Monthly research review – March 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 March 2021.

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

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So, what happened during March 2021?

In world news:

March 5th – The UK Government has offered “claps” and a 1% pay rise to NHS nurses. Minister of State for Mental Health, Suicide Prevention and Patient Safety, Nadine Dorries said that a 1% offer “is the most we think we can afford” (you can’t make this stuff up – click here to read more about it).

 

March 8th – British shoe company “Shoezone” announced that Terry Boot would be replacing Peter Foot as their next finance director (Source) – you really can’t make this stuff up!

 

March 8th – Japanese researchers discovered that a species of sea slug (Elysia cf. marginata) can regenerate it’s entire body from a decapitated head (Click here to read more about this).

March 16th – Scientists reported the discovery of a new unknown bacteria species of Methylobacterium (designated IF7SW-B2T, IIF1SW-B5, and IIF4SW-B5). They were discovered… on the International Space Station (Source).

 

March 18th – COVID-19 pandemic: The number of vaccinations administered worldwide exceeded 400 million.

 

March 21st – Twitter turned 15 years old (makes one feel kinda… – click here to read more about this).

 

March 25 – COVID-19 pandemic: The number of vaccinations administered worldwide exceeds 500 million.

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

In March 2021, there were 986 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (3,449 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. Ultra-rare genetic variants may be important

Researchers reported that among Accelerating Medicines Partnership Parkinson’s disease (or AMP PD) participants, all of the individuals with LRRK2 p.R1441G genetic variants (N=89) also carry the more common Parkinson’s-linked LRRK2 p.M1646T variant. In addition, nearly all of the carriers of the LRRK2 p.N2081D variant also carry the LRRK2 rs76904798 variant (Click here to read more about this).

 

2. That gut feeling…

Researchers used metagenomics & serum metabolomics to achieve insights into key microbial species linked with disease severity, GI dysfunction, & age of individuals with Parkinson’s. They recruited 25 male patients with early-stage L-DOPA-naïve Parkinson’s & 25 matched controls, and found an increased microbial capability to degrade mucin & host glycans found in the Parkinson’s group. Modeling revealed the microbial contribution to folate deficiency & hyperhomocysteinemia in PD cases (Click here to read more about this).

 

3. Diabetes and Parkinson’s

Researchers conducted a meta‐analyses of traditional observational studies & genetic data, & observe “convincing evidence for an effect of T2 diabetes on Parkinson’s risk & new evidence to support a role in PD progression“; “Future observational & genetic studies should include greater representation of minority ethnic groups, many of whom experience a greater burden of T2DM“; Could better treatment & management of T2DM help to slow down the progression of Parkinson’s? (Click here to read more about this and click here to read the press summary associated with this research).

 

4. The smell of Parkinson’s

Metabolomics of sebum reveals lipid dysregulation in Parkinson’s. New data involving LC-MS analysis on 274 sebum samples (from 80 drug naïve PD, 138 medicated PD & 56 matched control); Pathway enrichment analysis shows alterations in lipid metabolism related to the carnitine shuttle, sphingolipid metabolism, arachidonic acid metabolism, & fatty acid biosynthesis; “This study shows sebum can be used to identify potential biomarkers for Parkinson’s”; “Insufficient clinical data is available for these patients to hypothesise on the ability of a sebum analysis to help stratify disease progression” (Click here to read more about this, click here to read the press summary associated with this research, and click here to read a SoPD post on this research).

 

5. Patching into Levodopa levels

Researchers have developed a wearable patch for continuous analysis of thermoregulatory sweat at rest. This could be an ideal platform to continuously/routinely monitor users’ medical conditions & physiological status during daily routines. Using this technology, the researchers explored sweat levodopa levels in relation to broad beans intake in healthy volunteers. Levodopa concentration in sweat generally increases with increasing doses; Potential for monitoring Levodopa levels in Parkinson’s? The authors caution that “the exact relations between sweat levodopa concentration, plasma levels, & intake dose can depend on diet, hydration, other physiological conditions that impact absorption & metabolism rates, & on sweat rate & secretion mechanisms“. Larger studies required, but remarkable tech! (Click here to read more about this).

Articles of general interest

  • If you read nothing else on this website today, read this review article on The cell biology of Parkinson’s” (Click here to read more).
  • Parkinson’s research over the last 20 years – an easy to read article on new concepts and developments (Click here to read more about this).
  • Why participate in clinical trials for Parkinson’s? Dr Soania Mathur – Parkinson’s advocate – provides answers to this question. From participation in trials at every stage to raising awareness or funds, there cannot be progress in research without patient participation (Click here to read more about this).

  • A nice overview of the “busy year ahead for Parkinson’s” clinical trials in 2021; Useful table at the bottom of the piece (Click here to read more about this).
  • The International Linked Clinical Trials initiative is one of the world’s largest Parkinson’s drug repurposing program. This review provides an overview of this ambitious program (Click here to read more about this).
  • A useful review of the cellular & synaptic mechanisms of Parkinson’s-related chronic pain (Click here to read more about this).
  • Timely & interesting – Data sharing goals for nonprofit funders of clinical trials:
    #1: Encourage co-development of data sharing policies with patient/lay communities
    #2: Incorporate data sharing concepts/policies as early as possible in the clinical trial
    #4: Promote the development of a sustainable/feasible data sharing infrastructure
    #5: Promote/support the development/adoption of standards, standard language, & common data elements
    #6: Include incentives & enforce requirements in grants, contracts, & other funding structures
    #7: Provide funding for data sharing & include this activity as a line item in grants & contracts
    #8: Incorporate previous data sharing as a measure of impact when making decisions on whether to fund or support clinical trials
    Not simply a “check-the-box exercise” (Click here to read more about this).

 

Basic biology news

  • New data indicates that “intramolecular unfolding of α-synuclein is a prerequisite for protein aggregation that leads to rapid multiplication of α-synuclein amyloid fibrils via the secondary nucleation process” (in vitro – click here to read more about this).
  • New research supports involvement of a calcium-modulated, mitochondrial stress-activated PINK1/Parkin-dependent pathway in nicotine-induced neuroprotection (C elegans study – click here to read more about this).
  • A technical paper – Analysis of lysosomal hydrolase trafficking & activity in human iPSC-derived neuronal models – a useful assay in Parkinsons-based studies (Click here to read more about this).

  • Technical paper: Comparison of the expression & toxicity of AAV2/9 carrying the human Parkinson’s-associated A53T α-synuclein gene in presence or absence of WPRE; Presence of WPRE enabled to achieve greater nigrostriatal degeneration and synucleinopathy (Click here to read more about this).
  • New in vitro research finds defective GCase activity promotes release of extracellular vesicles (regardless of GBA mutation); Small EVs released from Parkinson’s fibroblasts carrying GBA mutations increased the intra-cellular levels of phosphorylated α-syn (Click here to read more about this)
  • Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation; multiplexing strategy to differentiate 215 human IPS cells towards dopamine fate, single-cell RNA-seq of 1M+ cells across 3 time points; “Expression quantitative trait loci were characterized at different stages of neuronal development & in response to rotenone-induced oxidative stress”; nearly half of which are not found in GTEx (Click here to read more about this).
  • New data reports TSPO is a pro-pathological conduit for mitophagy loss in neurotoxicity; TSPO amplifies ERK1/2 signalling, forming positive feedback, which represses TFEB & the controlled production of lysosomes (Click here to read more about this).
  • New research indicates that genetic variants associated with Parkinson’s modulate blood levels of 8 specific lipid species, possibly supporting a key role of these lipids in PD etiology (Click here to read more about this).
  • Knocking out Parkinson’s-associated alpha-synuclein in melanoma cells dysregulates cellular iron metabolism & suppresses tumor growth (Click here to read more about this).

  • New biorxiv manuscript supports a model in which Parkinson’s-associated LRRK2 & PPM1H are involved in the receiving & responding to critical Hedgehog signals in the nigral-striatal pathway (Click here to read more about this).
  • Researchers report that Parkinson’s-associated LRRK2 regulates ciliation probability upstream of tau tubulin kinase 2 (via Rab10 & RILPL1 proteins – Click here to read more about this).
  • SARM1, an inducible pro-degenerative NADase, “is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe & axonal demise” (Click here to read more about this and click here to read a press summary of the work).
  • Heterogeneity in α-synuclein fibril activity correlates to disease phenotypes in Lewy body dementia; “Broad heterogeneity of fibril-templating activities in DLB that may contribute to disease phenotypes” (Click here to read more about this).
  • New research points towards a novel interaction between nucleolar processes & Parkinson’s-associated α-synuclein, with DEAD-box RNA helicase Dbp4/DDX10 emerging an enhancer of α-syn toxicity & oligomerization (Click here to read more about this).
  • New research provides in vitro evidence that cannabidiol stimulates autophagy signal transduction (via crosstalk between the ERK1/2 & AKT kinases); Effect is reduced in the presence of CB1, CB2 & TRPV1 receptor antagonists (Click here to read more about this).
  • Researchers have a biorxiv manuscript suggesting the bacterial amyloids phenol soluble modulins from Staphylococcus aureus can catalyze Parkinson’s-associated alpha-synuclein aggregation; Potential synucleinopathy trigger? (Click here to read more about this).

  • Mechanistic insights into Ykt6 regulation: Ykt6 is phosphorylated at an evolutionarily conserved site (regulated by Ca2+ signaling); phosphorylated open form leads to defects in secretory & autophagy pathways, enhancing toxicity in Parkinson’s models (Click here to read more about this).
  • Extracellular α-Synuclein evokes post-translational modifications of Parkin which promotes mitochondrial dysfunction in neurons (Click here to read more about this).
  • New research provides a new framework for understanding the circuit basis of different behavioral deficits in the Parkinson’s state (Click here to read more about this).
  • In addition to inhibiting protein aggregation, new research indicates that O-GlcNAc also activates the anti-amyloid activity of certain small heat shock proteins; paper is focused on Alzheimer’s, but implications here for Parkinson’s too (Click here to read more about this).
  • New study indicates that Sulforaphane suppresses NLRP3 inflammasome (via the inhibition of NF-κB nuclear translocation & Nrf2 mediated miRNAs expression modulation) in murine microglia (Click here to read more about this).
  • New biorxiv manuscript presents automated machine learning on multi-modal data from the Parkinson’s Progression Marker Initiative (PPMI) study, identifying gene communities specific to PD (Click here to read more about this).

  • Computational analysis indicates that PARP1 acts as a histone deacetylases interactor, sharing common lysine residues for acetylation, ubiquitination, & SUMOylation in Alzheimer’s & Parkinson’s (Click here to read more about this).
  • Variants in lysosomal protease Cathepsin D (CTSD) that are associated with neurodegenerative conditions show dysregulated functionality & modified degradation of Parkinson’s-associated α-Synuclein (Click here to read more about this).
  • Rapid-scan electron paramagnetic resonance spectroscopy allows for imaging of Parkinson’s-associated alpha synuclein protein–vesicle interactions (in live cells) enabling time-resolved monitoring of protein–membrane interaction upon transfection into cells (Click here to read more about this and click here to read the press summary associated with this research).
  • Parkin is an E3 ligase for FAT10 – mediating FAT10ylation & proteasomal degradation of mitofusin2; in turn, FAT10 inhibits Parkin activation, translocation to damaged mitochondria, & mitophagy; FAT10 enhances neurotoxin (rotenone) model of Parkinson’s (Click here to read more about this).
  • New biorxiv manuscript explores IRE-bearing transcripts in the transcriptome data from homozygous Park7-/- mutant zebrafish brains (Click here to read more about this).
  • New biorxiv manuscript identifies β-AR signaling as an important regulatory pathway for ER-mitochondria coupling & highlights the role of these contacts in responding to physiological demands or stresses (Click here to read more about this).
  • New report demonstrates unexpected adverse effects of both anti-inflammatory cytokine Il-10 & its immunosuppressive variant, vIl-10; Over-expression REDUCES survival in mouse models of synucleinopathy; highlights pleiotropic functions of immune mediators (Click here to read more about this).

  • Deletion of the WDR81 homolog (SORF-2) causes accumulation of p62 bodies & exacerbates neuron loss induced by over-expression of Parkinson’s-associated α-synuclein; Overexpression of SORF-2 or human WDR81 restores neuron viability in worms (Click here to read more about this).
  • Researchers present the preparation, construction & high-throughput automated analysis of human brain tissue microarrays for neurodegenerative disease drug development (Click here to read more about this).
  • Researchers use super-resolution time-lapse imaging to investigate mitochondria-lysosome contacts in the context of GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s; Reduced levels of the untethering protein TBC1D15 (Click here to read more about this).
  • New research explores accumulation of Parkinson’s-associated alpha-synuclein within the liver (the main organ responsible for substance clearance & detoxification); Human + 3 transgenic mouse samples involved (Click here to read more about this).
  • Mice carrying VPS35 D620N variant (which involves mitochondrial fragmentation & dysfunction) present some features of Parkinson’s at 14 months of age (progressive motor deficits, loss of the DA neurons, neuroinflammation, & accumulation of α‐synuclein (Click here to read more about this).
  • New biorxiv manuscript presents a genome-wide screen to identify bacterial genes that promote host neurodegeneration; Genetically/pharmacologically inhibiting the curli major subunit CsgA in E. coli reduces Parkinson’s-associated α-syn-induced issues (Click here to read more about this).

  • Salvage NAD+ biosynthetic pathway enzymes moonlight as molecular chaperones to protect against proteotoxicity; Screens in yeast models of Huntington’s & Parkinson’s identify Npt1, Pnc1, & Qns1 as protectors against proteotoxic stress (Click here to read more about this).
  • Researchers combined micro particle induced X-ray emission (µPIXE) with nickel-enhanced immunocytochemical detection to explore cell type-specific patterns of iron accumulation in section of Parkinson’s brains. In control SNc, oligodendroglial & astroglial cells hold the highest cellular iron concentration, while in Parkinson’s, the iron concentration was increased in most nigral cell types (except astrocytes & oligodendrocytes); Ferritin in oligos seems to be depleted by almost half in PD (Click here to read more about this).
  • Researchers explore the effect of Parkinson’s-associated PINK1 deficiency on neurogenesis of dopaminergic neurons in zebrafish & human isogenic organoid model; PINK1-deficiency on global neuronal pop = ok, but DA neurogenesis = reduced (Click here to read more about this).
  • α-synuclein fibrils release soluble prefibrillar oligomeric species with cross-β structure & solvent-exposed hydrophobic clusters, which cross & permeabilise neuronal membranes, causing cellular insults; Short fibrils = more neurotoxic (Click here to read more about this).
  • New research reports increased LRRK2 kinase activity alters autophagy (via disruption of axonal transport of autophagosomes); Hyperactive LRRK2 recruits JIP4, causing a tug of war between autophagosome motors (Click here to read more about this).

  • A head-to-head comparison of equititer doses of AAV9 & AAV.PHP.eB (infused via the cisterna magna of older adult rodents) to determine which has the superior CNS transduction. The winner? AAV.PHP.eB! (Click here to read more about this).
  • Progression of phosphorylated α‐synuclein in primate brain, following delivery of fibrils into the left striatum; Propagation throughout the brain (via projection, association, & commissural fibers), but the progression of α‐synuclein pathology is limited (Click here to read more about this).
  • New data demonstrates the capacity for metazoan Hsp110 chaperones to suppress both general protein aggregation & amyloidogenesis, via a novel intrinsically disordered region (Click here to read more about this).
  • Establishment of an in vitro model for analysing mitochondrial ultrastructure in PRKN-associated Parkinson’s patient iPSC-derived dopaminergic neurons (Click here to read more about this).
  • Dementia with Lewy bodies-associated ß-synuclein mutations V70M & P123H (detected in a familial cases of DLB) aggravate the neurotoxic potential of ß-Syn via 2 mutually exclusive pathways (mitochondria & neuronal network activity, respectively – click here to read more about this).
  • Loss of Parkinson’s-associated Pink1 in Drosophila causes systemic growth defects (all independently of Parkin). Loss of Pink1 leads to hyperglycemia & limited systemic organismal growth (by inducing ImpL2 – click here to read more about this).

  • New data further implicates the renin-angiotensin-system as a functionally relevant neuromodulator in the substantia nigra, thus underscoring a need for additional inquiry; Angiotensin-II modulates nigral GABAergic neurotransmission (in mice – click here to read more about this).
  • iPSC-derived astrocytes from Parkinson’s patients carrying the LRRK2(G2019S) variant are characterised by marked decrease in astrocyte complexity, aberrant mitochondrial morphology & reduced ATP production (Click here to read more about this).
  • Researchers explore the genetic requirements for cell division in a genomically minimal cell (JCVI-syn3.0 – click here to read more about this and click here to read the press release associated with this work).
  • The absence of Lag3 significantly delays α-Syn pathology, decreases glial activation, & reduces the behavioral deficits in the hA53T transgenic mice model of Parkinson’s, resulting in prolonged survival (Click here to read more about this).

 

Disease mechanism

  • Autologous cell transplantation therapy (2-year period without immunosuppression) alleviates motor & depressive behaviours in a primate model of Parkinson’s (Click here to read more about this and click here to read a press summary).
  • New data indicates that for GDNF to be effective in patients with minimal motor deficits or Parkinson’s, there would likely need to be an up-regulation of RET & phosphorylated ribosomal protein S6 (Click here to read more about this and click here to read a SoPD post on this research).

  • Age-associated insolubility of Parkinson’s-associated Parkin protein in the human midbrain is linked to redox balance & sequestration of reactive dopamine metabolites (Click here to read more about this and click here to read a SoPD post on this topic).
  • New report finds that extended release GLP-1 agonist PT320 increases α-synuclein accumulation in the olfactory bulb injection of PFF prodromal mouse model of Parkinson’s; Microglia activation noted (Click here to read more about this).
  • Quinacrine & niclosamide promote neurite growth in midbrain dopaminergic neurons (via canonical BMP-Smad pathway) & protect against neurotoxin & α-synuclein-induced neurodegeneration (Click here to read more about this).
  • HDAC1/6 inhibitor with the catchy name N-(4-(hydroxycarbamoyl)benzyl)-1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (or simply HGC) protects dopamine neurons & alleviates motor features in models of Parkinson’s (via NDUFV1 acetylation – Click here to read more about this).
  • Researchers in China report NLRP3 inhibitor MCC950 administration prevents histological & functional changes in a mouse model of Parkinson’s; NLRP3 upregulated in the midbrain, but not NLRP1, NLRP2, NLRC4, or AIM2 (Click here to read more about this).
  • New research finds that Parkinson’s-associated LRRK2 kinase activity is not playing a major role in the induction of tau pathology in individual neurons (Click here to read more about this).
  • Researchers report that EGFR regulates the uptake of exogenous α-syn-PFFs; pharmacological inhibition of EGFR (via AstraZeneca’s BBB-penetrating inhibitor AZD3759) reduces α-syn pathology in a mouse model of Parkinson’s (Click here to read more about this).

  • Researchers provide further evidence that T cell responses associated with α-synuclein pathology may be damaging to key areas of the brain in mouse models of Parkinson’s; immunosuppressive drug fingolimod reduces the CNS myeloid MHCII response (Click here to read more about this).
  • New biorxiv manuscript explores the effect of nicotinamide riboside in multiple models of Parkinson’s (C. elegan a-synuclein & mouse lactacystin mouse model) – implications for the NOPARK study? “Long-term nicotinamide riboside supplementation, in conjunction with proteasome inhibition, resulted in decreased dopamine levels in both the lesioned & unlesioned sides of the substantia nigra with concomitant down-regulation of key genes in DA metabolism” (Click here to read more about this).
  • Sumitomo Dainippon Pharma researchers present a novel Phosphodiesterase 1 inhibitor (DSR-143136) that reverses Parkinson’s-associated L-Dopa-induced dyskinesias with no detrimental effects on motor function in primates; Does not impact motivation deficits (Click here to read more about this).
  • New data from Yumanity Therapeutics demonstrates pharmacological, physiological & behavioural pre-clinical proof of concept for YTX-7739 -a stearoyl-CoA desaturase inhibitor – in a mouse model of Parkinson’s (Click here to read more about this).

  • Kynurenine pathway again – An indolamine-2,3-dioxygenase-1 (IDO-1) inhibitor (1-MT) reported to improve locomotion & motor coordination, as well as reduce oxidative stress, neuroinflammation, mitochondrial dysfunction, & cell death in model of Parkinson’s (Click here to read more about this).
  • Researchers reveal a mechanism by which Parkinson’s-associated α-synuclein aggregation alters CSPα at the synapse, & show that CSPα rescues αsynuclein aggregation-related phenotype in 1-120hαSyn mice. CSPα is a member of the DNAJ/HSP40 family of co-chaperones & like αsynuclein, chaperones the SNARE complex assembly & controls neurotransmitter release. αSynuclein has previously been reported to rescue neurodegeneration in CSPαKO mice (Click here to read more about this).
  • Researchers report TNF-α & α-synuclein fibrils differently regulate human astrocyte immune reactivity & impair mitochondrial respiration (in healthy & in PARK2-variant Parkinson’s astrocytes – click here to read more about this).
  • Withaferin A has long been used in ayurvedic medicine, & demonstrated neuroprotective properties in models of Parkinson’s; Now researchers present data indicating that the DJ1-Nrf2-STING axis may mediate the effect (Click here to read more about this).
  • Is Fas‐associated factor 1 (FAF1) a negative regulator of autophagic α‐synuclein clearance? New data finds FAF1 activates the mTOR pathway (reducing autophagosome formation) resulting in accumulation of Parkinson’s-associated α‐syn in dopaminergic neurons (Click here to read more about this).
  • Ionis Pharma & Biogen publish rodent & primate data supporting “the development of α-synuclein antisense oligonucleotides as a potential disease-modifying therapy for Parkinson’s and related synucleinopathies” (Click here to read more about this).

  • New research demonstrates the anti‐dyskinetic potential of doxycycline (& its analog compound COL‐3) in a rodent model of Parkinson’s; L‐DOPA was not affected by doxy or COL‐3; Doxy was also associated with decreased FosB, cyclooxygenase‐2, GFAP, & OX‐42 (Click here to read more about this).
  • New study indicates the induction of α-synucleinopathy in dorsal motor nucleus of the vagus motoneurons causes shrinkage & dysregulates surface densities of Kv4 channels, leading to reduced firing rates, vagal tone, & slowed gut motility (Click here to read more about this and click here to read a SoPD post on the topic).
  • SGK inhibition reduces neuroinflammation & improved behavioural deficits/protects dopamine neurons in models of Parkinson’s; glial SGK1 inhibition suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, & CGAS‐STING pathways. They initially used the SGK inhibitor GSK‐650394 (low CNS-plasma ratio=0.03), but then shifted to silencing SGK using a gene therapy approach (intra‐nigral injection of sh‐SGK1 AAV9); A need to study the effects of SGK1 inhibition attained through T‐cell modulation in PD models (Click here to read more about this).

 

Clinical research

  • No evidence for a causal relationship between cancers & Parkinson’s. Researchers find no evidence to support a causal relationship between cancer & PD; Previously reported assoc.s may be due to genetic pleiotropy, shared biology, or biases (Click here to read more about this).
  • Oral dysbiosis & inflammation in Parkinson’s. New data finds that that the oral microbiome is altered in early & mid-stage PD; “Dental & periodontal parameters did not differ between groups“, but levels of IL-1β & IL-1RA were significantly increased in PD (Click here to read more about this).

  • Research report probable REM sleep behavior disorder is associated with longitudinal cortical thinning in Parkinson’s; “Results support the idea that RBD is a significant prognostic factor of poor evolution in PD” (Click here to read more about this).
  • A longitudinal observational study of α-synuclein in cerebrospinal (by RT-QuIC) in individuals with isolated rapid-eye-movement sleep behaviour disorder (iRBD) finds detection preceded conversion to synucleinopathy by ~3.2 years (range: 6 months to 9 yrs – Click here to read more about this and click here to read the press summary of the work).
  • The “Smell of Parkinson’s” – Researchers show an 84.4% correct classification of Parkinson’s cases using all detected volatile compounds; PD n=100 & control n = 29 (Click here to read more about this).
  • New research indicates that thalamic morphology predicts the onset of freezing of gait in Parkinson’s; “Validation using the PPMI cohort suggested FOG-specific non-linear evolution of thalamic local volume” (Click here to read more about this).
  • New research reports an association between peripheral blood monocytes & brain immune + dopaminergic changes in REM sleep behavior disorder (iRBD), suggesting a cross-talk among periphery & CNS in this Parkinson’s prodrome (Click here to read more about this).

  • A protective role for rheumatoid arthritis (RA) on Parkinson’s? A new 2-sample Mendelian randomization analysis obtained from large-scale GWAS summary data, researchers demonstrate that RA may reduce the risk of PD in the European-ancestry population (Click here to read more about this).
  • Another report exploring the relationship between rheumatoid arthritis and Parkinson’s also found that people with RA exhibit lower PD risk later in life (Click here to read more about this).
  • My treatment approach to Multiple System Atrophy” – a guideline based on what has worked in a clinic designed to provide care throughout the disease course, empowering a partnership with care providers (Click here to read more about this).
  • New data indicates that perivascular spaces in the basal ganglia could be an indicator of the progression of motor disability in newly diagnosed Parkinson’s; n=248 patients (Click here to read more about this).
  • Further data suggesting an association between higher IQ in adolescence with a higher risk of Parkinson’s later in life; An association between resting heart rate & PD suggests that altered cardiac autonomic function might start before 20 years of age in PD (Click here to read more about this).
  • A prospective observational cohort study of neurological outcome & quality of life three months after COVID‐19 has been published; n=135, 15% presented neurological syndromes that were not evident before COVID-19 (including 1 case of parkinsonism – click here to read more about this).

  • New medrxiv manuscript from Spanish EPIC cohort researchers explores prognostic biomarkers of early prodromal Parkinson’s via a multiplatform metabolomics approach; Changes in fatty acids metabolism, mitochondrial function, & oxidative stress (Click here to read more about this).
  • New study provides mechanistic insights into regional selective vulnerabilities in Parkinson’s, particularly into molecular processes involving iron accumulation (Click here to read more about this).
  • New research from ReSPOnD trial researchers finds a high prevalence of pre-frailty & frailty in patients with Parkinson’s who had a history of having fallen (Click here to read more about this).
  • Characterisation of advanced Parkinson’s: results from the Swiss subgroup of the OBSERVE-PD observational study (Click here to read more about this).
  • Researchers find a “subtle difference in executive functioning among some non-manifesting heterozygous GBA mutation carriers“; Combined with olfaction, could this act as a potential biomarker for pre-manifest & pre-clinical GBA-related Parkinsons? (Click here to read more about this).
  • Using NanoString & digital PCR, researchers screened for alterations in genes associated with Parkinson’s in erythrocytes from PD patients; CHCHD2 mRNA was significantly reduced even at the early stages of the disease; validated in larger cohort (n=205 PD – click here to read more about this).
  • Meta-analysis of Parkinson’s gut microbiome suggests alterations linked to intestinal inflammation; increases in Lactobacillus, Akkermansia, & Bifidobacterium; Reductions in Lachnospiraceae & Faecalibacterium members (Click here to read more about this).

  • New data indicates that motion artifacts in optical coherence tomography angiography (OCTA) images are equally common in medicated patients with Parkinson’s & age-/gender-matched controls; Longer disease duration & more severe symptoms were associated (Click here to read more about this).
  • Individuals with LRRK2-associated Parkinson’s may have significantly lower uric acid concentrations (compared to unaffected controls) up to 5 years follow-up; But no significant associations between uric acid levels & indices of disease severity (Click here to read more about this).
  • Researchers observed progressive & measurable decrease in neuromelanin‐based substantia nigra signal & volume in Parkinson’s; A noninvasive assessment of progression? A biomarker for disease‐modifying treatments? (Click here to read more about this).
  • “PDKit”: An open source data science toolkit for the digital assessment of PD – used in the CloudUPDRS Smartphone Software in Parkinson’s (CUSSP) study (Click here to read more about this).
  • New medrxiv manuscript suggests COVID-19 “does not affect motor & psychological aspects of Parkinson’s as much as it was expected”; PD patients may follow tighter preventive protocols which leads to lower prevalence & severity of Covid-19 (Click here to read more about this).
  • Researchers publish an interesting review on variations in the patterns of prevalence & therapy in Parkinson’s patients of different ethnicities across New Zealand & Australia; discussing the low incidence of PD in Māori & higher medication (Click here to read more about this).

  • New research finds that “postural sway shows potential as a possible measure of underlying disease status in Parkinson’s, either alone or in combination with other measures” (Click here to read more about this).
  • New medrxiv manuscript suggests no genetic associations between KTN1 & Parkinson’s (14,671 PD vs 17,667 healthy controls; European ancestry), but there is potential evidence of differences in mRNA expression which require further exploration (Click here to read more about this).
  • New data from Sweden suggests that intestinal inflammatory microscopic colitis may not be a risk factor for Parkinson’s; Instead, it may co‐occur with PD as a comorbidity or develop after a diagnosis of PD (Click here to read more about this).
  • New study reports gender effects on clinical features in LRRK2 G2385R carriers & non-carriers in terms of disease course for Parkinson’s (Click here to read more about this).
  • New paper reports a meta-analysis of genome-wide DNA methylation (in whole blood) that identifies shared associations across neurodegenerative conditions (ALS, Alzheimer’s & Parkinson’s – Click here to read more about this).
  • Further evidence that poorly controlled type 2 diabetes mellitus is an independent risk factor contributing to motor progression in Parkinson’s; A prospective cohort study from March 2009 to August 2020; N=379 (Click here to read more about this).
  • Underrepresented communities: An analysis of the burden of adult neurological diseases in Odeda Area, Southwest Nigeria reports an increased prevalence of non-communicable neurological disorders such as stroke & Parkinson’s (Click here to read more about this).

 

  • Under-represented communities: Identification of GBA variants among Parkinson’s (n=198), Parkinson’s with dementia (136), Parkinson plus (184), & Alzheimer’s (46) cohorts in eastern India; Variants more frequent in PDD (Click here to read more about this).
  • Could electroceutically induced subthalamic high-frequency oscillations & evoked compound activity explain the mechanism behind therapeutic deep brain stimulation in Parkinson’s? (Click here to read more about this and click here to read the press summary).
  • New research finds cortical gyrification changes in Parkinson’s are motor phenotype-specific & are possibly mediated by the microstructural abnormalities of the underlying white matter tracts; 64 akinetic-rigid & 26 tremor-dominant + 56 controls involved (Click here to read more about this).
  • Small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) associates with intracellular aggregates in some neurodegenerative conditions (Huntington’s disease & MSA, but not so much in ALS or Parkinsons – click here to read more about this).
  • Anatomical texture patterns identify cerebellar distinctions between essential tremor (n = 109) & Parkinson’s (n = 280); Anatomical differences between groups that were localised to the inferior part of the cerebellar cortex (Click here to read more about this).
  • COURAGE‐PD cohort (9673 PD patients; 8465 controls) researchers confirm the “role of SV2C locus as a novel risk factor for Parkinson’s irrespective of the population or ethnic group analyzed” (Click here to read more about this).

  • New medrxiv manuscript suggests “proteome-wide impairment of proteostasis in the Parkinson’s brain & strongly support the hypothesis that aberrant proteasomal function is implicated in the pathogenesis of PD” (Click here to read more about this).
  • Analysis of genetic risk factors in Japanese patients with Parkinson’s; n=221; PRKN & LRRK2 were the major PD-related genes (Click here to read more about this).
  • Peripheral AADC induction could underlie waning effect of L-dopa, necessitating dose increases to maintain therapeutic effect; Serum AADC enzyme activity is elevated in 3 independent Parkinson’s cohorts (Click here to read more about this).
  • Application of the updated Movement disorder Society criteria for prodromal Parkinson’s to a population‐based 10‐year study; “Predictive accuracy did not change when using the updated criteria, probably due to the low sample size” (Click here to read more about this).
  • Amyloid related cerebral microbleed & plasma levels of Aβ40 are associated with cognitive decline in Parkinson’s; N=135 PD patients & 34 unaffected controls; Higher prevalence of lobar microbleeds in PD patients compared to healthy controls (Click here to read more about this).
  • Spanish researchers propose a new methodology for classifying different stages of Parkinson’s, using an ordinal classifier from 3D-images obtained after the administration of 123I-ioflupane in 3 level of affliction (no PD, mild & severe – click here to read more about this).
  • Crowdsourcing digital health measures (from accelerometer & gyroscope data) to predict Parkinson’s severity from Sage Bionetworks researchers (& collaborators – from 40 teams from around the world) – part of the PD Digital Biomarker DREAM Challenge (Click here to read more about this).

  • The Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society (RMDSG) developed a survey to assess the worldwide barriers to genetic testing for movement disorders; They “highlighted major disparities in genetic testing among world regions, likely due to a variety of factors including financial barriers” (Click here to read more about this).
  • Small study, but result suggests that bilateral oophorectomy may be associated with increased risk of Parkinson’s (OR = 3.55, 95%CI = 1.75–7.20), after adjustment for education level, smoking status, exposure to pesticides, coffee & alcohol drinking (Click here to read more about this).
  • New research highlights a link between the integrity of the noradrenergic locus coeruleus & response inhibition in Parkinson’s; Locus coeruleus neuromelanin imaging may offer a marker of noradrenergic capacity (Click here to read more about this).
  • General increase in the activity of calpains in plasma of both Parkinson’s & essential tremor; “At the advanced stages of PD calpain activity in plasma was significantly higher” than early stage PD; The increase was observed in m-calpain activity (Click here to read more about this).
  • Researchers report that while variations in the TOMM40 ‘523’ polymorphism are not associated with Parkinson’s risk, it may be a modifying factor for age of symptom onset (warrants further investigation in other PD cohorts – click here to read more about this).
  • Towards adaptive DBS – A new medrxiv manuscript explores the advances/pitfalls of one of the first commercially available deep brain stimulation devices capable of recording brain local field potentials (Click here to read more about this).

  • Buried bumper syndrome occurs when the internal fixation of a levodopa intestinal infusion device migrates alongside the stoma tract out of the stomach. New 12 year study – involving 35 Parkinson’s cases – explores frequency & outcomes (Click here to read more about this).
  • Researchers report deep sequencing of small noncoding RNAs (sncRNAs) reveals hallmarks & regulatory modules of the transcriptome during Parkinson’s progression. SncRNAs in 5,450 blood samples of 1,614 individuals in PPMI yielded 323 billion reads! “Dysregulated microRNAs associated with disease & disease progression occur in two distinct waves in the 3rd & 7th decade of life. Originating predominantly from immune cells, they resemble a systemic inflammation response & mitochondrial dysfunction, two hallmarks of Parkinson’s“; A comprehensive resource encompassing massive amounts of data for testing of new hypotheses in the fields of small RNA research; “Small noncoding RNAs are on their way to become a class of new therapeutic targets for Parkinson’s & likely for other neurodegenerative disorders” too (Click here to read more about this).
  • New data reports that the LRRK2 p.M1646T variant is associated with risk of Parkinson’s (“small effect”) & with increased GCase activity in peripheral blood based on PPMI dried blood spot samples (Click here to read more about this)
  • Chimarrão is a common caffeinated drink consumed in Brazil made with the leaves & stems of Mate (Ilex paraguariensis). Researchers report Chimarrão consumption is inversely associated with Parkinson’s (after adjusting for coffee – small study – Click here to read more about this).

 

New clinical trials

  • New clinical trial registered: Pharma company Roche and Prothena Corp have registered a Phase IIB study to evaluate the efficacy & safety of intravenous Prasinezumab (a-syn immunotherapy) in 575 people with early Parkinson’s on stable symptomatic medication (PADOVA study – Click here to read more about this).

  • New clinical trial registered: Scion NeuroStim have registered an open label extension study evaluating their non-invasive neuromodulation device in 220 people with Parkinson’s (Click here to read more about this).
  • New clinical trial registered: Open label extension of Scion NeuroStim‘s ongoing STEM-PD study establishing safety & efficacy of a non-invasive neuromodulation device for treating symptoms associated with Parkinson’s (Click here to read more about this).
  • New clinical trial registered: A pretest-post-test control group design to evaluate the effect of a boxing exercise program on turning speed, gait speed, & functional lower extremity strength in 24 people with Parkinson’s (Click here to read more about this).
  • New clinical trial registered: BlueRock Therapeutics has initiated their safety & tolerability of surgical implantation of MSK-DA01 cells for advanced Parkinson’s; 10 participants will be treated & followed for 2 years (primary endpoint=12 months – click here to read more about this).

  • New clinical trial registered: An observational study without an intervention to determine the benefits of Parkinson’s-specific exercise programs & general exercise patterns on physical function & quality of life among 1000 people with Parkinson’s (Click here to read more about this).
  • New clinical trial registered: “Parkinson’s Disease with Mild cognitive Impairment treated with Nicotinic agonist Drug” (PD-MIND) study will be a Phase II study recruiting 160 participants to investigate AZD0328 (α7 nicotinic agonist – click here to read more about this).

 

Clinical trial news

  • Ionis Pharmaceutical has announced that its partner, pharma company Roche, has decided to discontinue dosing in the Phase III GENERATION HD1 study of tominersen in manifest Huntington’s disease; Decision was based on pre-planned independent data safety monitoring committee review of data from the Phase 3 study. Ionis has not seen the data, but the independent data safety monitoring committee has said that no new or emerging safety signals have emerged. The company has stated that it is too premature to reject the huntingtin lowering hypothesis, and there is no timing on Roche data review (Click here to read more about this).
  • Annovis Bio announces results of an interim analysis from a double-blind, placebo-controlled study of ANVS401 for the treatment of Parkinson’s & Alzheimer’s: Speed & coordination scores both improved after 25 days of treatment; No serious adverse events; This pre-planned interim analysis summarizes clinical data of the first 14 Parkinson’s patients that have completed treatment (9 on drug & 5 on placebo); Result (p=0.04) sounds intriguing, but this trial is…still ongoing right?!? (Click here to read more about this).

  • Protocol for the TOPAZ study: An entirely home-based (without geographical limits) trial of zoledronic acid – an FDA-approved treatment for osteoporosis – to prevent fractures in Parkinson’s (& associated parkinsonisms); Aiming to enroll 3,500 participants (Click here to read more about this).
  • Researchers report results of short-term tolerance study of nasally-administered NeuroEPO in Parkinson’s; 5 weeks treatment found to be well tolerated: NeuroEPO (n = 15) & placebo (n = 11); Adverse events: 20.0% in NeuroEPO & 9.1% in placebo groups (Click here to read more about this)
  • A new medrxiv manuscript presents the results of a randomized controlled trial on the effect of an 8 week online cognitive training program in Parkinson’s that suggests “tentative but consistent positive effect”; n=136 participants (Click here to read more about this).
  • Biotech firm Alkahest Inc announced positive data from their completed Phase 2 clinical trial safety & tolerability of GRF6021 in Parkinson’s & cognitive impairment at the ADPD meeting this month; Plasma fraction GRF6021 apparently demonstrated positive effects on cognitive endpoints & was safe + well tolerated by the 79 study participants (Click here to read more about this).

 

Conferences/lectures

  • Very much looking forward to the World Parkinson’s Congress virtual meeting on Advancing Science, Care, & Living with Parkinson’s, which will be held Monday-Friday 17 – 21st May. Amazing opportunity to learn more about everything going on (Click here to read more about this).

  • Planning for Prevention of Parkinson’s – A trial design symposium and workshop (Click here to read more about this).
  • The Davis Phinney Foundation are supporting a series of webinars focused on the issues faced by woman diagnosed with Young Onset Parkinson’s (Click here to read more about this).
  • Join the Van Andel Institute’s virtual lecture ‘Clinical Trials and Collaboration in Parkinson’s Disease’ on the 20th April, where the topic to be discussed is the International Linked Clinical Trials program ( to read more about this).

Other news

  • Pharma company Abbvie signs option positions to buy mitochondrial-focused biotech Mitokinin upon the completion of IND-enabling studies on the firm’s lead PINK1 compound (being targeted towards Parkinson’s (Click here to read more about this).
  • Clene Nanomedicine has been awarded a Michael J Fox Foundation research grant to accelerate the development of nanocatalyst CNM-Au8 as a potential treatment for Parkinson’s; Initiation of a Phase 2 proof-of-concept trial in PD expected in 2021 (Click here to read more about this).

  • Denali Therapeutics clinical data shows promise of blood-brain barrier shuttles (Click here to read more about this).
  • Parkinson’s UK invests up to £1.2m in a new virtual biotech exploring research from the University of Sheffield to develop “molecules that can boost the brain’s energy-producing function mitochondria, to halt Parkinson’s” (Click here to read more about this and click here to read a blog about this news).
  • DNA sequencing company Centogene has reached a 10,000 participant milestone in their global Parkinson’s study (Click here to read more about this).
  • Biotech firm Cortexyme announces partnership with Parkinson Study Group to form an advisory board to leverage the group’s expertise & further develop the company’s Parkinsons program (Click here to read more about this).

  • First European participant dosed in IRLAB Therapeutics‘s Phase IIb/III mesdopetam study for the treatment of levodopa-induced dyskinesias in Parkinson’s (Click here to read more about this).
  • GrapheneEU spin-off INBRAIN Neuroelectronics has been awarded a £12M grant to develop implantable, flexible nanoscale graphene electrodes for epilepsy, Parkinson’s & other neurological disorders (Click here to read more about this).
  • Oxford University spin-out gaitQ has been awarded a grant from the UK NIHR to continue development of its wearable, smart medical device that helps people with Parkinson’s overcome gait freezing episodes (Click here to read more about this).

 

Review articles/videos

  • Prof Patrik Brundin shares his journey and thoughts on Parkinson’s research:
  • A useful & relatively easy to approach short review of recent advances in understanding & treatment of Parkinson’s (Click here to read more about this).
  • A useful review on the dynamic control of the dopamine transporter (DAT) in neurotransmission & homeostasis; Interesting sections on involvement of Parkinson’s-associated proteins, like LRRK2, Parkin & a-syn (Click here to read more about this).
  • A review on how COVID-19 can boost remote exercise-based treatment in Parkinson’s, discussing recent studies on approaches to improve remote provision of exercise to patients (eg. telerehabilitation, motivational tools, apps, exergaming, & VR exercise – click here to read more about this).
  • The Great Indian Apomorphine Story: Challenges and Its Usage in Parkinson’s in the Indian Context” (Click here to read more about this).

  • The α-Synuclein Origin & Connectome (SOC) Model – A new model of Parkinson’s that takes into account the origin of the initiating α-synuclein pathology & the role played by the highly lateralized connectivity of the human brain (Click here to read more about this).
  • “Subtyping studies undertaken to date have significant methodologic shortcomings & most have questionable clinical applicability”; Parkinson’s subtypes: A critical appraisal & recommendations, from the Move Disorder Society Task Force for PD Subtypes (Click here to read more about this).
  • A Long Way to Go – Patient perspectives on digital health for Parkinson’s – 1) The right of PwP to access their own data needs to be recognised; 2) PwP should routinely receive personalised feedback on their data, & 3) Active involvement of PwP as an equal partner in digital health development needs to be the norm (maybe mandated &/or incentivised – Click here to read more about this).

  • A useful review on the challenges of assessing Parkinson’s severity via video & the emergence of video-based artificial intelligence/machine learning techniques to quantitate human movement (Click here to read more about this).
  • Useful review of function of SUMOylation & its roles in the development of neurodegenerative conditions like Parkinson’s, Alzheimer’s & Huntington’s disease (Click here to read more about this).
  • Amyloid-containing biofilms as a trigger for complex human diseases; Interesting review exploring how curli participates in pathological & immunological processes in GI, autoimmune, & neurodegenerative conditions (Click here to read more about this).
  • A new review explores whether voltage-gated Ca2+ channels in dopaminergic substantia nigra neurons are a therapeutic target for neuroprotection in Parkinson’s (Click here to read more about this).
  • Is LRRK2 the missing link between inflammatory bowel disease & Parkinson’s? (Click here to read more about this).

  • Can targeting inflammation be an effective neuroprotective strategy for Parkinson’s? Reviewed data “strongly suggests that inflammatory cascades do have an important impact on development of neurodegeneration in PD” (Click here to read more about this).
  • New review covers the structure/physiological function of α-synuclein, highlighting post-translational modifications (phosphorylation, ubiquitination, nitration, acetylation, truncation, SUMOylation, & O-GlcNAcylation) & the effect of them on aggregation (Click here to read more about this).
  • Researchers provide a useful short review on current knowledge about the link between Parkinson’s pathogenic mutations & mitophagy, with a particular focus on LRRK2 (Click here to read more about this).
  • A useful review/update on the role of neuropeptides in Parkinson’s (Click here to read more about this).
  • Mitochondrial complex I deficiency has been associated with Parkinson’s, but patients with complex I genetic disorders generally fail to manifest nigral cell loss. Researchers explore what’s possibly going on in this critical appraisal (Click here to read more about this).

  • The future of incretin-based approaches for neurodegenerative diseases in older adults: Which to choose? This is a great review of their potential efficacy and suitability (Click here to read more about this).
  • Useful review on the molecular mechanisms underlying synaptic & axon degeneration in Parkinson’s (Click here to read more about this).
  • New review on optimising experimental quantification of persistent pain in Parkinson’s using psychophysical testing (Click here to read more about this).
  • The role of noradrenaline in cognition & cognitive disorders, discussing human imaging advances & computational methods that quantify the locus coeruleus, & highlighting novel noradrenergic treatment strategies (Click here to read more about this).
  • A useful review & update on the NLRP3 Inflammasome, including a section on Parkinson’s (Click here to read more about this).

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

And there it is, just some of the highlights from March 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 April!!!

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.


One thought on “Monthly research review – March 2021

  1. Hi Simon, thanks very much for the great post (what’s the secret to summarising so much new knowledge?!) Could you provide the link for “Meta-analysis of Parkinson’s gut microbiome” please as it doesn’t work in the original. Many thanks!

    Liked by 1 person

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