Monthly Research Review – November 2019

~ Simon

 

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during November 2019.

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

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

 

So, what happened during November 2019?

In world news:

November 4th – Researchers reported that the spacecraft Voyager 2 has reached interstellar space, following Voyager 1’s historic passage six years ago.

November 7th – New Zealand wrote into law zero carbon immission the same day as Collins Dictionary announced that ‘Climate strike’ was the 2019 word of the year (Click here and here to read more about this).

November 18th – A new study suggests that Humpback whales in the South Atlantic have recovered from near-extinction. Counts show the population off Brazil has climbed from about 450 in the 1950s to 25,000 today (Click here to read more about this).

November 23rd – Max the dog put his owners car in reverse and…

 

November 27th – Researchers created strains of Escherichia coli bacteria that consume carbon dioxide for energy instead of organic compounds (Click here and here to read more about this).

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

In November 2019, there were 738 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (7538 for all of 2019 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 6 pieces of Parkinson’s news

1. Alpha Synuclein Antisense

A manuscript was posted on the OPEN ACCESS preprint database BioRxiv by the biotech firms ionis Pharma & Biogen and researchers from Michigan State University, which demonstrates antisense oligonucleotides targeting alpha synuclein mRNA reduces the production of the protein and reduces pathology in pre-formed fibril models of Parkinson’s (cells, mice & primates – to read more about this).

2. The Tau of LRRK2

Researchers examined proteins associated with neurodegeneration – α-synuclein, tau, & β amyloid – in 12 postmortem brains from individuals who carried a LRRK2 genetic mutation. They found α-synuclein pathology in 63.6% of cases, but tau pathology in 100% of cases (abundant in 91%). Abundant Aβ also be found ( to read more about this).

3. NLRP3 research is heating up (Part 1)

Researchers reported that that loss of NLRP3 inflammasome function reduces tau hyperphosphorylation & aggregation by regulating tau kinases & phosphatases. They also found that Tau activates the inflammasome ( to read more about this and click here to read the press release).

4. NLRP3 research is heating up (Part 2)

Korean researchers identify N,N′-diacetyl-p-phenylenediamine (DAPPD) as capable of restoring microglial dysfunction & improving cognitive function in Alzheimer’s mouse models via suppression of NLRP3 ( to read more about this and click here to read an interesting discussion)

5. New tool for protein aggregation

A new genetically engineered mouse (called the inducible split protein mouse) allows researchers to quantify α-synuclein oligomerization in vivo. It demonstrates that α-synuclein oligomerizes presynaptically and that there is an age-dependent accumulation of 8–16-mer oligomer species… oh & the researchers observed cell-to-cell transmission! ( to read more about this).

6. PD Gut microbiome points towards bile acids

Researchers conducted longitudinal metabolome analysis on 30 drug-naive, de novo Parkinson’s patients (& 30 matched controls) and revealed PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity. Key results: (1) longitudinal trajectory of certain metabolites differed between Parkinson’s & controls; (2) PD medication showed strong lipidomic signatures; (3) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with Parkinson’s incidence in the general population; & (4) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila & B. wadsworthia, which is consistent with the changed metabolome ( to read more about this).

 

Basic biology news

  • PTEN-induced putative kinase 1 knockout rat (Pink1−/−) is marketed as an established model for Parkinson’s,… but it isn’t. New report expresses concerns about the reproducibility of the Pink1−/− rodent model ( to read more about this).
  • Amyloid fibrils prepared using an acetylated & methyl amidated peptide model of the Parkinson’s-associated α-synuclein NAC 71–82 amino acid stretch contain an additional cross-β structure also found in prion proteins ( to read more about this).

  • Researchers conducted an in vitro screen for compounds that protect motor neurons from ER stress-mediated degeneration. Their findings highlight MAP4 kinase inhibitors as being potentially neuroprotective for ALS ( to read more about this).
  • Researchers have conducted a molecular characterisation of an aggregation-prone variant of Parkinson’s-associated alpha synuclein (SynT) & found it to be a valid model for a-syn aggregation (Click here to read more about this).
  • Researchers report that the opioid pain medication Tapentadol (a µ-opioid receptor agonist & norepinephrine reuptake inhibitor) prevents motor impairments in a Parkinson’s mouse model of L-dopa induced dyskinesia ( to read more about this).
  • Researchers propose a single gene therapy formulation (combining FGF21, αKlotho, & soluble TGFβR2) that is able to treat 4 mouse models of age-related disease (obesity, type II diabetes, heart failure, & renal failure – to read more about this).
  • Researchers report the cryo-EM structures of Parkinson’s-associated α-synuclein fibrils containing the H50Q hereditary mutation, & find that the H50Q mutation results in two polymorphs of α-synuclein: narrow & wide fibrils ( to read more about this).
  • Researchers have a manuscript on bioRxiv providing novel insights for Parkinson’s pathogenesis in Auxilin mutation carriers, also reinforcing a key role for clathrin-mediated trafficking in PD ( to read more about this).
  • Researchers developed a protocol based on transient expression of transcription factors by means of adeno-associated viral vectors, allowing 4 generation of consistent numbers of dopaminergic neurons from 4 human iPSC lines ( to read more about this).

  • A proteomic screen of the interactome of stabilized Parkinson’s-associated α‐synuclein oligomers identifies Rab‐3A as a target with possible disease relevance (Click here to read more about this).
  • Researchers have now published a follow up to their earlier report – this new one presenting the discovery, scope & potential of these new ligands of the NURR1/NOT nuclear receptor, “potentially useful in the treatment of Parkinson’s” ( to read more about this).
  • Researchers have an opinion piece asking if Myeloid cell leukemia-1 (MCL-1) – a member of antiapoptotic BCL-2 family proteins, is a key regulator of mitochondrial homeostasis – could be a therapeutic target in Parkinson’s? (Click here to read more about this).
  • Researchers have a bioRxiv manuscript presenting the 14-Å structure of Parkinson’s-associated LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double-helix around microtubules ( to read more about this).
  • Parkinson’s-associated α-synuclein regulates the development & function of cholinergic enteric neurons in the mouse colon. α-Syn KO mice have higher density of enteric neurons & a larger proportion of cholinergic neurons (Click here to read more about this).
  • A split-GFP tool reveals differences in the sub-mitochondrial distribution of normal & mutant Parkinson’s-associated alpha-synuclein ( to read more about this).

  • Ingestion of tryptamine-alkaloid-rich phalaris plants causes a disorder called Phalaris staggers, a neurological syndrome reported in kangaroos. Histological analysis demonstrates neuronal accumulation of neuromelanin & aggregated α-synuclein. Strong staining of α-synuclein was reported, restricted to neurons, but no Parkinson’s-associated Lewy bodies inclusions were not observed. Environmentally-acquired toxic synucleinopathy? ( to read more about this).
  • Early-onset somatic variants were found to be significantly increased in the substantial nigra & cortex of aged Parkinson’s-associated PINK1 knockout mice (Click here to read more about this).
  • In a new BioRxiv manuscript researchers reports robustness of substantia nigra dopaminergic neurons to potassium channel deletions is highly variable, due to channel-specific compensatory mechanisms ( to read more about this).
  • 3,4-dihydroxyphenylacetaldehyde (DOPAL – which is then oxidized to DOPAL-quinone) is far more potent than dopamine in oligomerizing Parkinson’s-associated alpha synuclein. DOPAL-induced protein modifications were inhibited by N-acetylcysteine (NAC –  to read more about this).
  • Researchers report Parkinson’s-associated alpha synuclein decorates a lipid vesicle surface obtaining properties similar to the fibril surface, enhancing fibril nucleation. aSN:lipid co-structures accelerate aSN fibril nucleation vs lipid vesicles alone (Click here to read more about this).
  • Researchers introduce a fully automated climbing behaviour assay for fly research & beautifully characterize climbing behaviour in different genetic models of Parkinson’s (at high resolution – to read more about this).

  • Researchers conducted a screen of druggable genes to identify the proteins that regulate Parkinson’s-associated α-Synuclein. They found Doublecortin like kinase 1 (DCLK1) regulates α-Synuclein levels post-transcriptionally (Click here to read more about this).
  • Researchers report that enzymatic glycosylation with N-acetylglucosamine protects against the aggregation of α-synuclein involved in Parkinson’s. Anti-aggregation effect is peptide dependent and glycosylation site specific ( to read more about this).
  • Researchers report that a single transvascular injection of α-synuclein preformed fibrils/modified rabies virus glycoprotein (RVG9R) complex triggers selective regional neuropathology resembling the premotor stage of idiopathic Parkinson’s ( to read more about this).
  • Researchers report behavioural & dopaminergic changes in double mutated human A30P*/A53T alpha-synuclein transgenic mouse model of Parkinson’s ( to read more about this).
  • Rresearchers introduce light-driven proton transporter (Delta-rhodopsin) to drosophila mitochondria, & report activation of mitochondrial proton-motive force improves motor behaviors in a fly model of Parkinson’s ( to read more about this).
  • Researchers report that Prolyl oligopeptidase (PREP) inhibition activates autophagy (via protein phosphatase 2A) in vitro & in vivo ( to read more about this).
  • Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson’s. Intrastriatal zinc chelation improves motor deficits ( to read more about this).
  • Forcing mitochondrial OXPHOS in human skin fibroblasts from males with sporadic Parkinson’s uncovers metabolic defects that were otherwise not obvious in high-glucose culture media (Click here to read more about this).
  • Researchers report that Parkinson’s-associated alpha synuclein fibrils formed in the presence of β synuclein are less cytotoxic, exhibit reduced cell seeding capacity & are more resistant to fibril shedding compared to alpha synuclein fibrils alone ( to read more about this).
  • New bioRxiv manuscript suggests that melanoma cancer cells produce, secrete & require Alzheimer’s-associated β amyloid beta protein for growth & survival in the brain. Pharmacological inhibition of β amyloid reduces brain metastatic burden ( to read more about this).

  • Researchers report that Parkinson’s-associated DJ-1 regulates the integrity & function of Endoplasmic reticulum-mitochondria association (via interaction with IP3R3-Grp75-VDAC1 complex). DJ-1 level also reduced in the brains of sporadic PD patients ( to read more about this).
  • Researchers suggest that fragile X mental retardation protein (FMRP) is decreased in cells overexpressing alpha synuclein & lost in the dopmine neurons of postmortem cases of Parkinson’s (Click here to read more about this).
  • Inhibition of calcium-calmodulin-dependent phosphodiesterase (PDE1) supresses pro-inflammatory genes in the microglia transcriptome. PDE1 inhibition could be useful in dampening inflammatory responses of microglia in conditions like Parkinson’s ( to read more about this).
  • Researchers have a manuscript on BioRxiv reporting a novel transgenic mouse (WT human alpha synuclein under control of noradrenergic-specific dopamine β-hydroxylase promoter) that develop pathology & non-motor features of Parkinson’s. “These mice developed asyn aggregates in LC neurons, alterations in hippocampal & LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal dopamine metabolism, & age-dependent behaviors reminiscent of non-motor symptoms of PD” ( to read more about this).

 

Disease mechanism

  • Researchers point to a previously unrecognized role for N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the regulation of dopamine neuron function. NAPE-PLD deletion protects models of Parkinson’s ( to read more about this).
  • Stepping was facilitated in a rat model of Parkinson’s with spinal cord stimulation (Click here to read more about this).

  • Further evidence of Parkinson’s-associated α-synuclein oligomers affecting neuronal excitability & Ca2+ dynamics (via aberrant form of spike-induced calcium release from IP3 receptor). L-VDCC blocker nifedipine canceled the modulation of spike frequency ( to read more about this).
  • Researchers have data suggesting delayed calcium deregulation, mitochondrial membrane issues & fall in ATP/ADP ratio in cells missing Parkinson’s-associated GBA, signposting reduced bioenergetic capacity & calcium dysregulation in GBA-PD (Click here to read more about this).
  • Researchers report that overexpression of Hsp110 is sufficient to prevent endogenous α-synuclein templating & spread following injection of aggregated α-synuclein seeds into brain. Novel target for Parkinson’s? ( to read more about this).
  • Ablation of RIP3 in mice protects them from dopaminergic neurodegeneration in a mouse model of Parkinson’s (induced by the neurotoxin MPTP). Inhibition of RIP1-dependent necroptosis using necrostatin-1s does not rescue the cell loss ( to read more about this).
  • Researchers report that chronic LRRK2 inhibition (using PFE-360) had a limited effect on motor function in an AAV-α-synuclein overexpression rat model. Plus, aberrant STN burst firing were unaffected by chronic LRRK2 inhibition ( to read more about this).
  • Researchers conducted an investigation of mitochondrial biogenesis defects in single substantia nigra neurons (using post-mortem human tissue). Sig. reduction in mitochondrial transcription factor A detected in Parkinson’s (vs other cases). The authors “hypothesize that impaired nuclear control of mitochondrial biogenesis is a critical aspect that pushes SN neurons towards early loss due to age-related mitochondrial dysfunction in Parkinson’s” ( to read more about this).
  • Researchers identify Cav2.3 calcium channels as regulators of nigral neuronal viability (in mice). Cav2.3 knockout provides full protection from degeneration in a neurotoxin Parkinson’s mouse model. Cav2.3 deficiency resulted in upregulation of NCS-1, a Ca2+-binding protein implicated in neuroprotection. NCS-1 knockout exacerbated nigral neurodegeneration, & NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. Therapeutic tartget for PD? ( to read more about this).
  • Could decreased amount of N-terminal truncated forms of vimentin contribute to impairment of cellular function in PARKIN-associated Parkinson’s? (Click here to read more about this).
  • Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells (Click here to read more about this).

  • Researchers demonstrate reductions in GBA activity in the Parkinson’s midbrain, & reductions in the activity of several other sphingolipid hydrolases. Significant reductions also seen in complex gangliosides in PD & ageing ( to read more about this).
  • Pharmacoidea Ltd researchers report that members of the syndecan family of heparan sulfate proteoglycans are important mediators of seeding & spreading of Parkinson’s-associated α-synuclein & tau ( to read more about this).
  • A manuscript on BioRxiv suggests α-synuclein aggregates induce c-Abl activation (via a redox stress mechanism). c-Abl promotes α-synuclein aggregation, & this potentially feed-forward process can be blocked by N-acetyl cysteine (NAC – to read more about this).
  • Researchers provide further evidence that mitochondrial damage by Parkinson’s-associated α-synuclein can cause cell death in human dopaminergic neurons. Also: a specific caspase-1 inhibitor significantly prevented aSYN-induced cell death ( to read more about this).
  • Treatment with a novel mild mitochondrial uncoupling agent (MP201) reduces motor deficits in the neurotoxin (6-OHDA) model of Parkinson’s (Click here to read more about this).
  • Researchers have a BioRxiv manuscript suggesting that nanomolar levels of Parkinson’s-associated α-syn fibrils (but not monomers) selectively disrupt K-ATP channel-dependent pacemaking in nigral (but not VTA) dopamine neurons. K-ATP channels in nigral dopamine neurons appear to be necessary mediators for the α-synuclein fibrils-induced disruption of pacemaking activity as the K-ATP channel inhibitor glibenclamide corrects the disruption ( to read more about this).
  • Small molecule inhibitor of c-abl kinase, PD180970, has been identified as a modulator of “aggrephagy” (in an mTOR-independent manner) in models of Parkinson’s. It also regulates neuroinflammation by reducing microglial activation ( to read more about this).
  • New study suggests that the contents of exosomes from 2 types of Parkinson’s-associated LRRK2 mutant neural cells (iPSC & AHNP) is altered. Potential biomarkers? (Click here to read more about this).

  • Researchers report non-coding regulatory regions for the human brain. While psychiatric disorders are associated with variants in enhancers/promoters in neurons, Alzheimer’s is largely confined to microglia ( to read more about this and click here to read an interesting review of the work).
  • New data suggests early loss of noradrenergic activity & anterograde neurotrophin support could potentially contribute to degeneration of vulnerable midbrain dopamine neurons in Parkinson’s ( to read more about this).
  • Apoptosis signal regulating kinase 1 (ASK1) deletion blocks α-synuclein pre-formed fibril propagation in mouse model of Parkinson’s. Neuroinflammatory reaction to α-Syn PFF injection & propagation also attenuated in ASK1 knock-out mice ( to read more about this).
  • Elan Pharmaceuticals researchers identify a compound that inhibits Parkinson’s-associated α-Syn misfolding & is neuroprotective, multiple compounds that restore phagocytosis impaired by α-Syn overexpression, & one that block cellular transmission of α-Syn ( to read more about this).
  • A new publication of a novel study showing the importance of the DJ-1 protein in the onset and pathology of Alzheimer’s and Parkinson’s (Click here to read more about this).
  • Anxiety drug afobazole reported to have a neuroprotective effect in a 6-OHDA model of Parkinson’s (via activation of the sigma-1 receptor). Selective Sigma1R antagonist BD-1047 blocks the action of afobazole ( to read more about this).
  • Hematopoietic stem cells producing GDNF were transplanted into 14 week old MitoPark mice exhibiting Parkinson’s-like impairments. GDNF-expressing macrophages infiltrated the brain & markedly improved motor dysfunction & reduced dopamine neuron loss ( to read more about this).

  • Scientists report a “feed-forward” mechanism whereby Alzheimer’s-associated β amyloid plaques enhance Parkinson’s-associated α-syn seeding & spreading over time. Aβ/α-syn combo induces neurodegeneration & behavioral deficits. “Remarkably, hyperphosphorylated tau (p-tau) was induced in α-syn mpff-injected 5xFAD mice” (Click here to read more about this).
  • Researchers report the landscape of multiscale transcriptomic networks & key regulators in Parkinson’s. They identify Stmn2, reduction of which in mice causes dopamine neuron degeneration, increased phospho α-syn, & locomotor deficits ( to read more about this and click here to read the press release).
  • Researchers report that blocking dynamin-related protein 1 (Drp1) improves mitochondrial function & autophagic flux in models of Parkinson’s-associated α-synuclein toxicity. Blocking Drp1 also reduces exosome release ( to read more about this).
  • Korean researchers identify a loss‐of‐function variant of LIN28A (R192G substitution) in two early‐onset cases of Parkinson’s, & then reveal that Lin28 conditional knockout mice show degeneration of dopamine neurons & PD‐related behavioral deficits ( to read more about this).
  • ‘Compound R6’ prevents apoptosis by activating autophagy through mTOR inhibition, as well as protecting mitochondrial integrity & respiration ( to read more about this).
  • Researchers have an intriguing BioRxiv manuscript suggesting that α-synuclein-induced Kv4 channelopathy in the vagal motoneurons of mice can cause non-motor symptoms similar to Parkinson’s ( to read more about this).

 

Clinical research

  • New results from the COPPADIS-2015 study suggest that serum ultrasensitive C-reactive protein level may be related to freezing of gait in people with Parkinson’s. Inflammation could also be linked to FOG development (Click here to read more about this).
  • Further evidence of inflammasome involvement in Parkinson’s. IL-1β & NLRP3 levels significantly increased in PD serum; linear correlation of NLRP3 with α-synuclein ( to read more about this).

  • Researchers report the effects of Parkinson’s-associated GBA1 mutations on cerebrospinal fluid alpha‐synuclein profiles & find that phenotypical characteristics seem dependent on GBA1 mutation severity (Click here to read more about this).
  • New research indicates the existence of a distinct metabotype in older persons with Parkinson’s. Higher levels of β-amino butyric acid, cystine, ornithine, phosphoethanolamine, & proline defines the circulating amino acid profile of older people with PD (Click here to read more about this).
  • New report suggests systemic activation of the Nrf2 pathway in people with Parkinson’s (compared to controls). Nrf2 transcript levels correlate with PD duration (Click here to read more about this).
  • An anonymous questionnaire was sent to movement disorders specialists at 146 Parkinson’s research sites in the US (n = 131) & Canada (n = 15) to assess knowledge & attitudes about genetic testing for Parkinson’s. Interesting results. “Thoughtful initiatives to facilitate clinical trials for genetic-based interventions in Parkinson’s are necessary. Educating clinicians, caregivers, & people with PD is a critical first step; ensuring that genetic counseling & testing are accessible to all patients is imperative” ( to read more about this).
  • New study of sex differences in Parkinson’s presentation & progression involving 914 males & 549 females found ladies had significantly less social support, more psychological distress, & worse self-reported disability & QoL at initial visits (vs males – to read more about this).
  • Vibrating socks – I love this idea! “External cues that act as temporal or spatial stimuli can help to shift from automatic control of gait towards goal-directed control of walking, thereby bypassing the defective basal ganglia circuitry” (Click here to read more about this).
  • Researchers analyse GBA mutations in REM-sleep behavior disorder, and found that they robustly and differentially increase the risk of REM sleep behaviour disorder (Click here to read more about this).

  • Researchers have a manuscript on medrXiv reporting a machine learning approach to discriminating Progressive Supranuclear Palsy (PSP) from Parkinson’s using wearable technology ( to read more about this).
  • Researchers conducting the Oxford Discovery prospective cohort study, suggest a simply, low‐cost serum‐based approach to stratify Parkinson’s patients for immunomodulatory approaches & monitor treatment response (Click here to read more about this).
  • Results of an interesting feasibility study evaluating effectiveness of the Leap Motion Controller® video game-based therapy for upper limb rehabilitation in 23 people with Parkinson’s. Possible benefits for coordination, speed of movements & dexterity ( to read more about this).
  • A meta analysis of 64 studies – involving 32452 Parkinson’s patients – supports the idea that contrary to idiopathic PD, no sex difference was observed in prevalence of patients carrying the LRRK2 G2385R variant (Click here to read more about this).
  • The protocol for the “Promoting independence in Lewy body dementia through exercise” (PRIDE) study has been published (Click here to read more about this).
  • Sniffin’ Sticks test olfactory screening of Parkinson’s – a cross-cultural study of 80 PD patients & 170 healthy subjects in China & Germany ( to read more about this).
  • Differentiation of multiple system atrophy (MSA) from Parkinson’s (by structural connectivity derived from probabilistic tractography – to read more about this).
  • Researchers in Mexico analysed blood from 32 untreated Parkinson’s patients + 20 healthy controls & found that people with PD may exhibit a deficient suppression of the pro-inflammatory response ( to read more about this).
  • Researchers report that exposure to certain types of oral antibiotics seems to be associated with an elevated risk of Parkinson’s. Data “supports the hypothesis that effects on gut microbiota could link antibiotics to PD” ( to read more about this).

  • Researchers suggest that subthalamic nucleus neurons in people with Parkinson’s have multiple stable states, brief electrical stimuli can lead to transitions between states, & different states could influence key motor circuits of the basal ganglia ( to read more about this).
  • Higher average urate concentrations were associated with a lower likelihood of having possible REM sleep behavior disorder. The observed association between urate concentration & pRBD risk appeared to be modified by sex ( to read more about this).
  • New research suggests a reduced prevalence of prodromal features associated with Parkinson’s in older individuals who were more physically active in midlife – consistent with hypothesis that high levels of physical activity may reduce risk of PD (Click here to read more about this).
  • The protocol for the “EXPANd” study has been published. It will be a double-blinded randomized controlled trial to investigate the effects of exercise & explore neuroplastic changes in people with Parkinson’s ( to read more about this).
  • New paper highlighting the potential role of over night core body temperature as a predictive biomarker for Parkinson’s and Lewy body dementia (Click here to read more about this).
  • New BioRxiv manuscript provides evidence that diets rich in saturated fat & refined sugars are associated with changes in indirect measures of central dopamine levels in humans (independent of body weight status – to read more about this).
  • People with REM sleep behaviour disorder may exhibit less neocortical 11C‐donepezil binding, indicating reduced cholinergic innervation from the nucleus basalis of Meynert. Could such changes predictive of future cognitive impairment? (Click here to read more about this).
  • Normal Cu/Zn-superoxide dismutase (SOD1) is reported to be misfolded in cerebrospinal fluid (CSF) of sporadic amyotrophic lateral sclerosis (ALS). Misfolded SOD1 also detected in CSF from a subset of Parkinson’s & progressive supranuclear palsy (PSP – to read more about this).

  • Higher cerebrospinal fluid (CSF) to plasma ratio of uremic toxins (p-cresol sulfate & indoxyl sulfate) in patients with Parkinson’s. Patients with motor fluctuations had higher level of uremic toxins in CSF ( to read more about this).
  • Chinese meta-analysis of 26 case-control studies finds plasma levels of homocysteine are significantly higher in people with Parkinson’s (than controls). In addition, plasma folate & vitamin B12 levels were lower in the PD patients than controls ( to read more about this).
  • Apathy is independently associated with β-amyloidopathy in patients with Parkinson’s at risk of dementia (Click here to read more about this).
  • Neurofilament light chain levels in cerebrospinal fluid were 42% higher in 139 Parkinson’s patients (vs 52 matched controls). Serum levels 37% higher. Higher serum neurofilament associated with a lower MMSE scores. No assoc with duration, UPDRS‐III, or HY ( to read more about this).
  • Reseachers report that a composite alpha synuclein-based biomarker differentiates a Parkinson’s subgroup – presenting motor symptoms without dementia – from a healthy controls ( to read more about this).
  • Researchers report the results of a study using machine learning to determine the optimal combination of gait characteristics to discriminate people with & without Parkinson’s. 5 clinical gait characteristics were identified: mean step velocity, mean step length, step length variability, mean step width, and step width variability) that accurately classified Parkinson’s ( to read more about this).
  • Researchers report on the long-term complications associated with levodopa use in Parkinson’s, in our CamPaIGN cohort (Click here to read more about this).
  • A nationwide, population-based study (2010 to 2015) explores trends in the incidence & prevalence of Parkinson’s in Korea. Interesting: The incidence and prevalence of PD in Korea were HIGHER in women & increased gradually from 2010 to 2015 ( to read more about this).

  • Researchers explore the ethical challenges & future directions of advance care planning in Parkinson’s, in which patients, families, & clinicians can collaborate to identify values, goals, & preferences early & throughout cause of condition ( to read more about this).
  • Variation in GBA confers a spectrum of increased risk for Parkinson’s disease. Researchers show that an individual’s overall Parkinson’s disease genetic risk score modifies the effect of GBA variants on disease risk and age at onset ( to read more about this.
  • Million Women Study Collaborators report no association between alcohol intake & Parkinson’s risk in women (Click here to read more about this).
  • researchers confirm previously reported effects of COMT inhibitors on the fecal microbiota of Parkinson’s patients & suggest a possible effect of L-dopa & entacapone medication on the relative abundance of several bacterial genera ( to read more about this).
  • Researchers report abnormal pattern of brain glucose metabolism in people with Parkinson’s – these results were replicated across 3 European cohorts. 18F-FDG PET data consistently revealed a characteristic PD-related brain pattern (PDRP – to read more about this).
  • Applications of the European Parkinson’s disease Association sponsored Parkinson’s Disease Composite Scale (PDCS – click here to read more about this).
  • No sign of Parkinson’s in 90 centenarians from the “Centenari a Trieste” (CaT) study ( to read more about this).

 

New clinical trials

  • New clinical trial registered by Aptinyx evaluating their NMDA receptor modulating small molecule, NYX-458 in 135 people with mild cognitive impairments associated with Parkinson’s (Click here to read more about this).
  • New clinical trial registered by VistaGen Therapeutics to evaluate AV-101 (L-4-Chlorokynurenine, which is an orally active small molecule prodrug of 7-chlorokynurenic acid, a NMDA receptor antagonist) in Levodopa-induced dyskinesia (Click here to read more about this).
  • A new Phase II study has been registered to assess the safety, tolerability & efficacy of Neuraly Inc’s GLP1 agonist “NLY01” (a pegylated form of exenatide) in 240 subjects with early untreated PD. A 36 weeks study, reporting 2021 (Click here to read more about this and click here to read a SoPD post on this topic).

  • New clinical trial registered in China: The “Study of Efficacy and Safety of Idebenone vs. Placebo in Prodromal Parkinson’s Disease (or SEASEiPPD) will evaluate nootropic & antioxidant idebenone in 180 prodromal PD subjects for 24 months (Click here to read more about this).
  • Interesting new clinical trial registered looking at whether non-invasive transcutaneous vagus nerve stimulation for 13 days is safe & effective in 30 people with Parkinson’s (Click here to read more about this).
  • New Phase I clinical trial registered to investigate the safety, tolerability, & pharmacokinetics of an orally administered drug called FB-101 in healthy individuals. This drug, from Korean biotech 1ST Biotherapeutics, is being developed for Parkinson’s I am unable to find any information regarding FB-101. I understand that it has an anti-inflammatory mechanism of action, & is different to FB-102 (which is a cABL inhibitor). Click here to read more about the FB-101 trial.

  • New Phase Ib clinical trial registered by Brain Neurotherapy Bio evaluating GDNF gene therapy for Parkinson’s. 12 participants will be recruited to receive different doses of AAV-GDNF, study expected to finish in 2022/23. Primary endpoint=tolerability (Click here to read more about this).
  • New Phase II clinical study registered – “Trial of Ondansetron as a Parkinson’s HAllucinations Treatment” (TOP HAT), recruiting 216 participants for this 24 week study (Click here to read more about this).
  • Interesting new clinical trial registered in Lille (France) investigating “PARKINSUN” – a new communication aid tool to favor global patient centered care for Parkinson’s patients during consultation with GPs & neurologists (Click here to read more about this).
  • New clinical study registered – the Dutch Parkinson’s & Cognition (DUPARC) study: a longitudinal cohort study to investigate the relationship between cognitive impairment & both cholinergic & dopaminergic neurodegeneration in newly diagnosed patients (Click here to read more about this).

 

Clinical trial news

  • A randomised controlled trial of prolonged-release melatonin (4 mg) reports no reduction rapid eye movement sleep behavior disorder in Parkinson’s ( to read more about this).
  • Herantis Pharma have published their Sept-Oct newsletter, providing a brief update on their CDNF in Parkinson’s clinical trial (fully recruited, ongoing, & scheduled for unblinding in Q1 2020 – to read more about this).

  • ResTORbio has reported that their Phase 1b/2a clinical trial of their mTORC1 inhibitor RTB101 in Parkinson’s is on track & the company expects data from this trial in 2020 ( to read more about this).
  • Prothena Corp report that their immunotherapy for Parkinson’s clinical trial of Prasinezumab (PRX002/RG7935) with Roche is fully enrolled (Dec 2018; N=316) & data from Part 1 of the PASADENA study are still expected to be announced in 2020 (Click here to read more about this).
  • Inflamazome‘s Inzomelid is a brain-penetrant drug intended for the treatment of neuroinflammatory and neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Motor Neuron Disease” (ALS), and it has now entered Phase I clinical testing (Click here to read more about this).

  • Antibiotic “Minocycline did not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s during a 2-year period” (Click here to read more about this).
  • A small randomised, placebo-controlled, double blind, clinical trial conducted in Iran reports that 6 months of licorice treatment as an adjunct therapy improved the symptoms of people with Parkinson’s (Click here to read more about this).

 

Other news

  • Merck bought Calporta Therapeutics for up to $576M – they have some interesting TRPML1 agonists for boosting autophagy in neurodegenerative conditions like Parkinson’s & other lysosomal storage conditions (Click here to read more about this).

  • Homegrown drug for treating Alzheimer’s has been approved by China’s National Medical Products Administration. Oligomannate (aka GV-971 – derived from brown algae) demonstrated statistically improved cognitive function among people with AD. Green Valley, a Shanghai-based pharmaceutical company, plans to launch Phase III clinical trials in the US & Europe in early 2020. Little is known about the mechanism of action, but the researchers behind the drug suggest that epidemiological data drew them to it. The Phase 3 Chinese trial was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 36 week study led by Peking Union Hospital & Shanghai Jiaotong University Medical School Mental Health Center (conducted in 34 Tier-1 hospitals across China). A total of 818 patients with mild to moderate Alzheimer’s completed the study. Unpublished results suggest a mean difference between Oligomannate & placebo groups in ADAS-Cog12 Score of 2.54 (p< 0.0001), sustained from first month of treatment to the end of 9 months of treatment ( to read the press release and click here to read a previous research report on this drug).
  • Interesting article about the research being conducted on soluble TNF in conditions like Parkinson’s and Alzheimer’s ( to read more about this).
  • Highlights from the Michael J Fox Foundation’s 13th Parkinson’s Disease Therapeutics Conference (Click here to read more about this).

 

Review articles/videos

  • The latest update of the Parkinson’s Hope List (by Kevin McFarthing) has 291 projects, 147 in research/pre-clinical and 144 in clinical ( to read more about this).
  • Literally everything you need to know about Glucagon-like peptide 1 (GLP-1) – a key target for Parkinson’s & neurodegenerative research with efforts to repurpose GLP-1 agonists. Very thorough review (but only a brief section on PD – to read more about this).
  • A presentations from The Cure Parkinson’s Trust Autumn Research Review providing an overview of the Linked Clinical Trials programme (Click here and here to read more about this).
  • The SoPD recommended reading for November: Researchers build on the idea of triggers, facilitators, & aggravators in Parkinson’s, and ask if infections can initiate alpha-synucleinopathies? (Click here to read more about this).
  • Interesting review of different studies on the expression & activity of autophagic & lysosomal proteins associated with Parkinson’s, & their functional consequences, performed in peripheral human biospecimens ( to read more about this).
  • A useful review on the contributions of gut bacteria & (importantly) diet to drug pharmacokinetics in the treatment of Parkinson’s ( to read more about this).
  • Interesting discussion about the involvement of caspases in the activation of the inflammasome, autophagy, & non-apoptotic forms of cell death such as necroptosis and pyroptosis (Parkinson’s gets a couple of mentions – to read more about this).
  • Prof Roger Barker discussing the progress that has been made in the last 10 years for Parkinson’s research:
  • For the unitiated, this mini review provides a good introduction to glucagon-like peptide-1 (GLP-1) research on neurodegenerative conditions like Parkinson’s & Alzheimer’s ( to read more about this).
  • A useful review of our current models of multiple system atrophy (MSA – to read more about this).
  • New review on Parkinson’s epidemiology, pathology, genetics, & pathophysiology (all the bases are covered here) – & how these factors converge on specific biological pathways ( to read more about this).
  • A presentations from The Cure Parkinson’s Trust Autumn Research Review providing an overview of the Exenatide clinical trial programme for Parkinson’s (by Prof Tom Foltynie):
  • A new interwoven hypothesis proposes that some of the non-motor manifestations accompanying Parkinson’s may be caused by intestinal dysbiosis ( to read more about this).
  • Parkinson’s Foundation introduces “Parkinson’s Revolution“, an indoor cycling event taking place February 8th 2020 ( to read more about this and click here to read more about this).
  • Could lysosomal dysfunction lie the Centre of Parkinson’s & frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)? ( to read more about this).
  • Interesting review from some of the biggest names in the field: Recent developments & future perspectives on Multiple System Atrophy (MSA) – similar to Parkinson’s (Click here to read more about this).
  • Did you know Parkinson’s-associated α-synuclein has an essential role in the development & activation of the hematopoietic system & immunity? Now researchers provide an interesting review summarising basic genetic & structural findings ( to read more about this).
  • A presentations from The Cure Parkinson’s Trust Autumn Research Review in which Prof Annette Schrag discusses depression and Parkinson’s:
  • Researchers provide a review of the mechanisms by which Parkinson’s-associated LRRK2 regulates lysosomal degradative pathways in neuronal & non‐neuronal cells & how PD mutations contribute to lysosomal dyshomeostasis ( to read more about this).
  • Researchers explore the human genetics evidence of cellular waste disposal (autophagy/lysosomal pathway) dysfunction in Parkinson’s (Click here to read more about this).
  • Researchers provide us with everything we need to know about Parkinson’s-associated LRRK2 & how it is involved with the regulation of immune-pathways & inflammatory diseases – very timely! ( to read more about this).
  • A useful review on targeting microglial & neuronal Toll-like Receptor 2 (TLR2) in synucleinopathies, such as Parkinson’s ( to read more about this).
  • Interesting interview of Elon Musk regarding artificial intelligence, Neuralink & singularities (Parkinson’s doesn’t get a mention, but readers are always asking about Neuralink):
  • A review of modifiable risk & protective factors in disease development, progression & clinical subtypes of Parkinson’s ( to read more about this).
  • Researchers suggest that “a monomer-only, lipid-centric view of endogenous alpha-synuclein aggregation can explain how alpha-synuclein pathology is triggered” ( to read more about this).
  • A review of promising potential disease-modifying therapies for Parkinson’s ( to read more about this).
  • A useful minireview on the emergence of exosomes as a promising new avenue for the identification of novel biomarkers & therapeutic targets aimed at GBA-associated Parkinson’s (Click here to read more about this).
  • A presentations from The Cure Parkinson’s Trust Autumn Research Review in which Dr Stephen Mullin discusses the genetics of Parkinson’s, with a strong emphasis on GBA-associated PD:

 

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

And there it is, just some of the highlights from November 2019 – another very busy month of Parkinson’s research. Hopefully there will be bits and pieces of interest for everyone in the list. Much of the material used here was collected from the Science of Parkinson’s Twitter feed (and there is a lot more posted there each day).

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

And now: on to December (WHERE HAS THIS YEAR GONE?!?!?)

 

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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.

Published by Simon

I am the Director of Research at Cure Parkinson's. Before that I was working as a Parkinson's research scientist at the University of Cambridge where I conducted both clinical- and lab-based research on Parkinson's. I have worked in the Parkinson's research field for over 15 years - both academically and in biotech ventures. All of my views/opinions expressed here are solely my own, and may not reflect the views of my employer or associated parties.

3 thoughts on “Monthly Research Review – November 2019”

  3. I really don’t know how you do this with a regular job, a family and all of this. Well done.

    It takes me the best part of a month to go through it all.
    A couple of posts ago you asked for feed back as how your site should go into the future.

    My thoughts which other may disagree, is that you only do this monthly round up with ad hoc posts in between only when there is something urgent, or particular relevant.

    This would free you up and perhaps reduce any burnout.

    Like

    Reply

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