Monthly Research Review – August 2021

# # # #

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 August 2021.

The post is divided into 10 parts based on the type of research:

# # # #


So, what happened during August 2021?

In world news:

August 6th – SpaceX stacked the Super Heavy Booster 4 and Star Ship 20 (Click here to read more about this)

 

August 9th – The Intergovernmental Panel on Climate Change releases the first part of its Sixth Assessment Report, which concludes that the effects of human-caused climate change are now “widespread, rapid, and intensifying“.

 

August 13th – Gino Strada passed away – and shame on you if you don’t know who he is

 

August 15th – The 50th anniversary of Nixon closing the “gold window” to foreign countries and ‘temporarily‘ abandoning the Bretton Woods Agreement, removing the gold standard and starting a new age of fiat currencies.

 

August 28th – The world’s northernmost island – a small patch of land measuring 60 x 30 metres – was announced by scientists off the coast of Greenland. The name Qeqertaq Avannarleq is proposed, which means “the northernmost island” (original!).

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

In August 2021, there were 765 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (8,101 for all of 2021 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 4 pieces of Parkinson’s news

1.  RePoopulating the gut:

Researchers reported that gut microbiota transplantation from young donors could reverse some aging-associated differences in peripheral & brain immunity in mice. Bi-weekly fecal microbiota transplants (FMT) for 8 weeks was also found to “attenuate aging-associated deficits in behavior“. At baseline (Pre-FMT), there were clear differences between young & aged mice in the diversity of the gut microbiota. But after 8 weeks of FMT treatment those differences were no longer significant. Exactly how “Young FMT into an aged host may selectively modulate peripheral immunity” is not clear. But in the aged brain, some aspect of the behaviour of resident immune cells – microglial – was reversed by young FMT treatments – click here to read more about this, click here to read the press release and click here to read an SoPD post on this topic).

 

2. Where genetics and environment meet:

Researchers reported evidence for overabundance of opportunistic pathogens in the Parkinson’s gut microbiota. Short-chain fatty acid (SCFA)-producing bacteria were reduced in PD (Click here to read more about this). Further research from this same group found “evidence that the overabundance of opportunistic pathogens in Parkinson’s gut is influenced by the host genotype at the alpha-synuclein locus, & that the variants responsible modulate alpha-synuclein expression“. They reported that “Genetic susceptibility to disease & the dysbiosis in the gut microbiome are not operating independently“. This research leads to testable hypothesis regarding the incomplete penetrance of Parkinson’s susceptibility genes (Click here to read more about this).

 

3. Epigenetic dysregulation of the autophagy–lysosomal pathway:

Lots of gut related research this month! Researchers reported epigenetic dysregulation of the autophagy–lysosomal (waste disposal) pathway of cells in the appendices of people with Parkinson’s. They found that the autophagy–lysosomal pathway changes in DNA methylation occurred in response to gut inflammation & α-synuclein aggregation. The DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology (Click here to read more about this).

 

4. There’s gold in them tha brains:

Clene Nanomedicine reports positive top-line results from its Phase 2 REPAIR clinical trials in Parkinson’s & Multiple Sclerosis. The company’s gold nanocrystal suspension, CNM-Au8, significantly improved brain energetic metabolism based on MRS imaging. 13 Parkinson’s patients were involved in the REPAIR-PD study. NAD+/NADH ratio demonstrated a statistically significantly elevated by an average of 0.589 units (10.4%) following 12-weeks of CNM-Au8 treatment (p=0.037). The study also found that CNM-Au8 was safe & well tolerated. The company is now seeking to take their molecule into Phase II testing for Parkinson’s (Click here to read more about this and click here for a old SoPD post on this technology).

 

Articles of general interest

    • The 2021 update of the Parkinson’s Drug Therapies in the Clinical Trial Pipeline has been published in the Journal of Parkinson’s (Click here to read more about this).
    • The PDTrialTracker website also has a wealth of useful information on the topic of clinical trials for Parkinson’s (Click here to read more about this).
    • “Individuals are not averages” – very interesting discussion on the recent Cure Parkinsons, Van Andel Institute, and Journal of PD supported webinar on “Genetic markers & the progression of Parkinson’s”:

 

Basic biology news

  • Endogenous DNAJB6 protein: mainly expressed in the cytoplasm & neurites (more in dendrites than in axons) in vitro; Isoform b (DNAJB6b) is reduced in brain material from people with Parkinson’s & MSA, but total DNAJB6 was up-regulated (Click here to read more about this).
  • New biorxiv manuscript suggests NAD+ repletion by PARP inhibition prevents Sarm1 activation & rotenone-induced cell death in in vitro & fly models of Parkinson’s (Click here to read more about this).

  • Mature Aβ42 fibrils catalyze biological reactions, particularly reactions associated with Alzheimer’s pathophysiology – such as neurotransmitter degeneration; Fibrils are more catalytic than both monomers & oligomers; “Aβ42 fibrils also catalyzed oxidation of the prominent neurotransmitters dopamine & adrenaline”; Maximal catalytic activity=full-length Aβ42 fibrils, fibrillar assemblies comprising Aβ42 subdomains were significantly less catalytic; Implications for Parkinson’s & a-synuclein? (Click here to read more about this).
  • Hi-through put mapping of a whole rhesus monkey brain at micrometer resolution; “Serial sectioning & clearing, 3D microscopy with semiautomated reconstruction & tracing (SMART), enables effective connectome-scale mapping of large primate brains” (Click here to read more about this).
  • Parkinson’s-associated α-synuclein selectively impairs motor sequence learning & value sensitivity; Using intracerebral injection of WT or A53T mutant α-Syn fibrils, researchers find adenosine A2A receptor antagonists (KW6002) reverse effect (Click here to read more about this).
  • Researchers present in vivo evidence that Parkinson’s-related pathogenic LRRK2 impairs basal mitophagy; GSK’s LRRK2 kinase inhibitor, GSK3357679A rescues impaired mitophagy in LRRK2-G2019S mice (Click here to read more about this).

  • New biorxiv manuscript presents evidence for local translation in the regulation of dopamine release from substantia nigra neuron dendrites, but not axons in mice; Interesting molecular signature for the sparse dopamine neurons that reside in the mouse SNr: Enrichment of Atp2a3 mRNA, which encodes the sarco/endoplasmic reticulum Ca2+-ATPase isoform 3 (SERCA3 – click here to read more about this).
  • “TrendyGenes”: A computational pipeline for the detection of literature trends in academia & drug discovery (Click here to read more about this).
  • New research indicates that Parkinson’s-associated alpha synuclein only forms fibrils in vitro when larger than its critical size of 70 monomers (Click here to read more about this).
  • New biorxiv manuscript reports glutamate transporter (EAAT2) trafficking is impaired in LRRK2-related Parkinson’s; Neurodegeneration in LRRK2-associated PD = extracellular glutamate overload? The investigators report that “EAAT2 is nearly absent in post-mortem basal ganglia from Parkinson’s disease (PD) patients carrying the LRRK2 G2019S mutation”, + associated with increased gliosis; Correction in vitro with LRRK2 inhibitor indicates LRRK2 kinase activity involved; Lrrk2 G2019S perturbs Glt-1 recycling & favors its degradation (Click here to read more about this).
  • Studying the effect of alpha-synuclein & Parkinson’s-linked mutants on inter pathway connectivities (Click here to read more about this).

  • New biorxiv manuscript reports crystal structures of the entire cytosolic domain of insect PINK1, revealing autophosphorylation dimer & provides insights into binding to the TOM complex (Click here to read more about this).
  • Cell specific photoswitchable agonist for reversible control of endogenous dopamine receptors; Ligand & cell type-specificity with temporally precise & reversible activation of dopamine receptors to control specific aspects of movement (Click here to read more about this).
  • Researchers report that cerebral organoids derived from a (single) Parkinson’s patient exhibit unique pathogenesis from Chikungunya virus infection when compared to a non-PD IPS cell line; A differential anti-viral response (Click here to read more about this).
  • Researchers use multiple microscopy techniques to track individual mitochondria in neurons lacking Drp1 & delineate the kinetics of Parkinson’s-associated PINK1-dependent pathways of mitochondrial quality control (Click here to read more about this).
  • Merck researchers from the company present data on the discovery, evolution, & optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors, being developed for Parkinson’s (Click here to read more about this).

  • A biorxiv manuscript introduces PhenoPLIER – a polygenic approach that maps both gene-trait associations & pharmacological perturbation data into a common latent representation for a joint analysis; Highlights disease etiology & drug mechanisms (Click here to read more about this).
  • Quantitative measurement of the affinity of toxic & non-toxic misfolded protein oligomers for lipid bilayers & of its modulation by lipid composition & Trodusquemine (Click here to read more about this).
  • Researchers demonstrate a fully implantable, wireless, battery-free platform that allows for chronic deep brain stimulation in rodents with the capability to control stimulation parameters digitally in real time (Click here to read more about this).
  • New insights into the interacting partners of synaptojanin-1 (a Parkinson’s-related protein that is essential for regulating clathrin-mediated synaptic vesicle endocytosis – click here to read more about this).
  • Virtual screening & biological activity evaluation of new potent inhibitors targeting the Parkinson’s-associated LRRK2 kinase domain (Click here to read more about this).
  • New report finds Parkinson’s-associated α-synuclein can induce DRP1-dependent mitochondrial fragmentation (in drosophila); Excess PINK1/Parkin rescues the phenotype (Click here to read more about this).

  • New research presents a drosophila model of α-synucleinopathy in which they can independently manipulate Parkinson’s-associated gene expression in neurons & glia; They explore glial modifiers of α-syn pathology (Click here to read more about this).
  • New report finds Parkinson’s-associated alpha-synuclein activates the classical complement pathway & mediates complement-dependent cell toxicity (in vitro); Higher levels of C1q in the putamen of MSA cases vs controls (Click here to read more about this).
  • DAXX, a polyD/E protein, prevents aggregation, solubilizes pre-existing aggregates & unfolds misfolded species of model substrates & neurodegeneration-associated proteins (like Parkinson’s-related a-syn & Alzheimer’s-associated b-amyloid); ATP-independent (Click here to read more about this).
  • New research reports that Parkinson’s-associated α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons; Modulation of D2 receptor activity (via agonist quinpirole) can ameliorate the pathophysiology (Click here to read more about this).
  • New biorxiv manuscript suggests a feedforward mechanism of Parkinson’s-associated Parkin activation that confers robustness & rapidity to the PINK1-parkin pathway (Click here to read more about this).

  • Researchers offer new insights into normal function of Parkinson’s-associated α-synuclein; α-synuclein regulates microsecond fusion pore transitions (an intermediate of membrane fusion); Abnormal secretion occurs under pathological conditions (Click here to read more about this).
  • Using RNA-Seq & ATAC-Seq, researchers profiled differentially expressed transcripts & open chromatin regions during early dopaminergic neuron differentiation; Open regions decrease upon differentiation; Highlights CTCF (Click here to read more about this).
  • Researchers performed aptamer DNA-PAINT on serum samples & found the ratio of the number of β-sheet α-synuclein aggregates to β-sheet amyloid-β aggregates discriminated Parkinson’s (from controls – click here to read more about this).
  • Researchers tested whether the observed incidence of Parkinson’s is consistent with a multistep process; They propose a multi-step model of PD pathogenesis – on average six steps before age 45, & eight afterwards (Click here to read more about this).
  • Genetically deleting or pharmacologically inhibiting the gut microbiota-related curli major subunit CsgA in E. coli reduced Parkinson’s-associated α-syn–induced neuronal death, restored mitochondrial health, & improved neuronal functions in C. elegans (Click here to read the abstract and click here for a preprint manuscript of this paper).

  • Could Argininosuccinate lyase in ALDH1A1+ substantia nigra neurons metabolically contribute to degenerative processes in Parkinson’s? Loss of ASL in mice results in catecholamine deficiency, accumulation of tyrosine aggregates, & elevation of α-synuclein (Click here to read more about this).
  • New report outlines the discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo anti-Parkinson’s symptoms & anti-dystonic efficacy (Click here to read more about this).
  • CryoEM-based structural studies find cholesterol binding site in brain GIRK2 channel; Mutational & functional studies reveal key residues in cholesterol potentiation (Click here to read more about this).
  • Regulated gene therapy has been a goal for researchers for a long time, but “leakiness” and poor control has been a problem. Now researchers report regulation of gene therapies by a novel drug-induced splicing. The switch system, denoted “Xon”, does not require the co-expression of any regulatory proteins (Click here to read more about this).
  • Western equine encephalitis virus infection causes dopaminergic neurodegeneration & Parkinson’s-associated ⍺-synuclein aggregation in mice. New research reports microglia & astrocyte activation occurs prior to this; NFκB-/- in astrocytes protects (Click here to read more about this).

  • While Parkinson’s-related α-synuclein leads to a destruction of the lipid membrane upon membrane-catalyzed aggregation, other synuclein family members aggregated significantly less, did not harm the membrane, & reduced membrane damage triggered by α-Syn (Click here to read more about this).
  • New biorxiv manuscript suggests glycation modulates glutamatergic signaling & exacerbates Parkinson’s-like phenotypes; Glycation induces the accumulation of aSyn & AGEs in the midbrain (Click here to read more about this).
  • Removal of N-terminal residues of Parkinson’s-associated α-synuclein outside the canonical amyloid core weakens fibril seeding efficiency & hinders propagation; Results demonstrate vital role for the N-terminal residues in α-synuclein fibril structure/formation (Click here to read more about this).
  • New research presents the manipulation of nigrostriatal dopamine neurons in freely behaving marmosets; Also demonstrated the utility of non-invasive imaging methods for validating DREADD expression & assessing the functional effects of DREADDs (Click here to read more about this).
  • CRISPR systems are quite diverse, including some, like CRISPR-Cas13, which target RNA. Now researchers have found tiny versions of Cas13b (Cas13bt) that can be used to create RNA editors small enough to fit into a single AAV for in vivo delivery (Click here to read more about this).

 

Disease mechanism

  • New study finds deletion of NEK1 gene in mice results in accumulation of Parkinson’s-associated alpha synuclein; Inhibition of RIPK1 reduces neuroinflammation & aggregation of α-synuclein in the brains of NEK1 deficient mice (Click here to read more about this).
  • New research reports Alterity Therapeutic‘s ATH434 reverses colorectal dysfunction in the A53T mouse model of Parkinson’s (after dysfunction was established – click here to read more about this).

  • New biorxiv manuscript suggests significant homeostatic plasticity (mediated by Kv4.3 downregulation) in surviving dopamine neurons after a single-hit, non-progressive lesion; Could this relate to the initially surviving dopamine neurons in Parkinson’s? (Click here to read more about this).
  • High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, & perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson’s (Click here to read more about this).
  • Is the TREM2 pathway druggable with ligands for thyroid hormone receptor? Thyromimetics (synthetic analogs of thyroid hormones) produce anti-inflammatory effects & reduced clinical scores in model of Multiple Sclerosis (EAE); Implications for Parkinson’s? (Click here to read more about this).
  • Researchers from Stellate Therapeutics present new data on queuine, a gut bacterial-derived hypermodified nucleobase, which shows protection in in vitro models of neurodegeneration; Significantly reduced in hyperphosphorylated alpha-synuclein in a model of Parkinsons; Plasma queuine levels are not age-dependent, but higher in females (both healthy humans & mice – click here to read more about this).

  • A translational systematic review & meta-analysis protocol of clinical & preclinical studies of GLP-1 & GIP receptor agonists for the treatment of Parkinson’s (Click here to read more about this).
  • New research reports that overexpression of DNAJB6 suppresses alpha-synuclein induced pathology in a rodent model of Parkinson’s & rescues motor impairments (Click here to read more about this).
  • Further support for the rationale for repurposing anti-diabetics for Parkinson’s treatment: Researchers report higher levels of IRS-1pS312 immunohistochemistry in postmortem PD brain; Evidence for brain insulin resistance in PD? (Click here to read more about this).
  • New research reports experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation & Parkinson’s-related neuropathology; RGS10 levels reduced in blood immune cells of PD patients (Click here to read more about this).
  • New biorxiv manuscript suggests KATP inhibitor, glyburide, altered Alzheimer’s-related pathology in APP/PS1 mice via reduced arterial stiffness, improved vasoreactivity, & normalize pericyte-endothelial cell morphology (Click here to read more about this).

  • New research reports constitutive silencing of the Parkinson’s-associated LRRK2 kinase in vivo (data in mice) results in early deregulation of GCase activity followed by late impairment of macroautophagy & chaperone-mediated autophagy (Click here to read more about this).
  • Researchers asked whether analysis of Miro1 in fibroblasts could serve as a molecular marker for risk of Parkinson’s; They find Miro1 is resistant to degradation in iPSCs from individuals at risk of PD (Click here to read more about this).
  • New research reports that the GLP-1 receptor agonist, liraglutide, failed to slow disease progression in SOD1G93A & TDP-43Q331K transgenic mouse models of ALS (Click here to read more about this).
  • Impaired dopamine metabolism is linked to fatigability in mice & fatigue in Parkinson’s patients; Reserpine-induced striatal dopamine depletion in mice was rescued by reestablishing BH4 levels (Click here to read more about this).
  • New report finds Anavex Life Science‘s sigma-1 receptor (S1R) agonist ANAVEX2-73 (blarcamesine) rescues a mouse model of fragile X syndrome (Click here to read more about this).

  • Telmisartan, an angiotensin II type 1 receptor antagonist, improves mitochondria-specific genes expression in a mouse MPTP model of Parkinson’s (Click here to read more about this).
  • Rescue of lysosomal storage dysfunction in Grn–/– mice via a brain penetrant progranulin biologic (PGRN fused to a human transferrin receptor binding Fc to increase CNS exposure – PTV:PGRN from Denali Therapeutics); Potential for Parkinson’s here? (Click here to read more about this).
  • Using novel monoclonal antibodies to neo-epitopes resulting from specific cleavages in the carboxy terminal region of α-synuclein, researchers report significant disease-, region-, & cell-type specific differences in the profile of α-synuclein cleavage (Click here to read more about this).

 

Clinical research

  • Some of the complexities of clinical classification systems & long-term outcomes (~8yrs in this case) in mid- & late-stage Parkinson’s are explored in this paper (Click here to read more about this).
  • The Michael J Fox Foundation PPMI dataset is such an amazing resource! Using the data, researchers developed a statistical progression model of early Parkinson’s that accounts for intra-individual + inter-individual variability AND medication effects; 8 state model (Click here to read more about this).

  • Data from PPMI database indicates apathy could be present in the premotor period of GBA & LRRK2 variant carriers; GBA non-manifesting carriers = 3x higher risk to develop apathy (vs controls); Anxiety more prevalent in GBA asymptomatic carriers (vs LRRK2 – click here to read more about this).
  • Under-represented communities: Clinical and genetic analysis of Costa Rican patients with Parkinson’s (Click here to read more about this).
  • Different profiles of senescence‐associated secretory phenotype (SASP) & immune defense factors in urine-derived extracellular vesicles between elders with Parkinson’s (n=24) & without (n=10); Anti-inflammatory IL-10 levels reduced; Pro-inflammatory MCP-1 increased (Click here to read more about this).
  • New medrxiv manuscript presents longitudinal clinical-genetic data of 2536 individuals in the “Tracking Parkinson’s” & Oxford Discovery cohorts that suggests no association between RIMS2 & PD dementia (Click here to read more about this).
  • 500 drug-naïve Parkinson’s patients who underwent DATScan imaging were divided into 2 groups based on prior statin use; Longitudinal changes suggests that statin use may have a detrimental effect (faster increase in levodopa & dementia conversion – click here to read more about this).

  • Researchers representing the American Association of Neurology present the second update of the Parkinson’s Quality Measurement Set, attempting to decrease documentation burden without sacrificing quality (Click here to read more about this).
  • Risk disclosure in prodromal Parkinson’s; Literature review + questionnaire based on a Delphi approach; Guidelines are required for a complicated task (Click here to read more about this).
  • Researchers tested whether the observed incidence of Parkinson’s is consistent with a multistep process; They propose a multi-step model of PD pathogenesis – on average six steps before age 45, & eight afterwards (Click here to read more about this).
  • Nationwide (South Korea) retrospective cohort study evaluating any link between periodontitis & risk of Parkinson’s finds a weak association after adjusting for confounding factors; People with periodontitis + metabolic syndrome had the highest HR (1.16 – click here to read more about this).

  • New study assesses dietary fiber’s effect on fecal short chain fatty acids (SCFA) production of Parkinson’s patients found PD diagnosis limited SCFA production & negatively influenced both Clostridium-group abundances; Butyrate production is reduced vs controls (Click here to read more about this).
  • Researchers identify a novel coding DAT variant (DAT-K619N) in an early-onset parkinsonism patient with comorbid neuropsychiatric disease. They dig deeper & find the variant causes reduced dopamine uptake & increased DAT turnover (Click here to read more about this).
  • New study provides evidence for clinically relevant structural damage to the cortical hubs of the salience network in Parkinson’s, possibly due to extensive local neuropathology & loss of interconnecting anterior insular cortex + anterior cingulate cortex (Click here to read more about this).
  • Search for objective diagnostic biomarkers continues: Systematic assessment of 10 candidates focused on α-syn-related conditions finds “some interesting diagnostic markers in CSF and peripheral blood but need further and independent validation” (really? Click here to read more about this).
  • Whole-blood RNA species in 4,871 longitudinal samples from 1,570 clinically phenotyped individuals with Parkinson’s in PPMI cohort suggests sig. altered RNA expression (>2K DEGs); Early & persistent increase in neutrophil gene expression, reduced lymphocyte cell counts (Click here to read more about this).

  • New report examines the performance & limitations of smartphones in collecting real world data in the remote mPower observational study of Parkinson’s; n=960; Performance correlated with in-clinic evaluations (Click here to read more about this).
  • 123I-MIBG myocardial uptake imaging experiment in 227 PD patients finds that cardiac sympathetic burden reflects Parkinson’s burden, regardless of high or low orthostatic blood pressure changes (Click here to read more about this).
  • New medrxiv manuscript suggests the choroid plexus in Alzheimer’s has pro-inflammatory signature with aberrant protein accumulations; MRI reveals the choroid plexus in AD displays pathological signal & increased volume, inversely correlates with cog decline (Click here to read more about this).
  • A multiplatform metabolomics analysis of Parkinson’s in the Spanish EPIC cohort revealed alterations in free fatty acids metabolism, mitochondrial dysfunction, oxidative stress, & gut–brain axis dysregulation long before the development of PD (Click here to read more about this).
  • Biofluids profile of “anti-aging” α-Klotho in patients with Parkinson’s; CSF α-Klotho is increased in PD patients & inversely correlated with CSF α-synuclein; Serum α-Klotho reduced in PD patients (Click here to read more about this).

  • New research finds impaired sensory evidence accumulation & network function in Lewy body dementia; n=13 Parkinson’s dementia, 18 dementia with Lewy bodies, 16 Alzheimer’s, & 23 controls; Slower drift rates in LBD vs AD (Click here to read more about this).
  • A new medRxiv manuscript suggests that carrying a single PRKN mutation (heterozygous) is not associated with an increased risk of Parkinson’s disease (Click here to read more about this).
  • New report presents a non-invasive olfactory bulb measure (electrobulbogram; EBG ) that differentiates Parkinson’s patients from controls; Components of EBG are also linked to clinical PD measures (Click here to read more about this).
  • Of 30 704 males, 386 of 7676 former professional soccer players (5.0%) and 366 of 23 028 matched population control individuals (1.6%) were diagnosed with neurodegenerative disease. Goalkeepers less at risk (Click here to read more about this).

  • New medRxiv manuscript presents data from a population-based case-control study of 1.5 million veterans & finds synergy between post-traumatic stress disorder & traumatic brain injury up to 8 years before Parkinson’s (Click here to read more about this).
  • New medRxiv manuscript explores a non-invasive method of stratifying individuals with de novo  Parkinson’s, using PPMI clinical & imaging data from 318 cases (Click here to read more about this).
  • New research finds preexisting bipolar disorder can influence the subsequent phenotype of Parkinson’s (Click here to read more about this).
  • A mendelian randomization approach finds that increased menopausal age reduces the risk of Parkinson’s, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective; Multiple large cohorts used in the study (Click here to read more about this).
  • Does height & weight matter in terms of orthostatic hypotension (oH) in Parkinson’s? New study reports BMI did not differ between patients with either cOH or tOH compared with those without OH (Click here to read more about this).

  • New research finds cortical connectivity with the STN at high beta frequencies reflects activity within the hyper-direct pathway; Parkinson’s may lead to the generation of subcortical synchrony at lower beta frequencies (Click here to read more about this).
  • The contribution of beta-amyloid to dementia in Lewy body diseases: a 1-year follow-up study; findings suggest that in Lewy Body Diseases, amyloid deposition enhances cognitive deficits, particularly attention-executive & language dysfunctions (Click here to read more about this).
  • Connectivity of EEG synchronization networks increases for Parkinson’s patients with freezing of gait; Approach may be useful for evaluating FoG propensity (Click here to read more about this).
  • New report investigates the longitudinal impact of Rapid Eye Movement Sleep Behavior Disorder on the change in motor & non-motor symptoms in patients with Parkinson’s; Oxford Discovery cohort data finds PD + RBD = a more aggressive PD (Click here to read more about this).

New clinical trials

  • New clinical trial registered: The Personalized Parkinson Project de Novo Cohort (Click here to read more about this).
  • New clinical study registered: Development of a central repository for Parkinsons-related genomic data for future research; Parkinson’s Foundation PD GENEration Genetic Registry (n=15,000 – click here to read more about this).

  • New clinical study registered: The Personalized Parkinson’s Project de Novo Cohort (PPP-novo) will focus on validate novel digital biomarkers for disease progression; N=144 participants being monitored with the Verily Life Sciences Study Watch (Click here to read more about this).
  • New clinical study registered: Researchers are setting up the “Parkinson’s Disease & Movement Disorders Clinical Database“, seeking 250 participants to be monitored & assessed over 5 years (Click here to read more about this).

 

Clinical trial news

  • Design of the “CYClical Lower extremity Exercise for Parkinson’s II (the CYCLE-II Study) – multisite, single-rater blinded randomized trial assessing effectiveness of a long-term, home-based aerobic exercise intervention on slowing the progression of PD (Click here to read more about this).
  • A Phase II, randomized, placebo-controlled trial of safety & efficacy of anti-Tau monoclonal antibody gosuranemab in progressive supranuclear palsy (n=486) results indicate N-terminal Tau neutralization (98% reduction in CSF) does not translate to clinical efficacy (Click here to read more about this).

  • Programming directional deep brain stimulation in Parkinson’s: A randomized prospective trial comparing early vs delayed stimulation steering; Equally effective in the short term, but delayed steering=less time consuming (Click here to read more about this).
  • New study finds zonisamide (25 or 50 mg/day) was effective in the long-term (52 weeks) treatment of parkinsonism in dementia with Lewy bodies patients, without worsening psychiatric symptoms or cognitive function; No increase in concomitant Ldopa treatment (Click here to read more about this).

  • A preliminary analysis of the PD COMM pilot randomised controlled trial – a study comparing Lee Silverman Voice Treatment vs standard speech & language therapy vs no treatment control in 89 people with Parkinson’s & voice/speech problems; Result=no effect (Click here to read more about this).
  • New study finds that long-term success of low-frequency (<100 Hz) subthalamic nucleus stimulation for Parkinson’s depends on tremor severity & symptom duration (Click here to read more about this).

 

Conferences/lectures

  • On the 7th October at 19:00 (UK), the Edinburgh Parkinson’s Lecture will be given by Prof Roger Barker, entitled “Repairing the brain in Parkinson’s Disease – Is this possible?” (Click here to read more about this).

  • It’s all happening in Edinburgh – I am also really looking forward to the NECTAR 2021 meeting in Edinburgh in November. An extremely impressive line up of speakers/presenters – basically everyone in the field of regenerative therapy for PD (Click here and here to learn more about this). There is also a public event exploring clinical trial participation (Click here to learn more about this). And there are some really interesting podcasts being made to promote this event (Click here to listen to an example).
  • Parkinson’s UK have their 2021 PAR-CON virtual research conference lined up for October – lots of interesting topics (Click here to learn more about this).

 

Other news

  • BioVie Inc. announces its IPO & plans for a Phase 2 study of NE3107 (an Alzheimer’s-targetted inhibitor of inflammatory ERK signaling) in Parkinson’s to start later this year (Click here to read more about this).
  • Mission Therapeutics & Abbvie have announced progression of selected deubiquitylating enzyme (DUB) targets into the next phase of research in their neurodegenerative disease collaboration focused on Parkinson’s & Alzheimer’s (Click here to read more about this).

  • Roche enters into a strategic research collaboration with Shape Therapeutics (potentially exceeding $3 billion!!!) to support development of gene therapies for Alzheimer’s & Parkinson’s; Comes on the heels of $112 million Series B investment in June; This deal involves Shape’s RNA editing technologies – correcting RNA with disease associated variants, so that normal functioning protein can be made; Any products from the collaboration will be developed & commercialized by Roche (Click here to read more about this).

  • Amneal Pharma announces positive topline results from pivotal Phase 3 RISE-PD clinical trial of IPX-203 (CD/LD extended-release capsules) in individuals with Parkinson’s who experience motor fluctuations; 0.53 more hours of “Good On” time (Click here to read more about this).
  • Virtual biotech company NRG Therapeutics has received a further £490k in funding from Parkinson’s UK, bringing the total amount invested by the charity to £2.5m, to support the development of disease modifying drugs for the treatment of Parkinson’s (Click here to read more about this).

  • Elixiron Immunotherapeutics raised a US$27M Series A funding to advance clinical testing of EI-1071 (a CSF1R inhibitor) for Alzheimer’s; Can inhibiting microglia activation have potential in Parkinson’s? (Click here to read more about this).
  • The Silverstein Foundation for Parkinson’s with GBA announces grant funding to AcureX Therapeutics to support the development of a novel class of small molecule Miro1 targeting drug candidates for the treatment of Parkinson’s (Click here to read more about this).

Review articles/videos

  • A useful review on liquid–liquid phase separation in human health & diseases (including Parkinson’s); “it is clear that LLPS plays an essential role in the development of pathophysiological conditions” (even COVID – click here to read more about this).
  • A useful review of AMPK in the brain – its roles in glucose & neural metabolism (Click here to read more about this).
  • Digital health technology for non-motor symptoms in people with Parkinson’s: Futile or future?” from the Non Motor Parkinson’s Disease Study Group colleagues (Click here to read more about this).

  • LRRK2 inhibitors could be promising therapeutic agents for Parkinson’s; A new review presents an overview of recent developments & challenges in developing LRRK2 inhibitors, & discusses the potential targeting strategies from the protein perspective (Click here to read more about this).
  • The genetic landscape of Parkinsonism-related Dystonias & atypical Parkinsonism-related Syndromes – summarizing the plethora of available genetic information, outlining limits, & exploring future directions (Click here to read more about this).
  • New review on the therapeutic potential of Celastrol in central nervous system disorders, like Parkinson’s; Explores the in vitro & in vivo evidence (Click here to read more about this).

  • A systematic review of preclinical & clinical evidence of neurogenic & anti-inflammatory effects of probiotics in Parkinson’s (Click here to read more about this).
  • New review explores PLGA-based nanoparticles for neuroprotective drug delivery in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • An update on gene therapy approaches for Parkinson’s, focusing on restoration of dopaminergic function (Click here to read more about this).
  • New review explores genetic & environmental risk factors for neurodegenerative conditions, like Parkinson’s; Discussing communication among microbiota-gut-brain axis components + fecal microbiota transplant treatment strategies (Click here to read more about this).
  • A short, but very useful review on next-generation gene therapy for Parkinson’s using engineered viral vectors; “While a challenging road ahead, the future is bright for gene therapy” (Click here to read more about this).

  • Improved delivery methods for gene therapy & cell therapy in Parkinson’s; “Most important factor in delivering a biologically-based treatment is getting enough of the therapeutic to the target to produce a clinically meaningful change” (Click here to read more about this).
  • A short review of GBA1-associated Parkinson’s: Molecular aspects & potential treatment approaches (Click here to read more about this).
  • Negative innovation: when patents are bad for patients (Click here to read more about this).
  • A useful review on modelling the functional genomics of Parkinson’s in Caenorhabditis elegans, using the current knowledge on LRRK2 as an example (Click here to read more about this).
  • Useful overview on structural biology of Parkinson’s-related LRRK2 & its interaction with microtubules; LRRK2 inhibition: “type 1 inhibitors may have the unwanted effect of promoting binding of LRRK2 to microtubules” (Click here to read more about this).
  • Useful review on diabetes mellitus & Parkinson’s: Dangerous liaisons between insulin & dopamine… (Click here to read more about this).

  • Interesting commentary on using gene therapy in the putamen for “curing” AADC deficiency & Parkinson’s; “Although the pathophysiologies of #Parkinsons & AADC deficiency differ—the former is a neurodegenerative disease, while the latter is an enzyme deficiency—lessons from intraputaminal gene therapy in PD were crucial in developing its applications in AADC deficiency” (Click here to read more about this).
  • A useful primer on Rab GTPases in the context of Parkinson’s; “Aberrant Rab GTPase function can cause atypical PD (Rab39b) or regulate PD risk (Rab29), & phosphorylation of a small subset of Rab GTPases may relay aberrant LRRK2 kinase signaling” (Click here to read more about this).
  • An excellent primer on Genome-wide association studies (or GWAS), with everything you need to know about GWAS and different downstream analyses (Click here to read more about this).

  • A useful review on how the gastrointestinal tract may be modulating amyloid formation by amyloidogenic proteins in conditions like Parkinson’s; “Microbial & food amyloids can modulate a-Syn amyloid formation via direct interactions” (Click here to read more about this).
  • A new viewpoint suggest that “specific non-motor symptoms could be used as an additional anchor to motor symptoms & not as exclusion criteria to deliver bespoke & patient-specific personalised therapy for advanced Parkinson’s” (Click here to read more about this).
  • A useful review on Fyn kinase activity & its role in the pathology of neurodegenerative conditions (including Parkinson’s – click here to read more about this).
  • New review provides a template for considering disease stage when implementing diagnostic & progression imaging biomarkers in both clinical trials & clinical care settings for Parkinson’s (Click here to read more about this).

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

And there it is, just some of the highlights from August 2021 – 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 September (Christmas is coming!)

All of the material on this website is licensed under a
Creative Commons Attribution 4.0 International License
You can do whatever you like with it!


EDITOR’S NOTE: The author of this post is an employee of the Cure Parkinson’s Trust, so he might be a little bit biased in his views on research and clinical trials supported by the trust. That said, the trust has not requested the production of this post, and the author is sharing it simply because it may be of interest to the Parkinson’s community.

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.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.