset in Parkinson’s-associated LRRK2 p.G2019S carriers; no evidence for linkage disequilibrium between DNM3 & VAMP4 (Click here to read more about this).
  • Interim analysis of DUOGLOBE study provides confirmation that the 5-2-1 criteria may be an objective way to identify patients with advanced Parkinson’s using simple & reproducible measures (Click here to read more about this).
  • A genetic analysis of a Spanish population with early onset Parkinson’s (Click here to read more about this).
  • New research reports that monocyte chemoattractant protein 1 (MCP-1) levels in cerebrospinal fluid cannot distinguish between PD, MSA, & controls, but do correlate with progression of Parkinson’s (Click here to read more about this).
  • “No change in the age‐adjusted incidence of Parkinson’s in Finland for more than 25 years” – I am wondering if coffee intake could be involved here? Rest of the world has increasing incidence of PD (Click here to read more about this).
  • New data suggest that tobacco & black tea have a protective effect on age at onset in LRRK2-associated Parkinson’s. Age at onset was 60 years for tobacco users, compared to 52 years for non‐users (Click here to read more about this).

  • PD laterality: a PET brain imaging study. Curiously TRANSEURO consortium researchers report asymmetry in striatal dopaminergic degeneration becomes less prominent in moderate-stage Parkinson’s, but asymmetry of motor symptoms is maintained (Click here to read more about this).
  • French COPARK researchers report excessive buccal saliva in Parkinson’s cohort. It was more frequent in PD patients than controls, worsened in the “OFF” condition & correlated with indices of bradykinesia, dysphagia, & autonomic dysfunction (Click here to read more about this).
  • A nationwide (Korea) study using propensity score matching reports association between metabolic syndrome & Parkinson’s incidence. Interesting: High triglycerides exerted a protective effect against PD incidence particularly in men (OR, 0.66; P < 0.001 – Click here to read more about this).
  • Dopaminergic amacrine cell number are reduced between 58% & 26% in different retinal regions in Parkinson’s, involving a decline in the number of synaptic contacts with aII amacrine cells (by 60%) & melanopsin cells (by 35%). Biomarker? (Click here to read more about this).

  • New medrxiv manuscript suggests that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy in Parkinson’s (Click here to read more about this).
  • New resesearch report explores the effect of ketogenic diet (vs regular diet) on voice quality of patients with Parkinson’s (Click here to read more about this).
  • Researchers report a de novo Parkinson’s patient with age of onset of 28, who carries novel compound heterozygous variants in the FBXO7 gene (c.1162C>T, p.Gln388X; c.80G>A, p.Arg27His – Click here to read more about this).
  • There is no protective effect of gout for the risk of developing Parkinson’s in the Taiwanese population (Click here to read more about this).
  • Evidence from a multi-center survey in Tuscany region explores the prevalence & impact of COVID-19 in Parkinson’s. Of 740 PD patients interviewed, 7 (0.9%) were affected by COVID-19, & with 0.13% mortality. Hypertension & diabetes risk factors for COVID-19 (Click here to read more about this).
  • Karate & Parkinson’s – an interesting combo! Researchers explore feasibility & quality of life for a pilot karate intervention to change kinematic outcomes in PD. Their 10 week, unblinded study finds quality of life improved significantly (Click here to read more about this).

  • Researchers analysed levels of hypoxia markers in postmortem brain tissue from cases of Parkinson’s & Multiple Systems Atrophy (MSA) cases (+controls), & they propose “a new alternative pathway associated with α‐synucleinopathies”. “In association with the pronounced respiratory & cardiovascular autonomic disturbances throughout a disease course of 6 to 8 years, MSA patients are likely to suffer events of hypoxia in the brain, which could lead to an aggravation of disease progression as compared with PD” (Click here to read more about this).
  • A review of 16 studies investigating EMG activity of lower limb muscles in people with Parkinson’s during walking reports greater proximal & decreased distal activity of lower limb muscles (Click here to read more about this).
  • Of mice & men: An analysis of metabolic alterations in Parkinson’s plasma finds increase in levels of unconjugated bile acids (cholic acid, deoxycholic acid & lithocholic acid) plus purine base intermediary metabolites (in particular hypoxanthine – Click here to read more about this).
  • New study uses data from the UK Biobank to reproduce several well-known associations with Parkinson’s, & to demonstrate a novel gene–environment interaction (diabetes & PD risk appears to depend on genetic background – Click here to read more about this).

  • New research reports fermented milk intake is not associated with increased risk of Parkinson’s. Cohort=81,915 Sweds. They also found a weak association between milk intake & increased risk of PD, but no dose–response relationship (Click here to read more about this).
  • Researchers report that reduced ventricular cerebrospinal fluid cell-free-mtDNA is a feature specific to Parkinson’s – consistent throughout the disease course; & curiously it is elevated in dementia (Click here to read more about this).
  • Levels of acute phase proteins (APPs; plasma proteins synthesized in the liver) are elevated in blood of ALS, but not Alzheimer’s, frontotemporal dementia, or Parkinson’s. APPs accurately reflect disease burden, progression rates, and survival times (Click here to read more about this).
  • Association of transient orthostatic hypotension with falls & syncope (fainting/passing out) in individuals with Parkinson’s (Click here to read more about this).
  • New paper reports their analyses did not find evidence to support the hypothesis that RHOT1 & RHOT2 are disease causing (or modifying) genes for Parkinson’s risk or age at onset (Click here to read more about this).
  • Penetrance involves the proportion of individuals carrying a particular genetic variant that also present the associated trait. Parkinson’s-associated LRRK2-G2019S penetrance is is incomplete. Could mitochondria be involved? (Click here to read more about this).

  • Researchers report a safe & effective virtual clinic template for Parkinson’s, combining phone consultations & reports from wearable technology (PKG wrist-worn device – Click here to read more about this).
  • New research explores turning detection during gait analysis; their paper discusses algorithm validation, influence of sensor location, & turning characteristics in the classification of Parkinson’s (Click here to read more about this).
  • Researchers have a medrxiv manuscript suggesting that lower lymphocyte counts (up to 8 yrs before diagnosis) is associated with higher risk of subsequent Parkinson’s diagnosis (Click here to read more about this).
  • Researchers have a medrxiv manuscript suggesting the LRRK2 M1646T variant is associated with increased risk of Parkinson’s & increased glucocerebrosidase activity (in peripheral blood; 2 cohorts, slight difference – Click here to read more about this).
  • New report explores the health burden of non-communicable neurological disorders in the USA between 1990 & 2017; largest increase in the proportions of disability-adjusted life-years (DALYs) was evident in Parkinson’s (58.5%) & ALS (55.3% – Click here to read more about this).
  • Is orthostatic hypotension a prodromal marker for Parkinson’s? Researchers report it is not associated with an increased risk of PD (Click here to read more about this).

  • Longitudinal prediction of falls & near falls frequencies in Parkinson’s: a prospective cohort study. Tandem gait & cognition (MMSE) scores predict the number of falls/near falls in short & long term (Click here to read more about this).
  • A new biorxiv manuscript explores the appendix microbiome of PD patients. Data suggests microbially-derived toxic bile acids are elevated in Parkinson’s & biliary changes may even precede the onset of motor symptoms (Click here to read more about this).

 

New clinical trials

  • New clinical trial registered: the GEnetic counseling Through Virtual visits in Parkinson’s (GET-VIRTUAL) study will compare methods of virtual genetic counseling for people with PD (Click here to read more about this).
  • New clinical trial registered: Detection of alpha-synuclein aggregate as a biomarker in diagnosing Parkinson’s at early stage (using Protein Misfolding Cyclic Amplification – PMCA – Click here to read more about this).

 

Clinical trial news

  • A preliminary observational study (n=15) of fecal microbiota transplantation therapy for Parkinson’s suggests the treatment is safe & well tolerated. Between nasointestinal FMT & colonic FMT, colonic seemed better & more preferable (Click here to read more about this).
  • Herantis Pharma have announced that their CDNF in Parkinson’s Phase I-II clinical study has met the primary endpoints of safety & tolerability at 12 months. Additional exploratory outcome measures expected to be completed Q4 2020 (Click here to read more about this).

  • Dual therapies: Improved Parkinson’s motor score in a single-arm open-label pilot trial of febuxostat & inosine; treatment was relatively safe for 56 days; larger blinded study required to assess efficacy (Click here to read more about this).
  • Amylyx Pharmaceuticals published the results of their 24-week, randomised, double-blind, placebo-controlled Phase 2/3 CENTAUR clinical trial of AMX0035 (a combination of sodium phenylbutyrate & taurursodiol) in 137 individuals with amyotrophic lateral sclerosis (ALS). The study met its predetermined primary endpoint – exciting news for the ALS community (Click here to read the study results and click here to read the press release).

  • Results of the AFFiRiS Phase I safety/tolerability study of the alpha-syn vaccines PD01A & PD03A in patients with early Multiple Systems Atrophy (MSA) have been published. The treatment triggered “a rapid & long‐lasting antibody response” (Click here to read more about this).
  • Annovis Bio announced first patient dosed in their Phase 2a Alzheimer’s & Parkinson’s trial of ANVS401 (PosiphenClick here to read more about this).

  • CuraSen Therapeutics announced that the first participants dosed in Phase I clinical trial of CST-2032, a brain-permeant, selective adrenoceptor modulator, targeting neurodegenerative conditions like Parkinson’s (Click here to read more about this).
  • Clene Nanomedicine presented interim results from REPAIR-PD Phase 2 study at 2020 MDS Congress; data indicate catalytic bioenergetic improvements with CNM-Au8 across CNS bioenergetic metabolites (NAD+/NADH, ATP, etc) in Parkinsons; small study (Click here to read more about this).

Other news

  • Plasma giant Grifols announced that it is going to buy Alkahest. Alkahest has been developing a combination of specific blood proteins for age-related diseases like Alzheimer’s & Parkinson’s (Click here to read more about this).

  • New report explores the feasibility, reliability, & value of remote video-based trial visits in Parkinson’s. Visits are shorter, reduce participant burden, & enable safe conduct of research visits (Click here to read more about this).
  • Researchers have received a grant from Agora Open Science Trust’s Medicines for Neurodegeneration (M4ND) to explore Parkin protein as a potential therapeutic target for Parkinsons (Click here to read more about this).

  • The Cure Parkinson’s Trust announced that another partner has joined the international Linked Clinical Trials (iLCT) program. The initiative is now worth USD$6.75 million over the next 3 years after The John Black Charitable Foundation joins the iLCT program (Click here to read more about this and click here to read a previous SoPD post about the iLCT initiative).
  • ESCAPE Bio closes $73 Million in crossover financing to advance clinical development of therapies for genetic neurodegeneration; the company is advancing a mutant-selective LRRK2 G2019S kinase inhibitor for Parkinson’s to IND-enabling studies (Click here to read more about this).

  • Cantabio Pharmaceuticals has been awarded a grant from the Michael J Fox Foundation to develop a novel DJ-1 protein-based biomarker for Parkinson’s (Click here to read more about this).
  • Singapore-based biotech start-up LiberaTx is developing a slow-release pill technology that floats in the stomach & slowly delivers medication over 24 hrs to individuals with Parkinson’s (Click here to read more about this).

 

Upcoming conferences/Lectures

  • For readers interested in neural transplantation and regenerative research, registration for the 2020 virtual NECTAR meeting is now open! They have a great line-up of speakers and registration is completely free of charge (Click here to read more about this).
  • Looking forward to the Edinburgh Parkinson’s Lecture – “Genetic factors in Parkinson’s: cause or modifier?” Prof Christine Klein will be speaking on Tuesday 6th October at 7pm. It’s free & watchable from anywhere in the world! (Click here to read more about this).

Review articles/videos

  • Ketotherapeutics” – a useful book chapter on ketone body metabolism & signaling, & how ketone bodies (particularly d-β-hydroxybutyrate), may serve as a potential adjunctive nutritional therapy for Parkinson’s & Alzheimer’s (Click here to read more about this).
  • Connecting the dots in Parkinsons pathophysiology: How VPS35 & the mitochondria fit into the picture & the potential for targeting VPS35 as a neuroprotective strategy (Click here to read more about this).
  • Interesting webinar on the prodromal phase of Parkinson’s:
  • New literature review explores the relationships of vitamin D, vitamin D receptor gene polymorphisms, & vitamin D supplementation with Parkinson’s (Click here to read more about this).
  • A review of calcium, bioenergetics & Parkinson’s (Click here to read more about this).
  • Emerging targeted therapeutics for genetic subtypes of Parkinsonism. Reviewing the current obstacles towards the development of precision interventions, primarily on trials for SNCA, GBA & LRRK2 in Parkinson’s (Click here to read more about this).
  • Interesting discussion on Parkinson’s and your pillow:
  • A useful review of research on GDNF/RET signaling in dopamine neurons. Has implications for ongoing clinical trials in Parkinson’s (Click here to read more about this).
  • The Parkinson’s Hope List now has a total of 361 projects, 175 in discovery/pre-clinical and 186 in clinical phase Parkinson’s (Click here to read more about this).
  • New commentary discusses new research on two different axes (CALCOCO2-RB1CC1 & OPTN-ATG9A), and how they initiate Parkinson’s-associated PARKIN-mediated mitophagy (Click here to read more about this).
  • A great video from the 2020 Rallying to the Challenge meeting, in which PD advocate Ben Stecher interviews Prof Ziv Gan Or about the genetics of Parkinson’s – this video offers a great entry level explanation of the topic for anyone completely unfamiliar with genetics:
  • Genome-wide association studies (GWAS) have taught us a great deal. But now we are in a post-GWAS world, & researchers use Parkinson’s in this review to as an example to explore the knowledge gaps (how, where, & when risk loci contribute – Click here to read more about this).
  • A useful review on noncoding RNAs & midbrain dopamine neurons: Novel molecular mechanisms & therapeutic targets in health & conditions like Parkinson’s (Click here to read more about this).
  • Another fantastic video from the 2020 Rallying to the Challenge meeting. This one involves PD advocate and dietitian Richelle Flanagan talking to Dr Vivian LaBrie and Prof Per Borghammer about the role of the gut in PD – this was one of my favourite discussions from the meeting:
  • And another review of noncoding RNAs & Parkinson’s – this one explores the evidence for functional interactions between the heart & the brain (Click here to read more about this).
  • Present challenges & future opportunities in pluripotent stem cell therapies for Parkinson’s. Immuno-compatible, pathology-resistant, pure A9 dopamine neurons are required (+ stage, dose, location,… – Click here to read more about this).
  • A useful review of pharmacodynamic biomarkers for emerging LRRK2 therapeutics for Parkinson’s (Click here to read more about this).
  • Useful review of using machine learning approaches to mine genetic & transcriptomic data in order to identify biomarkers & reveal clues about the underpinning pathology & pathogenesis in Parkinson’s (Click here to read more about this).
  • Another interesting video from the 2020 Rallying to the Challenge meeting in which PD advocate Chris Maycock talks to Dr David Beckham about the  possibility of viruses being involved in Parkinson’s in some way:
  • A useful review of peroxisome quality control & dysregulated lipid metabolism in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • Cell therapies for Parkinson’s gets brief mentions in this systematic multi-database analysis of global trends in clinical trials involving pluripotent stem cells (Click here to read more about this).
  • A useful review of small molecules/peptides targeting Glial Cell Line-Derived Neurotrophic Factor (GDNF) receptors for the treatment of neurodegeneration (Spoiler alert: Parkinson’s gets a big mention! – Click here to read more about this).
  • Interesting review of PARKIN-linked Parkinson’s: From clinical insights to pathogenic mechanisms & novel therapeutic approaches (Click here to read more about this).
  • A nice short summary of massive collaborative efforts to develop therapies for Parkinson’s provided by the editors of the Lancet Neurology journal (Click here to read more about this).
  • Another wonderful video from the 2020 Rallying to the Challenge meeting in which Dr Alison Bernstein discusses how environmental factors may be influencing PD:
  • The natural killers in all of us… A good review of the role of natural killer cells in Parkinson’s (Click here to read more about this).
  • Interesting review of methods employed in investigating the structure of neurotoxic protein aggregates inside cells. The authors focus on Huntington’s disease, but very relevant to Parkinson’s (Click here to read more about this).
  • If you are interested in the Phase III exenatide clinical trial for Parkinson’s, you should watch this great video from the 2020 Rallying to the Challenge meeting, in which PD advocate Rachel Gibson talks with Prof Tom Foltynie and Dr Dilan Athauda about whether insulin resistance/diabetes make a difference in Parkinson’s:
  • “A Critical LRRK (read ‘Look’) at the Synapse?” New review of the neurobiological function & pathophysiological dysfunction of Parkinson’s-associated LRRK2 (Click here to read more about this).
  • Further examination of research into the gut-brain axis in Parkinson’s (Click here to read more about this).

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

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

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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.


2 thoughts on “Monthly Research Review – September 2020

  1. Hi Simon – Thanks for all you do.

    I look through your reports to see if there are gems that I can put into practice now – so not so much new drugs that may or may not be useful and at best are some years away but practices now. However I do not always understand so would you be able to answer the questions below?

    Changes in the cellular fatty acid profile drive the proteasomal degradation of α‐synuclein & enhance neuronal survival; α‐syn‐fatty acid interaction=determinant of conformation & fate of α‐syn in cells, cPLA2 inhibitors may reduce α‐syn burden Parkinson’s

    OK not sure what his means. As these fatty acids as I understand it are found mainly in chicken and eggs. So should we eating more or less of chicken and eggs?

    Like

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