Monthly Research Review – June 2019

 

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 June 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 June 2019?

In world news:

7th June – British Prime Minister Theresa May resigned as leader of the Conservative Party… and then,… well, as if the BREXIT situation couldn’t get any worse…

9th June – The second reading on a controversial extradition bill in Hong Kong led to hundreds of thousands of people marching in protest.

(Photo:HECTOR RETAMAL/AFP/Getty Images)

14th June – NASA released a photo of a curious chevron shaped plateau on the surface of Mars which got Star Trek fans excited (Click here to read more about this).

21st June – A 2018 research report got a lot of folks excited when the BBC ran an article on how technology is changing our bodies. The article suggested that millenials are growing horns out of the back of their heads due to cell phone use. Needless to say, there are now concerns about the validity of the original results (Click here to read more about this).

22nd June – “Scamp the Tramp” was declared the winner of the 2019 ugliest dog contest (Click here to learn more about this).

 

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

In June 2019, there were 948 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (4408 for all of 2018 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 10 pieces of Parkinson’s news

(June is usually a quiet month – 2019 seems to be an exception)

1. WPC 2019:

The World Parkinson’s Congress was a 4 day meeting held in Kyoto (Japan) at the start of this month. It brought together not only patients and researchers, but also Eastern & Western cultures – a truly unique event. Over the course of the conference, there was a continuous stream of presentations, workshops and discussions about all aspects of Parkinson’s.

One of the presentations from the WPC2019 meeting that will stay with me for a long time was given by Dr Linda K Olson – triple amputee & Parkinson’s advocate – an amazing & truly inspiring talk (take a couple of minutes and watch this remarkable woman speak):

It was my first WPC and I felt extremely grateful for the opportunity to attend and take part in the meeting. So much so that I tried to provide a blow-by-blow account of the presentations and activities of the event:

2. The other GDNF clinical trial results

Results from the Phase I glial cell line‐derived neurotrophic factor (GDNF) gene therapy clinical trial have been published. The treatment in 13 people with advanced Parkinson’s was safe & well tolerated. Increased [18F]FDOPA uptake (a measure of dopamine activity) in the putamen was also reported ( to read more about this and click here to read a SoPD post on the topic)

3. The CuATSM clinical trial results

Biotech firm Collaborative Medicinal Development reported the results of a 24 weeks, Phase I, non-placebo controlled, dose-finding study of treatment with CuATSM in 18 people with Parkinson’s. Cu-ATSM is an orally administered, blood-brain barrier permeable synthetic molecule that contains copper. It has traditionally been used as an imaging agent for hypoxic tissues, but preclinical evidence has been accumulating that it could be useful in the treatment of neurodegenerative conditions. The results of this new trial suggest that the treatment is safe & well tolerated. In addition, there were indications that clinical symptoms improved (based on total UPDRS score) and participants reported improvements in quality of life scores. Important to note that this was an open label trial, but the researchers behind the study are planning a larger trial to properly test the efficacy of the compound (Click here to read more about this).

4. The NAC clinical trial results

Researchers report that 3 months of N‐acetyl‐cysteine (NAC) significantly increased DAT binding in the caudate & putamen (3.4% to 8.3%) compared to controls & significantly improved Parkinson’s symptoms. This was also an open label study – using a combination of oral & intravenous NAC. 42 participants were involved in the study: 28 in treatment group & 14 standard care ( to read more about this & click here to read more about the details of the study).

5. Monitoring serotonin

Researchers reported the presence of serotonergic pathology in people with a rare genetic mutation, which makes them vulnerable to Parkinson’s (A53T SNCA). Importantly, these issues were apparent before signs of dopaminergic pathology or motor symptoms. “Findings provide evidence that molecular imaging of serotonin transporters could be used to visualise premotor pathology of Parkinson’s”. It will be interesting to see if this applies to wider Parkinson’s community. If so, serotonin transporter imaging could be a useful tool for screening & monitoring progression for individuals at risk of developing PD or  or as a marker of PD burden in clinical trials ( to read more about this, click here to read a media report on the study).

6. Is Parkinson’s going viral?

Evidence from Taiwan suggested that the incidence of Parkinson’s is lower in people with chronic Hepatitis C viral infection who received interferon-based antiviral therapy. This finding may support the hypothesis that HCV could be a risk factor for PD ( to read more about this).

 

7. A gut feeling (Part 1)

Researchers reported that microbial L-dopa decarboxylase can be inactivated by (S)-α-fluoromethyltyrosine (AFMT), raising possibilities of developing combinations of Parkinson’s drugs that circumvent microbial inactivation ( to read more about this, click here to read the editorial, and click here to read the press release). This new research validates & builds on results published earlier this year (Click here to read more about that research and click here to read a SoPD post on the topic).

8. A gut feeling (Part 2)

Researchers reported previously detected gut microbiota differences between people with Parkinson’s & controls, persists after 2 years. There was also some support for decreased abundance of Prevotella bacteria in faster-progressing individuals ( to read more about this).

And a week after this report was published, an independent grup of researchers published an analysis of two independent conhorts (200 subjects) reveals altered gut microbiota in Parkinson’s. They reported correlations with clinical phenotypes & severity, and altered plasma cytokine profiles associated with gut microbiome composition alterations ( to read more about this).

(I have had a guts full of all this gut research)

9. A gut feeling (Part 3)

An analysis of health claims data from the largest German health insurer of 228 485 individuals (aged >50 years) found that gastrointestinal infections are associated with an increased risk of Parkinson’s (HR=1.42; 95% CI 1.33 to 1.52). “Our results point to the missing link of what may cause alpha-synuclein pathology in the enteric nervous system: bacterial & viral pathogens, which breach the mucosal lining of the gastrointestinal tract (GI) during GI infections, may trigger aggregation of alpha-synuclein in enteric neurons”. I have questions regarding the definitions of GI infections (eg “infectious gastroenteritis & colitis of unspecified origin”?), but interesting result – needing independent validation & further investigation ( to read more about this).

(I really can’t stomach it)

10. A gut feeling (Part 4)

An animal model added weight to the idea that alpha-synuclein aggregation can spread from the gut to the brain, and possibly play a role in Parkinson’s pathogenesis. Interestingly, vagotomy or the genetic removal of alpha synuclein protected the mice against the development of pathology (Click here to read more about this and click here to read a media article about it).

And just days after that report was published, an independent group of researchers presented evidence for bi-directional & trans-synaptic parasympathetic & sympathetic propagation of alpha-synuclein in rodent ( to read more about this).

(Apparently “what happens in Vagus” doesn’t stay in Vagus – ok, enough of the silly puns!)

 

Basic biology news

  • New report finds that synapsin I is a LRRK2 substrate & also describes a novel mechanisms of regulation of glutamate release by LRRK2 kinase activity. Implications for LRRK2-associated Parkinson’s? ( to read more about this).
  • A screening study suggests that strategies to reduce the formation & propagation of β-sheet fibrillar α-synuclein species could be an important route for therapeutic intervention in Parkinson’s ( to read more about this).

  • Could pathological α‐synuclein & Tubulin Polymerization Promoting Protein (TPPP/p25) complexes represent a target for future Parkinson’s therapies? ( to read more about this).
  • New data suggests that macrophage migration inhibitory factor (MIF) can be S-nitrosylated by a physiological nitric oxide donor, preventing induction of BDNF expression. Implications for Parkinson’s & Alzheimer’s? ( to read more about this).
  • New data suggests that spermine synthesis and N1,N8‐diacetylspermidine in blood serum may be useful diagnostic & severity‐associated biomarkers for Parkinson’s, respectively ( to read more about this).
  • Cullin-RING ubiquitin ligase targets exogenous alpha synuclein & inhibits Lewy body–like pathology in models of Parkinson’s. SCF-FXBL5 regulates alpha synuclein in vivo, & SCF ligases may constitute potential targets for the treatment of PD ( to read more about this).
  • Tau is required for progressive synaptic & memory deficits in a transgenic mouse model of α-synucleinopathy. Implications for Parkinson’s? ( to read more about this).
  • CCAAT/enhancer binding protein δ is a transcriptional repressor of Parkinson’s-associated α-synuclein. In addition, decreased expression was observed in the substantia nigra & in iPSC-derived dopaminergic neurons from people with PD ( to read more about this).
  • Parkinson’s-associated Leucine‐rich repeat kinase 2 (LRRK2) inhibitors differentially modulate glutamate release & Serine935 LRRK2 phosphorylation in striatal & cerebrocortical synaptosomes ( to read more about this).

  • A combination of focused ultrasound & intravenous neurotrophic (protein or gene) delivery attenuates the damage to the nigrostriatal pathway in model of Parkinson’s, by allowing the entry of these agents into the brain ( to read more about this).
  • A manuscript on BioRxiv suggests that Parkinson’s-associated misfolded α synuclein protein causes hyperactive mitochondrial respiration without causing any functional deficit ( to read more about this).
  • Multi-omics analysis suggests that Gmeb1 is a master transcriptional regulator of dopamine neuron gene expression/function, & provides a method for identifying cell type-specific transcriptional regulators. Implications for cell therapy in Parkinson’s? ( to read more about this).
  • A manuscript on BioRxiv used Allen Institute human postmortem brain datasets of non-neurological adults to identify expression patterns related to Parkinson’s progression (including PD GWAS genes: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, & SCARB2 – to read more about this).
  • PARKIN-knockout mice have improved viral clearance & survival after viral infection. But deficiency doesn’t affect antiviral signaling & interferon production. PARKIN deficiency augments innate antiviral inflammation (via mtROS-mediated NLRP3 inflammasome – to read more about this).

  • Researchers report that glial HMOX1 expression promotes central & peripheral α‐synuclein dysregulation & pathogenicity in a Parkinson’s mouse model. 2 microRNAs (miR‐153 & miR‐223) negatively regulate α‐synuclein in these mice ( to read more about this).
  • Spanish researchers report mitochondrial & autophagic alterations in skin fibroblasts from people with Parkinson’s who carry PARKIN mutations ( to read more about this).
  • And other Spanish researchers report on small fiber neuropathy & phosphorylated alpha-synuclein in the skin of people with E46K-SNCA associated Parkinson’s ( to read more about this).
  • Herbal extracts (Berberis, Quercus robur, Zizyphus vulgaris, Salix aegyptica) containing flavonoids were investigated for their effects on fibril formation of α-syn, using various methods (ThT, CD spec & TEM). Salix aegyptica had highest inhibitory effect ( to read more about this).
  • Studies investigating mitochondrial DNA variations in Parkinson’s have produced conflicting results (may be due to methodological differences between studies). New review of previously published work outlines limitations & difficulties associated mtDNA ( to read more about this).

  • New data suggests that Parkinson’s-associated protein DJ-1 enhances dopaminergic cell metabolism & neuronal process outgrowth by its regulation of ATP synthase protein components ( to read more about this).
  • Normal skin cells (fibroblasts) display rhythmic oscillations of both mitochondrial respiration & glycolytic activity. Fibroblasts from people with Parkinson’s-associated PARKIN variants exhibit dysregulation of the bioenergetic oscillatory patterns ( to read more about this).
  • Analysis of Parkinson’s microarray datasets from the Gene Expression Omnibus (GEO) database & analysis of blood samples points towards 9 differentially expressed genes (read: potential biomarkers! – to read more about this).
  • A systematic review & meta-analysis reports that levels of neurofilament light in cerebrospinal fluid is a marker of neuronal damage that may be useful in differentiating frontotemporal dementia from Alzheimer’s & Parkinson’s from atypical PD syndromes ( to read more about this).
  • Deep brain stimulation (yes), Spinal cord stimulation (working on it), colonic stimulation (???) (Click here to read more about this).

  • Traumatic brain injury (TBI) has been associated with increase risk of Parkinson’s. New study mapping the spatiotemporal landscape of signature markers in rat TBI model reveals increase in protein families implicated in PD (GPR158, HGMB1, & Synaptotagmin –  to read more about this).
  • New research suggests Parkinson’s-associated extracellular α-synuclein protein (monomeric & fibrillar) facilitate DAT endocytosis, down-regulating its transporter activity. α-syn enters dopamine neurons by modulating flotillin-1–assisted DAT endocytosis ( to read more about this).
  • Researchers identify extracellular N-linked glycans – the glycoprotein neurexin 1β specifically – as key modulators in the neuronal uptake of Parkinson’s-associated N-terminally acetylated alpha synuclein (Click here to read more about this).
  • Levels of the NMDA receptor co-agonist D-serine are reduced in the substantia nigra of primate model of PD (MPTP-lesioned macaques) & in the cerebrospinal fluid of people with Parkinson’s ( to read more about this).
  • Traditional Chinese medicine ingredient gastrodin has been reported to protect dopamine neurons (via insulin-like pathway) in two C. elegans models of Parkinson’s ( to read more about this).

  • In a new manuscript on BioRxiv, researchers report the 1.6 A crystal structure of the GTPase domain of Parkinson’s-associated protein LRRK2 ( to read more about this).
  • Researchers present a system for the creation of inducibly α-Syn-overexpressing cell lines holding high potential for the screening of modulators of Parkinson’s-associated α-synuclein aggregation & α-Syn-mediated toxicity ( to read more about this).
  • CYP2D6 inhibitors – quinidine & ajmalicine – reduce the detrimental effect of MPTP-mimicking chemicals. Complex I is significantly affected by these toxins in normal mice, but remains unchanged in Cyp2d6 locus knock out mice ( to read more about this and click here for the press release).
  • Researchers have a manuscript on BioRxiv describing the use of an organotypic hippocampal slice model for studying Parkinson’s-associated α-synuclein aggregation & inter-neuronal spreading (using preformed α-syn filaments – to read more about this).
  • Researchers identify alpha synuclein as a novel target for the human Fic protein, HYPE, which is a key regulator of ER homeostasis. HYPE adenylylates alpha synuclein & reduces its aggregation ( to read more about this and click here to read the press release).

  • Cerebral Dopamine Neurotrophic Factor (or CDNF – which is being clinically tested in Parkinson’s) injected into the midbrain diffuses around the brainstem, but does not undergo anterograde transport to the striatum ( to read more about this).
  • Further evidence that the interaction of Parkinson’s-associated α-synuclein with membranes plays a key role initiating the formation of α-synuclein aggregates & the overall aggregation process. Efficiency of aggregation depends on the membrane composition ( to read more about this).
  • Researchers presents a systems biology approach for evaluating mouse models of late-onset Alzheimer’s. Could the NanoString nCounter Mouse panel be applied to Parkinson’s mice? ( to read more about this).
  • A manuscript on BioRxiv reports that small molecule PIKFYVE inhibitor ‘Apilimod’ rescues model of ALS/frontal temporal dementia (both loss- & gain-of-function C9ORF72 disease mechanisms in vivo) by increasing the number of endosomes & lysosomes. Could this compound  be useful in Parkinson’s? ( to read more about this).

 

Disease mechanism

  • Loss of FBXO7 (PARK15) results in a Parkinson’s‐like loss of dopamine neurons via an RPL23‐MDM2‐TP53 pathway. Unexpectedly, a late compensatory restoration of TH+ fibre innervation in the striatum (DARPP32+/TH+ cells???), but nigral cell loss irreversible ( to read more about this).
  • The response of mice with no LRRK2 protein & mice with Parkinson’s-associated LRRK2-G2019S protein to a neurotoxic agent (paraquat) demonstrates a role for LRRK2 in the general inflammatory & stressor effects induced by environmental toxin exposure ( to read more about this).
  • Interesting comparison of the protective effects of bee venom extracts with varying PLA2 compositions in a mouse model of Parkinson’s ( to read more about this).

  • Researchers report a new transgenic mouse line (MI2 – human, aggregation-prone truncated 1–120 α-synuclein under TH promoter), & find that treatment with anle138b, from 9 to 12 months of age hasa beneficial effects ( to read more about this and click here to read the press release).
  • GM1 ganglioside modifies α-synuclein toxicity & is neuroprotective in a rodent model of Parkinson’s. Even delayed treatment (3 weeks post AAV-A53T) protects against dopamine cell loss ( to read more about this).
  • The Barcelona LRRK2 Study Group reports detection of alpha synuclein aggregation (using RT‐QuIC) in cerebrospinal fluid in a significant number of people with LRRK2‐associated Parkinson’s, but less frequently than in idiopathic PD ( to read more about this).
  • Human myeloperoxidase (hMPO) is present in neurons in the substantia nigra in cases of Parkinson’s, & causes an exacerbation of motor impairment in a transgenic mouse model of PD (hMPO-A53T mouse – to read more about this).
  • Gene therapy delivery of the L-DOPA synthesizing enzymes (tyrosine hydroxylase & guanosine-tri-phosphate-cyclohydrolase-1) reverses motor impairments in a primate model of Parkinson’s – with no adverse dyskinetic effects ( to read more about this).

  • The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations. Implications for the whole diabetes, Alzheimer’s & Parkinson’s connection? ( to read more about this).
  • Further evidence of the neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS model. Results support a broader neuroprotective role for CuATSM beyond mutant SOD models of ALS ( to read more about this).
  • Oxidative stress in vagal neurons promotes Parkinson’s-like pathology & intercellular transfer of α-synuclein. A greater propensity for cell transfer under pro-oxidant conditions, & nitrated forms of α-synuclein are highly transferable protein species ( to read more about this).
  • Researchers designed, synthesized & tested an amido-bridged nucleic acids (AmNA)-modified antisense oligonucleotide that targets Parkinson’s-associated alpha synuclein with improved stability & cellular uptake in vivo. Rescued PD mouse model ( to read more about this, click here to read the press release, and click here to read a SoPD post on the topic).
  • Using correlative light, electron microscopy & tomography on human brain tissue from Parkinson’s brains, researchers discovered “an aggregated protein–lipid compartmentalization not previously described”. A crowded environment of membranes in Lewy bodies ( to read more about this).

  • Gene expression systematic comparisons between host response to viral infections (EBV, CMV & HHV6) and Alzhiemer’s/Parkinson’s provide new insights into host genes/pathways important for neurodegeneration + convey potential drug repurposing opportunities ( to read more about this).
  • Oh boy, you can imagine the headlines… Oral & intravenous transmission of Parkinson’s-associated α-synuclein fibrils to mice (1x 50 µg oral dose of α-syn fibrils caused disease in 2/8 mice by 350 days, & 1x 500 µg caused disease in 4/8 mice by 384 days ). The researchers investigated the ability of α-syn fibrils to cause neurological disease in TgM83 mice. These are mice that express human A53T α-syn under mouse prion protein promoter. No normal wild-type mice were used ( to read more about this).
  • New study suggests that blocking Cav1.2 calcium channels in microglial cells exacerbates symptoms in a Parkinson’s model. Calcium antagonists enhanced the neuroinflammatory M1 transition & inhibited neuroprotective M2 transition of microglia. “The effect of a calcium antagonist on dopaminergic neuron death may be determined by the balance between the direct beneficial effect on the neurons & the indirect detrimental effect exerted by microglial cells” ( to read more about this).
  • “Suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s & related α-synucleinopathies” Researchers suggest ZFP746 could be a pathological mediator in PD (Click here to read more about this).

  • E46K mutant α-synuclein protein is more degradation resistant & exhibits greater toxic effects than normal α-synuclein in fly (drosophila) models of Parkinson’s ( to read more about this).
  • Enhancement of ATP production (via ethyl pyruvate or cutamesine) ameliorates motor & cognitive impairments in a mouse model (MPTP) of Parkinson’s. Daily treatments started 24 hours after the final MPTP injection, & protected dopamine neurons ( to read more about this).
  • Researchers report that axonal pathology in human SNCA-A53T dopamine neurons (in vitro model of Parkinson’s) results from loss of Nrf2 transcriptional activity at the Map1b gene locus ( to read more about this).
  • Researchers report regulation of exocytosis & mitochondrial relocalization by Parkinson’s-associated alpha-synuclein in vitro. Specific structural features of a-syn may regulate vesicle release & perturb mitochondrial function under stress ( to read more about this).

 

Clinical research

  • New research reports that levels of somatic mtDNA deletions in LRRK2 mutation carriers is associated with Parkinson’s status even after adjusting for age ( to read more about this).
  • A biomechanical system vs observational rating scale for Parkinson’s tremor assessment finds that the predicted rating is significantly more reliable than the average clinical ratings by three raters ( to read more about this).
  • New BioRxiv manuscript demonstrates how deeply phenotyped cohorts can be used to identify latent heritable disease-modifying traits in Parkinson’s. 3 axes explain over 75% of the observed clinical variation across 3 independent UK & US cohorts ( to read more about this).
  • The Michael J Fox Foundation Global Genetic Parkinson’s Disease Study Group has established a team science approach to better understand the genetics of the condition ( to read more about this).
  • Interesting analysis & characterisation of Parkinson’s in the Western Pacific region. “Gaps in awareness of the disease & inequitable access to treatments pose challenges” ( to read more about this).

  • NINDS NET-PD Investigators report that that supplementation with vitamin B12 (≥100 μg) is uncommon in early Parkinson’s. They found a trend towards a lower hazard ratio for the development of sensory symptoms in those taking multivitamins or B12 ( to read more about this).
  • A BioRxiv preprint suggests connectivity from the subthalamic deep brain stimulation electrode to the left PFC predicts worsening of depressive symptoms in Parkinson’s across 3 international DBS cohorts ( to read more about this).
  • A BioRxiv manuscript that effective subthalamic deep brain stimulation increases overall connectivity in the motor network in people with Parkinson’s, normalizing the network profile towards healthy controls ( to read more about this).
  • In Parkinson’s & dementia with Lewy bodies, Myelin‐associated oligodendrocytic basic protein (MOBP) was found in the core of Lewy bodies in the brainstem, cingulate cortex, etc. No MOBP was found in inclusions in a variety of other neurological disorders. Other conditions examined included multiple system atrophy (MSA), Alzheimer’s, Pick’s disease, progressive supranuclear palsy (PSP), corticobasal degeneration, argyrophilic grain disease, amyotrophic lateral sclerosis (ALS) & frontotemporal lobar degeneration ( to read more about this).
  • Manuscript on BioRxiv analyzed copathology (Alzheimer’s amyloid-β-containing plaques, Parkinson’s α-synuclein inclusions, tau neurofibrillary tangles, etc) across 18 brain regions in 1389 autopsies & found transdiagnostic “disease clusters” ( to read more about this).

  • New BioRxiv manuscript suggests that impaired memory strength in Parkinson’s is associated with reduced beta desynchronization. Longer disease duration, larger reduction in beta desyn ( to read more about this).
  • Severity of Parkinson’s-associated GBA1 mutations is associated with a younger age at onset, higher prevalence of rapid eye movement sleep behavior disorder, & lower levels of cerebrospinal fluid alpha‐synuclein in dementia with Lewy bodies ( to read more about this).
  • Temporomandibular disorders are a group of conditions that cause pain & dysfunction in the jaw joint & muscles that control jaw movement. Taiwanese researcher report a significantly higher risk of these conditions in people with Parkinson’s (2.11 fold – to read more about this).
  • The protocol for a pseudo-randomised clinical study called “Adaptive deep brain stimulation as advanced Parkinson’s treatment (ADAPT study)” has been published ( to read more about this).
  • “The concept of “discordance” in Parkinson’s twin pairs needs to be revisited & refined” Deep clinical phenotyping, combining motor, nonmotor, & imaging modalities suggests concordance rates in monozygotic twins may be higher than previously appreciated ( to read more about this).

  • New study finds that deep-learning-based imaging classification was useful for an objective & accurate differentiation of dementia with Lewy bodies from Alzheimer’s; & for predicting clinical features of DLB ( to read more about this).
  • Researcher reports deep brain stimulation has both behaviour-independent effects on basal ganglia connectivity, as well as behaviour-dependent modulatory effects ( to read more about this).
  • In a 6-year-long longitudinal study of GBA1 mutation–positive individuals without Parkinson’s, researchers found a worsening in motor & non-motor prodromal PD features (Click here to read more about this).
  • New report suggests that optical coherence tomography imaging of the human retina can distinguish between healthy controls, people with Alzheimer’s, & people with Parkinson’s ( to read more about this).
  • A large cross-sectional study (of 2M Spanish medical records) suggests that the presence of inflammatory bowel disease (IBD) &/or treatment with aminosalicylate may play a protective role against development of Parkinson’s among under 65-year olds ( to read more about this).

  • An analysis of the Korean National Health Insurance Database suggests that people with Behçet’s disease (a rare inflammatory disorder) have a significantly higher risk of developing Parkinson’s ( to read more about this).
  • Analysis of nationwide Korean National Health Insurance Database reveals that people with Parkinson’s have a lower overall cancer risk & lower risk of specific cancers. Despite environmental, ethnic, etc differences, results consistent with western data ( to read more about this).
  • Striatal DAT imaging does not correlate with nigrostriatal neuronal counts (Click here to read more about this).
  • Researchers reported that genetic variability in the mTOR pathway contributes to the effects of SNCA genetic variants (in a nonlinear epistatic manner) to modulate differential age of onset in Parkinson’s ( to read more about this).
  • Interesting analysis on the impact of levodopa therapy-induced complications on quality of life in people with Parkinson’s in Singapore, but few surprises: “levodopa-induced complications had significant adverse impacts on QoL” ( to read more about this).
  • Researchers report that remotely gathered typing data allows for the accurate, objective & nonobtrusive monitoring of motor features & predicting of drug response in people with Parkinson’s ( to read more about this).

  • Researchers report that subtle gait & balance impairments occur in idiopathic rapid eye movement sleep behavior disorder (a prodrome for Parkinson’s), which likely reflect early progressive degeneration in brainstem regions (Click here to read more about this).
  • 4 cognitively normal people with Parkinson’s, 4 with PD+cognitive impairments, & 10 with Lewy body dementia underwent amyloid imaging (PiB) & DAT imaging. PiB scans accurately reflected cortical amyloid deposits seen at autopsy (Click here to read more about this).
  • Circulatory microRNA miR-223-3p discriminates between Parkinson’s & Alzheimer’s ( to read more about this).
  • researchers have a manuscript on BioRxiv presenting the normative baseline for the substantia nigra using Neuromelanin sensitive MRI, & demonstrate the importance of diffusivity measures rather than anisotropy of white matter in Parkinson’s ( to read more about this).
  • New research suggests “oral microbiome may represent a highly-accessible and informative microenvironment that offers new insights in the pathophysiology of early stage” Parkinson’s. Better than analysing the output of the entire GI tract! ( to read more about this).

 

New clinical trials

  • Biogen & ionis Pharmaceuticals have registered a Phase I single- & multiple-ascending-dose study evaluating the safety, tolerability, & pharmacokinetics of BIIB094 (LRRK2 antisense oligonuclieotide) in people with Parkinson’s. 62 individuals will be recruited & administered (via intrathecal injection). Primary outcome will be safety; secondary objectives will be to evaluate the pharmacokinetic profile of BIIB094. Results due in 2022 (Click here to read more about this & click here to read a SoPD post on this topic).

  • Interesting new clinical trial has been registered looking at use of an oral multi-strain probiotic in the treatment of anxiety in people with Parkinson’s. 72 individuals will be tested for 12 weeks in this phase II/III study (Click here to read more about this).
  • A placebo-controlled, double-blind clinical trial has been registered that will investigate the safety & tolerability of molecular hydrogen, a promising antioxidant agent, in people with early-stage Parkinson’s. 70 participants for 52 weeks (Click here to read more about this).
  • Interesting new clinical study has been registered seeking to investigate the evidence of dopaminergic toxicity causing by Hepatitis C virus infection using brain imaging (18F-FDOPA PET & MRS) as imaging biomarkers (Click here to read more about this).
  • New clinical study has been registered to investigate the effect of regular vigorous aerobic exercise training (running) on motor, non-motor symptoms, & quality-of-life in people with Parkinson’s (Click here to read more about this).
  • Biotech firm Enterin have announced that their “DEMET Study” has enrolled its 1st patient with Parkinson’s dementia. Study will test the safety, tolerability & efficacy of orally administered ENT-01, a synthetic derivative of squalamine ( to read more about this).

  • Researchers have published the protocol for their new multicentre observational VIP study (investigating visual impairments in Parkinson’s). 750 PD patients & 250 controls will be recruited ( to read more about this).
  • A new clinical trial registered in China investigating Butylphthalide (a celery oil component which alleviates oxidative damage & mitochondrial dysfunction) in delaying the progression of Parkinson’s ( to read more about this).
  • Interesting clinical trial registered in California investigating mindfulness based stress reduction for Parkinson’s (Click here to read more about this).
  • The clinical trail protocol for “ParkProTrain” – an individualized, tablet-based physiotherapy training programme aimed at improving quality of life & participation restrictions in Parkinson’s – has been published ( to read more about this).

 

Clinical trial news

  • Walking to your right music in Parkinson’s is important! The results of a clinical trial find that the usefulness of cueing strategies during gait training consists of a reshape of sensorimotor rhythms & fronto-centroparietal/temporal connectivity ( to read more about this).
  • Biogen researchers have published the results of the Phase I clinical trial of BIIB054 (an antibody-based immunotherapy treatment for Parkinson’s). It has favorable safety, tolerability, & pharmacokinetic profiles in healthy volunteers & PD participants ( to read more about this).

  • The results from the baseline evaluations of the COPPADIS‐2015 (COhort of Patient’s with PArkinson’s DIsease in Spain, 2015) have been published. This is an ongoing global PD project investigating disease progression in more than 1,000 PD subjects ( to read more about this).
  • A randomized controlled pilot clinical study finds cognitive & motor dual task gait training exerted specific training effects on dual task gait performance in individuals with Parkinson’s (Click here to read more about this).
  • Axovant has provided the 6 month results from the first cohort of the ongoing Phase II SUNRISE-PD clinical trial investigating their gene therapy treatment AXO-Lenti-PD in Parkinson’s. Only 2 patients thus far, but treatment is generally well tolerated ( to read more about this).

 

Other news

  • The Economic burden of Parkinson’s. Published by the Michael J Fox Foundation with support from Parkinson’s Foundation, AbbVie Inc., ACADIA Pharmaceuticals, Acorda Therapeutics, Adamas Pharmaceuticals, and Biogen Inc., along with American Parkinson Disease Association and The Parkinson Alliance. The total cost of Parkinson’s to individuals, families & the US government is $51.9 billion per year, with $25.4 billion attributable to direct medical costs (e.g., hospitalizations, medication) & $26.5 billion in non-medical costs like missed work, lost wages & early retirement (Click here to read more about this).
  • Prevail Therapeutics announces that the US FDA has accepted their Investigational New Drug (IND) application for a Phase 1/2 Trial of their lead gene therapy product (PR001) to treat GBA1-associated Parkinson’s ( to read more about this, click here for the press release, and click here to read a SoPD post on this topic).

  • VistaGen announced positive preclinical data of AV-101 – an oral NMDA receptor glycine site antagonist – in treating Levodopa-induced dyskinesia in a primate model of pariParkinson’s ( to read more about this).
  • Shimmer Research & ClearSky Medical Diagnostics have announced a new partnership to improve analysis of wearable sensor data for neurological conditions, like Parkinson’s ( to read more about this).
  • Drug discovery company C4X Discovery Holdings & PhoreMost have announced a collaboration to “accelerate Parkinson’s drug discovery pipeline” ( to read more about this).
  • MODAG launches out of stealth mode with series A financing of EUR12 million to develop treatments for Parkinson’s disorders, including Multiple System Atrophy” (MSA). The biotech is preparing a Phase I trial for anle138b ( to read more about this and click here to see the company website).

  • A grant from Quebec’s Ministry of Economy and Innovation is contributing to a $4M open science drug screening fund (called NeuroOme) to support precision therapies for ALS & Parkinson’s diseases (Click here to read more about this).
  • Korean biotech firm ABL Bio has presented new data for ABL301 (a bispecific antibody targeting Parkinson’s-associated alpha-synuclein). ABL301 is “superior to conventional antibodies in the ability to cross the blood-brain barrier”. Apparently ABL301 also has more “favorable aggregation preference compared to competitor antibodies in clinical trials currently”. No information on plans for clinical evaluation ( to read more about this).
  • New US event series called “Parkinson’s IQ + You” has been launched by the Michael J Fox Foundation & ACADIA Pharma to educate & empower people with Parkinson’s & care partners to manage the disease, learn about research participation & connect with local resources ( to read more about this).

 

Review articles/videos

  • Interesting discussion of “the active participation of autophagy impairment in alpha-synuclein accumulation and propagation, as well as alpha-synuclein-independent neurodegenerative processes in the field of synucleinopathy” – a lot regarding Parkinson’s ( to read more about this).
  • Interesting review of how Parkinson’s-associated α-synuclein could be involved in the pathophysiology of Alzheimer’s (“either as an active or passive player” –  to read more about this).

  • How to peddle hope. An interesting analysis of how YouTube patient testimonials are being used to capitalise on unproven stem cell treatments. 159 videos analysed, patients discussed health improvements in 91.2%; praised providers in 53.5% ( to read more about this).
  • “Is the phenomenon of α-syn pathology spread relevant to disease? Based on current understanding, spreading of α-syn pathology may not be the main driving factor in Parkinson’s” – a very interesting overview discussing the spread of α-synuclein in Parkinson’s ( to read more about this).
  • Useful webinar about stem cell-based cell replacement therapy for Parkinson’s:

  • Interesting review on the bidirectional relationship between the gut & Parkinson’s ( to read more about this).
  • Is α-Synuclein causal or just a bystander in Parkinson’s? German researchers evaluate the evidence. Perhaps rare SNCA gene mutations are causal for a minority of familial PD patients. Should targeted a-syn approaches (eg immunotherapy) be tested on them? ( to read more about this).
  • Interesting review exploring the connections between bacterial infection, immune dysregulation, & CNS disorders – dissecting this interplay & how bacterial pathogenesis may contributes to the “multiple-hit hypothesis” of Parkinson’s ( to read more about this).

  • Great discussion on somatic mutations in Parkinson’s (Click here to read more about this).
  • Five points where action is needed – this is brilliant! (Click here to read more about it).
  • A nice use of Lego to illustrate the spectrum of species (& toxicities) in Parkinson’s-associated alpha‐synuclein oligomers & fibrils. Oligomers = collapse of neuronal homeostasis, the fibrillar state = most efficient at propagating ( to read more about this).
  • A useful review of ketone bodies in neurological conditions, with a focus on neuroprotection & underlying mechanisms – plus a section on Parkinson’s ( to read more about this).

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

And there it is, just some of the highlights from June 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 July!


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.


8 comments

  1. alan green

    From perspective of anything new of practical value, there were 2 interesting studies:
    NAC study, 600 mg twice a day was good. Researchers also including 50 mg IV once a week,( no idea why anybody would do that.)
    Also Herbal extract study from Iran. That study was almost worthless as used crushed up seeds instead of pure chemicals in a know amount. They did show lots of flavinoids have effect on a-syn fibrils.(we all knew that, as 20 prior studies using pure Berberine) They used Berberis (has some berberine); but rather worthless study from quantatative viewpoint as no idea how much berberine in some crushed Berberis seeds, plus very many other chemicals.

    Bur very nice to know 600 mg NAC, twice a day is worhwhile.

    Liked by 1 person

    • jeffreyn

      “NAC injections were given once a week.”

      “On the days that subjects did not receive the intravenous NAC, they took 600mg NAC tablets orally 2 times per day,”

      Maybe the NAC injections provided most of the benefit?

      Needs another trial.

      Like

    • Simon

      Hi Alan,
      Thanks for your comment. I agree that the NAC study is of great interest. I am desperately trying to find some free time to write a post on it.
      Kind regards,
      Simon

      Like

  2. Oliver Alabaster, MD

    Simon,
    I greatly appreciate and admire all you do for the Parkinson community. However, I have a question for you: Do you sense any concern among researchers and neurologists that clinical trials of Nilotinib have the unintended effect of delaying its availability for Parkinson’s patients? Repurposing a drug at lower dose that already is well known for its side effects and which has the unique potential to reverse the devastating deterioration faced by patient’s with advancing disease, should in my opinion be made available immediately to patients at their own risk, given they face the far worse side effects of the disease.
    Data could simultaneously be collected that records the clinical impact of Nilotinib treatment in a wide variety of clinical stages and manifestations of the disease. This approach would provide patients with the opportunity to determine if they would benefit from Nilotinib treatment or not with a few months. Waiting for a series of clinical trials while valuable, only prolongs patient suffering: The risks of the disease being far greater than the risk of taking a repurposed drug at lower dose.
    What are your thoughts?

    Liked by 1 person

    • Simon

      Hi Oliver,
      Thanks for your comment and kind words. Very much appreciated. And thanks also for the really interesting question.
      My opinion here is very clear: We can not simply assume “The risks of the disease being far greater than the risk of taking a repurposed drug at lower dose”. Clinicians are caught between a rock and a hard place: on the one hand they want to help patients, but on the other hand they must keep the patient in their care safe. And they will always err on the side of caution in this balancing act. Regardless of whether a drug may be able to help a person or not, the clinician has to be thinking of the individuals safety first.
      And while there are a lot of compounds that are acknowledged as relatively safe (vitamin B12, NAC, other supplements, etc), kinase inhibitors (like Nilotinib) definitely do not fall into that basket. I need to be careful what I write here as there are ongoing clinical trials for some of these drugs, but even at a lower doses there can be signifcant side effects (there is a reason why some of these drugs have black box warnings on their packaging).
      I have long hoped for testing of safe compounds/supplements by the community, but the issue is assessement. How do we objectively know if a particular treatment is working? If you can suggest some ideas/methods, I’d be very interested to hear them.
      Kind rergards,
      Simon

      Like

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