Monthly Research Review – May 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 May 2021.

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

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So, what happened during May 2021?

In world news:

May 5th – Tech company SpaceX successfully flew and landed their Starship prototype for the first time:

May 9th – The 100th anniversary of the birth of Sophie Scholl (Click here to learn more about her)

 

May 10th – A pan-coronavirus mRNA nanoparticle vaccine with activity against all major SARSCoV2 variants was described in the science journal ‘Nature’, showing potent effect in non-human primates (Click here to read more about this).

May 14th – The China National Space Administration landed its Zhurong rover at Utopia Planitia on Mars, making China the fourth country to land a spacecraft on the planet and the second to land a rover (Click here to read more about this).

May 26th – Oil company Shell became the first company to be legally mandated to align its carbon emissions with the Paris climate accord, following a landmark court ruling in the Netherlands (Click here to read more about this).

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

In May 2021, there were 911 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (5,459 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. Denali Phase I results:

Biotech company Denali Therapeutics announced the final results from Phase 1 & Phase 1b studies of their small molecule LRRK2 inhibitor, DNL151 (also known as BIIB122), which is being developed in collaboration with Biogen as a potential treatment of Parkinson’s. A total of 184 healthy volunteers (145 BIIB122/DNL151, 39 placebo) and 36 patients with Parkinson’s (26 BIIB122/DNL151 + 10 placebo) were enrolled in the studies & treated with different doses of the drug for 28 days. DNL151 was found to be safe and generally well tolerated. No serious adverse events were observed. Looking forward to seeing next steps in clinical development (Click here to read more about this and click here to read a SoPD post about this topic).

2. DBS goes wireless

Researchers reported long-term wireless streaming of neural recordings from deep brain stimulation devices in 5 individuals for up to 15 months. “At home” recordings (made over 2,600 hours) were paired with behavioural data collected from wearable monitors, and this data could be used to identify individual-specific neurophysiological biomarkers during normal daily activities & the researchers used those patterns for adaptive DBS (Click here to read more about this and click here to read an open access preprint manuscript of the study).

3.  Oligodendrocytes again!

Researchers at the biotech company Sanofi analysed 87,000 single nuclei collected from the putamen region of the human brain. Samples were collected from healthy controls, Parkinson’s & MSA cases. Oligodendrocytes – a type of helper cell – displayed distinctive pathological alterations in both PD & MSA cases. Seven subpopulations of oligodendrocytes were identified and curiously, alpha synuclein expression was found to be significantly higher in Parkinson’s oligodendrocytes (vs control as well as in comparison to MSA – click here to read more about this). The researchers also found a possible expansion & activation of microglia & astrocytes in Parkinson’s (vs MSA & controls), as well as altered expression of major neurodegeneration associated genes (SNCA, MAPT, LRRK2, APOE & APP) at cell-type resolution (LRRK2 in OPCs?? – click here to read more about this).

4. Smog in Seoul

A large cohort study (N=79K) from Seoul, Korea reported a statistically significant association between NO2 exposure & Parkinson’s risk. Interestingly, there was no statistically significant associations between exposure to PM2.5, PM10, O3, SO2, or CO (Click here to read more about this and click here to read the associated editorial).

 

5. Gene therapy for Parkinsonism

Using a gene therapy approach (AAV2.SLC6A3), researchers have demonstrated that they can restore dopamine transporter (DAT) function & ameliorates pathology in patient-derived stem cells (iPS cells) & mouse models of infantile parkinsonism (Click here to read more about this).

 

Articles of general interest

  • “Bringing advanced therapies for Parkinson’s to the clinic: The patient’s perspective” (Click here to read more about this).
  • Nice interview with Parkinson’s expert/researcher Prof Patrik Brundin (Click here to read more about this).

  • Potential Anti-Aging and Neuroprotection Strategy for Parkinson’s (Click here to read more about this).
  • Really interesting interview of Dr Jon Stamford – the Parkinson’s scientist who developed Parkinson’s:

Basic biology news

  • New biorxiv manuscript asks if the lack of the fibrillar form of alpha synuclein in Parkinson’s-associated Lewy bodies be explained by its catalytic activity? (lots of math & modelling – click here to read more about this).
  • New biorxiv manuscript suggests that mitochondrial protein import defects may contribute to protein homeostasis impairment; A possible mechanism for mitochondrial involvement in ND conditions; “Upon mitochondrial protein import impairment, high-risk precursor & immature forms of mitochondrial proteins form aberrant deposits in the cytosol”; These deposits cause accumulation of other mitochondrial & disease-related proteins, such as Parkinson’s-associated α-synuclein (Click here to read more about this).

  • New study reports fatty acid-binding protein 7 (FABP7) triggers Parkinson’s-associated α-synuclein protein oligomerization in glial cells & oligodendrocytes through oxidative stress; Authors identify a ligand that inhibits FABP7-induced syn oligomerization (Click here to read more about this).
  • New paper reports that the porphyrin heme targets a His50 residue critical for Parkinson’s-associated alpha synuclein fibril-formation & stabilizes it into a minimally-toxic oligomeric state (Click here to read more about this).
  • New research suggests that increased TBK1 activation may promote tau hyperphosphorylation & neuronal loss in Alzheimer’s & related tauopathies (Click here to read more about this).
  • New paper presents the first genome-wide study of histone acetylation in the Parkinson’s brain; H3K27 acetylation may be decoupled from gene expression in PD; “PD-associated genes are particularly prone to epigenetic dysregulation” (Click here to read more about this).
  • New research describes “a unique metabolomic profile associated with Parkinson’s-associated PARKIN dysfunction; Demonstrating how combining metabolomics with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight; PARKIN-/- neurons displayed increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure, ATP depletion, dysregulation of glycolysis & carnitine metabolism, increased lactate & decreased pyruvate levels (Click here to read more about this).

  • New paper presents the first evidence for a neuroprotective role of TP53INP1/dDOR; Highlights its involvement in the regulation of autophagy & mitophagy, in parallel to PINK1/Parkin-mediated pathways (Click here to read more about this).
  • New biorxiv manuscript uses a protein mimetic approach to identify Parkinson’s-associated alpha synuclein sequences based novel targets that are essential for aggregation & may have significant therapeutic implications (Click here to read more about this).
  • New paper reports that human α-synuclein in a mouse model of Parkinson’s promotes striatal dopamine transporter function, in a manner supported by extracellular cholesterol; Implications for PD pathophysiology? (Click here to read more about this).
  • New biorxiv manuscript explores how mechanisms of aging contribute to multiple age-related diseases & to patterns of human age-related multi-morbidity; Raises possibility that many conditions may be prevented by targeting common signaling pathways (Click here to read more about this).
  • New paper reports the oligomerization of LRRK, which is promoted by dominant Parkinson’s-associated mutations, reduces actin severing activity in vitro & promotes excess stabilization of F-actin (in flies – click here to read more about this).

  • New biorxiv manuscript compares Type I (GSK3357679A, MLi-2) & Type II (Ponatinib, GZD-824) LRRK2 kinase inhibitors that bind to the closed or open conformations of LRRK2 kinase domain, respectively; “We strikingly find that Type II inhibitors, in contrast to Type I compounds, fail to induce dephosphorylation of a set of well-studied LRRK2 biomarker phosphorylation sites at the N-terminal region of LRRK2, including Ser935”; Type II inhibitors = higher potency towards WT LRRK2 (Click here to read more about this).
  • Parkinson’s-associated protein Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder; PARKIN-/- rats self-administered more METH & spent more time in the METH-paired environment than wild-type rats (Click here to read more about this).
  • Food additive fast green FCF reported to inhibit Parkinson’s-associated α-synuclein aggregation, disassembles mature fibrils & protects against amyloid-induced neurotoxicity in cell cultures (Click here to read more about this).
  • New research reports that presynaptic accumulation of Parkinson’s-associated α-synuclein impairs the active zone & neuronal function, resulting in synaptopathy, behavioural deficits & progressive loss of dopaminergic neurons (in flies – click here to read more about this).
  • Researchers report on the identification of genes associated with the progressive loss of dopamine neurons (in flies), which could help to uncover factors that render these neurons vulnerable in Parkinson’s (Click here to read more about this).

  • New research provides “further insights into the function of LRRK2 in immune response, & has relevance for understanding cellular dysfunctions when developing LRRK2-based inhibitors for clinical treatment”; Parkinson’s-related work (Click here to read more about this).
  • An in depth analysis of the conformational ensemble of Parkinson’s-associated alpha synuclein, reveals essential structural properties & potential conformations that might promote various functions in membrane interaction or aggregation (Click here to read more about this).
  • Researchers report that cells respond to seed-induced disruption of protein homeostasis predominantly by secreting nanoscopic aggregates; A protective response to protein aggregation? (SH-SY5Y cells – click here to read more about this).
  • Researchers report that MiR-193b deregulation is associated with Parkinson’s, possibly affecting regulation of the PGC-1α/FNDC5/BDNF pathway; Down-regulations of PGC-1α, FNDC5, BDNF & TFAM inversely correlated with miR-193b up-regulation in PD PBMCs (Click here to read more about this).
  • Genome-wide CRISPRi/a screens identifies a neuron-specific role for lysosomal protein prosaposin in controlling survival during oxidative stress, linking to ferroptosis (Click here to read more about this).

  • New paper highlights the importance of addressing retrotransposon SINE-VNTR-Alus (SVAs) variants & possibly other types of retrotransposons in Parkinson’s genetics (Click here to read more about this).
  • New biorxiv manuscript suggests an unrecognized critical role for Parkinson’s-associated DJ-1 in regulating “immunoaging”; PD patient with DJ-1 deficiency showed Downwards arrow in many critical immunoaging features (eg. 2x frequency of non-senescent T cells – click here to read more about this).
  • Could studies characterising the differential effects of protein misfolded oligomers on the peripheral immune system lead to the development of blood-based diagnostics? New research suggests distinct responses (Click here to read more about this).

 

Disease mechanism

  • A new report finds that Cerebral dopamine neurotrophic factor (CDNF) interacts with α-synuclein & modifies its aggregation, spreading, & associated behavioural alterations; “Remarkably, CDNF reduces the neuronal internalization of α-synuclein fibrils & induces the formation of insoluble phosphorylated α-synuclein inclusions”; Intra-striatal CDNF alleviated motor deficits in PFF rodent model, but it did NOT reduce the number of nigral phosphorylated α-syn inclusions (Click here to read more about this).

  • New biorxiv manuscript suggests that amyloid beta precursor-like protein 1 (Aplp1) forms a complex with Lag3 facilitating the binding, internalization, transmission, & toxicity of pathologic a-syn; Deletion of both Aplp1 & Lag3 eliminates a-syn PFF induced loss of dopaminergic neurons & behavioral deficits; Anti-Lag3 prevents the internalization of a-syn PFF vai disruption of Aplp1 & Lag3 interaction; Anti-Lag3 also blocks neurodegeneration induced by alpha-syn PFF in vivo (Click here to read more about this).
  • New research provides further evidence that c-Abl activation promotes α-synuclein aggregation & neuronal loss in Parkinson’s models; Also shows that N-acetyl cysteine suppresses c-Abl activation & neurodegeneration (Click here to read more about this).
  • New study investigates the potential of carbon quantum dots for the treatment of amyloid-based conditions (including Parkinson’s – click here to read more about this).
  • New research identifies functional variants at the ANKK1 locus highlighting the possible relevance of rare variants & non-coding regulatory regions in both the genetics of Parkinson’s & vulnerability of dopamine neurons (Click here to read more about this).
  • New research reports neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s; A mechanism linking neuronal ApoE to MHC-I, to tau pathology & selective neurodegeneration (Click here to read more about this).

  • New research reports that wild-type α-synuclein inherits the structure & exacerbated neuropathology of Parkinson’s-associated E46K mutant fibril strain by cross-seeding (Click here to read more about this).
  • New research reports endogenous tau reduction does not influence formation of templated α-synuclein inclusion formation or loss of dopamine neurons; Tau-/- mice do not show a reduction in PFF-induced inclusions (Click here to read more about this).
  • Non-lysosomal Gba2 deletion in Gba1 KO medaka (rice fish) resulted in the exacerbation of glucosylceramide accumulation & no improvement in neuronopathic Gaucher pathological changes, alpha syn accumulation, or swimming abnormalities; Authors propose deletion of Gba1 & Gba2 = changes in the sphingolipid metabolism; This might induce conformational changes in a-syn, resulting in a-syn accumulation; Gba1 deletion results in autophagic dysfunction, leading to a-syn accumulation (Click here to read more about this).
  • From a minimal model for rostrocaudal patterning to an integrated 3D model: New research provide insights into neural tube patterning; Implications for Parkinson’s cell transplantation (Click here to read more about this).

  • Tool cool, beautiful images, interesting results; New study presents the generation of a DAT-P2A-Flpo mouse line for intersectional genetic targeting of dopamine neuron subpopulations (they explore NeuroD6+ VTA neurons – click here to read more about this).
  • Using human iPS cells, researchers report that α-syn binds LC3 on endomembrane compartment surfaces; Parkinson’s-associated mutant α-syn draws LC3 into aggregates; LC3 LOF leads to α-syn secretion via exosome; Restoration of LC3 activity rescues (Click here to read more about this).
  • Researchers report that the chemical dopamine differentially modulates the size of projection neuron ensembles in the intact & dopamine-depleted striatum; This modulation is drastically altered in models of Parkinson’s (Click here to read more about this).
  • The complexity of complex deficiencies; New imaging mass cytometry reveals generalised deficiency (& also complexity) in OXPHOS complexes in Parkinson’s; Widespread decrease in expression of all complexes (Click here to read more about this).
  • New biorxiv manuscript reports intranasal delivery of exosomal α-synuclein initiates Parkinson’s-like pathology in mice (including motor impairments); No effect in Snca knockout mice (Click here to read more about this).

  • New biorxiv manuscript presents analogs of dopamine metabolite 5,6-Dihydroxyindole (DHI) that bind directly to & activate nuclear receptor Nurr1; DHI is an unstable compound, but 5-chloroindole maybe more interesting (Click here to read more about this).
  • New biorxiv manuscript suggests that neuronal NOX2 could be a major contributor to oxidative stress in Parkinson’s; NOX2 is involved in accumulation, post-translational modification & oligomerization of a-synuclein (Click here to read more about this).
  • Transmission of cerebral amyloid pathology by different peripheral routes of administration of pre-formed Aβ aggregates (including intra-peritoneal & intra-muscular – click here to read more about this).
  • Modulation of mitochondrial-associated ER membranes-associated palmitoylated APP in axons (via regulation of S1R), may be a useful “therapeutic strategy for ameliorating Aβ-induced neurodegeneration in Alzheimer’s” (Click here to read more about this and click here to read the press release).
  • New study investigates therapeutic potential of a 2nd generation RET agonist (BT44) on in vitro & vivo models of Parkinson’s; Promoted the survival of the WT neurons (not RET-/-) & improved 6-OHDA rat model (Click here to read more about this).

  • Could cytosolic leakage of mitochondrial DNA be involved in the pathogenesis of Parkinson’s? A new study reports accumulation of cytosolic dsDNA of mitochondrial origin in the PD brains; The authors also report depletion of PINK1, GBA &/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin, leading to type I interferon (IFN) responses (in vitro); Reducing cytosolic dsDNA (via DNase II overexpress) rescues mutant GBA zebrafish model of Parkinson’s (Click here to read more about this).
  • New research proposes a mechanistic model for the cooperative inhibition of SNARE-mediated vesicle fusion by Parkinson’s-associated α-Synuclein monomer & oligomers (Click here to read more about this).
  • New study reports lycorine – a natural alkaloid – promotes the degradation of alpha-synuclein (via PKA-mediated UPS activation) in A53T transgenic mouse model of Parkinson’s (Click here to read more about this).
  • New research indicates multiple system atrophy (MSA)-associated oligodendroglial protein p25α stimulates the formation of a novel α-synuclein strain with enhanced neurodegenerative potential (Click here to read more about this).

  • New research evaluates the ability of human stem cells harboring a “suicide” gene (allowing for regulated termination of the cells) to improve the safety & standardisation of neural transplants in rodent models of Parkinson’s (Click here to read more about this).
  • New biorxiv manuscript suggests edaravone can activate the GDNF receptor RET (in vitro & in vivo) & protects models of ALS; Edaravone also induces GRB2 & RASD2, (2 key signaling molecules of GDNF/RET signaling). Implications for Parkinson’s? (Click here to read more about this).
  • New study finds a shift towards a pro-inflammatory peripheral response in Parkinson’s; Loss of Treg suppressive functions may contribute; Restoration & enhancement of Treg suppressive functions (via ex vivo expansion) a potential cell therapeutic approach? (Click here to read more about this)

 

Clinical research

  • New study reports that plasma P‐tau217 is independently associated with higher levels of both β‐amyloid & tau pathology in the brain; P‐tau217 mediates the association between β‐amyloid & tau accumulation; “Accumulation of β‐amyloid pathology may induce changes in phosphorylation & release of soluble tau, resulting in increased plasma P‐tau217 before tau accumulation spreads in the neocortex. Later in the Alzheimer’s process, as tau aggregation spreads, plasma P‐tau217 reflects the widespread accumulation of neocortical tau. Soluble phosphorylated tau may be investigated further to understand the pathobiological mechanisms of Alzheimer’s”; Parkinson’s samples were also examined (Click here to read more about this).
  • Timely stuff – A nested case-control study of non-motor features of Parkinson’s in women (Click here to read more about this).

  • Investigating extracellular vesicles, researchers have “identified a novel miRNA signature in Parkinson’s cerebrospinal fluid composed of miR‐126‐5p, miR‐99a‐5p, & miR‐501‐3p”; Potential diagnostic aid, plus possible pathophysiological mechanisms (Click here to read more about this).
  • New study reports that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson’s-associated variants collectively increase the penetrance of LRRK2 mutations (Click here to read more about this and click here to read an open access preprint manuscript of the study).
  • New study reports significant differences in monocyte glucocerebrosidase activity can be detected using cryopreserved cells; Monocyte GCase activity inversely correlated to motor symptom severity in Parkinson’s (Click here to read more about this).
  • Could robust α-synuclein pathology in select brainstem neuronal populations (the pontine nuclei & medullary inferior olivary nucleus) be a potential instigator of multiple system atrophy (MSA)? (Click here to read more about this).
  • Researchers report higher proportion of social app interactions correlates with lower dopamine synthesis capacity in the bi-lateral putamen; Supporting dopamine’s role in digital social behaviour (Click here to read more about this).

  • New medrxiv manuscript explores the sensitivity of 7T LC imaging to detect sub-regional locus coeruleus changes in Parkinson’s & progressive supranuclear palsy (PSP – click here to read more about this).
  • Uvu-lopa-lato-phary-n-go-plasty (say that 3x really fast). New research indicates that uvulopalatopharyngoplasty ( remove tissue and/or remodel tissue in the throat) may decrease the incidence of Parkinson’s-associated with obstructive sleep apnea (Click here to read more about this).
  • New paper presents a cross-sectional analysis of the Parkinson’s Non-motor International Longitudinal Study baseline non-motor characteristics, geographical distribution & impact on quality of life (Click here to read more about this).
  • Expectations of benefit in a trial of a candidate disease‐modifying treatment for Parkinson’s: “Participants of a disease‐modification trial in PD had likely unrealistic expectations of benefit…, which may affect clinical trial interpretation & calls for improved education in future disease‐modification trials in Parkinson’s” (Click here to read more about this).
  • Levels of HVA & DOPAC in cerebrospinal fluid found to mirror nigrostriatal pathway damage in early Parkinson’s cases (n=161; compared to 115 controls); No metabolite changed over 2 yrs in drug‐naive individuals, but some changed with levodopa treatment (Click here to read more about this).
  • Clinical profiles & mortality of COVID‐19 inpatients with Parkinson’s in Germany (Click here to read more about this).

  • Can analyzing longitudinal item scores, instead of the total score, reduce the sample size of placebo‐controlled trials of Parkinson’s? New paper explores this idea using item response theory (Click here to read more about this).
  • Glycoprotein NMB (GPNMB) is really interesting, but an evaluation of cerebrospinal fluid levels of GPNMB as a potential biomarker for Alzheimer’s indicates “No” (not a perfect control/comparative group though); Validates a commercial GPNMB immunoassay (Click here to read more about this).
  • A post-mortem pilot study indicates alteration in the cerebrospinal fluid lipidome in Parkinson’s; N=30, 257 metabolic features detected; Multiple lipid species tend to be increased in PD; Lipid profile varies depending on the disease duration & staging (Click here to read more about this).
  • A large longitudinal genome-wide survival study of 11.2M variants in 3,821 patients with Parkinson’s (over 31K visits) identifies RIMS2 as a locus for cognitive progression & confirms associations for GBA & APOE (Click here to read more about this and click here to read the press summary).
  • Under-represented communities: The epidemiology of Parkinson’s in Rural Gujarat, India (Click here to read more about this).

  • New report explores leveraging both individual-level genetic data & GWAS summary statistics to increase polygenic risk score prediction accuracy (Click here to read more about this).
  • A biorxiv manuscript investigates the genetic basis of cognitive resilience (in n=330K) & identifies 13 independent genome-wide significant loci resulting in 366 mapped genes & 33 prioritized genes for “Resilience”; “Functional analysis showed sig. expression of associated genes in all brain tissues, & particularly in the frontal cortex. Sig. enrichment of associated genes was also found at the cellular level in both GABAergic & glutamatergic neurons indicating an excitatory/inhibitory control in the prefrontal cortex, & within biological processes related to neuron differentiation & synaptic activity”; Resilience had small nominally sig. correlations with ALS, stroke & Parkinson’s (PD rg=-0.08, P=4.58 x 10-02), but NOT Alzheimer’s (Click here to read more about this).
  • A 1/4 (22/97) of a Parkinson’s cohort had enlarged fasting gallbladder volume (compared to 3.1% (2/64) of control & 4.8% (1/21) of iRBD cases); Gallstone frequency was not increased in PD; The authors ask if biliary dysfunction is overlooked in PD research (Click here to read more about this).

  • Longitudinal (2 yrs) plasma neurofilament light chain (NfL) concentration were measured in 92 individuals with Parkinson’s (& 45 controls) & found to correlate with motor & non-motor symptoms; Increased plasma NfL associated with malignant PD phenotype (Click here to read more about this).
  • New data supports the use of skin punch biopsies & the real‐time quaking‐induced conversion (RT-QuIC) assay “as an alternative or in support of CSF analysis to demonstrate α‐syn seeding activity in patients with Parkinson’s” & DLB (Click here to read more about this).
  • New study reports decreased salivary caffeine correlates with Parkinson’s progression; Study involved 98 PD patients and 92 control participants, and assessed caffeine and its major metabolite, paraxanthine in saliva samples collected before and 4 hours after the oral intake of caffeine (100 mg); Caffeine levels were reduced in patients with moderate/advanced Parkinson’s, but normal in early & de-novo PD; Absorption & metabolism = normal (Click here to read more about this).
  • Pre‐existing Type 2 diabetes contributes to faster disease progression & reduced survival in a Parkinson’s cohort study, but this is not driven by increased vascular, Lewy or Alzheimer’s pathologies (Click here to read more about this).

  • New study suggests that “analysis of observational healthcare data, emulating otherwise costly, large, & lengthy clinical trials, can highlight promising repurposing candidates, to be validated in prospective registration trials”; Example used was Parkinson’s (Click here to read more about this).
  • Brain imaging study (involving 19 PD & 24 controls) finds cholinergic muscarinic M1/M4 receptor modulation within key brain networks in Parkinson’s; Cognition & motor severity associated with a similar topography – inferring cholinergic mechanisms? (Click here to read more about this).
  • Longitudinal changes in movement-related functional MRI activity in Parkinson’s, finds changes consistently observed in the ipsilateral cerebellum; May represent an attempt to partially restore motor function (Click here to read more about this).
  • New report explores serum metabolic biomarkers for synucleinopathy conversion in isolated REM sleep behavior disorder; N=82 iRBD & 29 controls; Potential to identify high-risk-of-conversion iRBD patients in the short-term (Click here to read more about this).
  • Desulfovibrio bacteria associated with Parkinson’s? Researchers report PD patients harbored Desulfovibrio bacteria in their gut microbiota; Small study (n=20 vs 20); Desulfovibrio species concentration correlated with severity of PD (Click here to read more about this).

  • Dopaminergic striatal dysfunction & cell loss in the substantia nigra are interrelated with increased nigral iron content in Parkinson’s; 1st striatal denervation, 2nd abnormal iron metabolism & 3rd neuromelanin changes (Click here to read more about this).
  • Longitudinal randomized controlled study in 40 people with Parkinson’s + MCI finds “physical therapy has a positive effect on cognitive functions, which extends beyond the duration of the treatment itself to, at least temporarily, reducing cognitive decline” (Click here to read more about this).
  • New study finds cerebrospinal α‐Synuclein oligomers reflect disease motor severity in the DeNoPa longitudinal cohort (consisting of 146 CSF samples of de novo Parkinson’s patients & matched controls; Oligomeric CSF α‐syn increased over 4‐year follow‐up, correlating with H&Y staging, while total α‐syn showed a longitudinal decrease followed by an increase in both Parkinson’s & control groups; Advanced stage presented with increased CSF oligomeric α‐syn levels compared with controls (Click here to read more about this).
  • New study suggests α4β2* agonists may be worth further evaluation for gait & balance disorders in Parkinson’s; Varenicline was tolerated well, enhanced attention, & altered gait performance in N=33 crossover study; Results consistent with target engagement (Click here to read more about this).
  • Basic Tips: How do I start programming Deep Brain Stimulation in Parkinson’s patients? (Click here to read more about this).

  • “The successful 3‐year outcome of Deep Brain Stimulation in Gaucher disease Type 1 associated Parkinson’s: A Case Report (Click here to read more about this).
  • A case study of the neuropsychological profile over 3yrs of an individual with an alpha-synuclein gene (SNCA) duplication-associated Parkinsonism; Highlights the important role that neuropsychologists can play in such cases (Click here to read more about this).
  • New research identifies patterns of altered disease-specific DNA methylation & associated gene expression in whole blood from 15 people with Parkinson’s (vs 15 controls); 30 differentially expressed genes & 31 differentially methylated regions (Click here to read more about this).
  • New study reports cardiac 18F‐Dopamine PET distinguishes Parkinson’s with orthostatic hypotension from the parkinsonian form of multiple system atrophy (MSA‐P) (N=50 PD + OH & 68 MSA‐P patients; Sensitivity of 92% & specificity of 96% – click here to read more about this).
  • Multiple Parkinson’s risk alleles may modify clinical manifestations to influence PD motor subtype. Novel variant at STK32B offers possible overlap between essential tremor & tremor-dominant PD (Click here to read more about this).

  • New medrxiv manuscript presents the results of the Four Winds Clinical Trial on Dementia; 25 participants get a precision medicine approach to AD/MCI; 25 patients with Alzheimer’s or MCI (MoCA>19) were initially evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation,…(everything)…, genetic predisposition & other biochemical parameters associated with cognitive decline; Encouraging results: Gray matter volumes increased ~0.3% on an annualized basis (vs 2.2% decrease in typical AD); Improvements also seen in AQ-C & MoCA (Click here to read more about this).
  • New medrxiv manuscript finds evidence of a long prodromal course in Progressive Supranuclear Palsy (PSP) – up to 7yrs pre-diagnosis – with subtle changes in motor & cognitive function (Click here to read more about this).
  • New study assesses the effect of levodopa on bilateral coordination & gait asymmetry in Parkinson’s using inertial sensor (Click here to read more about this).
  • New paper shows that pain is prevalent even in the early stages of Parkinson’s, yet the frequency & type of pain fluctuates as symptoms progress; N=154 PD & 99 controls in the ICICLE-PD study, 18m intervals over 72 months (Click here to read more about this).

  • Quality of Life in Neurological Disorders (Neuro‐QoL) is a publicly available health‐related QoL measurement system. New study explores longitudinal change in QoL measures over 3 years in 310 individuals with recently diagnosed Parkinson’s (Click here to read more about this).
  • A serum metabolic & proteomic characterization in Parkinson’s cohorts finds 1-oleoyl-sn-glycero-3-phosphocholine [LPC(18:1)] is inversely associated with cognitive; Abnormal lipid metabolism associated with cognitive status + potential immune/inflammation involvement (Click here to read more about this).
  • Analysing peripheral blood mononuclear cells from 25 newly diagnosed cases of Parkinson’s (& 25 controls) at baseline & after 12 months of pharmacologic treatment finds a “hyper‐expression of the P2X7R/NLRP3 inflammasome platform” that modulates α‐syn (Click here to read more about this).
  • New report indicates that α-synuclein in blood exosomes immunoprecipitated using neuronal & oligodendroglial markers may be able to distinguish Parkinson’s from multiple system atrophy (MSA – click here to read more about this).
  • Small study, but vitamin B12 & folate reported to lower homocysteine levels in levodopa-treated Parkinson’s patients; Authors conclude that “Supplementation with inexpensive vitamin B12 & folate is beneficial for levodopa-treated patients”(Click here to read more about this).

  • New study explores the feasibility of a multidisciplinary, intensive, outpatient rehabilitation program (MIOR) for moderate to advanced Parkinson’s (Click here to read more about this).
  • New study looks at T-cell subsets & immunoglobulins in 761 Parkinson’s patients (+ 761 matched controls); Higher proportion of CD3+ T & CD4+ T lymphocytes in PD; CD8+ T cell % similar in PD patients & controls; IgG level +ively correlated with duration (Click here to read more about this).
  • New study examines 531 cases of neuromelanin imaging in Parkinsonisms; Contrast of locus coeruleus is useful for discriminating Parkinson’s & Progressive supranuclear palsy (PSP); Nigra compacta in PD & PSP was significantly smaller than controls (Click here to read more about this).
  • New study reveals a social inequality in dementia diagnostic evaluation in Denmark; Higher income individuals seem to receive an earlier diagnosis; Public strategies should target people with lower socioeco status for earlier dementia detection & intervention (Click here to read more about this).
  • New study did not detect any pro-inflammatory signal related to disease risk or phenotype among GBA & LRRK2 Parkinson’s patients or non-manifesting mutation carriers (peripheral blood & CSF: TNF-α, IL-1β, IL-2, IL-4, IL-6, etc – click here to read more about this).

  • New data from two cohorts reveals concentration of α‐synuclein in plasma extracellular vesicles may serve as a potential diagnostic biomarker for Parkinson’s; Initial cohort includes PD, DLB, PSP cases & controls (Click here to read more about this).
  • Has the COVID-19 global pandemic permanently changed the state of practice for pre-DBS neuropsychological evaluations? The Parkinson’s Study Group Functional Neurosurgical Working Group viewpoint suggests ‘Yes’ (Click here to read more about this).
  • New study from Korea indicates that the risk of incidental Parkinson’s in kidney transplant recipients was similar to that in general population & significantly lower than that in end-stage renal disease patients (Click here to read more about this)
  • New research finds decoupling between global brain activity & associated cerebrospinal fluid flow is related to cognitive impairment in Parkinson’s (Click here to read more about this).
  • Accelerating diagnosis of Parkinson’s through risk prediction: new machine learning approach may allow for “guiding clinical decisions such as the initiation of neuroprotective interventions & … the possibility of earlier diagnosis for clinical trials” (Click here to read more about this).
  • The Biomarkers in Parkinson’s (Mark-PD) study provides evidence of an association between low Sphingosine-1-Phosphate (S1P) levels & motor severity and progression in PD patients; Does fingolimod represent a valid therapeutic approach for PD? (Click here to read more about this).

  • New study using two independent cohorts indicates that GBA haplotypes do not affect age at diagnosis of Parkinson’s; 1417 participants analyzed & there was no significant difference in age at PD diagnosis between the two main haplotypes of the GBA gene (Click here to read more about this).
  • “Class IV evidence that a de novo Parkinson’s disease pattern on FDG-PET predict future conversion to neurodegenerative disease in patients with isolated rapid-eye-movement sleep behavior disorder” (Click here to read more about this).
  • New data suggests that “non-mitochondrial sirtuins, SIRT1 & -6 but not SIRT2 might contribute to the pathogenesis of Parkinson’s in the Hungarian population, both via their altered mRNA levels & via gene alterations identified as specific SNPs” (Click here to read more about this).
  • Newly published data suggests that the impact of deep gray matter dopaminergic & serotonergic deafferentation on cortical function is mediated by striatal & thalamic metabolism in drug-naive Parkinson’s (Click here to read more about this).
  • New study reports on the dietary habits of Parkinson’s patients; Increased daily sugar intake vs controls (153 g/day vs. 119 g/day, p = 0.003); associated with an increase in non-motor symptoms, poorer QoL, increased constipation severity & Levodopa requirements (Click here to read more about this).

  • A case–control study investigating food addiction in Parkinson’s patients reports that counterintuitively dopaminergic agonist treatment should not be used as an indication for screening food addiction in patients with PD (Click here to read more about this).
  • New study explores ICICLE-PD study data & finds that verbal fluency, attention & memory neuropsychological tests were sensitive to change in early Parkinson’s dementia (Click here to read more about this).
  • “The Parkinson’s Real-World Impact Assessment (PRISM) Study sheds light on the lives of people with PD & those who care for them, re-emphasising the many challenges they face in everyday life” – a European survey of the burden of PD in patients & carers (Click here to read more about this).
  • Clinical utility of DaTscan in patients with suspected Parkinsonian syndrome: a systematic review & meta-analysis (Click here to read more about this).
  • Could fMRI brain responses to DBS in Parkinson’s patients represent an objective biomarker of clinical response? New model predicts optimal stimulation settings in unseen datasets (a priori clinically optimized & stimulation-naïve PD patients – click here to read more about this).
  • New report supports “the importance of studying constipation in Parkinson’s, showing that the presence & severity of this symptom around the time of diagnosis is predictive of subsequent progression to dementia” (Click here to read more about this).

  • Could low blood flow in the brain be an early sign of Parkinson’s in some cases? New research reports cortical blood flow abnormalities are present in patients with isolated REM sleep behaviour disorder & associated with cognitive dysfunction (Click here to read more about this and click here to read the press release).
  • New biorxiv manuscript presents proof-of-concept in humans of closed-loop evoked interference deep brain stimulation (eiDBS) for Parkinson’s, controlling pallidal oscillations in real-time (Click here to read more about this).
  • New medrxiv manuscript used whole-genome sequencing to assess mitochondrial DNA heteroplasmy levels in 1,361 human brain samples; Result: mtDNA heteroplasmy burden is unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases (Click here to read more about this).
  • New study reports soluble serum & plasma neurofilament light chain concentration remains stable when unprocessed blood samples are stored up to 7 days at room temperature (Click here to read more about this).
  • In a cohort of 1315 Parkinson’s patients, 43 (3.3%) have written books. Is writing a novel “parkinsonian trait”? (Click here to read more about this).

 

New clinical trials

  • New clinical trial registered: Pharma company UCB is initiating a Phase I study in 84 healthy volunteers & people with Parkinson’s to evaluate safety, tolerability, & blood levels of UCB0022… but what is UCB0022?!? (Click here to read more about this).
  • New clinical trial registered: Kissei Pharmaceutical have registered a small study of their orally administrable non-ergot dopamine agonist KDT-3594 in Japanese patients with early Parkinson’s (Click here to read more about this).

  • New clinical trial registered: Researchers have registered a study recruiting 30 individuals with Parkinson’s to investigate the effect of vibrotactile coordinated reset on motor ability (Click here to read more about this).
  • New clinical study registered: French Parkinson’s Disease Cohort (NS-PARK); A longitudinal cohort of PD patients, recruiting 30000 participants for 15 year follow up (Click here to read more about this).
  • New clinical trial registered: A Phase 4 study investigating the role & mechanism of Probiotics (Live Combined bifidobacterium, lactobacillus & enterococcus capsules) in improving motor symptoms in 240 people with mild to moderate Parkinson’s (Click here to read more about this).

 

Clinical trial news

  • Helicobacter pylori eradication improves motor fluctuations in advanced Parkinson’s patients: A prospective cohort study (the HP-PD trial – click here to read more about this).
  • Pharma company Roche & biotech firm Prothena Corp announced the first participant has been dosed in the Phase 2b PADOVA study of their alpha synuclein immunotherapy (prasinezumab) in early Parkinson’s – this is the follow up to the Pasadena study (Click here to read more about this news and click here to read more about the trial).

  • New study reports the results of a small study exploring safety, tolerability, & immune-biomarker profiling for 12 months of sargramostim treatment in Parkinson’s; “helps to support the idea of utilizing Tregs as a therapeutic target” (Click here to read more about this and click here to read the press release associated with this study).
  • The results of a double-blind, sham-controlled crossover trial investigating 1 month of non-invasive vagus nerve stimulation improves clinical & molecular biomarkers of Parkinson’s in 33 patients with freezing of gait have been published (Click here to read more about this).
  • Pimavanserin results from over 400 patients from 14 countries support its efficacy for treating psychosis in Parkinson’s (Click here to read more about this).
  • Results of Phase I first-in-human trial find mesdopetam (IRL790; a small molecule dopamine D3 receptor antagonist being developed by IRLAB Therapeutics) was well-tolerated up to a 120 mg single dose & up to 80 mg upon multiple dosing; Half-life: ~7hrs (Click here to read more about this)
  • The protocol of the ‘Exenatide-PD3’ study has been published – An ongoing multicentre, double blind, parallel group, placebo controlled, Phase 3 clinical trial is assessing once weekly Bydureon treatment in Parkinson’s over 2yrs (Click here to read more about this).

 

Conferences/lectures

  • This month the World Parkinson’s Congress virtual meeting on Advancing Science, Care, & Living with Parkinson’s was held between Monday-Friday 17 – 21st May. Amazing opportunity to learn more about everything going on and the videos are available to until August if you missed the meeting (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

  • Gain Therapeutics has announced new pre-clinical data from its GBA-associated Parkinson’s program; Their two lead chaperones GT-02287 & GT-02329 increase levels of GCase protein, its transport to the lysosome, & reduce levels of pathogenic α-synuclein in ips cells (Click here to read more about this).

  • Valted Seq announces exclusive right from Johns Hopkins Medical School to develop PAR & c-Abl pathway biomarker assays for neurodegenerative conditions like Parkinson’s (Click here to read more about this).
  • Accelerating Medicines Partnership: Parkinson’s (AMPD) Genetic Resource. This is version 1. It contains whole‐genome sequencing data from 3941 participants (2005 iPD); Democratizing data access (Click here to read more about this).
  • Genotyping company Centogene is extending its Global Parkinson’s Disease “ROPAD” study by 2500 more participants; 40 targeted sites across 11 countries (Click here to read more about this).

  • Alligator Bio announced a joint research agreement with Bioarctic; “Alligator will employ its proprietary antibody generation technologies in collaboration with BioArctic to develop new product candidates” (Click here to read more about this).
  • Gene4PD: A comprehensive genetic database of Parkinson’s“; Integrating “5 layers of genetic data (8302 terms) on PD with different levels of evidences from more than 3,000 studies & prioritized 124 PD-associated genes with strong or suggestive evidences” (Click here to read more about this study).
  • Voyager Therapeutics announces that development of their experimental gene therapy VY-AADC (NBIb-1817) treatment for Parkinson’s is still on hold; Prioritising VY-HTT01 program for treating Huntington’s Disease for now (Click here to read more about this).

Review articles/videos

  • Lots of 4 letter acronyms in this one: A review of the “Emerging disease-modifying therapies in neurodegeneration with brain iron accumulation (NBIA) disorders” (Click here to read more about this).
  • An interesting update on how embryonic stem cells are moving from the bench to the bedside for Parkinson’s (Click here to read more about this).
  • An interesting perspective discussing lessons from past viral infections & the link with Parkinson’s (Click here to read more about this).
  • New review of recent advances in the development of stem‐cell‐derived dopaminergic neuronal transplant therapies for Parkinson’s (Click here to read more about this).
  • Interesting short perspective: “The viral hypothesis – how herpesviruses may contribute to Alzheimer’s”. The same could be written for Parkinson’s? (Click here to read more about this).

  • The promise of crowdfunding to finance R&D of novel diagnostics & therapeutics for incurable diseases that are underfunded”, such as Alzheimer’s & Parkinson’s (Click here to read more about this).
  • Interesting piece on “Recall by genotype” studies – balancing scientific interests & the rights of participants in designing a recall by genotype study. Researchers explore the test case of heterozygosity in Parkinson’s-associated Parkin variants (Click here to read more about this).
  • New review on CNS-draining meningeal lymphatic vasculature: It’s roles, conundrums & future challenges (section on Parkinson’s – click here to read more about this).
  • How to understand visual hallucinations (Click here to read more about this).

  • Editorial on recent studies of α-synuclein distribution in tissues & biofluids in Parkinson’s; “Exchange highlights enduring methodological uncertainties, tradeoffs, & debates regarding the detection of antigens such as synuclein in tissue samples” (Click here to read more about this).
  • A useful review of splicing defects & the potential therapies for neurodegenerative conditions, including interesting sections on Parkinson’s & Alzheimer’s (Click here to read more about this).
  • Data suggests that individuals with Parkinson’s have a higher risk of melanoma (& vice versa). A new perspective explores the interplay between α-Synuclein & Pmel17 amyloid formation as a possible explanation for this odd association (Click here to read more about this).

  • Evading the immune system – new review explores immune modulation & immune matching in cell replacement therapies for Parkinson’s (Click here to read more about this).
  • Useful review on pain in Parkinson’s, exploring the role of the subthalamic nucleus (Click here to read more about this).
  • The 2021 update on International Society for Stem Cell Research (ISSCR) guidelines for stem cell research & clinical translation has been published (Click here to read more about this).
  • The current state of play in the development of inhibitors of LRRK2 as a therapeutic strategy for Parkinson’s; “Opportunities for a rich variety of strategies, but also increases the risk of unintended consequences” (Click here to read more about this).
  • The 2021 Alzheimer’s drug development pipeline has been published – a useful breakdown & analysis of clinical trials during 2020-2021 (Click here to read more about this).

 

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

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

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.

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