Monthy research review – December 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 December 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 December 2019?

In world news:

December 1-31st – Bush fire continued to rage across Eastern Australia. In New South Wales alone more than 3 million hectares have burned (compared to a total of 900,000 hectares in the Amazon for all of 2019 – Source). Prime Minister Scott Morrison returned home from holiday and signaled “no change” to Australia’s climate policy.

 

December 10 – Sanna Marin, at the age of 34, became the world’s youngest serving prime minister after being selected to lead Finland’s Social Democratic Party.

December 13th – “Away from the manger” – Sully the camel, Gus the donkey and Rufus the cow were discovered by authorities wandering (towards a Northern star) when they should have been part of the nativity exhibit at the Tanganyika Wildlife Park (Click here to read more about this).

December 30 – Chinese authorities announced that researcher He Jiankui, who claimed to have created the world’s first genetically edited human babies, has been sentenced to three years in prison and fined 3 million yuan (US$430,000) for his genetic research.

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

In December 2019, there were 792 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (8075 for all of 2019). 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. Global Parkinson’s Genetics Program (GP2):

This is huge! The ASAP-supported Global Parkinson’s Genetics Program (GP2) “study will engage existing global consortia & cohorts to expand genetic analysis efforts with samples from more than 150K people, including those with Parkinson’s, people at risk for PD, & control volunteers”. “GP2 will use cutting-edge techniques to analyze samples from people around the world living in or with ancestors from Africa, Asia, Europe, & Central+South America. These efforts will transform understanding of the genetic architecture of Parkinson’s across populations”. Importantly, the project will be focusing on “those currently underserved in research”. GP2 is a huge five-year study (Click here to read more about this, click here to read an editorial, and click here to read a previous SoPD post about ASAP).

2. More personalised deep brain stimulation

Researchers reported precision functional mapping identifies subcortical integration zones in individuals. Integration zones map onto variably effective deep brain stimulation sites. Implications for Parkinson’s? ( to read more about this, click here for the press release, and click here to read a SoPD post on this research).

3. A lot of alpha synuclein data

Researchers demonstrated that inoculation of transgenic mice with different strains of recombinant or Parkinson’s brain-derived α-synuclein aggregates produces clinically & pathologically distinct diseases. “Strain-specific clinical, pathological & biochemical differences were faithfully maintained after serial passaging, which implies that α-synuclein propagates via prion-like conformational templating” ( to read more about this and click here to read the press release).

Researchers also amplified α-synuclein aggregates from Parkinson’s & Multiple System Atrophy (MSA) brain extracts & analyzed their conformational properties. They found greater structural heterogeneity among α-synuclein fibrils from the PD brains. PMCA used to amplify a-syn aggregates from brain extracts of 10 patients (5 PD & 5 MSA). Amplyfication of samples from 1 control subject did not exhibit any a-syn aggregates. The a-syn fibrils amplified from patient brain extracts were structurally different to ALL of the in vitro polymorphs analyzed. Highlights potential differences between in vitro & in vivo aggregates. Also, a-syn fibrils propagated from Parkinson’s & MSA brains do not exhibit distinctive structural properties. So no to the “one disease-one strain” hypothesis? ( to read more about this and click here to read the press release).

In addition, researchers reported a master regulatory mechanism of Parkinson’s-assocaited α-synuclein function & aggregation, extending the repertoire of molecular chaperones & highlighting new therapeutic avenues ( to read more about this).

4. Microglia in humans are different

Microglia are the resident immune cells of the brain. Recently researchers conducted single cell analysis of microglia from 10 different species (covering more than 450 million years of evolution). They reported that microglia are only heterogeneous in humans, not other species. They also found that Parkinson’s genes are conserved only in primates (Click here to read more about this).

 

5. The Nilotinib results

The results of the Georgetown Nilotinib clinical trial in Parkinson’s were published. Drug appeared to be reasonably safe. A couple of the exploratory biomarkers were altered in response to Nilotinib ( to read more about this). “No significant differences were seen in motor and nonmotor outcomes between the nilotinib groups and the placebo group”, but the authors point out that “the study was underpowered for this analysis”. The NILO-PD Steering Committee also announced that although safe & tolerable, Nilotinib does not demonstrate any change in clinical symptoms or biological measures in the Phase II Nilotinib for Parkinson’s (NILO-PD) Trial (Click here to read more about this).

 

6. Inhibition of LRRK2 kinase activity results in increased GCase activity

Researchers reported that Parkinson’s associated LRRK2 protein activity regulates the Parkinson’s-associated lysosomal enzyme GCase in neurons. They identified the LRRK2 interacting protein Rab10 as a key mediator of this LRRK2 regulation of GCase activity. They report that overexpression of normal Rab10 increases GCase activity in fibroblasts & dopamine neurons. Interesting possibilities here regarding experimental therapeutics. “Recent observations have described an increase in WT LRRK2 kinase activity in idiopathic Parkinson’s. Intriguingly, based on our results, this increase in LRRK2 activity in idiopathic PD may also contribute to reduced GCase activity in the absence of GBA1 mutations”. In addition to LRRK2 inhibition, “our observation that GCase is consistently reduced in LRRK2 mutant neurons suggest that LRRK2 patients could benefit from GCase activation” ( to read more about this).

 

Basic biology news

  • Researchers report that Bcl-2-associated athanogene 5 (BAG5) may regulate the bi-modal activity of Parkinson’s-associated Parkin, promoting cell death by suppressing mitophagy & enhancing Parkin-mediated Mcl-1 degradation ( to read more about this).
  • Parkinson’s & Multiple Sclerosis research is heading for space! ( to read more about this).

  • Researchers identify a phosphatase antagonistic to Parkinson’s-associated PINK1, protein phosphatase with EF-hand domain 2 (PPEF2). It dephosphorylates ubiquitin & suppresses PINK1-mitophagy. Knockdown of PPEF2 amplifies baseline mitophagy ( to read more about this).
  • Researchers report lipids co-assemble with Parkinson’s-associated α-synuclein molecules to give “thin & curly” amyloid fibrils. Interesting new insights into the properties of protein-lipid assemblies (Click here to read more about this).
  • Things that make you go hmmm… Researchers have a bioRxiv manuscript suggesting that the vagus nerve is necessary for the rapid neuronal activation in the brain after oral dose of psychoactive bacteria. Sub-diaphragmatic vagotomy corrects that effect. You have to wonder what the levels of Parkinson’s-associated alpha synuclein or other neurodegeneration amyloid proteins look like in the chronic setting in this model??? Perhaps the wrong bacteria, but still… hmmm… ( to read more about this).
  • Researchers report the impact of the genetic variants (SNPs) distributed throughout the Parkinson’s-associated SNCA gene on the epigenetic landscape. Furthermore, they provide structural insights into the intron-1 region of SNCA as binding site of DNMT1 ( to read more about this).
  • Levels of BRCA1–BRCA2-containing complex subunit 3 (BRCC3) are increased in Parkinson’s mouse & cell models. BRCC3 promotes the activation of neuronal NLRP3 inflammasome. Inhibition of Cdk5 suppresses inflammatory effect (Click here to read more about this).

  • Researchers report that luminescent conjugated oligothiophenes can distinguish between α-synuclein inclusions on postmortem section of Parkinson’s & multiple system atrophy (MSA), providing evidence for existence of distinct conformers ( to read more about this).
  • Researchers provided further evidence that metabolites of colon microbiota (e.g. short-chain fatty acids) may influence the brain & behaviour. Implications for Parkinson’s? ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that the Parkinson’s-associated alpha synuclein E46K mutation alters the structure of in vitro assembled alpha synuclein fibrils, unlocking a more stable, pathogenic structure ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that O-GlcNAcylation of small heat shock proteins enhances their anti-amyloid chaperone activity on Parkinson’s-associated alpha synuclein aggregation ( to read more about this).
  • Researchers report that Parkinson’s-associated PINK1 phosphorylates ubiquitin predominantly in astrocytes ( to read more about this).
  • And another bioRxiv manuscript provides a structural view to the severe pathology of the Parkinson’s-associated E46K mutation of α-synuclein, & highlights the importance of electrostatic interactions in defining the fibril polymorphs ( to read more about this).
  • Researchers report 2 new polymorphic atomic structures of Parkinson’s-associated alpha-synuclein fibrils (termed polymorphs 2a & 2b – click here to read more about this).
  • Love this: “AttoBright“, the 3D printed, single-molecule confocal, plug & play portable device. Researchers used this system to detect individual Parkinson’s-associated α-synuclein amyloid fibrils. Amazing! ( to read more about this).

  • The folks at MODAG have a new small molecule inhibitor, called anle145c, which thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers. Given the association between diabetes & Parkinson’s – this is interesting ( to read more about this).
  • Researchers have a manuscript on bioRxiv suggesting that a novel neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated “Synucleinphagy“. Induction of autophagy receptor p62 is necessary ( to read more about this).
  • Korean researchers demonstrate the important role of primary cilia in cellular pro-survival responses during mitochondrial stress in dopamine neurons. Implications for Parkinson’s? ( to read more about this).
  • Omi, a fly homologue of the bacterial heat shock protein HtrA, specifically recognizes & degrades Parkinson’s-associated oligomeric (but not monomeric) α-synuclein. Knockout of Omi in the PD Drosophila exacerbated α-synuclein-induced neurotoxicity ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting amyloid-like protein aggregates cause lysosomal defects in neurons (via gain-of-function toxicity – to read more about this).
  • Researchers report specific, shared genetic architecture between Parkinson’s & melanoma that manifests at the level of gene expression; highlighting 7 genes including PIEZO1, TRAPPC2L, & SOX6 as potential mediators ( to read more about this).
  • Researchers present “Menagerie“: A text-mining tool to support animal-human translation in neurodegeneration research & they evaluate it on models of Parkinson’s ( to read more about this).
  • BRAVE new world. Researchers present a technique for developing targeted synthetic viruses. Viruses can be designed to target human dopamine neurons in vivo & to transport along the connective pathways ( to read more about this).
  • Microglia play a dual role in maintaining blood brain barrier (BBB) integrity. Vessel-associated microglia initially maintain BBB integrity, but during sustained inflammation, microglia phagocytose astrocytic end-feet & impair BBB function ( to read more about this).

  • Researchers identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation (Click here to read more about this).
  • High levels of CXCL12/CXCR4 in postmortem Parkinson’s & transgenic brain tissues. α-Synuclein upregulates CXCL12 in microglia, & induces secretion of CXCL12 (via TLR4/IκB-α/NF-κB). CXCL12/CXCR4/FAK/Src/Rac1 signaling involved in microglial migration ( to read more about this).
  • Environment appears to play a key role in determining the anti-amyloid efficacy of EGCG. For Parkinson’s-associated α -synuclein, “a small change in pH value, from 7 to 6, transforms EGCG from an efficient inhibitor to completely ineffective” ( to read more about this).
  • Arterial spin-labeling MRI & diffusion tensor imaging on genetically engineered mice (overexpressing human α-synuclein) & age-matched controls found that the α-syn mice exhibited a significant reduction in cortical cerebral blood flow ( to read more about this).
  • Researchers report DUF3669 sequences within both ZNF746 (aka “PARIS”) & ZNF777 & identify it as a novel protein-protein interaction module that confer oligomerization. Also transcriptional repression (looking forward to more PARIS data in 2020 –  to read more about this).
  • Curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of Alzheimer’s. In AD models, TFEB is required for compound C1 to degrade APP & MAPT/Tau. Could we possibly test C1 in models of Parkinson’s maybe? ( to read more about this and click here to read previous research about this molecule).

  • Researchers report lipid molecules co-assemble with α-synuclein into amyloid fibrils and this process affects both the thermotropic properties and the dynamics of the lipids (Click here to read more about this).
  • Researchers report a organotypic slice culture models (derived from genetically engineered mice or manipulated using viral vectors) that demonstrates inter-neuronal spreading of Parkinson’s-associated alpha-synuclein aggregates ( to read more about this).
  • Researchers report chaperone Hsp60 (& a derivative of the isolated apical domain of Hsp60) suppress formation of Parkinson’s-associated amyloid fibrils of α-Synuclein ( to read more about this).
  • Researchers conducted a high throughput screen which identified 38 genes regulating the cell to cell transfer of α-synuclein (Click here to read more about this).
  • Antiviral immune response as a trigger of FUS proteinopathy in Amyotrophic Lateral Sclerosis (ALS – click here to read more about this).
  • Researchers propose that somatic mutations in the SNCA (alpha synuclein) gene may contribute to the aetiology and pathogenesis of synucleinopathies (Click here to read more about this).
  • Researchers report a nanocarrier strategy to combine antioxidants (curcumin) with iron chelators (deferoxamine) to fully utilise their therapeutic benefit for Parkinson’s ( to read more about this).
  • Researchers report work supporting the role of Parkinson’s-associated α-synuclein in physiologically preserving mitochondrial functions & homeostasis. Specifically, α-syn null mice display impaired mitochondria-endoplasmic reticulum interactions ( to read more about this).

  • Researchers present a reconstitution of the human nigro-striatal pathway on-a-chip. And they reveal OPA1-dependent mitochondrial defects & loss of dopaminergic synapses ( to read more about this).
  • Anti-neuroinflammatory, protective effects of a synthetic neurosteroid, called BNN-20, protects dopamine neurons in ‘Weaver’ mice even when the treatment begins in a late neurodegenerative stage. Also increases dopamine levels & improves motor activity ( to read more about this).
  • Researchers posted a bioRxiv manuscript suggesting that one of the functions of vesicular-glutamate transporter 2 (Vglut2) in adult dopamine neurons is to promote post-lesional recovery of meso-striatal axons ( to read more about this).
  • Saniona AB finished the year with characterisations of AN317, a novel α6β2* agonist exhibiting functional selectivity toward other nAChRs (α4β2, α3β4 & α7 receptors). Good bioavailability, crosses the blood-brain barrier, & protects models of Parkinson’s (Click here to read more about this).
  • And Saniona AB also discovered AN6001, a novel selective α6β2* nAChRs PAM. It increased agonist-induced dopamine release & global cellular responses. Potential novel symptomatic treatment for Parkinson’s? ( to read more about this).

  • Microglia are the resident immune cells in the brain. Comparison of microglia transcriptomes from Alzheimer’s, ALS, Niemann-Pick disease, type C1 & mucolipidosis type IV mouse models points towards an enrichment in “disease-associated microglia” pattern among these conditions (also overlaps with Parkinson’s –  to read more about this).
  • Researchers provide insights into how GBA1 mutations influence Parkinson’s pathogenesis & provides a platform for testing novel therapeutics. Reduced GCase activity does not result in α-syn aggregation, but can modulates neuronal susceptibility ( to read more about this).

 

Disease mechanism

  • The phosphodiesterase 10 inhibitor Papaverine exerts anti-inflammatory & neuroprotective effects (via the PKA signaling pathway) in mouse models of Parkinson’s ( to read more about this).
  • P2X7 receptor antagonism with Brilliant Blue G (BBG) “re-established the dopaminergic nigrostriatal pathway” in rat neurotoxin model of Parkinson’s. BBG was administered for 7 days, starting 1 week post 6OHDA lesion ( to read more about this).
  • Intrastriatal injection of preformed alpha-synuclein fibrils (PFFs) alters central & peripheral immune cell profiles in non-transgenic mouse model of Parkinson’s (at 5 months post administration –  to read more about this).
  • Researchers report that the neuroprotective effect of xenon on dopamine neurons exposed to low-level excitotoxic insults is not reproduced by other noble gases ( to read more about this and click here to read a previous SoPD post on this topic).

  • Researchers report exercise intensity may influence training-induced adaptation on endothelial reactivity & aerobic capacity in individuals with Parkinson’s ( to read more about this).
  • Researchers provide further evidence that G2019S-LRRK2 genetic mutation enhances neurotoxin (MPTP)-induced mouse model of Parkinson’s, and they find LRRK2 kinase inhibitors can rescue the model ( to read more about this).
  • Researchers report increased levels of acetyl-CoA in cell culture & mice (via the inhibition of acetyl-CoA carboxylase 1 using 2 drugs, CMS121 and J147) results in neuroprotection in mouse model of dementia ( to read more about this and click here to read the press release).
  • Japanese researchers propose a mouse model of prodromal Parkinson’s – α-Synuclein BAC transgenic mice exhibited REM sleep behaviour disorder-like behaviour & hyposmia ( to read more about this).
  • Japanese researchers have identified a role for LRRK2 in endoplasmic reticulum–mitochondrial tethering, which is essential for mitochondrial bioenergetics. May be a control point for pathogenesis in Parkinson’s? ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that targeted neurotrophic (GDNF) gene therapy strategies could improve human cell transplantation outcomes in models of Parkinson’s (some stunning images as always from Lachy & Claire! to read more about this).

  • By crossing Sirt1-overexpressing mice with Spinocerebellar ataxia type 7 (SCA7) mice, researchers rescued neurodegeneration & calcium flux defects. Nicotinamide riboside treatment also rescues phenotypes in SCA7 mice & patient stem cell-derived neurons ( to read more about this).
  • Researchers screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic α-synuclein & show potent inhibition of pathology seeding in a neuronal & mouse model of Parkinson’s ( to read more about this).
  • Behavioral defects associated with amygdala & cortical dysfunction in mouse model of Parkinson’s with seeded α-synuclein inclusions ( to read more about this).
  • Researchers publish follow up work on a brain penetrant agonist of GDNF receptor RET. The small molecule called BT13 demonstrates potential in cellular models of Parkinson’s, but appears to affect dopamine release rather than synthesis ( to read more about this and click here to read previous research on BT13).
  • Researchers present a case study of a female patient with a novel variation in POLG1 (p.Q811R), who was diagnosed with early-onset parkinsonism. IPS-derived midbrain spheroids raise cellular alterations ( to read more about this).
  • Researchers report that chronic treatment of adult rats with non-absorbable antibiotics reduces the neurodegeneration observed in a rodent neurotoxic model of Parkinson’s (6-OHDA). Degree of motor dysfunction also attenuated in antibiotic-treated animals ( to read more about this).

  • Aged (110 weeks) PARKIN knockout mice exhibit motor dysfunction & dopaminergic neuronal loss. In their dopamine neurons, fragmented mitochondria with abnormal internal structures accumulated, suggesting impairment of mitochondrial clearance ( to read more about this).
  • Genetically engineered mice (B4galnt1(-/-) devoid of ganglioside GM1 acquire characteristic symptoms of Parkinson’s. Administering soluble oligosaccharide of GM1 to the B4galnt1+/− mice, rescues motor impairment & reduces α-syn in the substantia nigra ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase & GTPase activity ( to read more about this).
  • Interactions between soluble species of Alzheimer’s-associated β-amyloid & Parkinson’s-associated α-synuclein promote oligomerization while inhibiting fibrillization ( to read more about this).

  • Researchers report Chondroitinase ABC treatment provided significant protection against a model of Parkinson’s (partial 6OHDA lesion of nigrostriatal tract) although the degree of protection was not sufficient to improve motor outcomes ( to read more about this).
  • Researchers have a bioRxiv maunscript in which they probed several reliable unfolded protein response (UPR) markers in Tauopathy brain samples (AD, Picks, PSP). Markers of UPR were not changed ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated alpha synuclein aggresomes inhibit ciliogenesis & multiple functions of the centrosome ( to read more about this).
  • Intrastriatal infusion of non-competitive NMDA receptor antagonist Memantine reported to reduce Levodopa-induced dyskinesia & motor deficits in a mouse model of hemi-Parkinsonism ( to read more about this).
  • Researchers report that brain-penetrant, dopamine D2/D3 agonist, D-520 inhibits the formation of Alzheimer’s-asssociated β-amyloid aggregates & promotes the disaggregation of both β-amyloid & Parkinson’s-associated α-syn aggregates ( to read more about this).
  • It has been reported that PARKIN substrates transcriptionally activate deubiquitinase USP29. Korean researchers now identify 160 kDa myb-binding protein (MYBBP1A) as a novel substrate of USP29, & report upregulation of MYBBP1A in the Parkinson’s brain ( to read more about this).
  • Researchers propose a key role for potassium channel KCa3.1 in driving a pro-inflammatory microglia phenotype in Parkinson’s. They report potential sickle cell anemia drug Senicapoc reduces effects of MPTP toxicity ( to read more about this).
  • Further evidence of beneficial effects of diabetes drug metformin in models of Parkinson’s: Thai researchers report metformin inhibited α-synuclein aggregation & improved lipid deposition in C. elegans PD model. It also reduced 6-OHDA neurodegeneration ( to read more about this).

  • Researchers previously found that Polo-like kinase 2 (PLK-2) regulates Parkinson’s-associated α-synuclein mRNA levels. Now they report this process in GSK-3β dependent. Also found LRRK2 increase in α-syn levels is GSK-3β dependent ( to read more about this).
  • Ucf-101, a specific inhibitor of HtrA2, reported to activate Wnt/β-catenin pathway & significantly reduce neurotoxic (6OHDA) model of Parkinson’s, (via inhibition of endoplasmic reticulum stress – click here to read more about this).
  • Compared to the age-matched controls, differentiated embryonic chondrocyte gene 1(DEC1) deficient mice exhibit the loss of dopamine neurons in the substantia nigra (via inhibition of PI3K/Akt/GSK3β pathway). Lithium treatment helps to rescue cell loss ( to read more about this).

 

Clinical research

  • “Although beneficial for people living with Progressive Supranuclear Palsy (PSP), exercise and physical therapy interventions have been inadequately reported” – does the same apply for Parkinson’s? (Click here to read more about this).
  • “Our data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects”. The take home message from this genetics study: randomization ≠ stratification ( to read more about this).

  • Related to that whole red hair association with Parkinson’s thing: Skin fairness is a better predictor for impaired physical & mental health than hair redness ( to read more about this and click here to read a previous SoPD post on this topic).
  • Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson’s cohort ( to read more about this).
  • Researchers report no genetic evidence for involvement of alcohol dehydrogenase genes in risk for Parkinson’s ( to read more about this).
  • Researchers report that while two genetic forms of Parkinson’s (LRRK2- & GBA-associated PD) express the same disease-specific networks as iPD, information flow through these networks differs profoundly across the patient groups. They “applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks”. They recruited 14 cases of LRRK2-associated PD, 12 GBA-associated PD, 14 idiopathic PD & 14 controls. LRRK2-associated Parkinson’s exhibited increased functional connectivity within the metabolically active PD-related pattern core zone. By contrast, GBA-associated PD gains in connectivity extend outside the core – could this correlate with more aggressive phenotype? ( to read more about this).
  • “No significant increase in tau tangles occurred after a 2-year follow-up of Parkinson’s patients using flortaucipir PET” – could aggregation be a sudden phenomenon (resulting in low chronic inflammation) rather than a slow accumulation process? ( to read more about this).
  • Researchers report that >25% of REM sleep behaviour disorder patients have abnormal dorsal substantia nigra hyperintensity reminiscent of Parkinson’s, which is associated with a greater dopaminergic deficit. Interesting result – could help to enrich future neuroprotective clinical trials with potential early converters ( to read more about this).

  • Researchers report a comparison of walking protocols & gait assessment systems for machine learning-based classification of Parkinson’s ( to read more about this).
  • Researchers identify novel candidate variants for Parkinson’s (using a gene prioritization based on protein-protein interaction), which may be involved in the pathogenesis of PD ( to read more about this).
  • “In Germany, inpatient Parkinson’s Disease Multimodal Complex Treatment (PD-MCT) is a well-established & frequent approach”. New data from a real world observational study of 47 participants provides support for this approach ( to read more about this).
  • New research analyzes in detail the importance of the distinct phonemic groups for the automatic identification of Parkinson’s ( to read more about this).
  • Research from Taiwan suggests patients with herpes zoster (n=13 083) had an increased risk (HR: 1.80, 95% CI: 1.43-2.28) of developing Parkinson’s in later life compared to the control group (n=52 332 – to read more about this).
  • New research suggests a disproportionately high number of agricultural workers (66.7% vs. 54.3% of all neurology admissions) & reduced circulating uric acid are both associated with initial hospital admission for Parkinson’s ( to read more about this).

  • Cerebrospinal fluid levels of neurogranin are decreased in parkinsonian disorders (Parkinson’s, DLB, MSA, PSPS, etc) compared to controls, possibly emphasizing the importance of synaptic dysfunction in these conditions (Click here to read more about this).
  • Combined brain imaging from a European consortium finds that “relative glucose hypermetabolism & disturbed metabolic connectivity of limbic & basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies” ( to read more about this).
  • Interesting viewpoint on freezing of gait and its levodopa paradox ( to read more about this).
  • New bioRxiv manuscript suggests Sarcopenia (progressive and generalized loss of skeletal muscle mass & strength) & Parkinson’s share common pathways & may affect each other’s prognosis and patients’ quality of life (Click here to read more about this).
  • Deletion of lymphocyte-activation gene 3 (LAG3) in mouse models of Parkinson’s was shown to limit α-syn spreading. Now Chinese researchers report LAG3 SNPs increase the PD risk of Chinese female population & the soluble LAG3 may be a potential biomarker. “Three LAG3 SNPs were genotyped at first time in a case-control cohort of Chinese patients with Parkinson’s”. Small numbers, needs to be replicated in a larger data set ( to read more about this).
  • Researchers report a correlation between cerebellar vermal functional connectivity & cognitive impairment in Parkinson’s (Click here to read more about this).
  • Profile of nonmotor symptoms & the association with the quality of life of Parkinson’s patients in Nigeria. 105 patients with PD & 105 healthy controls were assessed for various non-motor symptoms “Financial support & sponsorship: Nil” – respect! ( to read more about this).

  • 64 people with Parkinson’s (+ 27 controls) completed longitudinal resting-state MRI scans, biochemical, & clinical assessments. Baseline CSF α-synuclein protein levels predicted decline in the sensorimotor network ( to read more about this).
  • Researchers report how clinically available markers may be predictive of cognitive impairment in 294 early drug-naïve Parkinson’s. Results of “Predict cognitive decline with clinical markers in Parkinson’s disease” (PRECODE-1) study ( to read more about this).
  • Researchers present a portable device to assess reaction time (RT) & stop signal reaction time optimal combination (or ocSSRT). Administration of L-dopa significantly improved ocSSRT & RT measures in Parkinson’s patients (Click here to read more about this).
  • Researchers report olfactory dysfunction in early Parkinson’s isn’t correlated with striatal 18Fluorodopa uptake as a measure for dopaminergic degeneration, but with putaminal dopamine turnover as a marker 4 dopaminergic presynaptic compensatory processes (Click here to read more about this).
  • Cerebellar blood flow in Multiple Systems Atrophy (MSA) found to be significantly decreased compared with Parkinson’s & progressive supranuclear palsy (PSP). No significant difference between PD & PSP ( to read more about this).
  • 123 newly diagnosed de novo Parkinson’s patients with no focal or systemic inflammatory diseases had their blood analysed. Data suggests that components of peripheral blood leukocytes reflect some clinical symptoms of PD ( to read more about this).

  • Researchers share the 4 year UK-wide PROSPECT study results, suggesting that subtypes of progressive supranuclear palsy (PSP) & corticobasal syndrome have distinct characteristics that may help with early diagnosis ( to read more about this).
  • Researchers assessed substantia nigra hyperechogenicity, hyposmia, & mild parkinsonian signs as long term risk markers for Parkinson’s. They found all 3 associated with long-term risk, but only hyposmia was a marker of short- & long-term risk (Click here to read more about this).
  • Researchers report that both inflammatory & senescence blood-derived markers are valuable predictors of clinical progression in Parkinson’s. PD patients have shorter telomeres at both baseline & 18 months ( to read more about this).
  • Researchers report integrative metabolomic & metallomic analysis in a case–control cohort (n=134) with Parkinson’s. p-cresol sulfate & the trace element nickel showed up as potentially important factors in PD ( to read more about this).
  • Brain imaging from 85 de novo, drug‐naïve Parkinson’s patients (& 85 age‐matched controls) in Italy & US finds disease-relevant patterns were elevated in drug‐naïve PD relative to controls (across the 2 independent cohorts – click here to read more about this).
  • Researchers provide a timely evaluation of evidence on benefits & risks of boxing exercises for people with Parkinson’s. Conclusions: implementation has accelerated beyond the current research evidence. Need for randomized trials ( to read more about this).

  • Researchers detect Parkinson’s tremor from inertial measurement unit (IMU) collected “in-the-wild” (using deep multiple-instance learning). Dataset of accelerometer data from 45 subjects collected entirely outside the clinic ( to read more about this).
  • Researchers analysed the effects of the position of the deep brain stimulation electrode within the subthalamic nucleus on subjective emotional experience in 20 people with Parkinson’s, & find a complex emotion topography in the motor STN ( to read more about this).

 

New clinical trials

  • Sialorrhea (drooling or excessive salivation) is a common feature of Parkinson’s. New clinical trial data supports long-term efficacy & safety of repeated incobotulinumtoxinA treatment for sialorrhea over 64 weeks ( to read more about this).
  • Further details have been posted regarding the Biogen & ionis pharma REASON clinical trial of BIIB094 – an antisense oligonucleotide targetting Parkinson’s-associated LRRK2 (Click here to read more about this).

  • “PARK-FIT” – a new clinical study registered in Spain to assess Treadmill vs Cycling in Parkinson’s at the most effective model in gait reeducation (Click here to read more about this).
  • MODAG’s Phase I 1st-in-human clinical study of single & multiple doses of anle138b in 92 healthy participants has been registered. This treatment is being targetted at Multiple Systems Atrophy (MSA) & Parkinson’s. Results in late 2020 (Click here to read more about this and click here to read a previous SoPD post on this topic).

 

Clinical trial news

  • Clene Nanomedicine has today announced the 1st patient enrolled in their Phase II REPAIR-PD clinical trial for their experimental nanocatalytic therapeutic – CNM-Au8 – in Parkinson’s ( to read more about this and click here to read a recent SoPD post on this topic).

  • Results of the Phase 3, randomised, double-blind, placebo-controlled trial of CTH-300 – an apomorphine sublingual film for off episodes in Parkinson – have been published. 1/3 of patients discontinued treatment primarily because of oropharyngeal side-effects, Despite the dropouts, the apomorphine sublingual film provided an efficacious, on-demand treatment for OFF episodes for most patients with Parkinson’s. Long term safety/tolerability now being investigated ( to read more about this).
  • Some positive news for motor neurone disease (ALS) – look forward to seeing the full results. AMX0035 (developed by Amylyx Pharmaceutical) is a combination of two compounds — sodium phenylbutyrate & tauroursodeoxycholic acid (TUDCA – click here to read more about this).

  • Researchers present the results of a clinical study evaluating multimodal balance training supported by rhythmical auditory stimuli in Parkinson’s. Finding: RAS-supported multimodal balance training has better & more sustained effects ( to read more about this).
  • MODAG announces that they have initiated their first-in-human Phase 1 clinical trial for Anle138b. This study is in healthy volunteers, but the compound is being developed for the treatment of Multiple System Atrophy (MSA) & Parkinson’s ( to read more about this).

  • An interesting interview with Prof Charbel Moussa (principal investigator on the Georgetown Nilotinib study) – “Probably we are telling the story of Nilotinib here, & not the story of Abl inhibition in this study” – CM (Click here to read more about this).

 

Other news

  • MISSION Therapeutics & pharma company Abbvie today announced the identification of several deubiquitylating enzymes (DUB) that will be further characterization as potential drug targets in their Alzheimer’s & Parkinson’s R&D collaboration ( to read more about this, and click here to read a previous SoPD post on this topic).

  • RightEye receives breakthrough device designation from the US FDA for their Parkinson’s diagnostic aid technology. The tech can apparently detect small ocular tremors before other symptoms appear ( to read more about this).
  • The AAV-GAD gene therapy biotech firm MeiraGTx hosted a Parkinson’s-focused R&D day on December 13th (from 9:00-11:30 a.m. ET in New York). A live webcast will be available on the Investors page of the company’s website ( to read more about this and click here to read a previous SoPD post on the topic).

  • Interesting write up – apparently Surmount Bio’s molecule S-181 needs some more work before it is ready for clinical testing in Parkinson’s ( to read more about this).
  • Parkinson’s Foundation announced the addition of 5 new sites for PD GENEration: Mapping the Future of Parkinson’s – a first-of-its-kind US initiative that offers free genetic testing & counseling for clinically relevant Parkinson’s-related genes ( to read more about this).

  • “A newly unearthed patent reveals that Apple is exploring how a future Apple Watch could help doctors monitor the symptoms of Parkinson’s patients” ( to read more about this).
  • Aspen Neuroscience announced Thursday that it has raised a seed round of $6.5 million to support the development of their cell therapy approach for Parkinson’s ( to read more about this).

  • Researchers present the “Quebec Parkinsons Network” – an open-access patient registry, & data/bio-samples repository. Also discuss the upcoming “Canadian Open Parkinson Network” ( to read more about this).

 

Review articles/videos

  • A useful review of autophagic & endo-lysosomal dysfunction in neurodegenerative conditions like Parkinson’s ( to read more about this).
  • “The traditional paradigm of moving from small data to big data in biomedical research is shifting toward big data-based identification of small actionable alterations” A discussion on translational informatics for Parkinson’s. “The 5 Vs of PD” ( to read more about this).
  • A nice review of the work that the International Parkinson’s Disease Genomics Consortium (or IPDGC) has conducted over the last 10 years ( to read more about this and click here to read an old SoPD post on this topic).
  • A useful review exploring epidemiological as well as the molecular & cellular clues supporting the potential susceptibility of nigrostriatal dopaminergic neurons to hyperglycemia – on that curious connection between diabetes & Parkinson’s ( to read more about this).
  • Researchers provide a useful review of research into the subtle motor dysfunction during the prodromal phase of Parkinson’s (I like the historical touch – Wilson, JP, Charcot, Gowers,… –  to read more about this).
  • Researchers provide a review of clinical & neuroimaging phenotypes of ‘juvenile’ forms of parkinsonism – from infancy to adolescence (≤21 years old – click here to read more about this).
  • Researchers review current understanding of sleep dysfunction & its treatment in Parkinson’s ( to read more about this).
  • This is an awesome blog post on Parkinson’s & pesticide exposure – sad to say that while Paraquat is banned in UK/EU, the UK is still producing & exporting it… ( to read more about this).
  • A useful review of the microbiome-gut-brain axis in acute & chronic brain diseases (including Parkinson’s – to read more about this).
  • The Parkinson’s Foundation sponsored an expert meeting on anxiety in Parkinson’s in 2018. This paper summarizes the findings/discussions from that meeting ( to read more about this).

  • One can sense a recent shift in Parkinson’s research from the substantia nigra in the midbrain to the locus coeruleus in the pons. This is a useful review on the topic ( to read more about this).
  • Interesting commentary: Does developmental variability in the number of midbrain dopamine neurons affect individual risk for sporadic Parkinson’s (Click here to read more about this).
  • “To stage, or not to stage” by Heiko Braak & Kelly Del Tredici Their review covers the development & challenges of neuropathological staging of the sporadic Alzheimer’s & Parkinson’s (required reading – to read more about this).
  • A good review of LRRK2 biology – from structure to dysfunction (Click here to read more about this).
  • The majority of genetic loci involved in late onset neurodegenerative conditions (like “Parkinson’s disease(s)”) are involved in damage response processes. Prof John Hardy provides short review & call for action on this topic. “Anti-amyloid therapies have not so far convincingly worked for Alzheimer’s & while it is clear that the reasons for many of these failures may relate in part to the details of their execution, clearly we should constantly question their underlying assumptions. I would now suggest we consider their pathogeneses as a damage response failures. This is not to say that the deposited proteins are not important but to suggest we should think of them, in part, as markers of more general failures” ( to read more about this).

  • A short review exploring the selective neuronal death observed in neurodegenerative conditions, like Parkinson’s, ALS & Huntington’s. “It has become somewhat accepted that more than one mechanism is involved in the onset of neuronal vulnerability; however, it is tempting to predict that a “first” insult triggers a long-term “tsunami” in the disease progression” ( to read more about this).
  • Researchers review advances in therapeutic efforts targeting alpha-synuclein as a therapy for Parkinson’s. “While caution is warranted when manipulating global α-syn levels, we conclude that targeting toxic α-syn seems a compelling strategy” ( to read more about this).
  • Dyskinesia matters: “As researchers & clinicians, we should aspire to make that goal a reality. To this end, translational research on Levodopa-induced dyskinesias is to be encouraged & persistently pursued” (Click here to read more about this).
  • Researchers review the ethnic variations in the manifestation of Parkinson’s. Interesting discussion of contributors (particularly “non-biological” – to read more about this).

  • Systematic review of the relationship between Type II Diabetes Mellitus & Parkinson’s ( to read more about this).
  • A Parkinson’s UK poll of more than 2,000 people with Parkinson’s found 26% were first told they had something else, while 21% saw their general practitioner 3 or more times before being referred to a specialist. Women more likely to be misdiagnosed (Click here to read more about this).

 

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

And there it is, just some of the highlights from December 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 2020!!!

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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.

The author of this post is an employee of the Cure Parkinson’s Trust. The trust has not requested the production of this post, and the views/opinions expressed here do not necessarily refect those of the Trust. The author provided this post as he considered it interesting and important to share with the Parkinson’s community.

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.

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