Monthly research review – October 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 October 2020.

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

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

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So, what happened during October 2020?

In world news:

October 7th – Emmanuelle Charpentier and Jennifer Doudna won the 2020 Nobel Prize for Chemistry “for the development of a method for genome editing” (aka CRISPR technology – Click here to read more about this).

October 12th – One of the winners of the 2020 Nobel Prize in economics, Paul Milgrom found out that he had won when his neighbour came knocking on his door at 2am (Click here to read more about this):

 

15th October – the John Snow Memorandum was announced in the medical journal The Lancet, providing a current evidence-based consensus on COVID-19 and partly in response to the many assumptions made in the Great Barrington declaration”.

18th October – Birdwatchers flocked to a salt marsh in the East of England to see a rufous bush chat – a bird that has not been seen in Britain for 40 years (Click here to read more about this).

29th October – NASA’s “Origins, Spectral Interpretation, Resource Identification, Security, Regolith Explorer” (OSIRIS-REx) mission successfully landed for a few seconds on an asteroid and collected a rock for return to Earth – all more than 205 million miles (330 million km) from Earth (Click here to read more about this).

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

In October 2020, there were 957 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (8926 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. Diabetes drugs and the risk of Parkinson’s:

Researchers report that use of DPP4 inhibitors &/or GLP-1 agonists (eg. Exenatide) is associated with a lower rate of Parkinson’s compared to the use of other oral antidiabetic drugs (Click here to read more about this, click here for the press summary, and click here to read an SoPD post on this topic).

2. A role for inflammation in PRKN/PINK1-associated Parkinson’s:

New research highlights potential of IL6 as progression marker in PRKN/PINK1-assoc. PD; Plus increased circulating cell-free mitoDNA serum levels in patients with PRKN/PINK1 mutations. The authors point towards cGAS-STING pathway (Click here to read more about this, click here to read the press summary, and click here to read a SoPD post on this topic).

3. Caffeine levels in individuals with Parkinson’s

A new research report found that plasma caffeine concentrations are lower in people with Parkinson’s (vs control subjects; p<0.001), more so among LRRK2+ carriers (-76%) than among LRRK2- subjects (-31%). Similar results were also observed for caffeine metabolites. Given that caffeine intake has previously been associated with a reduced risk of developing Parkinson’s, could raising caffeine levels in people with Parkinson’s have beneficial effects? (Click here to read more about this).

 

4. Recording and stimulating at the same time

Researchers present a multimodal system allowing for simultaneous, chronic recordings of dopamine release & beta-band activity in the striatum of primates during behavioral performance. Task-elicited beta suppressions preceded dopamine peaks; Relative dopamine-beta timing & polarity depends on reward value, performance history, movement, & striatal domain”; Important implications for novel strategies being developed for treating Parkinson’s (Click here to read more about this).

5.  Parkinsons + Alzheimer’s + air pollution

Researchers find evidence that annual exposure to mean “fine particulate matter” (PM2.5) in the USA is significantly associated with an increased hazard of 1st hospital admission with PD or AD. 16 years of data, 63M individuals (N=1M PD & 3.4M AD); Higher hazard ratios among those who identified as white, & for women compared with men. “Improving air quality to reduce PM2·5 concentrations to less than current national standards could yield substantial health benefits” (Click here to read more about this, click here to read the press summary, and click here to read an SoPD post on this topic).

6. What happens in very early PD?

Researchers conducted postmortem histological analysis and found CD8 T-cell cytotoxic attack may initiate and propagate both the neuronal death & synucleinopathy observed in Parkinson’s. They reported that “a high proportion of nigral CD8 T cells are tissue resident memory T cells” (Click here to read more about this – SoPD post in production).

7.  New PET imaging ligands

An alpha-synuclein PET ligand: Researchers have a bioRxiv manuscript presenting C05-05 – a bimodal imaging probe for visualizing Parkinson’s-associated α-synuclein inclusions in the CNS of living animals (mice & primates) modeling α-synuclein propagation (Click here to read more about this). The same researchers also published a report on another imaging probe, PM-PBB3, that captures pathological tau deposits in vivo with high contrast; allows an individual-based identification of Alzheimer’s & non-AD tauopathies (Click here to read more about this).

8.  The US Environmental Protection Agency gave the pesticidal paraquat a green light

From the Government agency that is supposed to protect everyone from harmful agents: the US EPA released a carefully worded interim registration decisions allowing use of the pesticide Paraquat, which is associated with Parkinson’s. “Based on this review, EPA concluded that there is insufficient evidence to link registered paraquat products to any of the health outcomes investigated, including Parkinson’s Disease, when used according to the label” (Click here to read more about this and to read the report).

Basic biology news

  • I like definitive titles: Metal ions shape α-synuclein. Researchers report the specific effects of metal coordination, & the associated electrostatic charge patterns, on the complex structural space of this Parkinson’s-associated protein (Click here to read more about this).
  • A new biorxiv manuscript suggests that Brazilin (a small molecule derived from red cedarwood trees in Brazil) eliminates seeding competence of synthetic & Parkinson’s brain-derived α-syn assemblies, & significantly reduces their toxicity (Click here to read more about this).

  • A new medrxiv manuscript presents single-cell sequencing of human midbrain (>41K cells; 6 Parkinson’s cases v 5 controls). Suggests microglia on a specific pro-inflammatory trajectory & elevated CADPS2 in dysfunctional dopamine neurons (Click here to read more about this).
  • A new biorxiv manuscript presents single cell RNA-seq to transcriptionally profile of different stages of ventral midbrain development during human development. 3D culture system recapitulates key aspects (Click here to read more about this).
  • Researchers report mitomycin‐C treatment during differentiation of iPS cell‐derived dopamine neurons reduces proliferation without compromising survival or function in in vivo models of Parkinson’s (Click here to read more about this)
  • A new study defines previously unappreciated & important roles for GABA uptake transporters & astrocytes in supporting dopamine release in striatum, & reveals a maladaptive plasticity in early parkinsonism (Click here to read more about this).
  • A new biorxiv manuscript explores disposal of Parkinson’s-associated DJ-1/PARK 7 missense mutants; Inhibition of proteasomal & autophagic-lysosomal pathways had no effect on degradation; Silencing of mitochondrial matrix protease LonP1 = a strong reduction (Click here to read more about this).
  • ALS-associated TDP-43 enters mitochondria & triggers mtDNA release (via mPTP), which accumulates & activates the cGAS/STING pathway. Inhibiting STING blocks inflammation & neurodegeneration (in vitro & vivo – Click here to read more about this).

  • A new biorxiv manuscript suggests Parkinson’s-associated LRRK2-regulated pathways of endolysosomal membrane damage & repair differ between macrophage subsets (Click here to read more about this).
  • A new report finds pathway-specific dysregulation of striatal excitatory synapses by Parkinson’s-associated LRRK2 mutations (Click here to read more about this).
  • Only in vitro experiments, but “The results suggest that not only GLP-1, but also GLP-2 has neuroprotective properties and may be useful as a novel treatment of Parkinson’s (Click here to read more about this).
  • It’s not just Parkinson’s that bile acid UDCA might be useful for: Researchers report that ursolic acid reduces hepatocellular apoptosis & alleviates alcohol-induced liver injury in vivo (via irreversible inhibition of CASP3 – click here to read more about this).
  • New report finds mice deficient for both Cul9 & Parkinson’s-associated Parkin do not display an enhanced phenotype compared to the effect of Parkin deficiency alone (Click here to read more about this).
  • New biorxiv manuscript suggests autophagy is required for midbrain dopaminergic axon development & their responsiveness to guidance cues; Atg-/- axons swell, have decreased branching, & have blunted response to guidance cues (Click here to read more about this).
  • Researchers report early disruption of cortical sleep-related oscillations in a mouse model of dementia with Lewy bodies (mice expressing human mutant (A30P) alpha-synuclein – Click here to read more about this).

  • Researchers report that clusterin can limit the uptake of extracellular α‐synuclein aggregates by astrocytes suggesting a role for this chaperone in the pathogenesis of Parkinson’s (Click here to read more about this).
  • Could mitochondrial DNA damage be a “surrogate” for LRRK2 kinase activity? Researchers propose mtDNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2-associated Parkinson’s. LRRK2 inhibitors=reversal of mtDNA damage (Click here to read more about this).
  • New bioRxiv manuscript addresses on-target-off-tissue drug engagement: Using brain-permeable mTOR inhibitor RapaLink-1 & brain-impermeable FKBP12 ligand RapaBlock. The researchers reduced brain mTOR activity, while sparing elsewhere in the body. They then apply this trick to Parkinson’s-associated LRRK2 protein (Click here to read more about this).
  • A second bioRxiv manuscript presenting brain-specific inhibition of mTORC1 by a dual drug strategy. The researchers co-administered RapaLink-1 & RapaBlock to inhibit alcohol-dependent mTORC1 activation in the nucleus accumbens (Click here to read more about this).
  • Astrocytes protect dopamine neurons from Parkinson’s-associated α-synuclein propagation, but ATP13A2 deficiency in astrocytes compromises this protective function (Click here to read more about this).
  • Researchers present single-cell transcriptomics of human dopamine neurons (in vitro), identifying subtypes with distinct profiles, revealing neuron-specific stress responses, & overlay with Parkinson’s GWAS associated gene expression. They see cell type-specific gene perturbations of cholesterol metabolism in response to stress (rotenone), which are ameliorated by felodipine. They also see glycolysis, cholesterol metabolism, synaptic signaling, & ubiquitin-proteasomal degradation in isogenic SNCA-A53T mutants (Click here to read more about this and click here to read the associated press summary).

  • New report proposes that synergistic LRRK2/IFN-γ activation serves as a potential link between inflammation & neurodegeneration in Parkinson’s. IFN-γ induces LRRK2 in neurons & microglia, suppressing NFAT (Click here to read more about this).
  • Ever wondered what happens to Parkinson’s-associated α-synuclein PFFs after endocytosis? A new bioRxiv manuscript presents a method for analysing the fate of internalized α-synuclein (Click here to read more about this).
  • A new bioRxiv manuscript evaluates the differential gene expression in the interactome of the Dopamine transporter in the context of Parkinson’s (Click here to read more about this).
  • A new bioRxiv manuscript suggests targeted expression of Parkinson’s-associated alpha-synuclein leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins & impaired function (in flies – click here to read more about this).
  • New paper reports a “novel mechanism for the selection of striatal circuit components, where fluctuating levels of dopamine shift the balance of compartment-specific striatal output” (Click here to read more about this).
  • A new medRxiv manuscript suggests DNA methylation-based predictors could be used as proxies for chronic inflammatory status in aging brain, but the associations are not regionally homogeneous across the brain (Click here to read more about this).
  • Gut bacteria C. sporogenes deaminates (removal of an amino group) the Parkinson’s treatment Levodopa, producing a metabolite that inhibits ileal (small intestine) motility (ex vivo – Click here to read more about this and click here to read the press summary)

 

  • New report finds dopamine neurons & microglia in the substantia nigra of people with Parkinson’s accumulate neutral lipids, whereas in the same tissues, astrocytes have reduced lipid content (Click here to read more about this).
  • Interesting new tool for the lab – deep learning-assisted comparative analysis of animal movement data with DeepHL; Parkinson’s mice (unilateral 6-OHDA) are used as an example (Click here to read more about this)..
  • Inhibition of protein phosphatase 1 activity in cell culture & zebrafish models of amyotrophic lateral sclerosis ALS prevents mitochondrial impairment & rescues neurodegeneration (Click here to read more about this).
  • Researchers report circulating unacylated-Ghrelin impairs hippocampal neurogenesis & memory in mice; acyl-ghrelin rescues deficit. Unacylated-Ghrelin levels are altered in cases of Parkinson’s Dementia (Click here to read more about this).
  • Love the names given to fly genes:  A new report finds that the Drosophila phosphatidylinositol 4-kinase IIIβ gene, Four wheel drive (Fwd) promotes mitochondrial fission & can suppress Parkinson’s-associated Pink1/parkin phenotypes (Click here to read more about this).

  • A new bioRxiv manuscript suggests neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment (Click here to read more about this).
  • A new bioRxiv manuscript suggests RIT2 (Ras Like Without CAAX 2) can inhibit overactive LRRK2 to restore autophagy/lysosome pathways; also counteracts Parkinson’s-associated a-synuclein aggregation & related deficits (Click here to read more about this).
  • A new bioRxiv manuscript suggests that the E3 ligase TRIM1 recruits Parkinson’s-associated LRRK2 to the microtubule cytoskeleton for ubiquitination & proteasomal degradation; “Critical regulator” TRIM1 controls the localization, degradation, & toxicity of LRRK2 (Click here to read more about this).
  • A new report finds that Parkinson’s-associated α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate (Click here to read more about this).
  • The Clinical Kinase Index: A method to prioritize understudied kinases as drug targets for the treatment of cancer. Could this sort of approach be applied to Parkinson’s? (Click here to read more about this).
  • Development/application of an untargeted, high-throughput, single cell lipid profiling platform. Using Parkinson’s-associated SNCA-A53T human dopamine neurons, they find the mutant neurons have impaired membrane function (Click here to read more about this).

  • Caution required with knocking down PTBP1 in in vivo reprograming study? A new bioRxiv suggests functional roles for the protein. Another twist in the tale… (Click here to read more about this).
  • Using manifold learning & postmortem brain RNA-seq data, researchers have a
    bioRxiv manuscript that defines an ordering of the trajectory of late onset Alzheimer’s progression (“disease pseudotime”) for each sample (Click here to read more about this).
  • “A roadmap for the epigenomic dissection of causal regulatory variation” in Alzhiemer’s & Parkinson’s. Researchers use a machine-learning classifier to integrate & predict dozens of functional SNPs, they go deep on MAPT (Click here to read more about this).
  • Researchers propose models of reactive oxygen species (ROS) networks, which propose “life-extending interventions” for Parkinson’s, involving mitochondrial synthesis, KEAP1 degradation, & p62 metabolism. The simulated effects of “coffee” are explored (Click here to read more about this).
  • Tip60 promotes neuronal health by protecting against early Tip60 HAT/HDAC imbalance in multiple fly models of neurodegeneration. Could disruption of Tip60 HAT mediated neural histone acetylation homeostasis be an early event in Parkinson’s? (Click here to read more about this).
  • Researchers report that amyloid formation of fish β-parvalbumin involves primary nucleation triggered by disulfide-bridged protein dimers (Click here to read more about this).

  • New research report fast kinetics of environmentally induced Parkinson’s-associated α-synuclein aggregation is mediated by structural alteration in NAC region & results in structure dependent cytotoxicity (Click here to read more about this).
  • Paradoxical mitophagy regulation by Parkinson’s-associated PINK1 and TUFm. A “self-antagonizing feature of PINK1/TUFm is critical for the robustness of mitophagy regulation” (Click here to read more about this).
  • GSK-J4 (a histone demethylase inhibitor) significantly reduced intracellular labile iron in dopaminergic neurons, suppressing oxidative stress, & rescuing abnormal changes of histone methylation (H3K4me3 & H3K27me3) in models of Parkinson’s (Click here to read more about this).
  • Is Parkinson’s-associated alpha synuclein involved with Huntington’s disease? A new bioRxiv manuscript suggests interactions between Protein Kinase CK2 α′ & a-syn alter features of HD-mouse model (Click here to read more about this).

 

Disease mechanism

  • A new biorxiv manuscript asks the question: Could alpha-melanocyte stimulating hormone (alpha-MSH) – a microglia-secreted anti-inflammatory mediator – be the culprit in Parkinson’s? Mice treated with alpha-MSH exhibited progressive decline in gait (Click here to read more about this).

  • Researchers report prolonged reduction of brain stearoyl‐CoA desaturase activity prevents Parkinson’s‐like neuropathology in multiple PD models. Are orally available SCD inhibitors an approach to treat α‐synucleinopathies? (Click here to read more about this)
  • New report presents a new synuclein-transgenic mouse model for early Parkinson’s that may reveal some of the molecular features of preclinical/prodromal disease (Click here to read more about this).
  • New data finds Tau has no effect on the A53T α‐syn‐mediated neurodegeneration in mice, but Tau knockout modestly promotes formation of Parkinson’s-associated α‐synuclein aggregates & accelerates degeneration of parvalbumin‐positive neurons in pars reticulata (Click here to read more about this).
  • A new biorxiv manuscript suggests inhibition of the mitochondrial pyruvate carrier (via MSDC-0160) does not reduce synucleinopathy in models of Parkinson’s in absence of inflammation or metabolic deficits (Click here to read more about this).
  • A new report finds treatment with a LRRK2 inhibitor enhances cognition, reduces TAU phosphorylation, & protects neurons in a mouse model of tauopathy (Click here to read more about this).
  • RNAi-knockdown of the C. elegans bcat-1 gene = Parkinson’s-like features. Researchers report that post–disease-onset administration of metformin reduces mitochondrial respiration & improves phenotype (Click here to read more about this).

  • Parkinson’s-associated alpha-synuclein found to be involved in manganese-induced spatial memory & synaptic plasticity impairments (via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors – click here to read more about this).
  • New research finds Parkinson’s-associated fibrillar α-synuclein toxicity depends on functional lysosomes. Loss of viability induced by α-synuclein PFFs is attenuated by lysosomal inhibitors, chloroquine & bafilomycin A1 (Click here to read more about this).
  • Over-expression of 4E-BP1 (key repressor of protein translation) prevents cell death in different models of Parkinson’s (eg rotenone, maneb, paraquat, & preformed fibrils of alpha-synuclein), via promotion of mitochondrial unfolded protein response (Click here to read more about this).
  • A new medRxiv manuscript investigates the alpha4beta2* nAChR partial agonist varenicline in Parkinson’s. Results suggests varenicline was well tolerated, enhanced attentional function, & improved dual task gait performance (Click here to read more about this).
  • A new bioRxiv manuscript suggests multiple systems atrophy (MSA) phenotype in mouse models is governed by both the strain of alpha synuclein & the host environment, plus strains can directly trigger a detrimental immune response (Click here to read more about this).
  • New study finds the cytoprotective effect of carnosic acid is related to the enhancement of mitochondrial biogenesis (via inhibiting PARIS & inducing PGC-1α by PARKIN); it prevents the degeneration of dopaminergic neurons in a model of Parkinson’s (Click here to read more about this).

  • c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation; Inhibition of c-Abl activates TFEB promoting cholesterol clearance in models of Niemann-Pick type C; Nilotinib for Parkinson’s – right target, wrong drug? (Click here to read more about this).
  • A new bioRxiv manuscript explores how mutations in Parkinson’s-associated LRRK2 may modulate susceptibility to Alzheimer’s brain-derived Tau pathology’s initiation & spread. Tour de force (Supp Fig 9 alone goes for 15+ pages! Click here to read more about this).
  • Further evidence that neuromelanin can make things worse (adverse effects on mitochondria). Is neuromelanin formation critical to translationally studies for Parkinson’s? (Click here to read more about this).
  • The herbicide paraquat is reported to cause endoplasmic reticulum stress-related neuroinflammation – which is alleviated by TUDCA treatment – in a mouse model of Parkinson’s (Click here to read more about this).
  • Multiple-gene chips of 244 human postmortem tissues from individuals with/without Parkinson’s identifies 1333 differential expressed genes; results point at synaptic vesicle trafficking (PPP2CA, SYNJ1, NSF, & PPP3CB); blood level differences – biomarkers? (Click here to read more about this).
  • A new bioRxiv manuscript explores a-syn antisense oligonucleotides (from
    Ionis Pharmaceuticals) in monomeric & pre-formed fibril models of Parkinson’s. ASO treatment reduced LB-like pathology & partially rescued motor issues, but some off target effects noted (Click here to read more about this).

  • Researchers report results that point to a role for α-syn as a modulator of tau pathology burden & spreading in models of Parkinson’s (based on mouse α-syn preformed fibrils & Alzheimer’s lysate–derived tau seeds – click here to read more about this).
  • New report proposes that Vesicle-associated membrane protein 8 (VAMP8) could be used to increase clearance of Alzheimer’s-associated tau & Parkinson’s-associated alpha-synuclein to prevent their intracellular accumulation (Click here to read more about this).
  • Upregulation of cellular palmitoylation (via depalmitoylase acyl‐protein‐thioesterase‐1 APT1 inhibition) mitigates Parkinson’s-associated α‐synuclein accumulation & neurotoxicity in iPSC-derived SNCA triplication neurons. Novel therapeutic strategy for PD? (Click here to read more about this).
  • New report provides evidences that Parkinson’s-associated LRRK2 phosphorylation in the mouse brain is differentially impacted by mutations, brain area, & age – implications for human research on diagnostic markers of disease progression & stratification? (Click here to read more about this).
  • Using mendelian randomization in a new medRxiv manuscript, researchers suggest that genetically-raised GLP-1R expression in blood is associated with lower BMI & possibly T2 diabetes risk, but NOT Parkinson’s risk, age at onset, or progression.”Data suggest that GLP-1 mimetics like exenatide, if ultimately proven to be effective in Parkinson’s disease, will be through a mechanism that is independent of GLP1R in blood”. Also, reduced DPP4 expression in brain tissue was significantly associated with increased risk of PD (Click here to read more about this).
  • A new bioRxiv manuscript suggests 4 NAD+ biosynthetic pathway enzymes moonlight as molecular chaperones to protect against proteotoxicity. New target for therapeutics to combat age-associated neurodegenerative conditions, like Parkinson’s? (Click here to read more about this).

Clinical research

  • “As there was no aSyn in the vagus nerve or stomach of subjects without brain aSyn, these results support initiation of aSyn in the brain” A new medrxiv manuscript questions the body-first hypothesis of Parkinson’s (postmortem analyses of 197 individuals – Click here to read more about this).
  • Further evidence of sex differences in Parkinson’s – new research highlights “the necessity of future research to determine the underlying mechanisms & importance of personalized clinical management” (Click here to read more about this and click here for an OPEN ACCESS version of the manuscript).

  • Novel compound heterozygous FBXO7 mutations in a Yemeni family with early onset Parkinson’s has been reported. Pyramidal signs lacking & the phenotype was consistent with PD rather than parkinsonian-pyramidal syndrome; good response to dopaminergic therapy (Click here to read more about this).
  • New research reports that loss of bacterial diversity in the sinuses is associated with lower smell discrimination scores. Implications for Parkinson’s? (Click here to read more about this).
  • A new report presents meta-analysis of whole-exome sequencing data from two independent cohorts that finds no evidence for rare variant enrichment in Parkinson’s-associated loci; Trends for 3 genes: GALC, PARP9 & SEC23IP, though not significant (Click here to read more about this).
  • We can be motivated when reward depends on performance (instrumental), or merely by the prospect of a guaranteed reward. New research finds that dopamine promotes instrumental motivation, but reduces reward-related vigour (Click here to read more about this).
  • A dual centre study of pain in Parkinson’s & its relationship with other non-motor symptoms finds interesting associations between sleep disruption & cardiovascular disturbance with pain (Click here to read more about this).

  • Alpha-synuclein protofibrils in cerebrospinal fluid: A potential biomarker for Parkinson’s? (Click here to read more about this).
  • Apathy in Parkinson’s – should we care? New research challenges the concept that apathy & impulse control disorders in PD are on opposite ends of a spectrum. Motivational disturbances are common comorbid conditions in patients with PD (Click here to read more about this).
  • Researchers provide further support for NOTCH2NLC intermediate‐length repeat expansions being associated with Parkinson’s (Click here to read more about this).
  • Another study investigating GGC‐repeat expansions in NOTCH2NLC finds that this genotype is rare in caucasians presenting with movement disorders – using 100,000 Genomes Project (Click here to read more about this).
  • Raised levels of TNF-α in isolated REM sleep behavior disorder cases at higher risk of phenoconversion. Longitudinal analyses: TNF-α levels > median show a higher incidence of phenoconversion than lower levels (47% vs. 7%; p = 0.008 – click here to read more about this).
  • Researchers report aberrant hyperphosphorylated Tau, Parkinson’s-associated ɑ synuclein, & TDP-43 in the brainstem of 186 young Mexico City residents (avg age: 27±11yrs – click here to read more about this and click here for the press summary).

  • Important pandemic-related implications in this study exploring social isolation & how it can affect Parkinson’s severity & quality of life. “Proactive use of virtual modalities for support groups & social prescribing” required (Click here to read more about this).
  • Under-represented communities: A small sample size, but another step towards doing more studies on non-European populations in PD. New medRxiv manuscript highlights genetic testing of individuals with Parkinson’s from Costa Rica finds some interesting results in the LRRK2 gene and a new GCH1 patient (Click here to read more about this).
  • Results from the COPPADIS cohort have been published exploring non-motor symptom burden in patients with Parkinson’s with impulse control disorders & compulsive behaviours: More nonmotor symptoms in individuals with PD who had ICDs/CBs vs those without (Click here to read more about this).
  • After following 131,625 Korean adults without diabetes, researchers propose that increased long-term glycaemic variability may be a precipitating risk factor for developing Parkinson’s in a midlife population without diabetes (Click here to read more about this).
  • New report presents “BUndle ANalytics” – flexible computational framework for real-world tractometric studies. They use Parkinson’s Progression Markers Initiative (PPMI) data to display its features (Click here to read more about this).
  • New medrxiv manuscript exploring how deep brain stimulation & levodopa affect gait variability in Parkinson’s. Both significantly improved stride length, while medication further significantly increased gait speed (Click here to read more about this).

  • Researchers evaluated the frequencies of Parkinson’s-associated PRKN, PINK1, & DJ‐1 genetic variants in a large multi-center cohort of 1,587 cases. Mutations were found in 14.1% of patients; (27.6% familial & 8% isolated – Click here to read more about this).Researchers report subthalamic deep brain stimulation improves sleep & excessive sweating in Parkinson’s. N=60; “A significant & lasting positive effect on overall sleep quality, nocturnal motor symptoms & restlessness, & daytime dozing” (Click here to read more about this).
  • In a new bioRxiv manuscript, researchers identify a novel coding DAT variant (DAT-K619N) in an early-onset parkinsonism patient with comorbid neuropsychiatric disease. They dig deeper & find the variant causes reduced dopamine uptake & increased DAT turnover. Importantly, they suggest (in mice) that “DAT-K619N has a dominant-negative effect which collectively implies that a single dominant-negative genetic DAT variant can confer risk for neuropsychiatric disease & neurodegenerative early-onset parkinsonism (Click here to read more about this).
  • DAT & neurovascular imaging study: “Combined perfusion MRI & DAT-targeted PET imaging may inform future prospective clinical trials, thereby providing an improved mechanistic understanding of Parkinson’s” (Click here to read more about this).
  • Researchers report that higher adherence to a “Mediterranean diet” at middle age is associated with lower risk for Parkinson’s; dietary information from >47,000 Swedish women in 1991–1992, association primarily from age 65-years onward (Click here to read more about this).

  • A new medRxiv manuscript suggests that the cross sectional area of the vagus nerve is NOT reduced in Parkinson’s; “not a reliable diagnostic tool in the diagnosis of PD” (Click here to read more about this).
  • A new medRxiv manuscript finds cerebrospinal fluid levels of sCD163 are elevated in late-stage Parkinson’s, correlating with a-synuclein, Tau, & phospho Tau; & inversely correlated with cognitive scores. Are monocytes involved in neurodegeneration & cognition in PD? (Click here to read more about this).
  • Does Parkinson’s genome-wide polygenic risk score (PD-GPRS) offer a promising screening tool to identify high-risk individuals for preventive lifestyle or new drug therapy trials? A new medRxiv manuscript explores this idea (Click here to read more about this).
  • Mild cognitive impairment can occur in Parkinson’s, but the underlying mechanism is not understood. New research points towards elevated caudate connectivity in cognitively unaffected PD patients, may be related to a compensatory mechanism (Click here to read more about this).
  • A new bioRxiv manuscript suggests “intrinsic adaptations in the motor cortex, together with pathological basal ganglia inhibition, underlie the decreased motor cortical output in parkinsonian state & exacerbate parkinsonian motor deficits” (Click here to read more about this).
  • A new report finds the rs708384 variant of the FAM171A2 gene (a regulator of progranulin expression) is associated with increased risk of Alzheimer’s, Parkinson’s, & frontotemporal dementia (FTD). No association with ALS (Click here to read more about this).

  • Could “naturally occurring antibody against α-Syn” be a potential biomarker for Parkinson’s dementia? (Click here to read more about this).
  • Researchers recruited 5 pairs of monozygotic twins discordant for idiopathic Parkinson’s, established skin fibroblast cultures, & investigated mitochondrial phenotypes. They found “disease‐related differences in mitochondrial integrity” (Click here to read more about this).
  • Researchers report reduced striatal vesicular monoamine transporter 2 in REM sleep behavior disorder. An imaging biomarker for prodromal Parkinson’s? Ongoing longitudinal follow-up to determine time-window (Click here to read more about this).
  • Researchers sequence 25 genes from Parkinson’s loci in 1,039 isolated REM-sleep behavior disorder patients (& 1,852 controls), and they propose BST1 & LAMP3 are associated with iRBD (Click here to read more about this).
  • A new medRxiv manuscript suggests no association of rare HFE variants (encoding the homeostatic iron regulator protein (aka hereditary hemochromatosis protein) with Parkinson’s (Click here to read more about this).
  • Shared genetics of Multiple System Atrophy (MSA) & inflammatory bowel disease (IBD), with an important potential role for the C7 gene; implications for immune & gut dysfunction in MSA pathophysiology (Click here to read more about this).

  • New research finds that individuals with PARKIN‐associated early onset Parkinson’s have a slower progression of motor symptoms & better spatial processing ability than other genetically undefined EOPD cases. Genetic subtyping for more accurate prognosis?
    (Click here to read more about this).
  • Initiators, facilitators & aggravators. Exploring dynamic pathogenesis of PD via blood transcriptomics. A new bioRxiv manuscript presents a longitudinal transcriptomics to identify associated genes underlying Parkinson’s pathogenesis at 3 temporal phases (Click here to read more about this).
  • New research explores genome‐wide association studies of cognitive & motor progression in Parkinson’s, & reports that the APOE ε4 allele drives progressive cognitive impairment (Click here to read more about this).
  • New study finds Lewy body disorders & Alzheimer’s are characterised by temporal cortical thinning on MRI, which directly correlates with post‐mortem histopathologic burden of tau, suggesting that tau pathology may influence the pattern of neurodegeneration (Click here to read more about this).
  • A multicentre retrospective cohort study focused on better quality of life & less caregiver strain in young-onset Parkinson’s, from The Parkinson’s Foundation Quality Improvement Initiative investigators (Click here to read more about this).
  • New research finds earlier initiation of Parkinson’s treatment does not lead to worse MDS‐UPDRS motor scores & may offer small improvements. Study used longitudinal, observational PPMI data (Click here to read more about this).
  • Respect: A High school student has a manuscript on medRxiv proposing the identification of blood-based biomarkers for early stage Parkinson’s. “ESR1, CD19, SMAD3, FOS, CXCR5, & PRKACA may be potential biomarkers & warrant further study” (Click here to read more about this).

  • A new medRxiv manuscript does not replicate the findings of previous studies & finds no significant association between ANG variants (a gene encoding angiogenin) & Parkinson’s risk (Click here to read more about this).
  • Identification of disease-associated variants by targeted gene panel resequencing in Parkinson’s; results suggest SYNJ1 variants may play a protective role against PD
    (Click here to read more about this).
  • Remote monitoring of Parkinson’s during the COVID19 lockdown using smartphones – an Italian pilot study (Click here to read more about this).
  • Using baseline MRI & longitudinal gait data, a new bioRxiv maunscript suggests Alzheimer’s-associated amyloid β impacts future freezing of gait in Parkinson’s (via white matter hyperintensities – click here to read more about this).
  • New research (using 2 resting-state fMRI imaging) provides a new perspective on the neural mechanisms underlying diphasic dyskinesia in Parkinson’s, highlighting dysfunction in superior frontal gyrus (Click here to read more about this).
  • Using the Michael J Fox Foundation PPMI data, reseachers find that lower urinary tract & gastrointestinal dysfunction are a common feature in early Parkinson’s (Click here to read more about this).

New clinical trials

  • New clinical trial registered: This will be a 48 week open label extension study for 120 individuals with Parkinson’s with dementia enrolled in the ANAVEX2-73-PDD-001 study being conducted by Anavex Life Science (Click here to read more about this).

  • New clinical trial registered: Acute effects of medium chain triglyceride (MCT) nutritional ketosis on Parkinson’s (studying the effects of a ketogenic diet on PD, using dietary supplement: Nestle MCT oil; n=32 participants – click here to read more about this).
  • New clinical study registered: The University of Delaware Parkinson’s registry, an observational study seeking 1000 participants (Click here to read more about this).
  • New clinical trial registered: Deep brain stimulation of the Pedunculopontine Nucleus (PPN) for Parkinson’s – recruiting 8 participants, by invite only (Click here to read more about this).
  • New clinical trial registered: The Michael J Fox Foundation have registered the FoxBioNet: ECV (Extracellular Vesicle) study to identify reliable markers of Parkinson’s-associated LRRK2 activity in human cerebrospinal fluid; recruiting 140 pariticipants
    (Click here to read more about this).

Clinical trial news

  • The results of a small randomized, placebo-controlled, crossover study exploring use of a Ketone Ester drink finds that it enhances endurance exercise performance in individuals with Parkinson’s (Click here to read more about this).
  • A randomized, double blind, placebo-controlled study finds that a multi-strain probiotic treatment was effective for constipation in Parkinson’s. N=72 (34 on treatment, 38 placebo) – 4 week study. Long-term efficacy & safety now required (Click here to read more about this).

  • Researchers report post hoc data that the cognitive benefits from rivastigmine are larger in individuals with Parkinson’s dementia when they also have orthostatic hypotension (Click here to read more about this).
  • Axovant Gene Therapies announced positive 6-month follow-up data from the 2nd cohort of their SUNRISE-PD Phase 2 trial of AXO-Lenti-PD gene therapy in individuals with Parkinson’s. Treatment well-tolerated in all 4 patients; >2-hr improvement in “good ON time” (Click here to read more about this).

  • The protocol of the PARK-BAND Study has been published. This study is investigating the potential benefits of power training using elastic devices in 50 participants with Parkinson’s (Click here to read more about this).
  • Back in September, Amylyx published the results of their pivotal CENTAUR trial results. The study was evaluating AMX0035 (Sodium Phenylbutyrate‐Taurursodiol combo) in 137 individuals with ALS, & they reported a postive result (Click here to read more about this). Now they have published the survival data – AMX0035 treatment at baseline resulted in a 6.5‐month longer median survival (vs placebo – click here to read more about this).

 

  • A 12-week randomised clinical trial of the tolerability of buspirone for anxiety in Parkinson’s (n=21) finds improvement in anxiety, but 41% of participants on buspirone stopped treatment prior to completion & 53% experienced worsening of motor function (Click here to read more about this).
  • Roche & Prothena announce that they will be advancing their alpha synuclein immunotherapy agent Prasinezumab into a Phase 2b study in individuals with early Parkinson’s, starting early 2021. The study will be designed to further assess the efficacy of prasinezumab by expanding upon the patient population enrolled in PASADENA to include individuals with early Parkinson’s on stable levodopa therapy (Click here to read more about this).

  • Population pharmacokinetics of levodopa gel infusion in Parkinson’s: a small open label pilot study (N=11) investigates the effects of entacapone infusion & genetic polymorphism (DDC & COMT genes). Individuals with higher DDC and COMT enzyme activity showed tendencies towards higher clearance of levodopa (Click here to read more about this).
  • Alterity Therapeutics has announced enrollment of individuals with early stage Multiple System Atrophy (MSA) in its bioMUSE Study in the US. The study will be evaluating ATH434 (an oral, brain penetrant, alpha-synuclein aggregation inhibitor – click here to read more about this).

Other news

  • Portuguese pharmaceutical company BIAL acquires Lysosomal Therapeutics (LTI). New US-based affiliate (BIAL Biotech) will be taking the LTI Parkinson’s research programs forward, including BIA 28-6156 (aka LTI-291 – Click here to read more about this).

  • “Another notable disease with a large increase in prevalence & disability-adjusted life-years (DALYs) was Parkinson’s” – From “The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017″ (Click here to read more about this).
  • Secarna Pharmaceuticals & Denali Therapeutics have entered into a research & option agreement to develop novel antisense therapies in the field of neurodegenerative diseases (such as Parkinson’s maybe? – click here to read more about this).

  • Dyno Therapeutics announces a collaboration & license agreement with pharmaceutical company Roche to develop next-generation adeno-associated virus (AAV) vectors for gene therapies for CNS conditions (Click here to read more about this).
  • Pharmaceutical company Bayer announces it is acquiring Asklepios BioPharmaceutical. Given Ask’s close ties with Brain Neurotherapy Bio‘s GDNF gene therapy program is this yet another move on Parkinson’s by Bayer? Bluerock in 2019, AskBio in 2020… (Click here to read more about this).

 

Review articles/videos

  • An interesting review on how microglia might be modulating neurodegeneration in Alzheimer’s & Parkinson’s (Click here to read more about this).
  • Pluripotent stem cell-based cell therapy—promise & challenges”, from Nobel laureate Prof Shinya Yamanaka (Parkinson’s gets discussed – Click here to read more about this).

  • Balancing expectations for success in stem cell-based clinical trials for Parkinson’s” – interesting perspective from one who was there at the beginning (Click here to read more about this).
  • An interesting review exploring gene products involved in neurodegeneration that undergo liquid–liquid phase separation & their involvement in the DNA damage response – Parkinson’s & Alzheimer’s get discussed (Click here to read more about this).
  • A nice review discusses the current state of Parkinson’s-associated LRRK2-focused biomarkers, advantages & disadvantages of outcome measures, the gaps that need to be addressed, & the priorities that the field has defined (Click here to read more about this).
  • Wonderful figures in this review of anti-inflammatory & neuroprotective agents in clinical trials for brain injury & neurodegeneration. The authors ask “Where do we go from here?” Parkinson’s get addressed (Click here to read more about this).

  • A new review discusses the use of patient-derived midbrain organoids to explore the molecular basis of Parkinson’s (Click here to read more about this).
  • A review outlining the search for effective treatments targeting Parkinson’s-associated α-synuclein toxicity in synucleinopathies – what are the pros & cons? (Click here to read more about this).
  • A review of the clinical aspects, cellular pathology & analytical methodology investigating how/if alpha synuclein connects the gut-brain axis in Parkinson’s (focused on patient-based data – click here to read more about this).

  • Everything you need to know about NAD+ metabolism: pathophysiologic mechanisms & therapeutic potential (Parkinson’s is discussed – click here to read more about this).
  • Are patient researchers the missing link? (Click here to read more about this).
  • A Parkinson’s nurse living with Parkinson’s (Click here to read more about this).
  • Researchers provide a useful mini-review of the role of lipids in the initiation of α-synuclein misfolding in conditions like Parkinsons (Click here to read more about this).
  • An interesting review of the emerging potential roles of RHOT1/Miro1 in the pathogenesis of Parkinson’s (Click here to read more about this).
  • This is wonderful! “How do you wish to be remembered?” – conversations with Dr Oleh Hornykiewicz (Click here to read more about this and click here if you don’t know who Oleh is).

  • Everything you need to know about Histone Deacetylase 6 & the disease mechanisms of α-synucleinopathies like Parkinson’s (Click here to read more about this).
  • Researchers provide a review of evreything you need to know about Parkinson’s-associated LRRK2 & the endolysosomal system (Click here to read more about this).
  • Nice write up about recent research on potential diagnostic methods/aids for Parkinson’s (Click here to read more about this).
  • Researchers provide a useful review of glycosphingolipids & neuroinflammation in Parkinson’s (Click here to read more about this).
  • Check out the new and improved Global Parkinson’s Genetics Program website from the team at Aligning Science Across Parkinson’s (or ASAP)
    (Click here to read more about this).

  • Making precision medicine for Parkinson’s even MORE personal. Researchers exploring LRRK2 & GBA variants, the need for biomarker toolboxes, & “one-size-fits-only-one-or-a-few” approaches – required reading (Click here to read more about this).
  • A concise review of mitochondria & Parkinson’s, covering on clinical, molecular, & translational aspects (Click here to read more about this).
  • A case study of foliglurax – the first experimental clinical mGluR4 PAM for symptomatic treatment of Parkinson’s: Translational gaps or a failing industry innovation model? (Click here to read more about this).
  • From synaptic protein to prion: The long & controversial (ongoing) journey of Parkinson’s-associated α-synuclein (Click here to read more about this).
  • A review of natural compounds that may influence autophagy – can they be called “Allies against neurodegeneration”? Lots of references to Parkinson’s (Click here to read more about this).
  • Is COVID-19 a perfect storm for Parkinson’s?” An interesting viewpoint regarding the development of acute parkinsonism following COVID-19 infection (Click here to read more about this and click here for the press summary).

  • Timely stuff: Adapting to post-COVID19 research in Parkinson’s: Lessons from a multinational experience (Click here to read more about this).
  • “Safety of long-term use of these ATP-competitive LRRK2 kinase inhibitors has been challenged by several studies. Therefore, alternative ways of targeting LRRK2 activity will have a great benefit” – a review of progress in allosteric inhibitors of LRRK2 (Click here to read more about this).
  • Palliative care for individuals living with Parkinson’s (Click here to read more about this).
  • Repair-or-dispose decisions under stress: By reacting to changes in neuronal health, glial cells carefully balance repair or disposal of injured neurons. Could a malfunction of this interaction be involved in neurodegenerative conditions like Parkinson’s? (Click here to read more about this).
  • New view point proposes LRRK2-associated Parkinson’s “should be considered a distinct, more benign form of PD”. Also explores the role of LRRK2 protein in modulating immune & infections responses, especially in the gut (Click here to read more about this).

  • A short review on the role of homocysteine in the development & progression of Parkinson’s (Click here to read more about this).
  • Can growth factors cure Parkinson’s?” – researchers take a deep dive (GDNF, CDNF, NRTN, MANF, etc – Click here to read more about this).
  • “Emerging microglia biology defines novel therapeutic approaches for Alzheimer’s” (relevance to Parkinson’s as well? – click here to read more about this).
  • Nice review of iPSC-based drug development for neurodegenerative conditions like Parkinson’s (Click here to read more about this).
  • Nice short write up on hallucinations in Parkinson’s – exploring new insights into mechanisms & treatments (Click here to read more about this).
  • Could GBA-associated synucleinopathies, like Parkinson’s be prime candidates for alpha-synuclein targeting compounds? (Click here to read more about this).
  • New review focuses on the interaction of Parkinson’s-associated alpha-synuclein with lipids, & asks if mitochondrial cardiolipin is a critical player in the pathogenesis of PD (Click here to read more about this).
  • A face for radio and a voice for silent film:

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

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

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

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


One thought on “Monthly research review – October 2020

  1. Especially interested to see the summary of effects of early therapy in PD. I have looked for that information ever since diagnosis 4 years ago, Because of the lack of any information on the pros or cons, I determined to delay levodopa until I had symptoms that interfered with my activities, especially since levodopa itself has side effects. The analysis presented should help many make a more intelligent choice about therapy. (I do take rasagaline, my only prescribed medication apart from involvement in a clinical trial.)

    Like

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