Monthly Research Review – February 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 February 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 February 2019?

In world news:

31st January – Not exactly February I know, but this is amazing: Forget everything you know about 3D printing, because now we can 3D print with light! (Click here for the research report and click here for the press release).

 

 

 

 

3rd February – Pope Francis visited Abu Dhabi, in the United Arab Emirates. He is the first pope to visit the Arabian Peninsula.

19th February – Star Wars Lightsaber duelling was registered as an official sport in France, as part of an effort to encourage young people to engage more in sports (Click here to read more about this).

21st February – Israeli tech firm SpaceIL launched the Beresheet probe – the world’s first privately financed mission to the Moon. The company is competing in the Google Lunar X Prize, and it is hoping that the craft will land on the surface of the moon on the 12th April.

22nd February – “Wallace’s giant bee” (Megachile pluto) was the world’s largest species of bee – with a wingspan measuring more than six centimetres (2.5 inches) – until the species disappeared in 1981. An international team of scientists and conservationists have now re-discovered it in an Indonesian rainforest, giving hope that other lost species may also be found.

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

In February 2019, there were 696 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (1555 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 7 pieces of Parkinson’s news

1.The GDNF clinical trial results

The Phase II GDNF in Parkinson’s clinical trial results have been published. As we already knew the study did not meet its primary endpoint (there appears to have been a placebo response), but the brain imaging (F-DOPA PET) results look very interesting! ( and here to read the research reports of the study results, click here to read the press release, click here to read a SoPD post on this topic, and click here to read an excellent summary of the results from Parkinson’s UK).

2. The UP study:

New clinical trial for Parkinson’s kicking off in Sheffield & London. UDCA (aka Ursodeoxycholic acid or ursodiol) a medication for the treatment of gallstones is being repurposed for Parkinson’s. Precinical data suggests the treatment has mitochondrial benefits in models of Parkinson’s (Click here to read the press release and click here to read a SoPD post on the topic).

3. Is Parkinson’s simply a consequence of evolution?

A new hypothesis has been proposed which proposes that some parts of the human brain (such as those affected by Parkinson’s) have been “left behind” by evolution as other parts of the brain have expanded. This expansion has placed greater burden on the ‘left behind’ regions which communicate with larger, newer areas, particularly as humans have started to live longer. This new theory could explain why the condition is associated with aging. It also “suggests that disease‐modifying therapies for Parkinson’s are most likely to come from a better understanding of the unique features of the human brain that drive pathogenesis, like axonal biology” ( to read more about this and click here to read a SoPD post on this topic).

4. A focus on beta glucocerebrosidase

In February, the Silverstein foundation and the Michael J Fox Foundation announced that they were collaboratively awarding nearly US$3 million in research grants to fund studies investigating an enzyme called beta glucocerebrosidase (or GCase). Genetic variations in the DNA that provides the instructions for making the GCase enzyme are some of the most common genetic risk factors associated with Parkinson’s. One can not help being impressed with the breadth of the areas being covered for just this one subtype of Parkinson’s. The projects cover everything from the genetics underlying the condtion, all the way through to new potential therapeutics. (Click here to read the press release and click here to read a SoPD post on the topic).

5. Twins and the genetics of Parkinson’s

A 25 year follow up of the genetic contribution to Parkinson’s risk in a large population‐based twin study has found that genetic heritability was 0.27 overall – that means that in this study 27% of pairs both developed Parkinson’s. Parkinson’s developed in 83% of twin pairs when one twin was diagnosed under the age of 50 years, and in 19% of twin pairs when one twin was diagnosed over the age of 50 years. The results reenforce a strong genetic component to young onset Parkinson’s, and suggest environmental influences in later forms of the condition (Click here to read more about this).

6. The big RBD study

REM sleep behaviour disorder (RBD) is considered an early sign of Parkinson’s. In this massive multi-centre study, 1280 RBD patients were recruited & followed. The overall conversion rate from RBD to a neurodegenerative syndrome was 6.3% per year, with the risk of phenoconversion after 12-year of 73.5%. The study found that there was no significant predictive value of sex, daytime sleepiness, insomnia, restless legs, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Actual rate of phenoconversion was significantly increased with features like abnormal quantitative motor testing, objective motor examination, olfactory deficit, mild cognitive impairment, erectile dysfunction, motor symptoms, an abnormal DAT scan, colour vision abnormalities, constipation, REM atonia loss, and age ( to read more about this).

7. Is my gut slowing me down?

Some of the bacteria in our gut secrete a molecule called nitric oxide (NOx). New research (in worms at least) suggests that this gut derived NOx can spread from the gut to the other areas of the host, where it promotes alterations (S-nitrosylation) of the host proteins, which ultimately affects the activity of that protein. Given the recent focus on the influence that the gut may be having on Parkinson’s (Click here for a SoPD post on this topic), this research could have important implications if if is found that gut derived NOx can spread from the gut to other areas of larger creatures ( to read more about this and click here for the press release).

 

Basic biology news

  • Researchers use correlative cryo-electron microscopy to characterise tunneling nanotubes, bringing into question the very concept of “a cell”. Amazing research – could this have big implications for the progressive nature of Parkinson’s? ( to read more about this and click here to read the press release).

 

 

  • The endolysosomal degradation process is critical for homeostasis. Researchers report that the G2019S variant of Parkinson’s-associated LRRK2 alters endolysosomal trafficking by impairing the function of the GTPase RAB8A ( to read more about this).
  • Researchers have a manuscript on BioRxiv in which they conducted a GWAS study, identifying LY6A as an essential receptor for AAV-PHP.B viral vectors in brain endothelial cells. Imagine a future where a Parkinson’s therapy will involve a simple injection in the arm, and the gene therapy virus will only infect the correct neurons in the brain, leaving the rest of the body unaffected. ( to read more about this).
  • Further characterisation of midbrain dopamine neuron development. 7 neuron subgroups divided in 2 major branches of developing Pitx3-expressing neurons. Implications for cell transplantation in Parkinson’s? ( to read more about this).
  • Recently direct in vivo reprogramming of astrocytes into induced neurons has been proposed for Parkinson’s. New research suggests astrocytes exhibit biological heterogeneity & possess distinct susceptibility to neuronal reprogramming ( to read more about this).
  • More direct in vivo reprogramming data: researchers demonstrate chemical reprogramming of human astrocytes into neurons with three to four small molecules. Potential for cell replacement therapy for Parkinson’s ( to read more about this).
  • Researchers have an interesting new manuscript on BioRxiv describing a brain penetrant small molecule agonist of the GDNF receptor RET (called BT13), which protects dopamine neurons in cell & rodent models of Parkinson’s ( to read more about this).

  • New research suggests that PARP inhibition may not only work for Parkinson’s, but also amyotrophic lateral sclerosis. PARylation regulates stress granule dynamics, phase separation, & neurotoxicity of disease-related RNA-binding proteins ( to read more about this).
  • Researchers provide further insight into the neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) using fly models of Parkinson’s ( to read more about this).
  • Researchers have a manuscript on BioRxiv suggesting that mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases ( to read more about this).
  • Genetic variants in the PTEN-induced kinase 1 (PINK1) gene can cause early-onset Parkinson’s. Now researchers uncover novel mechanisms regulating PINK1 activity ( to read more about this).
  • Researchers have a manuscript on BioRxiv reporting that progranulin interacts with the lysosomal enzyme, glucocerebrosidase (GBA), & it is essential for proper GBA activity. Implications for Parkinson’s? ( to read more about this).
  • Researchers find that reducing levels of the long noncoding RNA ‘HOTAIR‘ decreased the number of α-synuclein-positive cells & reducing the loss of dopamine neurons in models of Parkinson’s ( to read more about this).
  • Researchers demonstrate that early stage alpha synuclein amyloid fibrils are reservoirs of membrane-binding species. Matured, more stable fibrils protect cell integrity by efficiently embedding these soluble species within the fibril core ( to read more about this).
  • Nothobranchius furzeri, a rapidly aging fish with a short life span, exhibits age-dependent degeneration of dopaminergic & noradrenergic neurons & progression of α-synuclein pathologies similar to those observed in Parkinson’s. “Amelioration of the cell loss by genetic depletion of α-synuclein suggests that α-synuclein is not a bystander but a causative protein of neurodegeneration” ( to read more about this).

  • Researchers have a mansucript on BioRxiv in which they characterise the influence of the microbiota on the enteric-associated neurons lining the gut. The neurons are functionally adapted to their intestinal region ( to read more about this).
  • PINK1 protein interacts with & regulates the FKBP5 interaction with AKT/PHLPP. By doing so, it protects neurons from neurotoxin stress in models of Parkinson’s. High levels of FKBP5 promotes cell death in response to toxins in the absence of PINK1 ( to read more about this).
  • Researchers report that interations between Parkinson’s-associated alpha synuclein oligomers occur faster and to a greater extent than interactions between oligomers and monomers in solution ( to read more about this).
  • Mitophagy (removal of mitochondria) is impaired in the Alzheimer’s hippocampus. Mitophagy stimulation (via NAD+, urolithin A, & actinonin) reverses memory impairment via PINK-1, PARKIN, or DAF-16/FOXO- pathways. Implications for Parkinson’s? ( to read more about this).
  • Researchers report genetic removal of Furin1 or its substrate ligand glass bottom boat (Gbb) protects against pesticide or LRRK2-induced loss of dopamine cells in a fly model of Parkinson’s. And it’s all down to glial cells! ( to read more about this and click here to read the press release).
  • Canthin-6-one has been idenitified as an alpha synuclein lowering compound which promotes degradation of both wild type & mutant protein in an ubiquitin-proteasome-system dependent manner. CRISPR-Cas9 GWAS screen finds PSMD1 as a druggable target gene ( to read more about this).
  • Increased levels of Parkinson’s-associated A30P alpha synuclein impairs autophagy by enhancing ZKSCAN3 nuclear translocation &activity via inhibiting JNK signaling pathway (without altering the activities of AMPK & mTOR –  to read more about this).
  • Epigallocatechin-3-gallate (EGCG) inhibits aggregation of Parkinson’s-associated alpha synuclein via the the same final oxidation product as dopamine ( to read more about this).

  • A global quantification of ubiquitylated proteins using mice with mutated Parkinson’s-associated PARKIN genes points towards calcium homeostasis due to the mitochondrial dysfunction ( to read more about this).
  • “A striking example of the potential of RNA to control protein functions directly”. Vault RNA1-1 (a small non-coding RNA) directly regulates selective autophagy (by binding p62 and interference with oligomerization, a critical step of p62 function – to read more about this).
  • Parkinson’s targetted Mesencephalic Astrocyte-derived Neurotrophic Factor (or MANF) also found to protect against Alzheimer’s-associated β-amyloid toxicity (by reducing endoplasmic reticulum stress –  to read more about this).
  • Hyperosmotic stress induces Parkinson’s-associated alpha synuclein aggregation in vitro, but not in vivo. The effect is cell-dependent & specific for α-syn (not Tau or Huntingtin –  to read more about this).
  • Researchers have an interesting manuscript on BioRxiv suggesting that HDAC6 is a target of Parkinson’s-associated LRRK2. Disruption of LRRK2 impaired HDAC6-mediated aggresome formation ( to read more about this).
  • Researchers have an interesting manuscript on BioRxiv suggesting that quantum dots interfer with the self-assembly of bacterial biofilm amyloid fibers. Implications for Parkinson’s here? ( to read more about this).
  • Researchers find transplantation of young bone marrow to rejuvenate the hematopoietic system preserved cognitive function in old recipient mice, despite irradiation-induced suppression of neurogenesis. CCL11 administration had opposite effect ( to read more about this).
  • Not-so-deep brain stimulation. Researchers find optogenetic stimulation of the M2 cortex corrects motor dysfunction in a Parkinson’s mouse model. Stimulation + L-DOPA (but not L-DOPA treatment only) produced improvement in working memory (Click here to read more about this).

  • New research highlights important mechanism by which proteins genetically implicated in Parkinson’s (PINK1) & frontotemporal dementia (VCP) may interact to support the health & maintenance of neuronal branching ( to read more about this).
  • A manuscript in BioRxiv suggests that administration of a selective b2-adrenergic receptor agonist (Salbutamol) protects mice from neuronal loss in the lining of the gut post bacterial infection. Implications for Parkinson’s? ( to read more about this).
  • Parkinson’s-associated DJ-1 plays a pivotal role in the glycation & aggregation of α-synuclein. Reduced DJ-1 activity due to mutations or oxidative stress may lead to the accumulation of glycated α-synuclein & aggregation of the protein ( to read more about this).
  • Calpains are a family of calcium-dependent, non-lysosomal proteases. Mitochondrial stress & calcium dyshomeostasis induces calpain cleavage of Parkinson’s-associated Parkin. Could this be another argument for calpain inhibition for PD? ( to read more about this).
  • Researchers report that the Parkinson’s-associated LRRK2-R1441 genetic variant alters monomer-dimer dynamics of the protein & thereby traps LRRK’s GTPase domain in an activated state ( to read more about this).
  • Fascinating new report highlighting a new approach to generate astrocytes with region-specific features, defining key mechanisms of the gliogenisis, & enabling rapid (5 days!) production of human astrocytes ( to read more about this).
  • Researchers present new tools for neuron-specific genome modification in the adult rodent brain using CRISPR-Cas9 gene editing technology. Implications for Parkinson’s research? ( to read more about this and click here for the press release).

  • Researchers provide new insights into the unique contributions of parvalbumin & cholinergic interneurons in organizing striatal network activity which supports motor movement. Implications for Parkinson’s? ( to read more about this).
  • Further proof of MAGIC (mitochondria as guardian in cytosol) A BioRxiv manuscript suggests that interference of mitochondrial protein import aggravates the aggregation of Parkinson’s-associated alpha-synuclein. The report also demonstrates that mitochondrial protein degradation is relevant for the aggregation of Alzheimer’s-assocaited beta amyloid 42, “suggesting that mitochondria are directly linked to disturbances in cytosolic protein homeostasis of aggregation prone proteins” ( to read more about this).
  • Researchers report that mitochondrial transport proteins RHOT1 & RHOT2 serve as docking sites for Parkinson’s-associated PARKIN-mediated mitophagy (removal of stressed mitochondria – to read more about this).
  • Researchers report that increased levels of ceramide – the precursor of all complex sphingolipids – might be a common denominator of neuroinflammation in different neeurodegenerative conditions, including Parkinson’s ( to read more about this).
  • Cyclized analogs of nordihydroguaiaretic acid (NDGA) may serve as a platform for developing small molecules that stabilize aggregation-resistant Parkinson’s-associated alpha synuclein monomers without interfering with functional conformations. Hello EGCG! ( to read more about this).
  • Insulin-like growth factor 1 (IGF-1) is a hormone mainly produced in the liver. Now researchers have discovered that midbrain dopamine neurons synthesize & release IGF-1 in an activity dependent manner ( to read more about this).
  • Polydatin (aka Piceid) is a stilbenoid glucoside & a resveratrol derivative, which new research suggests induces Parkinson’s-associated PARKIN-dependent mitophagy (removal of stressed mitochondria), which provides protection against cell death ( to read more about this).

 

Disease mechanism

  • Researchers show that CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling in Parkinson’s models ( to read more about this).
  • Could early developmental deficits, at least partially, contribute to the pathology of Parkinson’s? Stress cells in culture, let them continue to grow/get old, & watch as the ones with Parkinson’s variants start to have autophagy issues ( to read more about this).
  • Researchers generated iPS cells from people with Parkinson’s + A53T SNCA mutation or triplication of the SNCA locus. They found correlation between α-syn cellular pathology & deficits in metabolic & cellular bioenergetics ( to read more about this).
  • Neurons with genetic mutations in Parkinson’s-associated DJ-1 are hypersensitive to ROS yet show a remarkable resistance to endoplasmic reticulum stress. DJ-1 modulates the unfolded protein response & cell death via upregulation of ATF4 ( to read more about this).
  • New preclinical study suggests long-acting GLP-1 analogue semaglutide (similar to Exenatide) was more potent compared with once daily liraglutide in MPTP mouse model of Parkinson’s ( to read more about this).

  • New Proximity ligation assay report suggests a more widespread distribution & abundant accumulation of oligomeric alpha synuclein protein in neurons as well as oligodendrocytes of Multiple system atrophy when compared to Parkinson’s ( to read more about this).
  • More MSA data: In early clinical stages of the parkinsonian phenotype of Multiple system atrophy, there is widespread microglial activation (in brain imaging) as a marker of neuroinflammatory changes without correlation to clinical parameters ( to read more about this).
  • Yet more MSA data: researchers investigated the distinct properties of various types of alpha synuclein inclusions present in multiple system atrophy brains & found epitope-specific immunohistochemistry varied greatly between different types of MSA inclusions. The differences were also found within different brain regions of same MSA brain. Immunoreactive profiles were significantly more consistent for dementia with Lewy bodies than for MSA. If spread of pathology in MSA is prion-like, “strains” of alpha synuclein must be inherently unstable ( to read more about this).
  • Parkinson’s-associated PINK1 preferentially accumulates on mitochondria enriched with mtDNA mutation. Defective mitochondria are starved of nuclear-encoded mtDNA replication factors, limiting generational transmission of damaged mtDNA mutations ( to read more about this).
  • Further evidence for neuroprotective properties of Simvastatin (Cholesterol drug) in neurotoxic model of Parkinson’s (via RhoA inhibition). Supportive data for the STAT-PD study ( to read more about this).

  • New data indicates that BDNF/NTRK2 signaling has a significant role in the development & maintenance of dopamine neurons in fish ( to read more about this).
  • The mitochondrial protein apoptosis-inducing factor (AIF) is an important cell death effector. Parkinson’s-associated PARKIN interacts with AIF & interferes with its translocation to the nucleus. Toxic insult = more nuclear AIF in parkin-deficient neurons ( to read more about this).
  • Pridopidine – a small molecule in clinical development for Huntington’s – induces functional neurorestoration via the Sigma-1 receptor in a mouse model of Parkinson’s ( to read more about this).
  • Parkinson’s-associated LRRK2 genetic variant distribution is different among various populations of people around the world. Major implications for decisions regarding the development of future therapeutics & genetic screening strategies ( to read more about this).
  • Researchers generate CRISPR-edited primates with mutations in Parkinson’s-associated PINK1 gene. The animals display a more severe phenotype than we see in humans ( to read more about this).
  • Constipation, deficit in colon contractions & alpha-synuclein inclusions within the colon all precede the motor abnormalities & neurodegeneration associated with a mouse model of Parkinson’s (human A53T αS mice – to read more about this).
  • Sanofi researchers set up a screen to identify NURR1/NOT agonists for potential treatment of Parkinson’s, which led to a potent & safe candidate drug displaying neuroprotection & anti-inflammation ( to read more about this).

  • The bioavailability of neuroprotective agent 3-hydroxymorphinan (3-HM) is very poor. Now researchers have generated a derivative of 3-HM that is protective in models of Parkinson’s ( to read more about this).
  • New data suggests that microglia may play a role in the transmission of Parkinson’s-associated alpha synuclein via exosomal pathways. Plasma exosomes from PD patients were found to dysregulate autophagy & increase accumulation of intracellular α-syn ( to read more about this).
  • More on microglia exosomes in neurodegeneration! Microglial activation increases exosomal release in midbrain cultures, triggers dopaminergic neurodegeneration, BUT GW4869 (a sphingomyelinase 2 inhibitor) reduces exosomal release & neurodegeneration ( to read more about this).
  • Rubicon is a negative regulator of autophagy. It increases with age in worms, flies & mice ~ an age-dependent increase in Rubicon impairs autophagy over time & curtails healthspan. Inhibiting Rubicon reduces α-synuclein accumulation in model of Parkinson’s ( to read more about this).
  • Researchers present a translational toolkit of methods to detect asymmetries in temporal & spatial walking metrics in PD mouse models AND in human subjects with Parkinson’s ( to read more about this).
  • Modeling G2019S-LRRK2-associated Parkinson’s using 3D midbrain organoids & analysis of the protein-protein interaction network reveals that TXNIP, a thiol-oxidoreductase, is functionally important ( to read more about this).
  • Inhibition of LRRK2 protein is being developed as a potential therapy for Parkinson’s, but now researchers suggest that LRRK2 inhibition may not protect against α-synuclein pathology & neuron death in a non-transgenic mouse model ( to read more about this).

  • A new study finds an association between SMPD1 variants, acid‐sphingomyelinase activity, & Parkinson’s. They also suggest that reduced acid‐sphingomyelinase activity may lead to alpha synuclein accumulation ( to read more about this).
  • Anti-anxiety drug Emapunil (a synthetic selective agonist of the mitochondrial translocator protein 18 (TSPO)) rescues degeneration of dopamine neurons, preserves dopamine metabolism & prevents motor dysfunction in model of Parkinson’s ( to read more about this and click here for the press release).
  • Inhibition of NADPH oxidase by apocynin (acetovanillone) prevents learning & memory deficits – as well as neurodegeneration & α-synuclein pathology – in a mouse model of Parkinson’s ( to read more about this).
  • Could the memory B-cell repertoire of people with Parkinson’s represent a potential source of biomarkers/therapies? Researchers report naturally occurring antibodies isolated from people with PD inhibit synuclein seeding in vitro. The antibodies also recognise Lewy body pathology on postmortem sections of brain from people who passed away with PD. Could this research help to define disease-relevant epitopes that could be leveraged as biomarkers and/or therapies? ( to read more about this).
  • Researchers investigated the structure & morphology of α‐synuclein aggregates generated via real‐time quaking‐induced conversion (RT‐QuIC). They found different seeding kinetics of α‐synuclein from Dementia w/ Lewy bodies compared to Parkinson’s ( to read more about this).
  • Smilagenin – a steroidal sapogenin from traditional Chinese medicine – has been reported to prevent the loss of dopamine neurons in a mouse model of Parkinson’s ( to read more about this).

 

Clinical research

  • The first case report of the synergistic action of both heterozygous pathogenic point mutation in the PARK2 gene & deletion mutation of exon 6 leading to an early onset form of Parkinson’s ( to read more about this).
  • Researchers use a systematic review of routinely collected healthcare data to identify Parkinson’s & parkinsonism cases ( to read more about this).
  • Deep brain stimulation (DBS) is a common surgical treatment for Parkinson’s. Most DBS systems rely on radiofrequency transmission for patient programming. Now researchers share a curious case of DBS radiofrequency programmer interference ( to read more about this).

  • Question: Does outcome of subthalamic deep brain stimulation vary among common monogenic forms of Parkinson’s? Answer: DBS for PD patients with LRRK2, GBA, or PRKN variants yielded similar motor outcomes but different changes other aspects of condition ( to read more about this).
  • Data relating to women is under represented in Parkinson’s research. New manuscript on BioRxiv investigates occupation & Parkinson’s using the Women’s Health Initiative Observational Study data. Increased risk among counselors & social service specialists ( to read more about this).
  • EMPOWER-PD – researchers in Brazil share their study protocol for an innovative feasibility trial of physical therapy intervention to empower individuals with Parkinson’s ( to read more about this).
  • Analysis of Israeli Healthcare database suggests increased risk for Parkinson’s in the group of patients with nonalcoholic steatohepatitis (NASH), raising possibility that liver disease per se is a risk factor for Parkinson’s rather than hepatitis viral infection ( to read more about this).
  • Researchers explored prevalence & duration of non‐motor symptoms in prodromal Parkinson’s & found they are common & a gender difference may exist. High prevalence of GI & urinary tract symptoms with instability/gait issues ( to read more about this).
  • New report provides insight into Parkinson’s with GBA genetic variations in Brazil ( to read more about this).

  • New BioRxiv manuscript suggests focal aggregation of neurofibrillary tangle density in clinically relevant regions among different clinical Alzheimer’s variants. Could similar differences exist for Parkinson’s? ( to read more about this).
  • Researchers have been awarded funding from the Michael J Fox Foundation to launch a multi-year, $1.7million effort to identify blood-based biomarkers for Parkinson’s using 2,500 blood samples collected longitudinally (3 years) in the PPMI study ( to read more about this).
  • Researchers compared hyperechogenic area of the substantia nigra (a prodromal Parkinson’s marker) in large cohorts of GBA mutation carriers. The findings “raise doubts regarding the contribution of substance reduction strategies” for Parkinson’s ( to read more about this).
  • EUROPAR researchers have published the first comparison of quality of life, nonmotor & motor outcomes in people with Parkinson’s undergoing deep brain stimulation, apomorphine infusion, or intrajejunal levodopa infusion ( to read more about this and click here to read more about the EUROPAR project).
  • Genetic variants in the PLA2G6 gene are associated with early onset Parkinson’s. Now there is the curious case of siblings with PLA2G6‐associated neurodegeneration but strikingly different clinical presentations ( to read more about this).
  • Dopamine agonist withdrawal syndrome is characterised by psychiatric, autonomic & sensory symptoms (similar to addictive drug withdrawal). New researchers report a prospective, multicenter observational study investigating this in Parkinson’s ( to read more about this).
  • A group of researchers evaluated the sensitivity & specificity of the 2017 International Parkinson & Movement Disorder Society criteria for Progressive Supranuclear Palsy and they report that it has higher sensitivity than the previous criteria ( to read more about this).
  • An interesting case study & curious remedy for freezing of gait: The Brazilian football player still on the pitch after 10 years of Parkinson’s with severe freezing of gait ( to read more about this).

  • Researchers provide a step-by-step overview of a new DIY, low-cost, quantitative, continuous measurement system for analysing movements in the extremities of people with Parkinson’s ( to read more about this).
  • The protocol of the Ambroxol as a novel disease-modifying treatment for Parkinson’s disease dementia clinical trial has been published. Hopefully the results will be available later this year ( to read more about this).
  • A sobering assessment of Parkinson’s medication in Nigeria. Access is limited. Only 2 medications (trihexyphenidyl tablets & biperiden injection) are affordable. Avg # of days of minimum wage for a 30‐day supply of Parkinson’s medicines = 41.3 days (?!? – to read more about this).
  • Another wearable gait analysis tool for Parkinson’s – researchers in Alberta validated the Ambulosono sensor system in 15 individuals & compare its performance to an ipod app ( to read more about this).
  • Researchers propose a low cost, non-invasive, wearable device for people with Parkinson’s with freezing of gait. ‘The intended purpose is to reduce the duration of FOG episodes, thus allowing prompt resumption of gait to prevent major injuries’ ( to read more about this).
  • Baseline Magnetic Resonance Parkinsonism Index 2.0 shows the best performance in predicting the clinical evolution toward a PSP‐parkinsonism phenotype, enabling progressive supranuclear palsy (PSP) patients to be identified at the earliest stage ( to read more about this).
  • Researchers from the PREDICT-PD study have published a risk algorithm which when applied to routine primary care presentations can identify individuals at increased risk of diagnosis of Parkinson’s within 5 years ( to read more about this).

  • The Inosine clinical trial may have failed to reach its primary end point, but new research finds that non‐manifesting LRRK2 mutation carriers have significantly higher levels of urate than those who develop Parkinson’s (across three independent cohorts – to read more about this).
  • Researchers examine the feasibility & informativeness of the Patient-Specific Functional Scale (PSFS) for identifying activities that people with Parkinson’s self-identified as difficult (many were not addressed by the MDS-UPDRS or PDQ-39 – to read more about this).
  • Analysis of the distribution & risk effect of GBA variants in a large cohort of people with Parkinson’s from Colombia & Peru suggsests mutations are strongly associated with PD risk & earlier onset. Very high frquency of GBA variants in this PD pop. ~10% ( to read more about this).
  • Large systematic review assessing wearable motion sensors for gait analysis in Parkinson’s finds no uniformity in their use in terms of: # of sensors, positioning, chosen parameters, & other characteristics. Future research should focus on standardisation ( to read more about this).
  • Researchers have an interesting manuscript on BioRxiv supporting the value of incorporating Parkinson’s genetic variants in data-driven classification algorithms & the usefulness of non-motor PD features ( to read more about this).
  • Abnormal alpha‐synuclein deposits in skin nerve fibres could potentially be used as a biomarker for Parkinson’s. Now new research suggests good intra‐ & inter‐laboratory reproducibility in the analysis ( to read more about this).
  • New study finds NO association between excess weight & Parkinson’s risk in a European cohort. High BMI decreases PD risk in smoking men & increases PD risk in smoking women ( to read more about this).
  • Polysomnographic (sleep study) data is similar between individuals with Dementia with Lewy Bodies or Parkinson’s. Dementia with Lewy Bodies patients have a specific difficulty with REM sleep initiation, & REM Sleep behavior disorder severity is lower ( to read more about this).

  • Researchers present BiRD (or Bionics Institute Rigidity Device) – a new palm-worn device to quantify rigidity in Parkinson’s ( to read more about this).
  • Regardless of diagnosis & pharmacological treatment, new study finds patients with alpha-synucleinopathies (like Parkinson’s) have a blood pressure circadian rhythm characterised by increased BP variability, increased BP load, & awakening hypotension ( to read more about this).
  • Interesting: Researchers used a stimulator to generate precisely controlled passive movements of the index finger & measured the induced cortical response activity using magnetoencephalography. Beta rebound was almost absent in people with Parkinson’s ( to read more about this).
  • People carrying mutation in the LRRK2 gene in their DNA represent an “at risk” group for future development of Parkinson’s. A study has explored carriers & non-carriers to determine differences. Machine learning separated groups with an accuracy of 0.8 ( to read more about this).
  • Researchers & colleagues report Neuromelanin (NM)-MRI signal correlates with NM concentration, dopamine in the striatum, SN blood flow, severity of psychosis in schizophrenia (in the absence of neurodegeneration!). Implications for Parkinson’s? ( to read more about this and click here for the press release).

  • Brain glucose metabolism (as measured with brain imaging) in early stage dementia with Lewy bodies (DLB) may shorten the diagnostic time, resulting in benefits for treatment options & management of patients. Very different imaging signature to Parkinson’s. “The diagnostic & prognostic accuracy of the disease-specific brain metabolic signature in DLB at the single-subject level argues for the consideration of [18F]FDG-PET in the early phase of the DLB diagnostic flowchart” – improving diagnostics for PD & DLB ( to read more about this).
  • Comparing the DNA of 571 people with Alzheimer’s, 348 with Parkinson’s, 991 pathologically-confirmed atypical parkinsonisms, & 591 healthy controls confirms association between APOE ε4 & increased risk for Lewy body dementia (APOE ε2 allele = reduced risk – to read more about this).
  • Analysis of data from the National Health Insurance Research Database of Taiwan suggests that atrial fibrillation (a form of cardiac arrhythmia) might be a premotor predictive biomarker & comorbidity of early Parkinson’s ( to read more about this).
  • Researchers have published results from a novel real‐time quaking‐induced conversion (RT‐QuIC) assay which could allow clinicians to differentiate α‐synucleinopathies from other forms of parkinsonisms. Diagnostic aid for Parkinson’s? ( to read more about this).
  • A new study suggests people with newly diagnosed Parkinson’s exhibit larger iron deposits in their substantia nigra (where the dopamine neurons reside) than people with untreated essential tremor or healthy controls. New biomarker? ( to read more about this).
  • A new BioRxiv manuscript has been released in which the analysis of 4.1M human genomes finds 1,358 people with loss of function genetic variations in the Parkinson’s-associated LRRK2 gene. Heterozygous LRRK2 genetic variants result in ~50% less protein being produced, but no obvious problems. Could this be good news for the development of LRRK2 inhibitors? ( to read more about this).

 

New clinical trials

  • A new clinical trial evaluating safety & tolerability of the sweetner Mannitol in Parkinson‘s has just been registered by researchers in Israel ( to read more about this).
  • A new clinical study – PARKIDENT – has been registered to investigate the oral health status (‘quality of the oral flora’) of people with Parkinson’s (Click here to read more about this).
  • The Theravance Biopharma Phase III clinical trial of their norepinephrine and serotonin reuptake inhibitor (called TD-9855) for the treatment of symptomatic neurogenic orthostatic hypotension has been registered. This study will include individuals with Parkinson’s (Click here to read more about this).
  • The UDCA in Parkinson’s (UP study) clinical trial in Sheffield has been registered (Click here to read more about this and click here to read a SoPD post on this trial).

  • Kyowa Hakko Kirin Co have inititated the Phase I clinical trial of their selective adenosine A2A antagonist, KW-6356 for Parkinson’s. This 2 week safety/tolerability study will involve the testing of the drug in Japanese & caucasian healthy adults (Click here to read more about this).
  • PDExercise – a new clinical trial investigating the impact of 3 distinct exercise types on fatigue, anxiety, & depression in Parkinson’s has been registered. The exercise types include spinning, yoga & dance (Click here to read more about this).
  • A new clinical trial has been registered to evaluate the use of a cognitive game-based treadmill exercise program to improve balance & gait in people with Parkinson’s (Click here to read more about this).
  • A study of 387 right-handed people with Parkinson’s with asymmetric motor issues (191 dominant-side & 196 non-dominant-side) suggests that L-dopa induced dykinesias develop earlier in non-dominant-side than in dominant-side people with PD ( to read more about this).
  • Korean Ministry of Food & Drug Safety has approved a revised Phase II clinical trial plan for Peptron Inc to test their experimental compound PT320 (a long acting GLP-1 agonist; like Exenatide) in Parkinson’s. Endpoints: Efficacy & safety; results in 2020 ( to read more about this).

  • A new clinical trial validating the Non-Motor Fluctuation Assessment Instrument (NoMoFA) for Parkinson’s has been registered. NoMoFA is a comprehensive questionnaire that assesses the presence of non-motor fluctuations in PD (Click here to read more about this).
  • A new Phase II clinical trial of KDT-3594 (a dopamine receptor agonist) in people with recently diagnosed Parkinson’s has been registered (Click here to read more about this).
  • A 5 week Mediterranean diet intervention clinical trial for Parkinson’s has been registered in Florida (Click here to read more about this).
  • New clinical trial has been registered to evaluate the inhibition of α-synuclein cell-cell transmission in Parkinson’s using the NMDAR blocker Memantine (Click here to read more about this).
  • A very interesting new clinical study in Oxford (UK) has been registered to look at whether a Ketone drink can reduce the severity of symptoms of Parkinson’s ( to read more about this).
  • Another very interesting new clinical study in Oxford (UK) has been registered to look at whether a Ketone drink can increase ATP in the brains of people with Parkinson’s ( to read more about this).
  • And a THIRD very interesting new clinical study in Oxford (UK) has been registered to look at whether a Ketone drink can improve exercise performance in people with Parkinson’s ( to read more about this).

 

Clinical trial news

  • As discussed in the intro (top of the post), the Phase II GDNF in Parkinson’s clinical trial results have been published ( and here to read the research reports of the study results, click here to read the press release, click here to read a SoPD post on this topic, and click here to read an excellent summary of the results from Parkinson’s UK).
  • The EARLYSTIM study group publish results of a prospective randomised trial comparing subthalamic nucleus-deep brain stimulation (n = 124) to best medical treatment (n = 127) in early Parkinson’s (2 yrs follow-up). Baseline quality of life predicts outcome ( to read more about this).
  • Prothena Corp announces that enrollment in the Phase 2 Prasinezumab/”PASADENA” study being conducted by Roche in people with early Parkinson’s has completed (N=316 participants). Data from Part 1 of this study are expected in 2020 ( to read more about this).

  • The results of a randomised clinical study suggest that bright light therapy has no impact on depression in Parkinson’s. Depression scores decreased in both treatment & placebo groups without a significant between-group difference at the end of treatment ( to read more about this).
  • The US Food and Drug Administration (FDA) issued a statement cautioning consumers against receiving young donor plasma infusions, which are unproven treatment for varying conditions, including Parkinson’s. There are no proven clinical benefit of infusion of plasma ( to read more about this).
  • Inhibikase Therapeutics has filed not one, but two Investigational New Drug (IND) applications with the US FDA for IkT-148009 (a c-Abl inhibitor) for Parkinson’s. This therapeutic approach is similar to Nilotinib ( to read more about this).
  • The results of the Voyager Therapeutics Phase I clinical trial of AADC (VY‐AADC01) gene therapy for Parkinson’s has been published. Increases in enzyme expression & clinical improvements were dose dependent & well tolerated. ( to read more about this).

 

Other news

  • resTORbio Inc hosted a Key Opinion Leader Symposium on TORC1 inhibition & neurodegenerative conditions, like Parkinson’s. Most importantly, during the event the company provided an overview of the company’s recent progress, including the clinical program planned for its selective TORC1 inhibitor, RTB101, in Parkinson’s. They are planning a Phase Ib/II clinical trial of their TORC1 inhibitor RTB101 (& Sirolimus). It will be a 4 week study involving 45 individuals with mild Parkinson’s with or without GBA mutations. Safety/tolerability = primary outcom. The study involves 5 cohorts: 1) 300mg RTB101, 2) 2mg Sirolimus, 3) 300mg RTB101 + 2mg Sirolimus, 4) 300mg RTB101 + 4mg Sirolimus, 5) 300mg RTB101 + 6mg Sirolimus (or matching placebo in each group; 2:1 randomisation). Study to start in Q1 of 2019 ( to read more about this).

  • $24M Parkinson’s project to collate whole-genome & transcriptome records from 4 large cohort studies (3,000+ PD patients & 1,700+ controls) into a knowledge portal is going live in March. Part of the NIH Accelerating Medicines Partnership initiative (Click here to read more about this).
  • Critical path for Parkinson’s (CPP) consortium – a public/private partnership funded by Parkinson’s UK – has published a manuscript describing the strategy to achieve qualification opinions by the European Medical Agency (EMA) for DATscan brain imaging in clinical trials ( to read more about this).
  • Gut-brain axis company Axial Biotherapeutics secures $25M in series B financing to advance their Parkinson’s & Autism programs. AB-4166 is a first-in-class intervention currently being evaluated for safety & tolerability in a subpopulation of PD subjects ( to read more about this).

  • The Michael J Fox Foundation submitted a petition with 107,000 signatories, urging the United States Environmental Protection Agency to ban the widely used herbicide paraquat, which has strong links to increased risk of Parkinson’s (Click here to read more about this).
  • Axovant gene therapies provided a SUNRISE-PD gene therapy trial update: 2 patients have been dosed with AXO-Lenti-PD in their clinical trials of Parkinson’s. Initial data is expected in March 2019 ( to read more about this).
  • Accorda Therapeutics announces the commercial launch of INBRIJA (Levodopa inhalation powder) for Parkinson’s in the US. Marketing Authorization Application (MAA) was submitted to the European Medical Agency in March 2018 – decision expected before the end of 2019. With the current situation with BREXIT, who knows when it will be available in the UK ( to read more about this).

  • Recommended reading: A review of therapies targetting alpha-synuclein in clinical trials (Click here to read more about this).
  • Korean biotech firm Kainos Medicine announced plans to expand its indications for FAS-1 inhibitor KM-819, which completed phase I trials for Parkinson’s, & is entering phase II trials. Watch out for a MSA clinical trial ( to read more about this).
  • IFM Therapeutics has launched its second subsidiary in less than a year – this one (called IFM Due) is developing a suite of cGAS inhibitors & STING antagonists that can target conditions like NASH, lupus & Parkinson’s ( to read more about this).
  • A systematic review of wearable devices that monitor spinal posture suggests that currently available devices are capable of assessing spinal posture with good accuracy in the clinical setting for conditions like Parkinson’s ( to read more about this).
  • BioArctic AB & pharmaceutical company Abbvie have been given permission by the US FDA to start clinically testing their alpha synuclein-targeting antibody (called ABBV-0805) as a potential treatment for Parkinson’s. Phase I study should launch this year ( to read more about this).

  • Pharma Abbvie & gene therapy firm Voyager Therapeutics announced a potentially $1.5 billion-plus gene therapy collaboration to develop/commercialize vectorized antibodies directed at alpha-synuclein for the potential treatment of Parkinson’s ( to read more about this).
  • Interesting write up from pharma GlaxoSmithKleine about their plans to use genetics to target Parkinson’s. Particularly discussing their tie up with genotyping company 23andMe to support their LRRK2 inhibitor programme (Click here to read more about this)
  • What a great tribute to the man, the myth, the legend: Tom Isaacs, co-founder of the Cure Parkinson’s Turst – a Parkinson’s advocate who helped to show us the path ahead. This month’s edition of the European Journal of Neuroscience is dedicated to his memory, with numerous research articles being made freely available (Click here to read more about this).

 

Review articles/videos

  • A useful, balanced, OPEN ACCESS discussion of “Stem Cell Treatments for Parkinson’s” ( to read more about this).
  • A nice OPEN ACCESS book chapter of the pathological mechanisms & clinical aspects of GBA1-associated Parkinson’s ( to read more about this).
  • Interesting Q&A session with Dr Tilo Kunath provided by the Parkinson’s research interest group on Facebook.

 

  • Everything you ever need to know about pesticide exposure & Parkinson’s ( to read more about this).
  • A magnificent OPEN ACCESS overview of the relation between genetic risk factors & immune processes in Parkinson’s ( to read more about this).
  • Researchers provide a comprehensive & critical overview of the research conducted on alpha synuclein aggregates in the retina of Parkinson’s (both animal models & patients – to read more about this).
  • A useful review of the molecular & cellular mechanism of glucocerebrosidase (Gcase) deficiency & GBA-Associated Parkinson’s ( to read more about this).
  • A nice overview on the effects of iron on protein aggregation in neurodegenerative conditions, like Parkinson’s. Also covers proposed mechanisms of iron-mediated toxicity, emphasizing the redox chemistry & protein-binding properties of iron ( to read more about this).
  • A book chapter on the substantia nigra – the region of the brain where the dopamine neurons affected in Parkinson’s reside ( to read more about this).
  • A book chapter on Lewy bodies – one of the cardinal features of the Parkinson’s brain ( to read more about this).

  • “Critical appraisal of the evidence did not allow to reach definite conclusions” – the conclusion of a review evaluating Th17 Lymphocytes & IL-17 contribute to Parkinson’s. A thorough & useful read in light of the Cosentyx (secukinumab) results last year ( to read more about this).
  • Interesting review of molecular targets for modulating the protein translation vital to proteostasis & neuron degeneration in Parkinson’s ( to read more about this).
  • A useful review summarising recent advances regarding the roles of mTOR & autophagy in Parkinson’s pathogenesis & treatment ( to read more about this).
  • Interesting discussion on Parkinson’s in this review of Nrf2/ARE pathway modulation by dietary energy regulation. ( to read more about this).
  • Interesting discussion on a recent study that reinforces prognostic value of Parkinson’s subtypes, but challenges the relevance of pathology in the brain to the clinical presentation. No difference in lewy pathology severity or distribution betwn subtypes ( to read more about this).
  • Made in Tasmanian – the photobiomodulation clinical trial for Parkinson’s. This is a great story about the DIY attitude of the Dorset Community Shed, light bucket helmets, & a proof-of-concept clinical trial being run by the University of Syndey & Parkinson’s SA ( to read more about this).

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

And there it is, just some of the highlights from February 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 March! (and Spring, here we come!)

 

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.

5 thoughts on “Monthly Research Review – February 2019”

  2. Hi Simon,
    Thanks for the monthly summary – it always helps to understand and take stock.
    There is so much going on – this month there seems to be as much variety and human interest stories in the ‘Parkinson’s news’ section (Evolution. The gut. REM sleep. Many, many wearable devices. A lovely dedication to Tom Isaacs) as there is in the ‘world news’!
    I was feeling overwhelmed, and then I got to the article about the light bucket, and things seemed ok again. What a good illustration that story is of how all of us can contribute.
    Regards,
    Paula

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  3. How *do* you keep up with all this? I’ve identified over 40 links of special interest in the above, but I’ll be lucky to actually read even a fraction of that in any depth. Very encouraging to see how much work is proceeding; I’m just looking for low-hanging fruit that might yield benefits in the here and now.

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