Monthly research review – April 2021

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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 April 2021.

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

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So, what happened during April 2021?

In world news:

April 4th

 

April 15th – Investigators in China and the United States reported the injection of human stem cells into primate embryos, to grow chimeras for up to 20 days (and the world asked “Why?!? What was the point?!?” – click here to read the report and click here to read the press summary).

April 18th – The Super league! (Just a really dumb idea – basically, when rich people have more dollars than sense)

April 19th – “117 years after the Wright brothers succeeded in making the first flight on our planet, Nasa’s Ingenuity helicopter has succeeded in performing this amazing feat on another world” – Thomas Zurbuchen, Nasa’s associate administrator for science

April 21st – No Super League! Following an outcry from football fans and the withdrawal of the English clubs, the Super League was placed “on standby” (yeah, good luck with that).

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

In April 2021, there were 1,099 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (4,548 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 5 pieces of Parkinson’s news

1. Lots of APOEε4 research coming through…

ApoE is a region of DNA that produces a protein (ApoE) that can have different forms – the three most common versions are called ApoE2, ApoE3 & ApoE4. A new research report found that APOE4 in particular is associated with faster cognitive decline rate in Parkinson’s, but none of the APOE versions were associated with Parkinson’s related motor progression. Determining a person’s APOE status could potentially be used to predict the cognitive trajectory in Parkinson’s (Click here to read more about this). Another study published this month provided (Class II) evidence that increased physical activity reduces APOE4-related vulnerability to early cognitive decline in Parkinson’s cohort (N=173 recently diagnosed PD patients; 27% were APOE4 carriers). Larger replication studies are required, but this data is encouraging (Click here to read more about this).

 

2. The unintended consequences of immunotherapy? 

Immunotherapy is an experimental method of removing potentially toxic proteins from the body by boosting the body’s immune system. Researchers have published data suggesting that experimental antibody therapies for neurodegenerative conditions like Parkinson’s & Alzheimer’s may have an unintended adverse effect: Neuroinflammation.  They found that immunotherapy treatments were triggering an inflammatory response in the immune cells of the brain, potentially eroding any positive effect of the treatment. This finding could have important implications for ongoing immunotherapy clinical trials and help to improve their possible utility (Click here to read more about this and click here to read the press summary associated).

 

3. When two genetic variations are better than one

Individuals with GBA-associated Parkinson’s have been found to be more at risk of developing cognitive issues during the course of their condition. Curiously, the results of a new study suggest that longitudinal cognitive decline in individuals with GBA-associated Parkinson’s is more severe than in those with a combination of two Parkinson’s associated genetic variants: LRRK2 plus GBA-associated PD. That is, a genetic variant in both LRRK2 and GBA. The LRRK2/GBA combo was found to more closely resembled LRRK2-PD. The biological basis of association/interaction is not clear, but 1193 individuals with Parkinson’s involved in the study (128 (10.7%) had GBA-associated PD, 155 (13.0%) had LRRK2-associated PD, 21 (1.8%) had LRRK2/GBA-combo PD; Remaining 889 (74.5%) had idiopathic PD). “These findings suggest that there was not a convergent deleterious association of LRRK2 & GBA variations in Parkinson’s progression, as would be expected based on prior cellular studies” (Click here to read more about this).

 

4. The critical path of LRRK2 progression

Genetic mutations in a region of DNA called LRRK2 are associated with an increased risk of developing Parkinson’s. The Critical Path Institute Parkinson’s Consortium have been quantifying the rate of disease progression in people with LRRK2-associated Parkinson’s (N=158) and people with Parkinson’s but no LRRK2 mutation (N= 598). Their findings have recently been published and they show that the rate of progression in the non‐motor symptoms of Parkinson’s (as assessed by MDS‐UPDRS Part I) is ~60% lower in people with LRRK2 mutations. This result could have important implications for clinical trials, especially in terms of balancing randomised groups and also those studies focused on LRRK2 inhibition (Click here to read more about this).

5. Diabetes drugs (again):

DPP4 inhibitors are a class of medication that are used to treat diabetes, but new research from South Korea indicates that these drugs may confer beneficial effects on people with diabetes who go on to develop Parkinson’s. Using brain imaging techniques, researchers reported that diabetic patients with Parkinson’s being treated with DPP4 inhibitors had higher availability of dopamine in the brain than those in non-diabetic patients with PD. In addition, the rate of levodopa-induced dyskinesia was significantly lower in diabetic individuals with Parkinson’s who had been previously treated with DPP4 inhibitors (compared to diabetic individuals with Parkinson’s, but no exposure to DPP4 inhibitors (Click here to read more about this).

Articles of general interest

  • “Bringing Advanced Therapy Medicinal Products (ATMPs) for Parkinson’s to the clinic: The investigator’s perspective”; The reality/challenges of clinical translation; ATMPs include tissue engineered products, cell & gene treatments (Click here to read more about this).
  • Dopamine cell therapy for Parkinson’s: From cell replacement to circuitry repair; “Maximal long-term impact of a fully circuit-integrated intranigral midbrain dopamine neuron graft would be achieved when used in combination with a protective intervention blocking the progression of the underlying disease” (Click here to read more about this).
  • Pearls of wisdom! I am really enjoying the new Reflections on Parkinson’s Disease podcast from Profs Bas Bloem and Werner Poewe (Click here to learn more about this).

  • Where James isn’t – in honor of James Parkinson’s birthday (Click here to read more about this).
  • The essential guide to our current understanding of Parkinson’s – “a recognisable clinical syndrome with a range of causes & clinical presentations” (Click here to read more about this).
  • How patient advocacy is changing research:
  • A brief correspondence highlighting the ‘International Parkinson Disease Genomics Consortium Africa‘, with special nod to the input from two international patient advocacy organisations: Parkinson’s Africa & PD Avengers (Click here to read more about this).
  • New research from Parkinson’s UK presents the results of an online survey exploring which symptoms matter most to people with Parkinson’s; 790 people participated, 2,295 issues grouped into 24 broad symptom domains; “Certain features of Parkinson’s become more or less important to patients as the condition progresses”; Non-motor symptoms highly cited from earliest stages of PD; “Problems with walking, balance & falls, speech problems, freezing & dyskinesia become increasingly important” (Click here to read more about this and click here to read the press summary).

Basic biology news

  • Researches report data indicating that VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, & results in neurodegeneration; Case studies & C. elegans model of Parkinson’s (Click here to read more about this).
  • New evaluation of a low-toxicity PARP inhibitors as a neuroprotective agents for Parkinson’s; The ideal PARP inhibitor needs to inhibit PARP-1 hyperactivity while also limiting downstream DNA damage & cellular toxicity (ideal for oncology – click here to read more about this).

  • New research identifies a mitochondrial pathway of degradation of DJ-1 missense mutants implicated in Parkinson’s pathogenesis; Silencing of mitochondrial matrix protease LonP1 = big reduction of the degradation of the mitochondrial-associated DJ-1 mutants (Click here to read more about this).
  • New biorxiv manuscript explores how α-synuclein alters dopaminergic neuronal dynamics & dopamine transmission prior to cell death; Dysregulation of D2R autoinhibition contributes to vulnerability of dopamine neurons; Implications for Parkinson’s? (Click here to read more about this).
  • Researchers report Hsp70 chaperone blocks Parkinson’s-associated α-synuclein oligomer formation, via a non-canonical interaction site in the C-terminal domain (Click here to read more about this).
  • Reactive microglia enhance the transmission of exosomal Parkinson’s-associated alpha-synuclein (via toll-like receptor 2). Intrastriatal injection of exosomes derived from PD patients resulted in propagation; TLR2 silencing in microglia mitigated effect (Click here to read more about this).
  • New report outlines the development of Cerevance‘s CVN424 – a highly potent & selective small molecule inverse agonist for GPR6 which is currently undergoing clinical evaluation; Targeted towards Parkinson’s (Click here to read more about this).

  • Researchers from Cerevance & Takeda Pharma present the discovery, pharmacological validation, & identification of CVN424, a selective GPR6 inverse agonist – currently in Phase II clinical testing for the treatment of Parkinson’s (Click here to read more about this).
  • New biorxiv manuscript defines ubiquitin architecture of damaged mitochondria, aiding future studies to understand Parkin activation in neurons; Also highlights potential biomarkers for PINK1 & Parkin activity (Click here to read more about this).
  • New data finds ULK1-dependent phosphorylation of Parkin nice residue (“ACT”) domain mediates & is required 4 maximal Parkin activity; “Unexpected & rapid new step in the biochemical activation of Parkin following mitochondrial damage” (Click here to read more about this and click here to read the associated press summary).
  • Postmortem analysis of pancreatic β cells suggests that amylin, pancreatic α-synuclein, Aβ, PrP & tau may contribute together to the pathophysiology of Type 2 diabetes & in the appearance of insulin resistance in Alzheimer’s & Parkinson’s; The authors also provide “the first histological evidence of an interaction between PrP & Aβ, α-synuclein, amylin or tau in the pancreas & locus coeruleus”; “Further prospective studies will be necessary to validate these findings” (Click here to read more about this).
  • New biorxiv manuscript suggests aging is associated with a degeneration of noradrenergic-, but not dopaminergic-neurons, in the short-lived killifish Nothobranchius furzeri (Click here to read more about this).

  • Molecular tweezer CLR01 (which has demonstrated neuroprotective effects in models of Parkinson’s) exhibits significant S. aureus biofilm inhibition; Disrupts PSMα1 self-assembly & fibrillation; A similar tweezer CLR05 is even better (Click here to read more about this).
  • Parkinson’s-associated aggregate seeding in vitro is predominantly mediated by small α-Syn fibrils, from which cytoplasmic fibrils grow unidirectionally; Direct interactions between α-Syn fibrils and membranes are infrequent (Click here to read more about this).
  • New biorxiv manuscript suggests 3D midbrain organoids from patients carrying SNCA gene multiplication can model key pathological features of Parkinson’s & provide a powerful system to study the pathogenesis of synucleinopathies (Click here to read more about this).
  • Researchers present a peptide derived from the C-terminal region of Parkinson’s-associated alpha-Synuclein (αSynP130-140), which acts as a decoy which competitively inhibits the binding of α-Syn to FABP3 in vitro (Click here to read more about this).

  • Netrin-1 receptor UNC5C is selectively cleaved by active δ-secretase, which escalates its proapoptotic activity. This process enhances neurodegeneration, promoting Alzheimer’s-like pathologies in mice; Netrin deficiency activates δ-secretase (Click here to read more about this).
  • New research explores trait associations of 14,100 long non-coding RNAs (across 49 tissues, 101 complex genetic traits); 1,432 lncRNA gene-trait associations, 800 not explained by effects of neighboring protein-coding genes. “Some trait categories had high proportions of lncRNA eQTL colocalization events” (e.g. lupus, Multiple Sclerosis, & blood cell counts). For other traits, such as ALS, Parkinson’s, & substance use, no lncRNA colocalization events were observed (Click here to read more about this).
  • A comprehensive landscape of 107 Parkinson’s-associated genes (PAGs), which display 1. higher expression levels in brain than in other tissues, 2. broader expression profiles in excitatory neurons than inhibitory neurons, & 3. spatiotemporal expression patterns (Click here to read more about this).
  • New research reports ageing promotes pathological alpha-synuclein propagation & autonomic dysfunction in wild-type rats; Implications for modelling of Parkinson’s? (Click here to read more about this).
  • New research reports that the C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide; The authors hypothesize that the mechanism of c subunit toxicity on mitochondrial membranes occurs through structural rearrangements (Click here to read more about this).

  • New report finds RE1 Silencing Transcription Factor (REST) & PGC-1α as potential mediators of dopaminergic vulnerability in Parkinson’s; α-syn BAC-transgenic mice & iPS cell-derived dopamine neurons (Click here to read more about this and click here to read the press summary).
  • New research finds that subthalamic burst discharges may play an important role in cortico-subcortical information relay, contribute to the pathogenesis of both hypokinetic & hyperkinetic Parkinson’s symptoms (Click here to read more about this).
  • New biorxiv manuscript applies paired bulk-tissue & single-nucleus RNA-sequencing to anterior cingulate cortex samples from 28 individuals (healthy controls, Parkinson’s, Parkinson’s dementia, & Dementia with Lewy bodies cases; n=7 per group); Implications for RNA-targeted therapies (Click here to read more about this).
  • New research reports VGLUT2 as a determinant of dopamine neuron resilience in a rotenone model of dopamine neurodegeneration (Click here to read more about this)
  • Researchers report a start-to-finish reconstitution of cargo-stimulated selective autophagy initiation from autophagy receptor engagement through LC3 lipidation, using purified human proteins (Click here to read more about this)
  • Oxidative modification impairs SERCA activity in models of Parkinson’s; CDN1163 is an allosteric activator of SERCA attenuates PD-related phenotypes in DJ-1 mutant flies & human cells (Click here to read more about this).

  • Neurotoxin (6-OHDA) & alpha-synuclein overexpression induced dopamine neuron axon destruction is not dependent on Sarm1 (Click here to read more about this).
  • New research finds Miro recruits the lipid transport protein VPS13D, bridging the ER to mitochondria & peroxisomes; Potential implications for Parkinson’s? (Click here to read more about this).
  • New biorxiv manuscript presents data suggesting that direct neural reprogramming can provide a patient-specific model to study aged neuronal features relevant to idiopathic Parkinson’s (Click here to read more about this).
  • New biorxiv manuscript suggests that small extracellular vesicles secreted by region-specific astrocytes can ameliorate the mitochondrial function in a cellular model of Parkinson’s (Click here to read more about this).
  • Intracerebral injection of homogenized human brain or stomach tissue (but NOT blood or muscle) from Parkinson’s patients resulted in a “subtle, yet distinctive stimulation of localized α-Syn aggregation” in the brains of transgenic mice (Click here to read more about this).
  • Proteomic profiling of 51 samples of human substantia nigra; Samples were divided into 3 groups: With Lewy body path., No Lewy body controls with neuronal loss, & Controls with no neuronal loss; The results highlight the Arp2/3 complex, synaptic function, poly(A) RNA binding, and oxidative stress (Click here to read more about this).

  • New report finds that cell loss may not follow a strict caudal to rostral trajectory in Parkinson’s; Symptom onset may relate to locus coeruleus pathology in people with reduced A9 substantia nigra neurons (Click here to read more about this).
  • New biorxiv manuscript presents super-resolution X10 expansion microscopy of the molecular architecture of alpha-synuclein inclusions in model systems & in the human brain; Interesting insights (Click here to read more about this).
  • Researchers report an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibril is driven by interactions between intrinsically disordered (ID) monomer N terminus & the ID flanking regions (IDR) on fibrils (Click here to read more about this).
  • Loss of function variants in LRP10 gene have been associated with autosomal-dominant Parkinson’s. New research reports LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in astrocytes & localises to Lewy bodies in PD & DLB (Click here to read more about this).
  • Researchers assessed brain tissue from models of 7 lysosomal storage conditions (Gaucher, Fabry, Sandhoff, Niemann–Pick A, Hurler, Pompe, & Niemann–Pick C) & found differences in brain protein aggregation & neuroinflammation (Click here to read more about this).

  • Researchers report neuronal IFN‐β is indispensable for mitochondrial homeostasis & metabolism; Rescues mitochondrial defects & neurodegen. in mouse models of Parkinson’s; Activates mitochondrial fission, via pSTAT5/PGAM5/S622Drp1 (Click here to read more about this).
  • New biorxiv manuscript characterises a benzenesulphonamide molecule (compound 39) – a highly selective USP30 inhibitor – & finds that it enhance peroxisome turnover (Click here to read more about this).

 

Disease mechanism

  • New study finds anti-oxidant apoferritin prevented MPTP-induced ferroptosis by inhibiting the up-regulation of long-chain acyl-CoA synthase 4 (ACSL4) & the down-regulation of ferroptosis inhibitor protein (FSP1) in mouse model of Parkinson’s (Click here to read more about this).
  • HGC is a new inhibitor for HDACs – especially HDAC1/6; New data reports that it acetylates NDUFV1 & rescues dopaminergic neuron loss & alleviates motor symptoms in models of Parkinson’s; knockdown of NDUFV1 abolishes the neuroprotective effect (Click here to read more about this).
  • Eleganolone – isolated from the brown seaweed Bifurcaria bifurcata – found to have neuroprotective effects (mitochondrial protection, reduction of oxidative stress, inflammation & apoptosis, via inhibition of NF-kβ) in in vitro models of Parkinson’s (Click here to read more about this).

  • Intracerebral administration of a indatraline-conjugated antisense oligonucleotide (IND-1233-ASO) that selectively reduces Parkinson’s-associated α-synuclein synthesis in monoamine neurons of mice, nonhuman primates & A30P*A53T*α-synuclein transgenic mice (Click here to read more about this).
  • Reducing acetylated tau is neuroprotective in mouse model of brain injury; Tau acetylation-inhibiting medications (salsalate & diflunisal) also reported to be associated with reduced incidence of Alzheimer’s (Click here to read more about this).
  • New biorxiv manuscript suggests robust nuclear NRF2 accumulation in post-mortem Parkinson’s midbrain (p-NRF2, S40); 4 publicly available microarray datasets & mouse model work is also presented to further support the finding (Click here to read more about this).
  • COVID vaccine company Moderna & collaborators report lipid nanoparticles containing granulocyte-macrophage colony-stimulating factor mRNA (Gm-csf mRNA) – to peripherally induce Tregs – offers neuroprotection in models of Parkinson’s (Click here to read more about this).

  • New paper reports proper regulation of PERK-eIF2α signaling in dopamine neurons is required for normal cognitive and motor function in a non-pathological state; Also highlights caution in sustained PERK inhibit (Click here to read more about this).
  • Definitive title to this new biorxiv manuscript: “LAG3 is not expressed in human & murine neurons & does not modulate α-synucleinopathies“; A53T α-syn transgenic mice & seeded α-syn lesions in hippocampal slice cultures were unaffected by LAG3 knockdown; The authors confirm that LAG3 interacts with α-syn fibrils, but “the specificity of this interaction appears limited”. They also find that overexpression of LAG3 in human neural cells cultures did not worsen α-syn pathology (Click here to read more about this).
  • Pharmacological inhibition (using cambinol/DDL-112) of neutral sphingomyelinase-2 (nSMase2) reduces brain exosome release & α-synuclein pathology in the Thy1-αSyn mouse model of Parkinson’s (Click here to read more about this).
  • New preclinical data indicates that Peptron‘s sustained release GLP-1 agonist PT320 delays progression in the MitoPark mouse model of Parkinson’s; Administered starts at 5 weeks of age; Behavioral/cellular parameters evaluated out to 24 weeks (Click here to read more about this).

  • New study reports N-ethylmaleimide sensitive factor (NSF) aggregation in brain samples of animals & people with Parkinson’s-associated LRRK2-G2019S genetic variants. Interesting: induction of autophagy (with trehalose) rescues animal models (Click here to read more about this).
  • Could activation of serum/glucocorticoid-regulated kinase1 (SGK1) via high-fat diet promote Alzheimer’s-associated tau pathology? High SGK1 in the mouse hippocampus led to neurodegeneration. Upregulation SGK1-GSK-3ß-tau complex also observed in AD cases; “SGK1 was activated under conditions of elevated glucocorticoid & hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance” (Click here to read more about this).
  • New research investigates the effect of alpha synuclein & Nurr1 age-related expression alterations in the pathogenesis of Parkinson’s models, by coupling Nurr1 hemizygous with a-syn heterozygote or homozygote transgenic mice; Aging a-syn homozygote/Nurr1+/− mice develop “kyphosis, severe rigid paralysis, L-DOPA responsive movement impairment, cachexia & died prematurely”; Pathological abnormalities included nigral neuron degeneration, extensive neuroinflammation, & enhanced a-syn aggregation (Click here to read more about this).
  • Researchers from Neuraly report that the GLP-1 pathway may play a critical role in microglia-reactive astrocyte associated neuroinflammation in Alzheimer’s; Agonist NLY01 (via a direct action on Aβ-induced GLP-1R+ microglia) inhibits astrocyte reactivity (Click here to read more about this and click here for the press summary).

  • Impaired meningeal lymphatic drainage exacerbates microglial inflammatory response in Alzheimer’s mouse model (5xFAD mice), worsening outcome of anti-Aβ passive immunotherapy. Therapeutic delivery of VEGF-C improved clearance of Aβ by monoclonal antibodies (Click here to read more about this and click here for the press summary).
  • New research may offer a novel mechanism for sex differences in selective dopamine neuron vulnerability in Parkinson’s; Female flies, rodents, & humans possess higher levels of VGLUT in DA neurons than males (Click here to read more about this and click here for the press summary).
  • New report finds acrolein scavenger dimercaprol reduces acrolein & reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels, providing neuroprotection in rodent (6-OHDA) model of Parkinson’s (Click here to read more about this).

Clinical research

  • Researchers from Kazakhstan explore the evolutionary changes in the interaction of microRNA with mRNA of candidate genes for Parkinson’s (Click here to read more about this).
  • Little is known about lung function in Parkinson’s – new report explores natural history of lung function in PD patients over a 1 year period as part of an open-label study of inhaled levodopa (CVT-301 – click here to read more about this).

  • Sex-based differences in the activation of peripheral blood monocytes in early Parkinson’s; Inflammatory activation of monocytes in females with PD, with enrichment of gene sets associated with interferon gamma stimulation; More heterogeneous in males (Click here to read more about this).
  • New medrxiv manuscript provides evidence that functional connectivity in striatum maps onto dopaminergic projections, tracking inter-individual differences in symptom severity & L-DOPA sensitivity in Parkinson’s (Click here to read more about this).
  • New study provides Class III evidence that skin biopsy immunofluorescence or real-time quaking-induced conversion (RT-QuIC) accurately distinguish synucleinopathies (SOPs) from non-SOPs (Alzheimer’s, tauopathies, & vascular parkinsonism) + controls (Click here to read more about this).
  • Under-represented communities: New study provides a glimpse of the genetics of young‐onset Parkinson’s in Central Asia; Whole‐exome sequencing on 50 YOPD cases from Kazakhstan (Click here to read more about this).
  • New research from the PredictPD team, presenting the enhanced PREDICT-PD algorithm: improving estimation of Parkinson’s risk; Yielding greater range of risk estimates than the basic algorithm (93–609-fold difference vs 10–13-fold – click here to read more about this).

  • All of the ALS cases held by the NSW Brain Bank (n=97) were screened for coexisting Lewy body disorders consistent with clinical disease (Braak ≥ stage IV); The researchers found 6 cases with coexisting pathology; 2 cases of dual diagnosis (Click here to read more about this).
  • New research explores corneal confocal microscopy as a means of identifying Parkinson’s with more rapid motor progression; “A useful tool to help enrich clinical trials” (Click here to read more about this).
  • Researchers highlight an under-recognized drug reaction: Levodopa/dopa decarboxylase inhibitor associated microscopic colitis (a form of inflammatory bowel disease characterized by diarrhea); More common than previously suspected (Click here to read more about this).
  • Researchers explore computerized voice analysis on recordings of multiple phonemes from people with Parkinson’s; Potential to identify early dysarthria & assess L-dopa response in established PD (Click here to read more about this).
  • New biorxiv manuscript uses ultra-deep whole genome bisulfite sequencing reveals a single methylation hotspot in human brain mitochondrial DNA; “Brain mtDNA methylation is unlikely to be involved in Parkinson’s” (Click here to read more about this).

  • A new population-based retrospective cohort study (n=107,207 newly diagnosed hypertension patients (2001-2013 in Taiwan) reports dihydropyridine calcium channel blockers (felodipine, isradipine, etc) are associated with reduced the risk of Parkinson’s (Click here to read more about this).
  • New study suggests incidence of Parkinson’s in tamsulosin users is 1.53%, which was significantly higher than that in terazosin/alfuzosin/doxazosin users (1.10%; p<0.0001) & controls (1.01%; p < 0.0001); No protective effect against PD from terazosin? (Click here to read more about this).
  • Researchers find that α‐synuclein level in L1CAM‐immunocaptured exosomes >14 pg/mL is “a robust biomarker across cohorts that distinguishes Parkinson’s from multiple system atrophy or 4‐repeat tauopathies” (Click here to read more about this).
  • New report presents a streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s & dementia with Lewy bodies (Click here to read more about this).
  • Starting to feel neurotic about associations. New meta‐analysis (utilising UK Biobank data; 12 years of follow‐up) of prospective studies indicates that neuroticism is consistently associated with a higher risk of incident Parkinson’s (Click here to read more about this).

  • The CNS Physiotherapy Study group reports data supporting the use of kinematic outcome measures to evaluate the efficacy of multidisciplinary interventions on Parkinson’s functional mobility (Click here to read more about this).
  • New biorxiv manuscript identifies 518 genes subject to regulation by 76 Parkinson’s-associated SNPs across 49 tissues, that encompass 36 peripheral & 13 CNS tissues; 9 pathway/processes clusters enriched (Click here to read more about this).
  • New data reports a longitudinal analysis of 2 cohorts that finds constipation is associated with development of cognitive impairment in de novo Parkinson’s; A clinical biomarker for risk for cognitive impairment? (Click here to read more about this).
  • New biorxiv manuscript investigates 18 inflammatory markers in the blood (n=144, aged 65-75yrs) at study endpoint, collected over 20 years (5-yr intervals); Strong associations in women, increasing sCD14 levels & frailty (possible monocyte overactivation? Click here to read more about this).
  • Researchers report on the use of smartphones to gather Parkinson’s data during the COVID-19 pandemic (Click here to read more about this)

  • New medrxiv manuscript presents the Australian Parkinson’s Genetics Study (APGS) – “the most extensive nation-wide genetic study of Parkinson’s in Australia“; (n=1,532 in the pilot phase – click here to read more about this)..
  • Researchers studied 275 Parkinson’s patients who underwent subthalamic nucleus deep brain stimulation (2003-2018) & then examined whether machine learning could predict the benefits of sign-specific stimulation ‘hot’ & ‘cold’ spots (Click here to read more about this).
  • Parkinson Study Group researchers report on uptake of telehealth in Parkinson’s clinical care & research during the COVID-19 pandemic (Click here to read more about this).
  • 2-to 4-year clinical & skin biopsy follow-up study of 33 individuals with isolated REM sleep behavior disorder (iRBD) finds consistent results over time in 24 cases; 5/23 (21.7%) with positive skin-biopsies at baseline had converted by follow up (Click here to read more about this).
  • An assessment of appendix morphology in 100 people with Parkinson’s (& 50 controls) using multislice spiral computed tomography finds 53% have chronic appendicitis‐like lesions; 7 cases underwent appendectomy & histopathological analysis (Click here to read more about this).

  • New medrxiv manuscript quantifies iron & neuromelanin-related markers using ultra-high field 7-Tesla MRI, & examines the clinical correlates in 25 people with Parkinson’s (& 26 controls – click here to read more about this).
  • New data finds that males experienced increased non-motor symptoms (NMS) burden in Parkinson’s; Laterality of motor symptoms did not significantly influence NMS progression, except in terms of anxiety (Click here to read more about this).
  • New medrxiv manuscript demonstrates that the 5’ LRRK2 non-coding GWAS signal rs76904798 is independently associated with Parkinson’s risk from LRRK2 coding variation (Click here to read more about this).
  • Impaired cerebral microcirculation in isolated REM sleep behaviour disorder (iRBD) is associated with cognitive performance; Potential for microvascular flow disturbances can identify iRBD (Click here to read more about this).
  • New report detects no significant genetic differences between male or female Parkinson’s cases; including UK Biobank samples, male n=13k PD cases + 89k controls, female n=7k PD cases + 90k controls (Click here to read more about this).
  • New report identifies no significant association between ANG variants & Parkinson’s risk – failing to replicate the findings of previous studies (14,671 cases & 17,667 controls; plus AMP-PD data – click here to read more about this).

  • Cross-sectional study (using 19M hospital discharge records; 8M men &11M women) from the 2004-2014 finds men were more likely to experience Parkinson’s with insomnia or parasomnia; women are more likely to experience PD with sleep-related movement disorder (Click here to read more about this).
  • New study finds “free water in the posterior substantia nigra is a valid imaging marker of neurodegeneration in idiopathic REM sleep behaviour disorder, which has the potential to be used as an indicator in disease-modifying trials” (Click here to read more about this).
  • New report explores the potential of a‐synuclein oligomers & neurofilament light chain to predict phenoconversion of pure autonomic failure; “αSyn‐PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α‐synucleinopathy” (Click here to read more about this).
  • New report presents a genome‐wide association study of genetic modifiers of age at onset for 5166 Chinese patients with Parkinson’s; Novel significant intergenic locus rs9783733 (NDN; PWRN4) was identified (Click here to read more about this).
  • New biorxiv manuscript presents a framework to aid the development of intelligent adaptive deep brain stimulation for Parkinson’s (Click here to read more about this).

  • The researchers behind the Colorado/Columbia cell transplantation in Parkinson’s clinical trial from the 1990s have published long-term follow up clinical features of the 5 patients who developed persistent dyskinesias; “Milder Parkinson signs at baseline” (Click here to read more about this).
  • New report finds a widespread cortical reduction of synaptic density in a cohort of Dementia with Lewy bodies/Parkinson’s dementia cases (using in vivo [11C]UCB‐J PET – click here to read more about this).
  • A new 3 year review report explores the guidelines in Sweden focusing on the economics of device‐aided therapies (DBS, pump‐based infusion of levodopa‐carbidopa intestinal gel, or apomorphine) for Parkinson’s (Click here to read more about this).
  • New study indicates that individuals with multiple system atrophy (MSA; n=20) have significant intraocular pressure & choroidal thickness postural changes compared with cases of Parkinson’s (n=21) & unaffected controls (n=14); Differentiating biomarkers? (Click here to read more about this).
  • New research explores gait analysis using wearable sensors with a focus on elderly & Parkinson’s patients (the smart-insole datasetClick here to read more about this).

  • Could ACE-inhibitors & AT1 receptor blockers help against levodopa-induced dyskinesias? A new retrospective case-control study provides some supportive data (Click here to read more about this).
  • New research indicates that gait analysis may be able to distinguish cases of progressive supranuclear palsy from cases of Parkinson’s from earliest stages (N=21 PSP & 83PD); Potential for early disease-specific rehabilitation strategies? (Click here to read more about this).
  • Hallucinations in Parkinson’s are a disturbing & frequent non-motor feature. New research uses a robotic method to induce hallucinations in individuals with PD to study the mechanisms behind this phenomenon (Click here to read more about this and click here for the press summary of this study).
  • Researchers have developed a new smell test (which uses capsules of aromatic oils) that has been found to be easy to use in a small study involving individuals with Parkinson’s (Click here to read more about this and click here for the press summary of this study).
  • It has been long believed that the cerebellum has no role in Parkinson’s. New research presents PET imaging results that “confirm the role of the cerebellum in non-motor domains of PD“, with differential but overlapping patterns of metabolic correlations (Click here to read more about this).

 

New clinical trials

  • New clinical trial registered: The effect of Psyllium & wheat bran on body weight in people with Parkinson’s & constipation symptoms; Recruiting 79 participants (Click here to read more about this).
  • New clinical trial registered: Athira pharma has registered a Phase II trial to evaluate the safety & effects of ATH-1017 (HGF/MET receptor activator) in 75 participants with Parkinson’s Dementia – a randomized treatment duration of 26-weeks (Click here to read more about this).

  • New clinical study registered: A smartphone-based titrated exercise study for individuals with Parkinson’s (The STEPWISE Parkinson study) has been registered; Recruiting 452 participants for 12 months (Click here to read more about this).
  • New clinical trial registered: Researchers are recruiting 48 Parkinson’s patients to evaluate fecal microbiome transplantation on motor & non-motor symptoms; Primary outcome=MDS-UPDRS I-III at 6 months; Scheduled to complete in December 2022 (Click here to read more about this).
  • New clinical trial registered: Addex Therapeutics are initiating a Phase 2/3 study to evaluate the safety & efficacy of dipraglurant (ADX48621) in people with Parkinson’s with dyskinesia; Recruiting 140 participants, reporting in 2023 (Click here to read more about this).

  • New clinical trial registered: The ExpoBiome project will analyze the impact of fasting on 180 individuals with Parkinson’s or rheumatoid arthritis; A 5-10 day fasting period; Scheduled to complete in May 2023 (Click here to read more about this).
  • New clinical trial registered: Researchers are initiating the “PECKO-D study” to investigate the effect of hypoestes rosea powder/Hypoestoxide in 30 people with Parkinson’s in Nigeria; 8 weeks treatment, finishing in October 2021 (Click here to read more about this).

 

Clinical trial news

  • New medrxivpreprint provides the rationale, design & baseline data for the PASADENA study: A Phase II clinical trial to evaluate the safety & efficacy of prasinezumab in early Parkinson’s (Click here to read more about this).

  • Is NAC back? Small open label pilot study, but interesting trends: Researchers report Glycine & N‐acetylcysteine (GlyNAC) combo in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, etc… (Click here to read more about this).
  • Clinical trial in 81 people with multiple system atrophy finds serotonin reuptake inhibitor fluoxetine (40 mg/d) has no effect on UMSARS score; Trends in motor & emotional secondary/exploratory outcomes, however, “deserve further investigation” (Click here to read more about this).
  • Yumanity therapeutics announces that their stearoyl-CoA desaturase inhibitor YTX-7739 displayed dose-dependent decreases in target fatty acids – evidence of in vivo target engagement – in their Phase 1a clinical trial in healthy volunteers (Click here to read more about this).

 

Conferences/lectures

  • This month, here at the SoPD we are very much looking forward to the World Parkinson’s Congress virtual meeting on Advancing Science, Care, & Living with Parkinson’s, which will be held Monday-Friday 17 – 21st May. Amazing opportunity to learn more about everything going on (Click here to read more about this).

  • The Davis Phinney Foundation are supporting a series of webinars focused on the issues faced by woman diagnosed with Young Onset Parkinson’s (Click here to read more about this).

Other news

  • The “Blue rockers” at BlueRock Therapeutics have received regulatory permission from Health Canada to initiate a “Phase 1 Safety & Tolerability Study of MSK-DA01 Cell Therapy for Advanced Parkinson’s”; The initial trial will enroll 10 patients in the US & Canada (Click here to read more about this).

  • Cerevel Therapeutics announces strategic $125M non-dilutive financing transaction for Phase 3 tavapadon TEMPO study program; Risk-sharing arrangement with NovaQuest & Bain Capital; Trial expected to begin in the first half of 2023 (Click here to read more about this).
  • Live Biotherapeutic company 4D pharma plc has announced a collaboration with Parkinson’s UK to establish a Patient Advisory Board focused on advancing the understanding of Parkinson’s & improving treatments (Click here to read more about this).
  • Escape Bio researchers (& collaborators) report that EB‐42168 (a G2019S LRRK2 selective inhibitor) lowers mutant G2019S LRRK2 phosphorylated biomarkers while simultaneously sparing WT LRRK2; Small study (13 Parkinson’s cases & 1 control – click here to read more about this).

Review articles/videos

  • New report explores smartphones for remote Parkinson’s symptom monitoring, + future prospects for this technology; “These tools will likely become a common “building-block” 4 special applications adapted 2 particular users’ circumstances” (Click here to read more about this).
  • For Parkinson’s α-Synuclein immunotherapy, is going later the key? (Click here to read more about this).
  • New review explores the importance of flies (Drosophila melanogaster) in research uncovering the cellular pathways underlying Parkinson’s (Click here to read more about this).

  • Could anti-inflammatory drugs combined with an iron chelator be a better approach to increase chelator efficacy in the context of Parkinson’s? A new review explores this idea (Click here to read more about this).
  • New review discusses the current state of precision medicine in the Parkinson’s field, exploring how genetics has become the engine to gain insights into the disease, helping develop potential etiological-based interventions (Click here to read more about this).
  • New review discusses the importance of mitochondrial dynamics during neuroinflammation, & how they correlate either with the amelioration or worsening of CNS disease (Click here to read more about this).
  • Does it all start to go wrong as we AGE? New review exploring research on the toxicity of Advanced Glycation End products (Click here to read more about this).
  • A useful short overview of probiotics for Parkinson’s, exploring current evidence as well as future directions (Click here to read more about this).

  • New review summarises our understanding of the relevance of the “gut-brain” axis to the pathogenesis of Parkinson’s, impact of gastrointestinal disorders in patients with PD, & practical guidance to their management (Click here to read more about this).
  • New review on understanding the multiple roles of mitochondria in Parkinson’s & related conditions; Lesson from genetics & protein–interaction networks (Click here to read more about this).
  • New review summarises known genetic contributors to the pathophysiology of Parkinson’s, the molecular mechanisms leading to disease development, & discusses the challenges/opportunities in clinical trial designs (Click here to read more about this).
  • New review on prodromal Parkinson’s subtypes explores the heterogeneity; “Variability in prodromal PD must result from different pathophysiological mechanisms; defining prodromal subtypes is the first step to identifying the biological difference” (Click here to read more about this).

  • Useful review on recent advances in wearable sensors & portable electronics for sleep monitoring – impressive progress; Implications for Parkinson’s research? (Click here to read more about this).
  • A review on the chemical tools for imaging dopamine release; “None of these tools observe dopamine itself, but instead harness the biology of the dopamine system – its synthetic and metabolic pathways, synaptic vesicle cycle, & receptors – in elegant ways” (Click here to read more about this).
  • The challenges in the diagnosis of Parkinson’s; “PD is evolving from a clinical to a biomarker-supported diagnostic entity, for which earlier identification is possible, different subtypes with diverse prognosis are recognised, & novel disease-modifying treatments are in development” (Click here to read more about this).
  • Interesting systematic review of ongoing & completed clinical trials for gene therapy in movement disorders (particularly Parkinson’s – 30 of 46 gene therapy trials – click here to read more about this).

  • New short review explores the alternative delivery systems for growth factor therapy for Parkinson’s; Extraordinary potential, huge challenges; Recent developments in ex vivo gene therapy delivery approaching the clinic (Click here to read more about this)
  • The latest Clinical Trial Highlights post from the Journal of Parkinson’s has Phase 3 in focus and looks at Ampreloxetine from Theravance Biopharma (Click here to read more about this).
  • New review discusses the role of PINK1 in the mitochondrial physiology & scrutinizes its role in the cascade of Parkinson’s pathology (Click here to read more about this).
  • New review on the role of exosomes in lysosomal storage disorders (Click here to read more about this).

  • New review summarizes available data on phenotypes of Parkinson’s-associated LRRK2 mutations in the clinic, patient-derived cells, & experimental models; Exploring molecular & cellular relationships & identifying trends & gaps in the data (Click here to read more about this).
  • A unique perspective behind this review of treatment options for motor & non-motor symptoms of Parkinson’s; Lots of bases covered here, including some complementary & alternative medicine (CAM) as well as integrative medicine approaches (Click here to read more about this).
  • Genetic & transcriptomic biomarkers in neurodegenerative conditions: Current situation & the road ahead; Parkinson’s, Alzheimer’s & ALS get covered (Click here to read more about this).
  • New review article explores advances in applying computer-aided drug design for neurodegenerative conditions; Alzheimer’s, Parkinson’s & ALS get discussed, plus a roadmap for implementing CADD in drug design (Click here to read more about this).
  • Ever wondered about the contribution of microglia to neuroinflammation in Parkinson’s? This review has got you covered (Click here to read more about this).

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

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

All of the material on this website is licensed under a
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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.


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