Monthly Research Review – March 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 March 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 March 2019?

In world news:

2nd March – SpaceX successfully launch their Crew Dragon rocket on it’s first un-manned mission into space. One day later it docked with the international space station.

 

5th March – A second case of sustained remission from HIV was reported. This news comes ten years after the original “Berlin Patient” (Click here to read more about this).

 

15th March – Cyclone Idai made landfall on Mozambique, causing loss of life, mass flooding, and power outages in south-eastern Africa.

25-26th March –  the International Parkinson Disease Genomics Consortium met in Lisbon (Portugal) for their annual meeting. 100+ genetics experts from around the world gathered to discuss all of their new research on the genetics of Parkinson’s – it was an amazing meeting (Click here to read a SoPD post on this meeting).

26-31st March – the 14th International Conference on Alzheimer’s & Parkinson’s Disease was held in Lisbon (Portugal). 4000 researchers from around the world invaded the city for five days of lectures & presentations. The results of many clinical trials were presented and exciting new data was discussed (a SoPD post is in the works on this meeting).

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

In March 2019, there were 869 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (2429 for all of 2019 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 6 pieces of Parkinson’s news

1. The smell of Parkinson’s

Several years ago, Joy Milne from Scotland proved that she could detect differences in the body odour of people with Parkinson’s. Since then, a tremendous amount of research has been conducted on the ‘smell of Parkinson’s’, including the training of dogs to sniff out PD. This month saw the publication of new research on the chemical components of the odour ( to read more about this, click here and here to read the press releases, and to read a SoPD post on the topic).

 

2. Neuromelanin:

Melanin is a pigment that the body produces which gives skin and hair their colour. There is also a form of melanin in the human brain, called neuromelanin, which accumulates with age (age being a risk factor for Parkinson’s). This month, Spanish researchers reported that they have generatated human-like neuromelanin in rodent dopamine neurons (which do not naturally generate neuromelanin). By doing this, the researchers observed Parkinson’s-like features in the animals overtime (movement issues and neurodegeneration). They also found that boosting the waste disposal system of the cells could rescue the effect (Click here to read more about this and click here to read a SoPD post on this topic)

 

3. When the undruggable becomes druggable:

NURR1 is a protein that has been shown to be neuroprotective for dopamine neurons in the brain – dopamine neurons being a population of cells badly affected by Parkinson’s. Extensive efforts, however, have failed to identify any compounds that could stimulate NURR1 activity… until last week – researchers from the University of California SF reported that a dopamine metabolite (5,6-dihydroxyindole or just DHI) binds directly to NURR1 and stimulates its activity. DHI is too unstable to be considered a potential therapy for Parkinson’s, but the researchers hope that the findings will suggest avenues for developing synthetic NURR1 stimulators (Click here to read more about this, and click here to read the press release).

 

4. Exenatide bacteria

Researchers reported that they have engineered gut bacteria that continually produce glucagon‐like peptide‐1 (or GLP‐1). This is the protein that the drug Exenatide is based on – Exenatide being the diabetes treatment that has given interesting results in a Phase II clinical trial for Parkinson’s). The researchers report that treatment with the bacteria significantly reduces motor impairments and dopamine cell loss in a model of Parkinson’s (Click here to read more about this).

 

5. Vitamin B12 & LRRK2

Researchers have discovered that 5′-deoxyadenosylcobalamin (AdoCbl) – a physiological form of the essential micronutrient vitamin B12 – modulates Parkinson’s-associated LRRK2 kinase activity via allosteric regulation and confers neuroprotection in worm, fly & mouse PD models ( to read more about this and to read a SoPD post on this topic).

 

6. Powering up Mitochondria?

Researchers conducted a post mortem examination of Parkinson’s brains & found a reduction in the number & volume of mitochondria. And here’s the curious twist: deep brain stimulation of subthalamic nucleus reversed the effect ( to read more about this, click here for the press release and click here to read a SoPD post on the topic).

 

Basic biology news

  • High levels of peripherally circulating microRNA miR-132 & low levels of its downstream target Nurr1 level may be a potential biomarker for aiding in the diagnosis of Parkinson’s & monitoring the progression of the condition ( to read more about this).
  • Pridopidine is an experimental drug that has demonstrated benefits in models of Parkinson’s. And now targeting the Sigma-1 Receptor with Pridopidine has also been shown to reduce the central features of an Amyotrophic Lateral Sclerosis (ALS/motor neurone disease) mouse model. “A profound reduction in mutant SOD1 aggregation in the spinal cord” ( to read more about this).

  • AMP-activated protein kinase (AMPK), the main intracellular energy sensor, is hyper-activated in several degenerative conditions like Parkinson’s. Researchers find that AMPK hyper-activation leads to synaptic loss via an autophagy-dependent pathway ( to read more about this).
  • Gene expression changes in the liver after 8 weeks of high-fat–high-carbohydrate diet in fish associated with mitochondrial metabolism & neurodegeneration (eg. Parkinson’s). Diet may have caused mitochondrial dysfunction & less mitochondrial biogenesis ( to read more about this).
  • Behavioral validation of the e-Particle – a wireless low-power neurostimulation technology. The future of deep brain stimulation for Parkinson’s? ( to read more about this).
  • An amazing volume of work! Researchers use toxin- & PFF α-Syn-induced mouse models of Parkinson’s to establish the physiological trajectory by which the substantia nigra reticulata transitions from healthy to diseased state ( to read more about this).
  • Further evidence that lipopolysaccharide (an endotoxin) released by gut bacteria modulates Parkinson’s-associated alpha synuclein aggregation & alters its biological function ( to read more about this).
  • Long non-coding RNAs help regulate gene expression. Now researchers report that 6 long non-coding RNAs (SNCA-AS1, AK127687; UCHL1-AS1, PINK1-AS1, AX747125, & MAPT-AS1) associated with Parkinson’s genes are reduced in the postmortem PD brain ( to read more about this).
  • There is a new a manuscript on BioRxiv suggesting that different cell types use alternative strategies to cope with mitochondrial DNA mutations, & Parkinson’s-associated PINK1 & PARKIN can shape mitochondrial genomic mosaicism across individuals ( to read more about this).
  • Researchers designed an auditory tone stimulation that drove gamma frequency neural activity in the cortex. 7 days of auditory treatment improved memory & reduced amyloid pathology in mouse model of Alzheimer’s. Implications for Parkinson’s? ( to read more about this).
  • Brain lymphatic clearance dysfunction may be an aggravating factor in Parkinson’s pathology. Cervical lymphatic ligation in a PD model caused severe accumulation of α-synuclein, glial activation, inflammation, dopaminergic neuronal loss & motor deficits ( to read more about this).
  • Mitochondria provide energy to cells. Researchers compared mitochondria in the synapses of cortical & striatal cells in the brain & found functional heterogeneity (eg Cortical have higher oxygen consumption). Implications for Parkinson’s? ( to read more about this).

  • Parkinson’s-associated pathogenic alpha synuclein binds to mitochondria, while physiological alpha synuclein does not. Mitochondrial binding is accompanied by defects in cellular respiration. A role in Lewy body formation? ( to read more about this).
  • Parkinson’s-associated alpha synuclein protein suppresses the mitochondrial matrix Clp protease (ClpP) to trigger mitochondrial oxidative damage & neurotoxicity. Overexpression of ClpP reduces αSyn-induced mitochondrial oxidative stress (via SOD2 – to read more about this).
  • New report suggests the plant triterpenoid celastrol blocks Parkinson’s-associated PINK1-dependent mitophagy by disrupting PINK1’s association with the mitochondrial protein TOM20 ( to read more about this).
  • A report on the discovery of VU2957 (Valiglurax) – a potent, selective, CNS penetrant, orally bioavailable mGlu4 Positive Allosteric Modulator – a candidate for the treatment of Parkinson’s ( to read more about this).
  • Researchers conducted genome-wide CRISPR screen & identified 50 novel genes, including Sall1 & Fam189a2, which mediate cellular reprogramming. RNA-seq also provides insight into downstream pathways of Sall1 ( to read more about this).
  • The genetic background modifies phenotypic & transcriptional responses in a C. elegans model of Parkinson’s-associated α-synuclein toxicity ( to read more about this).
  • Two conformationally distinct oligomers of Parkinson’s-associated alpha synuclein, share common epitopes & the ability to negatively affect long-term potentiation induction in the CA1 region of the hippocampus ( to read more about this).
  • Interesting manuscript on BioRxiv finds that neurodegeneration caused by Parkinson’s-associated LRRK2-G2019S requires Rab10 in select dopaminergic neurons in flies ( to read more about this).
  • A new bioRxiv manuscript finds Nilotinib is an inhibitor of the hedgehog pathway. Activation of sonic hedgehog has previous provided neuroprotection in models of Parkinson’s. Nilotinib is being clinically tested in Parkinson’s. These new results are all in cancer cell line (indicating good new for brain cancer! –  to read more about this).

  • An interesting manuscript on BioRxiv has looked at single-cell transcriptomics in human midbrain-specific organoids – the data reveals multiple neuronal cell types. Usefu drug discovery tool for Parkinson’s? ( to read more about this).
  • Using “nature-inspired design and evolution” researchers have developed a method for generating antibodies specific for amyloid aggregates. The model used in the report was Alzheimer’s-based, but could be applied to approaches for Parkinson’s ( to read more about this).
  • A new manuscript on BioRxiv suggests that Ten-eleven translocation 2 (TET2) could play a role in the neuroinflammatory response driven by microglia in Alzheimer’s & Parkinson’s ( to read more about this).
  • Deubiquitylating enzyme ubiquitin-specific protease 32 (USP32) has been implicated in the pathogenesis of various cancers & Parkinson’s. New research suggests loss of USP32 inhibits late endosome transport & recycling ( to read more about this).
  • Researchers report that mice with the Parkinson’s-associated D620N VPS35 genetic variation develop robust & widespread tau-positive pathology/axonal damage & dopamine cell loss, but lack alpha synuclein ‘Lewy’ pathology ( to read more about this).
  • Parkinson’s-associated alpha-synuclein targets the GluN2A NMDA receptor subunit in the brain causing striatal synaptic dysfunction & visuospatial memory alteration. Treatment with antibodies targeting α-syn prevents the loss of LTP ( to read more about this).
  • Dinosaur? No, Dynasore! Dynasore, inhibitor of dynamin, represses the lysosomal localisation of mTOR & blocks mTORC1 activity. Treatment of Dynasore significantly promotes clearance of protein aggregates in Huntington’s model. Implications for Parkinson’s? ( to read more about this).

Disease mechanism

  • The TWAS of PD! Researchers identify & prioritise Parkinson’s associated genes using population-scale transcriptomic-wide association study (TWAS) approach ( to read more about this).
  • New study proposes the potential therapeutic benefits of retinoic acid supplementation in moderating L-DOPA–induced dyskinesias in Parkinson’s model. Aldehyde dehydrogenase 1A1 (ALDH1A1) is required for postsynaptic MOR1 expression in the dorsal striatum ( to read more about this).
  • Researchers report that fasting-mimicking diet modulates microbiota (in both mice & humans) & promotes intestinal regeneration to reduce inflammatory bowel disease pathology (in mice) ( to read more about this).
  • Translational inhibition of alpha synuclein by treatment of QR Pharma’s Posiphen normalises distal colon motility in genetically engineered Parkinson’s. Three clinical trials of Posiphen have been conducted ( to read more about this).

  • Interesting new BioRxiv manuscript: Researchers engineered a protein (β-wrapin AS69) to bind to monomeric α-synuclein with high affinity. In cell, flies & model model of Parkinson’s, AS69 efficiently inhibits the proliferation of amyloid fibrils ( to read more about this).
  • Ghrelin receptor activation in dopamine neurons is neuroprotective in models of Parkinson’s, independent of the electric activity of these cells. Mitochondrial dynamics have a crucial role in some aspects of this process ( to read more about this).
  • Deletion or pharmacological inhibition of ALCAT1 prevents MPTP‐induced neurotoxicity, improved mitophagy (by promoting recruitment of Parkin to dysfunctional mitochondria) & motor deficits in model of Parkinson’s. ALCAT1 upregulated by MPTP or α‐synuclein ( to read more about this).
  • A manuscript on BioRxiv reporting that Fas Apoptosis Inhibitory Molecule (FAIM) counteracts stress-induced loss of viability. Levels of protein aggregates produced by cellular stress are greater in FAIM-deficient cells. Implications for Parkinson’s? ( to read more about this).
  • Researchers report that Parkinson’s-associated VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses & regulate synaptic activity ( to read more about this).
  • Researchers & colleagues report a systemic peptide mediated delivery of an siRNA targeting alpha synuclein in the brain rescues the neurodegenerative process in a transgenic model of Parkinson’s ( to read more about this).
  • Researchers find that Baicalein enhances the effect of low dose Levodopa on the gait deficits & protects dopaminergic neurons in models of Parkinson’s ( to read more about this).

  • The pedunculopontine nucleus is associated with Parkinson’s. New research finds elective decrease of cholinergic signaling from pedunculopontine & laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress ( to read more about this).
  • Researchers find that deficiency of Parkinson’s-associated LRRK2 in rodents affects insulin-dependent translocation of glucose transporter type 4 (GLUT4). Comparable alterations in fibroblasts from PD patients with G2019S variants ( to read more about this).
  • Parkinson’s-associated LRRK2 deletion, inhibition & mutations led to impaired mitochondrial Ca2+ extrusion (via Na+/Ca2+/Li+ exchanger (NCLX)) which in turn lowered mitochondrial permeability transition pore (PTP) opening threshold & increased cell death ( to read more about this).
  • Researchers report that unbalanced presynaptic calcium channel activity underlies selective vulnerability of nigrostriatal dopaminergic terminals in models of Parkinson’s ( to read more about this).
  • Evidence of sex difference in preclinical models of Parkinson’s. Researchers have found that sensitivity to the pesticide rotenone in rodents reflects the male-to-female ratio in human PD. Females showed less inflammation & less accumulation of α-syn ( to read more about this).
  • Researchers report that stimulation of noradrenergic transmission by the norepinephrine reuptake inhibitor Reboxetine is beneficial in a mouse model of progressive Parkinson’s (MPTP – to read more about this).
  • Researchers have colonized mice with a simplified intestinal microbiota composed of just 10 strains isolated from the human gut. A new tool for future studies to clarify how microbiota-diet interactions ( to read more about this).

  • Researchers reports that antipsychotic Phenothiazine normalizes the NADH/NAD+ ratio, maintains mitochondrial integrity & protects the dopamine neurons in a chronic rotenone model of Parkinson’s ( to read more about this).
  • Researchers suggest a strong interaction between Parkinson’s-associated LRRK2 & alpha synuclein transmission across mouse & human models. Could LRRK2 inhibitors being clinically tested slow/stop the spread of PD? ( to read more about this).

 

Clinical research

  • A 5 year study (assessing every 6 months) of 22 early Parkinson’s (<4 years since diagnosis), 18 mid stage-PD (>5 years) & 24 controls finds that wearables can quantify progressive gait deficits in early PD ( to read more about this).
  • A 9-year study of 41 people with PARK16-associated Parkinson’s (compared to 115 non-carriers) finds that PARK16 variant carriers exhibited greater motor progression after 5 years, suggesting that variants may influence disease progression over time ( to read more about this).
  • In Parkinson’s, REM sleep behaviour disorder is associated with isolated apathy & increased severity of depressive symptoms, independent of medication, motor & other non-motor symptoms ( to read more about this).

  • Researchers report that serum neurofilament light chain are markedly elevated in atypical Parkinson’s compared to idiopathic PD. The study involved 55 people with iPD, 29 with atypical PD (22=MSA, 7=PSP) & 53 controls ( to read more about this).
  • Genetic variability in inflammation & oxidative stress-linked genes does not play a major role in the occurrence of Parkinson’s or the adverse events of dopaminergic treatment ( to read more about this).
  • Researchers conducted differentially expressed genes (DEGs) analysis in datasets of 69 Parkinson’s & 57 control brains. Identified 1046 DEGs, majority (739/1046) were downregulated in PD. Significant overlap in DEGs between PD & Alzheimer’s ( to read more about this).
  • Researchers asked whether baseline brain imaging ([123I]FP-CIT SPECT) & cerebrospinal biomarkers can predict cognitive impairment in Parkinson’s. Reduced Aβ42, increased TAU & reduced caudate uptake = risk of cog. issues ( to read more about this).
  • Both low cerebrospinal fluid levels of Alzheimer’s-associated β-amyloid protein & the APOEɛ4 genotype are associated with cognitive decline in Parkinson’s according to a new study that followed 423 de novo PD participants for up to 5 years ( to read more about this).
  • New study suggests that Medicare beneficiaries who underwent tissue transplantation had a 37% lower risk of developing Parkinson’s than general Medicare population ( to read more about this).
  • Technology overuse lacks the taboo of other impulse control disorder behaviors (e.g., gambling, hypersexuality), but perhaps problematic mobile gaming (or internet & smartphone addiction) should be considerd such. Interesting case study in Parkinson’s ( to read more about this).

  • Researchers present longitudinal results, based on 5 yrs follow-up to identify potential markers of disease progression in Parkinson’s from the assessment of circular gait patterns with a single body-fixed-sensor mounted on the low-back. Interesting statement from the standpoint of clinical trial utility of wearables – “While the clinical assessment of gait-UPDRS III was more sensitive than objective gait features in early-stage PD, this was not the case in middle-stage PD” ( to read more about this).
  • Comparative assessment of cerebrospinal fluid α‐synuclein seeding aggregation assays using samples from 105 people with Parkinson’s (& 79 healthy control) showed 92% concordance (PMCA & RT‐QuIC assays). Implications for clinical trials? ( to read more about this).
  • Interesting case study: a 35‐year‐old Dutch man with “foot drop dystonia”/Dopa‐responsive dystonia resulting from a PARKIN mutation. DATscan suggests bilateral, asymmetrical loss of striatal DAT binding ( to read more about this).
  • People with Parkinson’s plus REM sleep behaviour disorder present cortical thinning in the right perisylvian & inferior temporal cortices. Also shape contraction in the putamen compared to people with PD without RBD. Useful imaging biomarker? ( to read more about this).
  • What a great idea! The “Parkinson’s Buddy Program” – pairing 1st year med students with people with PD to engage in a social relationship. Engaging with local community partners & learning the lived experience. Students attended monthly seminars on topics specific to Parkinson’s patient care & met with their PD buddies throughout the year ( to read more about this).
  • Researchers present a case report which suggests that adding a dopa-decarboxylase inhibitor to Mucuna pruriens coud fit well in a personalised approach for people with Parkinson’s who are reluctant to start levodopa ( to read more about this).

  • Repetitive elements (RE) constitute the majority of the human genome. Now researchers report analysis of RE in the blood & skin of people with Parkinson’s, identifying differential expression of satellite elements ( to read more about this).
  • Researchers report a lack of association between DJ-1 gene promoter genetic variants & the risk of Parkinson’s. “DJ-1 promoter polymorphisms may play little role in the dysregulation of DJ-1 expression and PD susceptibility” ( to read more about this).
  • Data collected from an Israeli medical database suggests chronic use of β-blockers confers a time- and dose-dependent increased risk for Parkinson’s. Adjusted hazard ratio for Parkinson’s among β-blocker users was 1.51 (95% CI; 1.28–1.77; p < 0.0001 – to read more about this).
  • Interesting manuscript on BioRxiv suggesting swallowing & chewing impairment is associated with decreased presynaptic dopaminergic integrity in caudate. Greater motor & non-motor burden in early drug-naïve Parkinson’s ( to read more about this).
  • Researchers present results from a study seeking to identify novel diagnostic protein biomarkers of atypical Parkinson’s syndromes using multiplex proximity extension assay. Lower group levels of FGF-5, FGF-19 & SPOCK1 in MSA vs PSP ( to read more about this).
  • Researchers report that non-motor features of Parkinson’s fluctuate over the year, with worsening during winter months, suggestive of dysfunction of the body’s master clock – the suprachiasmatic nuclei ( to read more about this).
  • “In today’s busy buzzing world, it seems wasteful not to make use of the various diagnostic clues that can be picked up readily while the patient is still in the waiting room” – researchers provide further key insights into Parkinson’s ( to read more about this).

  • Researchers investigated the association between Parkinson’s severity & fat distribution patterns. Data from 195 PD subjects finds a negative association between motor severity & total fat mass in PD, more specific to android pattern of fat distribution ( to read more about this).
  • Another reason for not wasting any tears on Parkinson’s! Researchers report that analysis of tear fluid from 36 PD & 18 control subjects finds PD-specific changes in the “tear proteome” (mainly involving immune response & lipid metabolism – to read more about this).
  • Retrospective data from 129 subjects indicates that deeper sleep relates to slower motor progression in Parkinson’s ( to read more about this).
  • Researchers provides a mechanistic basis for understanding the Parkinson’s OFF state & also provides further conceptual link with network-level reconfiguration ( to read more about this).
  • New report suggests Parkinson’s is associated with dysregulations of a dopamine-modulated gene network relevant to sleep & affective neurobehaviors in the striatum. Integrating multi-omics data to reveal insights into comorbid symptoms of complex conditions ( to read more about this).
  • Clinical assessment followed by postmortem brain analysis suggests that the rate of progressive parkinsonism in older adults with & without a clinical diagnosis of Parkinson’s is related to the burden of mixed brain pathologies (Click here to read more about this).
  • The Movement disorder society Task Force on Technology provide a tentative roadmap for implementation of patient‐centered digital outcome measures in Parkinson’s obtained using mobile health technologies. Nice use of “patient‐centered”, but not OPEN ACCESS. A shame – miss opportunity for them to further engage the community ( to read more about this).

  • And a viewpoint provided by the Movement Disorder Society Technology Task Force & the MDS Rating Scales Program Electronic Development Ad‐Hoc Committee on the new Parkinson’s disease e‐diary: Developing a clinical & research tool for the digital age. Again not OPEN ACCESS ( to read more about this).
  • Genome-wide association study of Parkinson’s progression biomarkers in (not 1 but) 12 longitudinal patients’ cohorts. 12 longitudinal cohorts (a total of 4,093 people with Parkinson’s) with 25,254 observations over a median of 3.81 years. Rs382940(T>A), within the intron of SLC44A1, is associated with reaching Hoehn and Yahr stage 3 or higher faster ( to read more about this).
  • The results of a randomised trial to test the effects on care quality of chronic care model–based management to improve PD care quality has been published (Click here to read more about this).
  • The Parkinson’s phenotype” – characteristics associated with PD (seriously, someone needs to explain chin dimple to me – to read more about this).
  • Metabolic profiles from people with PARK2-associated Parkinson’s show significantly higher levels of fatty acid metabolites & oxidized lipids, also significantly lower levels of antioxidant, caffeine, & benzoate‐related metabolites ( to read more about this).
  • Sequencing of 11 HLA genes in 1,597 Parkinson’s cases & 1,606 controls suggests that susceptibility to PD may be explained by a specific combination of amino acids on the HLA-DRB1 molecule (previously the primary risk factor in rheumatoid arthritis). Interesting to note that the effects are modified by history of cigarette smoking ( to read more about this).
  • The corpus callosum is a bundle of fibres that connect the two hemispheres of the cerebral cortex of the brain. Now researchers report a curious case study of an individual with Parkinson’s & no corpus callosum, suggesting that bilateral degenerative changes may occur independently ( to read more about this).

  • A new BioRxiv manuscript pairs genomic & transcriptomic data from putamen & substantia nigra dissected from 117 brains to investigate regulation at different stages of RNA processing. Finds Parkinson’s-relevant regulatory loci enrichment ( to read more about this).
  • Is Parkinson’s a disorder of motor habits? Spanish & English participants – with & without Parkinson’s – were tested on skilled typing test. Recently diagnosed PD patients made fewer habit errors than healthy controls. Previous research suggests pattern dopamine neurons loss – starting in the ventrolateral substantia nigra and their branches in the caudal putamen – should affect habitual behaviour. In this study, the researchers tested ‘action slips’ (eg writing ‘thing’ instead of ‘think’ out if force of habit), and they found that folks with PD made less if these errors. The idea being loss of dopamine fibres = reduction in errors. Folks with PD did have more motor errors, but less habit errors ( to read more about this).
  • Researchers report that manganese can promote the aggregation & prion-like cell-to-cell exosomal transmission of Parkiinson’s-associated alpha synuclein. Welders exposed to manganese had increased misfolded α-Syn content in their serum exosomes ( to read more about this and click here to read the press release).

 

New clinical trials

  • The ADepT-PD clinical trial of two antidepressants (escitalopram & nortriptyline) compared to placebo for the treatment of depression in Parkinson’s has been registered ( to read more about this).
  • A new clinical study has been registered to look at transnasal nicotine treatment (via nasal spray) in Parkinson’s (Click here to read more about this).
  • The Kick Out Parkinson’s Disease 2 clinical study has been registered. It will involve 6 months of twice-weekly karate classes (Click here to read more about this).

  • Interesting new clinical study has been registered: The Rostock international Parkinson’s (ROPAD) study will seek to identify 1,500 people with LRRK2-associated PD & 1,500 folks with non-LRRK2 PD for blood biomarker analysis. Supported by Centogene (Click here to read more about this).
  • A phase II/III gut microbiota transplantation clinical trial for Parkinson’s in Israel has been registered (100 participants; 1st endpoint: UPDRS III; 2nd endpoint constipation – Click here to read more about this).
  • The Great Database of China! The Chinese Parkinson’s disease Registry (CPDR) has been registered. This is an effort to develop a database of patients with Parkinson’s in China (Click here to read more about this).

 

Clinical trial news

  • Clinical study of 117 people with Parkinson’s finds increasing dose of carbidopa in combo with levodopa & entacapone should be considered in the treatment of fluctuating PD to improve daily OFF times. COMT genotyping may improve treatment strategies ( to read more about this).
  • A randomized controlled trial of photobiomodulation in Parkinson’s found treatment for 9 weeks (2 sessions/week) resulted in no difference between treated & control groups, but improved gait speed in the fast rythm of the 10 metre timed walk test ( to read more about this).
  • Neurocrine Biosciences & Voyager Therapeutics today announced the publication of interim results from the Phase Ib trial of VY-AADC, an investigational gene therapy treatment for Parkinson’s. Also provide an update on Phase II (RESTORE-1) plans ( to read more about this and to read the journal report ).

  • Interesting data from ongoing “PD Nilotinib” Phase II clinical trial in Parkinson’s – results suggest Nilotinib enters brain in a dose‐independent manner. A single dose increases DOPAC & HVA levels, and reduces plasma alpha‐synuclein & inflammation levels ( to read more about this and click here to read the press release).
  • The US FDA has approved an Investigational New Drug (IND) application from Neurolixis for a clinical trial of NLX-112 (a serotonin 5-HT1A receptor agonist) in people with Parkinson’s who suffer L-DOPA-induced dyskinesias (funding from Parkinson’s UK –  to read more about this).
  • Gene therapy company Axovant has reported 3 month data from the SUNRISE-PD Phase 2 trial. The data is from 2 patients treated with the lowest planned dose of its AXO-Lenti-PD gene therapy for Parkinson’s. Both have benefits across all UPDRS OFF subscales. Individual patient improvements in UPDRS Part III OFF score were 14-points and 36-points. Important to remember that this is just a symptomatic therapy for Parkinson’s. Reductions in ON state dyskinesias reported. First patient in second cohort expected to be dosed in Q2 2019 ( to read more about this).
  • Sanofi Genezyme presented clinical trial results at the Alzheimer’s & Parkinson’s (ADPD) meeting in Lisbon this month. Venglustat is an oral, brain penetrant GCS inhibitor being developed for people with GBA-associated Parkinson’s. The MOVE-PD clinical trial is a Phase II evaluating venglustat in early stage GBA-PD ( to read more about the trial). Safety/tolerability data was presented and it looked good. No difference between placebo & treatment in frequency of complications. No serious adverse events. Plasma & CSF GL1 levels decreased over 4 weeks in a dose dependent manner. Investigators are confident to move on to Part 2 of the clinical trial: To determine the efficacy of venglustat administered daily (compared to placebo) in 200+ people with early-stage GBA-associated Parkinson’s (52 weeks of treatment period, 104 weeks of follow-up).

  • The AIM-PD ambroxol clinical trial in Parkinson’s results were presented in the ADPD meeting and they look good. Brain penetration looks good, and GCase levels were raised. Soon to be published. Big new trial being proposed.
  • Very interesting set of talks at the ADPD meeting from Cortexyme on their Alzheimer’s clinical research program. This biotech firm has data suggesting that the bacteria P. gingivalis is found in the brains of people with Alzheimer’s. They are testing a drug that inhibit Pg’s neurotoxic protease. Phase I trial data suggest the drug (COR388) is safe, & a Phase 2/3 GAIN (GingipAIN Inhibitor for Alzheimer’s disease) clinical trial will begin enrollment in Q2 2019 at sites across the US & Europe. Fingers crossed. One has to ask: Could bacteria be involved with Parkinson’s?

  • Intra-Cellular Therapies presented the results of a Phase I/II clinical trial of their selective phosphodiesterase 1 (PDE1) inhibitor, ITI-214 in Parkinson’s for improved motor control & potential disease modification at the ADPD meeting. Results are based on small numbers, but the drug looks safe & well tolerated. The company is seeking to initiate a Phase II trial in Parkinson’s this year.
  • The results of the pivotal phase III “SIAXI” clinical trial – investigating the efficacy & safety of Xeomin (incobotulinumtoxinA) for the treatment of chronic sialorrhea (drooling or excessive salivation) due to Parkinson’s – have been published ( to read more about this).
  • The safety/toxicity data from the Phase I-II clinical trial of Cerebral Dopamine Neurotrophic Factor (CDNF) in Parkinson’s were presented by representatives from Herantis pharma at the ADPD meeting, and they look good. The study uses the same infusuon device as the Bristol GDNF clinical trial. Only 2 withdrawals (not due to CDNF). Efficacy measures will be available next year.

 

Other news

  • Resonate Forward LLC – a tech start up – has received a $440K grant from the Michael J Fox Foundation to test their new device (called VibeForward) that uses vibration therapy to reduce symptoms of freezing of gait in people with Parkinson’s ( to read more about this).
  • Cell Guidance Systems has received funding from Innovate UK for a £270k project that will assess the potential of their POlyhedrin Delivery System (PODS™) containing specific growth factors to treat Parkinson’s ( to read more about this).

  • StressMarq Biosciences Inc. patent application for a novel antibody therapeutic candidate to combat Parkinson’s has been published ( to read more about this).
  • UK Biobank researchers have put a manuscript on BioRxiv overviewing the first 50K participants in this mammoth 500K individuals study (65 people in the 1st 50K have Parkinson’s). This will be an amazing resource for research ( to read more about this and click here to read the press release).

  • Servier & Oncodesign_SA have announced a strategic partnership for R&D into potential drug candidates for Parkinson’s. Specifially, they are seeking to develop LRRK2 kinase inhibitors ( to read more about this).
  • Swedish biotechfirm Bioarctic & big pharma Abbvie have announced the initiation of their Phase I clinical trial of ABBV-0805 in healthy volunteers. ABBV-0805 is an immunotherapy treatment for Parkinson’s which targets alpha synuclein ( to read more about this).
  • The biotech firm Cerespir has announced the formation of an expanded Clinical Advisory Board to support Phase II clinical development of its lead compound Itanapraced in Parkinson’s ( to read more about this).
  • Prevail Therapeutics raises an additional $50 million in series B Financing to advance pipeline of gene therapies for neurodegenerative conditions like Parkinson’s ( to read more about this).

  • Swedish biotech firm Lobsor Pharmaceuticals has been granted a U.S. patent for its advanced Parkinson’s treatment Lecigon – a combination of levodopa, carbidopa & entacapone which is continuously infused into the small intestine ( to read more about this).
  • Aptinyx Inc to present preclinical data of the effects their NMDAr modulator NYX-458 has on cognitive impairment in a non-human primate model of Parkinson’s at the AD/PD meeting in Lisbon ( to read more about this).
  • The PDMitoQUANT consortium have been awarded €7 million by the Innovative Medicines Initiative to improve our understanding of Parkinson’s through deeper research of mitochondrial dysfunction ( to read more about this).
  • Il-yang Pharmaceutical announced today that it plans to initiate clinical trials in Europe to develop its Parkinson’s drug development program. Trials start in the second half of the year ( to read more about this).

 

Review articles/videos

  • Interesting discussion hypothesizing that T-cell-driven inflammation triggered in the gut mucosa may be mediating dopamine neuron degeneration in Parkinson’s ( to read more about this).
  • Everything you ever wanted to know about AAV-based gene therapy for conditions like Parkinson’s ( to read more about this).
  • Interesting review of how different aspects of inflammation & the immune system influence Parkinson’s, with particular focus on the possible role played by immune dysfunctions (autoimmunity & infectious agents) in PD ( to read more about this).
  • Interesting webinar on Sleep and Parkinson’s:

  • A useful book chapter on deep brain stimulation for Parkinson’s, providing a review of clinical effectiveness, cost-effectiveness, & guidelines ( to read more about this).
  • A discussion of autoimmunity in Parkinson’s – “If α-syn-specific T-cells are driving neurodegeneration in PD, then biomarkers, diagnostic tools, & treatments can be adapted to identifying autoimmune cells in patients & targeting them” ( to read more about this).
  • A fantastic review of the electrical, cellular, molecular, & neurochemical mechanisms of deep brain stimulation as applied specifically to Parkinson’s. A one-stop-shop, master class, all you need 2 know! ( to read more about this).
  • Interesting new Gates Foundation-sponsored study of global, regional, & national burden of neurological conditions (from 1990–2016) – including data on Parkinson’s – has been published ( to read more about this).

  • Researchers provide an “everything you ever wanted to know about” Freezing of Gait in Parkinson’s. From pathophysiology to pragmatic approaches for management ( to read more about this).
  • Genome-editing CRISPR (clustered regularly interspaced short palindromic repeats) technology is revolutionising Parkinson’s research. This review provides a pretty good overview of how it is being used to dissect neuroinflammatory pathways involved in PD ( to read more about this).
  • This review provides a master class on the brain circuit mechanisms of Parkinson’s, also delving into someof the unanswered questions ( to read more about this).
  • Interesting review highlighting the utility of the nematode roundworm Caenorhabditis elegans (C. elegans) to successfully uncover new conserved genetic modifiers, functional mechanisms, therapeutic targets for Parkinson’s ( to read more about this).

  • Love this title: “What Happens in Vagus…” – a brilliant review on the communication pathways that the gut microbiota use to influence brain & behaviour (with mention of Parkinson’s – to read more about this).
  • A nice review of the clinical & neuropathological differences between Parkinson’s, Parkinson’s dementia, & dementia with Lewy bodies. Providing an overview of current issues & future directions ( to read more about this).
  • Interesting review of compensation strategies for gait impairments in Parkinson’s. 59 unique compensation strategies identified from several 100 videos, classified into seven main categories ( to read more about this).
  • Ooh la la! Quelle magnifique website! The SoPD in français – merci Michel! C’est superbe! ( to read more).
  • The Eve of Parkinson’s – A conference by women with Parkinson’s for women with Parkinson’s (and anyone else who is interested!). A proactive effort coming from the community itself – & what an amazing line up of speakers! Great stuff! ( to read more about this).

 

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

And there it is, just some of the highlights from March 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 April!


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.


4 comments

  1. macgreene2701

    Thank you for putting together this summary and overview. I hope that someone is working on an integration of clinically relevant findings, addressed to the educated but non-scientific reader.

    Like

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