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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 July 2021.
The post is divided into 10 parts based on the type of research:
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So, what happened during July 2021?
In world news:
July 8th – The global death toll from COVID-19 surpassed 4 million lives (Click here to read more about this).
July 11th — Billionaire Sir Richard Branson flew really high. A new age of “space” tourism… blah, blah, blah.
July 20th — Billionaire Jeff Bezos flew really high (yawn)… Seriously, these folks have accumulated vast fortunes and this is how they chose to spend their money?!?!?
July 22nd – Dawn Butler was forced to leave the UK House of Commons by order of the acting Deputy Speaker, after she made comments referring to the Prime Minister Boris Johnson as a liar. Two questions: 1.) Why did her peers not walk out in solidarity with her? 2.) Why did the deputy speaker not point out the obvious (“All politicians are by nature“). Yes, I am a cynic.
July 23rd – the Tokyo Olympic games began.
July 29th – New Zealand-based Rocket Lab successfully reached orbit (actual space) – the 18th electron rocket to do so.
In the world of Parkinson’s research, a great deal of new research and news was reported:
In July 2021, there were 819 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (7,336 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. AC Immune buys a possible PD vaccine:
Biotech firm AC Immune announced the strategic acquisition of AFFiRiS‘s portfolio of therapeutics targeting alpha-synuclein (notably the alpha synuclein-targeting vaccine called PD01). It was an all-stock deal valued at US$58.7M. AC Immune plans to immediately launch an adaptive, biomarker-based Phase 2 study in Parkinson’s. This trial will evaluate a dose-response of the optimized formulation of PD01 (now called ACI-7104) and focus on the immunogenicity against a-syn & pathological a-syn species. Markers of progression of motor & non-motor symptoms of Parkinson’s will also be monitored (Click here to read more about this and click here to read a SoPD post about this announcement).
2. Farnesol – the farnesylator of PARIS:
A new study screened 230,000 compounds & identified ‘farnesol’ as an inhibitor of “Parkin Interacting Substrate” (or PARIS). It has previously been reported that PARIS levels can accumulate in some cases of PD – increasing due to Parkin inactivation. This increase results in the suppression of a neuroprotective protein called PGC-1α, and leads to dopamine cell loss in models of PD (Click here to read more about this). Screening for PGC-1α inducers, researchers report that farnesol administration inhibits PARIS directly, which stops PARIS from blocking PGC-1α. This leads to an increase in PGC-1α levels, that rescues models of Parkinson’s. Farnesol is a natural molecule produced by plants & mammals. It has anti-oxidant, anti-inflammatory, & neuroprotective properties and has recently been reported to protect a model of multiple sclerosis (Click here to read more about this). It is generally regarded as safe, but it has never been clinically tested in humans. Dosing/safety/tolerability studies will be required before exploring efficacy in Parkinson’s (Click here to read more about the new report, click here to read a press release on the study, and click here to read a SoPD post on this topic)
3. Are biomarkers going micro?:
MicroRNAs are small single-stranded non-coding RNA molecules (containing about 22 nucleotides) that are widely found in plants and animals. They play important roles in silencing other RNAs and in regulating biological activity in cells. An analysis of circulating microRNAs in blood samples from 3 independent cohorts (a total number of 151 Parkinson’s cases, 21 multiple system atrophy (MSA) patients, & 138 controls) found that increased levels of the microRNAs “miR-133b” & “miR-221-3p” could accurately distinguish PD vs controls with 84.8% sensitivity & 88.9% specificity (Click here to read more about this). In a second study, researchers have also identified miR-19b as a possible biomarker for monitoring the patients’ response to levodopa and predicting the efficacy of levodopa treatment. The result was validated in human dopaminergic neurons grown in culture exposed to L-Dopa, and further analysis indicated that miR-19b regulates ubiquitin-mediated proteolysis (Click here to read more about this).
4. Is my immune response all in my head?:
Two papers were published back-to-back reporting how the skull & vertebral bone marrow are reservoirs for myeloid cells to the meninges. The first report finds that in mice replenished myeloid cells in the dura mater are not blood derived rather they transit from cranial bone marrow thru specialized channels; In models of CNS injury & neuroinflammation, they demonstrate that these myeloid cells have an immunoregulatory phenotype compared with their more inflammatory blood-derived counterparts (Click here to read more about this); In the second paper, the researchers reported that the meninges host B cells that are also derived from skull bone marrow, mature locally, & likely acquire a tolerogenic phenotype. They further found that the brains of aging mice are infiltrated by a 2nd population of age-associated B cells, which come from the periphery & may differentiate into autoantibody-secreting plasma cells after encountering CNS antigens. Implications for future treatment of neurological diseases? (Click here to read more about this)
5. The Aducanumab saga rolled on…:
In July Biogen mounted a vigorous defense of its controversial Alzheimer’s drug, Aduhelm (Aducanumab), releasing an open letter to the Alzheimer’s community that took aim at critic’s “misinformation” of the approval (Click here to read that letter), while at the same time the company drew further criticism with their advertising messaging (Click here to read more about that). Meanwhile, those who should know better suggested that the “negative voices” are “not pro-patient” (???) (Click here to read more about this), and a new study revealed that the FDA appears to allow drugs without proven clinical benefit to languish for years on their accelerated pathway scheme (Click here to read more about this). You can’t make this stuff up…
Articles of general interest
- Researchers provide a scientist’s perspective to bringing advanced therapies for Parkinson’s to the clinic (Click here to read more about this).
- An interesting review on drug repurposing strategies of relevance for Parkinson’s (Click here to read more about this).
- A good write up by Parkinson’s UK on the Phase 3 CHIEF-PD study here in the UK investigating a treatment that has shown promise in reducing falls (Click here to read more about this).
Basic biology news
- A new biorxiv manuscript presents data demonstrating synaptic decline precedes dopaminergic neuronal loss in human midbrain organoids harboring a Parkinson’s-associated triplication of the SNCA gene (Click here to read more about this).
- A new report provides comprehensive study of a 29 capsid AAV library in the non-human primate CNS; Describes the most efficient AAV capsid variants for targeting specific areas (via different routes of administration – click here to read more about this).
- Researchers use α-syn oligomer proximity ligation assay (ASO-PLA) to visualize early oligomeric α-synuclein pathology & its impact on the dopaminergic system in the (Thy-1)-h[A30P]α-syn transgenic mouse model (Click here to read more about this).
- Researchers report Parkinson’s-associated α-syn fibrils alter the morphology & function of lysosomes; Cells transfer damaged lysosomes to neighbours (via tunneling nanotubes) & receive healthy lysosomes in return (Click here and here to read more about this, and click here to read a press release).
- Useful tool, interesting result: Continuous monitoring reveals protective effects of N-Acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit; “New possibilities for drug screening studies & personalized medicine”? (Click here to read more about this).
- Interesting that region-specific identity markers are maintained in in vitro conversion of spinal cord astrocytes into neurons (by proneural factors Ascl1 & Neurogenin2); Transcriptomics & eletrophys. analyses=V2 interneuron-like state (Click here to read more about this).
- α-Synuclein E46K mutation & involvement of oxidative stress in a drosophila model of Parkinson’s; “Noticeable decline in activity of catalase & SOD enzymes besides considerable increase in the levels of lipid peroxidation & reactive oxygen species” (Click here to read more about this).
- A new study reports inhibition of MAO-B enzymatic activity (by selegiline, rasagiline or siRNA-mediated knockdown) facilitated α-syn secretion in vitro (neuroblastoma SH-SY5Y cells); This action delays α-syn aggregation in rAAV-based rat model of Parkinson’s (Click here to read more about this).
- Researchers propose a new “anti-amyloid & antimicrobial hypothesis” to identify antimicrobial “α-defensins with a new repurposing function of amyloid inhibition, which serve as multi-target inhibitors to prevent microbial infection and amyloid aggregation” (Click here to read more about this).
- New study reveals a role for Parkinson’s-associated PARK7 (DJ-1) in the regulation of inflammatory bowel disease (IBD)-related inflammation (in vitro & in vivo); PARK7 silencing influenced the synthesis of IL1B, IL6, TNFA & TGFB1 (Click here to read more about this).
- Loss of UCHL1 destabilizes pyruvate kinase (PK) & rescues the Parkinson’s-associated phenotypes of PINK1 & Parkin mutants (in drosophila); PK is a direct target of UCHL1 to control mitophagy & loss of UCHL1 enhances mitophagy (Click here to read more about this).
- Could PIAS2-mediated blockade of IFN-β signaling be a basis for sporadic Parkinson’s disease dementia (PDD)? In mice, elevated PIAS2 blocked mitophagy, increased accumulation of senescent mitochondrial & oxidative stress; Converse=rescue of Ifnb–/– mice (Click here to read more about this).
- Nrf2 activation induces mitophagy & reverses Parkinson’s-associated Parkin or Pink1 knock down-mediated neuronal & muscle degeneration phenotypes in flies (Click here to read more about this).
- New research indicates that JNK pathway-associated phosphatase (JKAP) associates with disease risk & severity, correlates with Th1 & Th17 cells, + regulates CD4+ T-cell activation/differentiation in Parkinson’s; N=50 de novo PD cases (Click here to read more about this).
- A new biorxiv manuscript suggests an interface (like lipid membrane), can not only modulate α-synuclein amyloid aggregation but also play a role in formation of morphological variants (Click here to read more about this).
- New research finds oligomers can diffuse from the intestines to other tissues, leading to disease phenotypes (in C. elegans); Chaperone αB-crystallin & aggregation inhibitor squalamine reduce oligomer absorption (Click here to read more about this).
- New biorxiv manuscript suggests clusterin stabilizes highly potent, soluble seed species of Tau; this complex then enter cells via endocytosis, compromises endolysosomal function, & propagates aggregation of endogenous Tau; Curiously, “while having similar effects on aggregation kinetics in vitro, clusterin has opposite effects on the seeding activity of Tau & α-Syn aggregates in the cellular assay, enhancing the former & suppressing the latter” (Click here to read more about this).
- New biorxiv manuscript reports a chemical cocktail to induce senescence in iPSC-derived neurons; Utility was validated in motor neurons derived from ALS patient iPSCs, led to protein aggregation & axonal degeneration (quicker than no cocktail – click here to read more about this).
- Researchers report “Lewy-body like inclusions” in human midbrain organoid carrying Parkinson’s-associated glucocerebrosidase (GBA) & alpha synuclein variants (Click here to read more about this).
- A structure-based drug repositioning approach to identifies anti-cancer medication Crizotinib (Xalkori) as a moderate inhibitor and binder of Parkinson’s-associated LRRK2; Note: Crizotinib is not brain penetrant (Click here to read more about this).
- We’ve all heard of Parkinson’s-associated alpha-synuclein right? New report finds excess membrane binding of monomeric beta- & gamma-synuclein is invariably associated with inclusion formation & toxicity; Prevented by inhibiting stearoyl-CoA desaturase (Click here to read more about this).
- X-linked recessive genetic disorder Lesch-Nyhan disease causes impaired energy metabolism & reduced developmental potential in midbrain dopaminergic cells; Sig. loss of all purine derivatives, + impaired glycolysis & oxidative phosphorylation (Click here to read more about this).
- A new biorxiv manuscript explores how TREM2 impacts brain microglia, oligodendrocytes & endothelial co-expression modules, revealing genes & pathways important in Alzheimer’s (Click here to read more about this).
- A new paper reports Parkinson’s-associated DJ-1 inhibits microglial activation & protects dopaminergic neurons in vitro & in vivo (via interaction between IκBα & microglial p65); Loss of DJ-1 increases microglia activation in an NF-κB-dependent manner (Click here to read more about this).
- Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia (Click here to read more about this).
- A new report finds trophoblast glycoprotein (TPBG) is a marker for efficient sorting of ventral mesencephalic dopaminergic precursors derived from human pluripotent stem cells; Implications for cell transplantation in Parkinson’s? (Click here to read more about this).
- A new study reports that vesicle-associated membrane protein-binding protein B (VAPB) immunoreactivity is significantly decreased in multiple system atrophy brains, especially in oligodendrocytes & neurons with α-Syn aggregates (Click here to read more about this).
- iPSC-derived dopamine neurons from carriers of LRRK2 mutations associated with Parkinson’s displayed an elevated bursting behavior (in the absence of neurodegeneration); Need for more analysis of early dysfunction could highlight windows of opportunity (Click here to read more about this).
- MiR-335 directly targets Parkinsons-associated LRRK2 & its over-expression attenuates inflammatory events (in vitro – click here to read more about this).
- New biorxiv manuscript presents a novel post-translational proteomics platform that identifies neurite outgrowth impairments in Parkinson’s-associated GBA-N370S dopamine neurons; Central role for tau (Click here to read more about this).
- New paper reports glucosylceramide self-assembles to form amyloid-like fibrillar aggregates (in vitro), which in turn induces Parkinson’s-associated α-synuclein aggregation & stabilises its oligomers; Inhibitors explored (Click here to read more about this).
- Preformed fibrils generated from mouse alpha-synuclein produce more inclusion pathology in rats than fibrils generated from rat alpha-synuclein (Click here to read more about this).
- New biorxiv manuscript presents tissue-engineered nigrostriatal pathway (TE-NSP) technology: tubular hydrogels with a collagen/laminin core encasing dopamine neurons & their axons resembling the nigrostriatal pathway (Click here to read more about this).
- New low-expressing synucleinopathy mouse models based on oligomer-forming mutations & C-terminal truncation of α-synuclein; Neither model shows dopamine cell loss, but (even at moderate expression levels) both evoke measurable, progressive deficiencies (Click here to read more about this).
- New research explores squalamine, trodusquemine & related derivatives, des-squalamine & α-squalamine; Results = similar modifications, different effects on Alzheimer’s Aβ & Parkinson’s αS aggregation, in vitro (Click here to read more about this).
- New research reports Parkinson’s-associated mutations in the α-synuclein gene affect the biochemistry, architecture, & function of synapses; Hypothetical model proposed (Click here to read more about this).
- New research explores the effects of macromolecular crowding on the amyloid fiber formation reaction of Parkinson’s-associated α-synuclein; “The ability of cell environments to modulate reaction kinetics to a large extent, such as several-fold faster individual steps in α-synuclein amyloid formation, is an important consideration for biochemical reactions in living systems” (Click here to read more about this).
- Has L-DOPA “reprogrammed mitochondrial metabolism”? Researcher explored how oxygen tension effects the stability of Parkinson’s treatment L-DOPA; L-DOPA induced neurotoxicity is only of relevance under unphysiological normoxic conditions; “Under normoxic oxygen levels, auto-oxidation of L-DOPA & linked ROS production prevails, while under hypoxic conditions L-DOPA auto-oxidation is heavily reduced. With its catechol moiety, L-DOPA even acts as an antioxidant”; BUT, ATP levels were reduced by L-DOPA in a dose-dependent manner, plus “reduced mitochondrial membrane potential, indicating overall impaired mitochondrial activity”; NAD+ treatment = “a positive effect on the MMP in general & was able to counteract the impairing effect of L-DOPA”; The study is all in vitro, & as the authors suggest specific investigation of mitochondrial function upon L-DOPA treatment in a clinical setting is required (Click here to read more about this).
- New research suggests that Parkinson’s-associated “LRRK2 kinase activity may not be a direct regulator of ciliogenesis & ciliogenesis varies depending upon the cell type or genetic background”; Multiple cell types explored (Click here to read more about this).
- New paper finds Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits in flies. Could variations in Rab expression contribute to susceptibility of different dopamine nuclei to neurodegeneration seen in Parkinson’s? (Click here to read more about this).
- Single-cell transcriptome & TCR sequencing data from 110,000 T cells (8 PD cases & 6 controls) finds a group of cytotoxic CD4+ T cells (CD4 CTLs) “significantly clonally expanded in Parkinson’s patients”; Source of central infiltrating cytotoxic CD4+ T cells? (Click here to read more about this).
- New research finds that the mesencephalic locomotor region contains glutamatergic neuronal subpopulations stratified by projection target exhibiting roles in action control not just restricted to locomotion (Click here to read more about this).
- Poly (ADP-ribose) (PAR) is reported to interact with phosphorylated α-Synuclein in post mortem Parkinson’s samples; Interactions between negatively charged PAR & lysine residues on the N-terminal region of αSyn confirmed; “It is conceivable that the non-proteinaceous density in the cryo-EM structure of αSyn filaments reported in MSA may be PAR; however, additional research is warranted to confirm this hypothesis” (Click here to read more about this).
- A mechanistic link between Parkinson’s-associated LRRK2 & endocytosis; LRRK2 binds & phosphorylated the μ2 subunit of the adaptor protein AP2 (AP2M1; component of the clathrin-mediated endocytic machinery); LRRK2 calibration required for proper endocytosis (Click here to read more about this and click here to read a preprint of this study).
- Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo (Click here to read more about this).
- Could age-related increase in caveolin-1 (Cav-1) expression facilitates cell-to-cell transmission of Parkinson’s-associated α-synuclein in neurons? New research reports Cav-1 mediates “Lewy body-like inclusion body formation” (in vitro – click here to read more about this).
- Parkinson’s-associated LRRK2 is required for CD38-mediated NAADP-Ca2+ signaling & downstream activation of TFEB (regulator of the autophagy/lysosome function) in immune cells; LRRK2-G2019S mutant promotes hyperactivation of TFEB even in the absence of CD38 (Click here to read more about this).
- New report finds that dopamine neurons establish “a distinctive axonal arbor compared to glutamatergic or GABAergic neurons in both size & propensity of terminals to avoid direct contact with target neurons” (Click here to read more about this and click here for a preprint manuscript of this report).
- An under-appreciated role of lysosomal TPCN2 (two pore segment channel) in the macroautophagy/autophagy-lysosomal pathway? Lysosomal pH increased due to TPCN2-mediated Ca2+ release in Alzheimer’s model & TPCN2 inhibitor tetrandrine reduces amyloid plaques (Click here to read more about this).
- “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 (Click here to read more about this).
- New research finds that Parkinson’s-associated α-synuclein preformed fibrils induce neurotoxic astrocyte activation, marked by inflammatory responses, phagocytic function was reduced, & conferral of neurotoxic activity; Interesting that the α-synuclein PFF-mediated transcriptional activation in astrocytes requires RIPK1 & RIPK3 (Click here to read more about this).
- New paper reports on the neuroprotective effects of trehalose & sodium butyrate combo on preformed fibrillar α-synuclein-induced rodent model of Parkinson’s (Click here to read more about this).
- “In contrast to the traditional belief, MAO-A and MAO-B have profoundly different roles: MAO-A regulates dopamine levels, whereas MAO-B controls tonic GABA levels”; Implications for Parkinson’s treatment? (Click here to read more about this).
- New preclinical in vivo data reported by Seelos Therapeutics demonstrates 27% & 40% reduction in SNCA mRNA & a-synuclein protein (respectively) by SLS-004 – a DNA methyltransferase 3A gene therapy treatment – in models of Parkinson’s (Click here to read more about this).
- Pretreatment with microtubule-protecting drug candidate “SKIP” (based on the SxIP MT-interacting motif in NAP) has neuroprotective effects in neurotoxin models of Parkinson’s (Click here to read more about this).
- New biorxiv manuscript suggests “alpha-syn fibrils from a MSA patient are more potent in recruiting the endogenous alpha-syn & evoking a redistribution of TPPP/p25alpha protein in mouse primary oligodendroglial cultures” vs Parkinson’s case (Click here to read more about this).
- “Amyloid inhibitor design may be misguided if effects of lipid membrane composition & architecture are not considered during development”; Large unilamellar vesicles increased fibrillization of Parkinsons-associated α-synuclein, reduced impact of resveratrol & EGCG (Click here to read more about this).
- Loss of NRF2 accentuates Parkinson’s-like pathology & behavioral dysfunction in human α-Synuclein over-expressing mice; The mice also show sign. amplified oxidative stress, inflammatory markers, & autophagic burden, especially in the midbrain (Click here to read more about this).
- More preclinical data demonstrating the neuroprotective therapeutic potential of Neuraly’s glucagon-like peptide-1 receptor (GLP-1R) agonist, NLY01 – this time in experimental autoimmune encephalomyelitis (Click here to read more about this).
- New paper identifies 2 human metabolites (carnosine & kynurenic acid) that inhibit Aβ aggregation & rescue a C. elegans model of Alzheimer’s (via UPR thru HSF-1 & HSP40/J-proteins DNJ-12 & DNJ-19 – click here to read more about this).
- Researchers report that cytoplasmatic double-stranded RNA derived from G4C2 expansions is elevated in brains of patients with C9ORF72-associated ALS/FTD; Induces IFN1 signaling & cell death, reduced by JAK inhibitor treatment (Click here to read more about this).
- ATH434 (PBT434 from Alterity Therapeutics) is a brain-penetrant, oral inhibitor of α-syn aggregation that binds iron; New study reports it reduces α-syn-related neurodegeneration in a mouse model (6 month-old PLP-α-syn mice) of Multiple System Atrophy (MSA – click here to read more about this).
- Biogen researchers (and collaborators) report that elevated GCase prolonged stabilization of WT & Parkinson’s-associated-E46K–amplified 3K mutation α-Syn tetramers, reduces lipid-rich aggregates, & attenuates motor & cognitive deficits in mice (Click here to read more about this).
- Biogen researchers confirm stearoyl-CoA desaturase inhibition rescues α-Syn toxicity in models of Parkinson’s, but observe differential neurotoxicity induced by SCD inhibition based on neuron culture age; “This work supports SCD as a clinical target” (Click here to read more about this).
- Partial depletion & repopulation of microglia (using colony-stimulating factor 1 inhibitor PLX3397) has different effects in a mouse model (MPTP) of Parkinson’s; Microglial depletion has little effect, but replenishment elicits neuroprotection (Click here to read more about this).
- New research suggests dopamine-loaded nanoparticle systems can circumvent the blood–brain barrier problem & restores motor function in mouse model for Parkinson’s (Click here to read more about this).
- Researchers present data indicating that Alterity Therapeutics‘s PBT434 could chelate interstitial iron & inhibit re-uptake of iron by endothelial cells of the blood-brain barrier; A novel mechanism for therapeutic iron chelation in Parkinson’s (Click here to read more about this).
- A new report presents the first study to profile nigrostriatal O-glycome in healthy, Parkinson’s, & incidental Lewy body disease tissues; Potential biomarkers + benefits of employing orthogonal techniques for O-glycan analysis (Click here to read more about this).
- A biorxiv manuscript analyzed plasma from 201 Parkinson’s cases (+ 199 controls) & identified the diagnostic utility of N-acetyl putrescine (NAP) in combo with smell, depress./anxiety & RBD clinical tests (Click here to read more about this).
- Results of a pilot study attempting to correct Aromatic L-amino acid decarboxylase (AADC) deficiency in kids with midbrain gene therapy delivery; Primary & secondary endpoints of the study were met: Feasible & safe + clinical improvements (Click here to read more about this and click here to read the press release).
- Previous studies suggested that Parkinson’s disease and inflammatory bowel disease are associated. A new, very large study, does not find evidence for that (Click here to read more about this).
- New medrxiv manuscript suggests a possible role for rare PSAP variants in idiopathic/isolated REM sleep behavior disorder (iRBD) & potential genetic interaction with Parkinson’s-associated GBA; They identify loss-of-function mutations in PSAP in 3 iRBD cases (not present in 2,324 controls); None of the 3 individuals with PSAP LoF mutations have phenoconverted to an overt synucleinopathy, but all show initial signs suggestive of motor dysfunction (+ 2 dx-ed with MCI – click here to read more about this).
- A new medrxiv manuscript suggests significant associations between tyrosine decarboxylating (TDC) gene abundance, anti-Parkinson’s medication, & gastrointestinal symptoms; 2 year longitudinal study of PD cohort (Click here to read more about this).
- DNA repetitive elements account for >50% of the human genome, but little is known of their contribution to Parkinson’s etiology – a new medrxiv manuscript explores this topic in depth; This genome-wide meta-analysis of STRs in 16 cohorts adds another layer of genetic variation to our understanding of Parkinson’s; Novel signals – independent from current 90 risk variants – are located near TRIML2, NDUFAF2, MIR129-1 & NCOR1; 88% (30/34) of the associated STRs overlap with the current list of Parkinson’s GWAS risk variants; DNA from 39,087 individuals (16,642 PD cases & 22,445 controls of European ancestry) involved in the analysis (Click here to read more about this).
- All we want is a simple biomarker, is that too much to ask for? New research indicates that longitudinal changes in potential Parkinson’s biomarkers can be influenced by cognitive impairment & Aβ burden at baseline; Using PPMI data; 396 PD & 182 controls; Estimations of long-term temporal trajectories of CSF α-syn, Aβ, tau, & NfL in the PPMI cohort; “In all Parkinson’s patients, CSF α-syn & Aβ decreased in a negative exponential pattern before the onset of motor symptoms, whereas CSF t-tau & p-tau, & serum NfL increased” (Click here to read more about this).
- A new study does NOT find evidence that GBA-carrier status is associated with a higher risk of developing motor complications (dyskinesia & motor fluctuations) in Parkinson’s (N=884 PD cases – click here to read more about this).
- A 6-year longitudinal study from Taiwan on the severity progression of non-motor symptoms (NMS) in Parkinson’s; Severity was initially low & progressed slowly, similar for males & females; “Increment of medications was independent to NMSs evolution” (Click here to read more about this).
- I feel like I am flying & full of life: Contemporary Dance for Parkinson’s; An examination of psychological flexibility, creative self-efficacy & quality of life of PD patients participating in contemporary dance sessions (Click here to read more about this).
- New research reports diminished GLP-1 secretion postprandial (after a meal) in 16 individuals with Parkinson’s (compared to 19 household controls); Peak GLP-1 levels did not correlate with PD severity, motor function, or disease duration (Click here to read more about this).
- A new study uses multimodal imaging approach to reveal pronounced noradrenergic terminal loss relative to actual cellular locus coeruleus degeneration in individuals with Parkinson’s (n=53 vs 40 controls – click here to read more about this).
- Case-control study of hypertension & Parkinson’s; 1342 Chinese participants (671 PD & 671 matched controls); Hypertension increases PD risk by 1.9 times; Could early diagnosis & treatment of hypertension potentially reduce the risk of PD? (Click here to read more about this).
- The study protocol for a multi-centre, randomised, single-blind, parallel group trial to compare the effectiveness of a “Holter” for Parkinson’s symptoms against other clinical monitoring methods; Holter is Sense4Care’s hip worn monitoring device (Click here to read more about this).
- Systematic review of associations between common SNCA variants & clinical heterogeneity in Parkinson’s; “the mechanisms underlying the association of SNCA polymorphisms with PD risk may not be a major factor driving clinical heterogeneity in PD” (Click here to read more about this).
- New proof-of-concept study provides direct evidence that tracer 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment & Alzheimer’s; Increased astrocyte reactivity is found in cortical regions with high Aβ load (Click here to read more about this).
- A retrospective cohort study of a population attending primary care centres of Catalonia between 2006-2018 finds prediabetes increases the odds of subsequent Parkinson’s (replicating T2D association); Associations predominate in women & young individuals (Click here to read more about this).
- New case study reports an adult with early onset Parkinson’s who inherited 2 identical pathogenic PARK7 variants from her asymptomatic father, a carrier for the same variant, via complete uniparental isodisomy of chromosome 1 (Click here to read more about this).
- A 4-year observational, prospective study of long-term effect of bilateral subthalamic nucleus deep brain stimulation on non-motor symptoms in Parkinson’s finds beneficial effect in several but not all domains of non-motor symptoms up to 24 months post op. (Click here to read more about this).
- New medrxiv manuscript uses machine learning to identify 6 genetic variants & alterations in the heart atrial appendage as key contributors to Parkinson’s risk predictivity (Click here to read more about this).
- Can AI replace movement disorder specialists for diagnosing/managing Parkinsons? “AI models have been demonstrably useful in detecting changes in PD symptoms, but the diagnosis of PD, for now, remains clinical rather than biological” (Click here to read more about this).
- Do elevated levels of tyrosine hydroxylase (TH) in monocytes predict Parkinson’s onset or progression? Many questions arising from new study showing higher levels of TH in monocytes from PD cases (vs controls); TNFα increased the number of TH+ monocytes & quantity of TH (Click here to read more about this).
- New report presents the most comprehensive characterization of Parkinson’s genetic architecture in Latinos to date; 807 cases vs 690 controls, replication cohort=1,234 cases vs 439,522 controls (Click here to read more about this).
- When age was controlled, there was no increase in mortality rates from SARS-CoV-2 infection due to Parkinson’s in a NY-based cohort study. But certain unalterable factors (age >70 yrs) & alterable ones (reduction in PD medications) increased risk for mortality (Click here to read more about this).
- Understanding the effect of smoking & drinking behavior on Parkinson’s risk: a Mendelian randomization study supports the role of smoking as a protective factor against PD, but only when comparing current vs. former smokers (Click here to read more about this).
- New research finds TOMM40 ‘523’ allele length is a significant independent determinant & marker for the trajectory of cognitive decline & risk of dementia in Parkinson’s (when taken in conjunction with APOE genotype – click here to read more about this).
- New multimodal imaging study reveals regionally specific relationships between iron accumulation & neuromelanin depigmentation within the substantia nigra of Parkinson’s & provides in vivo insights in its neuropathology (Click here to read more about this).
- “North Carolina residents aged 65+ with long-term exposures to ambient PM2.5 levels exceeding the WHO standard had significantly increased risks of death and hospital admissions for Alzheimer’s”; The effects for Parkinson’s was less pronounced (Click here to read more about this).
- Further support for the terazosin story? New paper reports that increasing exposure to phosphoglycerate kinase 1 activators & tamsulosin were both associated with small reductions in Parkinson’s incidence (Click here to read more about this).
- New medrxiv manuscript suggests “a contribution of the noradrenergic system to apathy & potential benefit from noradrenergic treatment of people with Parkinson’s, subject to stratification according to locus coeruleus integrity” (Click here to read more about this).
- Abnormal interhemispheric resting state functional connectivity in cases of Parkinson’s with impulse control disorders; Evidence of asymmetry in functional connectivity of mesolimbic reward & response inhibition network in ICD (Click here to read more about this).
- New research finds “cortical β & γ oscillations are relevant in the pathophysiology of bradykinesia in Parkinson’s & that changes in inhibitory GABA-A-ergic interneuronal activity may reflect compensatory M1 mechanisms to counteract bradykinesia” (Click here to read more about this).
- The study protocol for a controlled trial exploring longitudinal, INterdisciplinary home visits vs. usual care for HOMEbound people with advanced Parkinson’s Disease (IN-HOME-PD) has been published (Click here to read more about this).
- Altered actinobacteria & firmicutes phylum associated epitopes in 69 individuals with Parkinson’s; “Altered microbiota-associated epitopes in PD may relate to abnormalities in immunity & glutamate & propionate metabolism” (Click here to read more about this).
- Longitudinal evolution of non-motor symptoms in early Parkinson’s – a 3-year prospective cohort study; N=224 recently diagnosed individuals; Overall evolution is mild & multidimensional; A high non-motor burden predicts faster motor progression; Curiously, the authors add “Notably, the number & the score of sexual dysfunctions decreased with the progression of the disease” (Click here to read more about this).
- New results suggests that simultaneously evaluating DAT- & FDG-PET brain imaging could hold clinical value in the diagnosis of dementia with Lewy bodies (Click here to read more about this).
- An analysis of serum lipid profiles among sporadic & familial forms of Parkinson’s (GBA & LRRK2) finds support for the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in cases of GBA-associated PD; N=403 PD cases (Click here to read more about this).
- A case report illustrates that a personally tailored approach to exercise in Parkinson’s is needed in; This may include the use of novel technological advances (such as a special walker – click here to read more about this).
- A new analysis of a large multinational sample of Parkinson’s patients (vs controls) finds widespread structural brain abnormalities on the cortical & subcortical level that may shed new light on the pathophysiology & progression of PD; correspond to Braak staging (Click here to read more about this).
- New paper reports that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment; L-dopa-induced shifts in the balance betwn these states can predict Parkinson’s clinical change (Click here to read more about this).
- A new study reports “how 4 major forms of Alzheimer’s genetic risk – APOE-ε4, APOE-ε2, polygenic risk & familial risk – are associated with 273 traits in ~500,000 individuals in the UK Biobank” (Click here to read more about this).
- A medrxiv manuscript presents the study protocol for the “Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease” (RAPSODI) study; To aid development of procedures for earlier diagnosis of Parkinson’s (Click here to read more about this and click here to see the Rapsodi study).
- Researchers report subsets & cytokine expression profiles of peripheral adaptive immune cells in early-stage Parkinson’s show distinct differences (vs controls); Naive CD4+ & naive CD8+ T cells sig. reduced in PD, while central memory CD4+ T cells are sig. elevated; Peripheral blood from 41 patients with early-stage Parkinson’s & 40 matched controls were evaluated; TNF-α–producing CD19+ B cells were sign. increased in PD; “Notably, some of the changes observed in CD4+ T cells & B cells were associated with clinical motor disease severity” (Click here to read more about this).
- A new research reports clear & temporally distinct progression patterns across Parkinson’s clinical subtypes (“Motor Only”, “Psychiatric & Motor”, & “Cognitive & Motor”), particularly in cognitive & psychiatric features (Click here to read more about this).
- A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies; The presence of Glutaminyl cyclase & pGlu79-α-synuclein is increased in neurons of the nigra & associated with pathological structures in Parkinson’s & DLB cases (Click here to read more about this).
- New research finds diplopia (double vision) is common & associates with motor & non-motor severity in Parkinson’s; Data from 26,790 PD & 9257 control cases in the Michael J Fox Foundation’s Fox Insight Study (Click here to read more about this).
- A new paper shows the potential of video-based Parkinson’s assessments in a nationwide cohort of the Michael J Fox Foundation’s Fox Insight participants; Single-site virtual studies can recruit large national cohorts (Click here to read more about this).
- The experience of OFF periods in Parkinson’s: Descriptions, triggers, & alleviating factors; N=2110 Fox insights participants; “Although OFF periods are common, the individual experiences of OFF vary” (Click here to read more about this).
- Researchers propose a multivariable clinical-genetic model for predicting dyskinesia in early-onset Parkinson’s; They propose this “may have good application prospects for L-dopa-induced dyskinesias prediction & dopamine replacement therapy management” (Click here to read more about this).
New clinical trials
- New clinical trial registered: InnoMedica have initiated a Phase 1 safety evaluation of intravenous Talineuren (nano particle carrier of ganglioside GM1) in Parkinson’s; N=12, SAD/MAD study (Click here to read more about this)
- The ADepT-PD trial is recruiting now. This placebo-controlled trial will be assessing the drugs nortriptyline and escitalopram for depressive symptoms in Parkinson’s; and to examine the effectiveness of nortriptyline to delay motor progression (Click here to read more about this).
- New clinical trial registered: Researchers are conducting a study exploring how a high fibre nutritional supplement affects bacteria, viruses, & fungi that live in different regions of the body in people with Parkinson’s, N=60, 4 week study (Click here to read more about this).
- The “Azathioprine in early Parkinson’s” (AZA-PD) trial is now active and recruiting. Have a look at the study website to learn more about this study (Click here to read more about this)
Clinical trial news
- Results of a pilot study of 2 low doses (100 & 250mg) of Niacin (vitamin B3 derivative) in 47 people with Parkinson’s; 3-month double-blinded (vs placebo) run-in + 12 month open label study; 3.5 point average improvement in the UPDRS III, inflammation reduced (Click here to read more about this).
- Pilot clinical study results indicate that probiotic PS128 supplementation for 12 weeks with anti-parkinsonian medication improved UPDRS motor score & quality of life in Parkinson’s; N=25; No obvious effect of probiotic on non-motor symptoms (Click here to read more about this).
- Results of a Phase 2 proof-of-concept trial of Solriamfetol (norepinephrine–dopamine re-uptake inhibitor) for excessive daytime sleepiness in Parkinson’s have been published; N=66, 4 wks treatment, no significant improvements; MWT suggests possible benefit (Click here to read more about this).
- The results of the HEADWAY-DLB study – an international, randomized, placebo-controlled, Phase 2b clinical trial of intepirdine for dementia with Lewy bodies – have been published; Intepirdine well tolerated, but no impact (Click here to read more about this).
- A pilot randomized, double-blind, placebo-controlled trial of hydrogen inhalation for Parkinson’s; N=20; Inhaled 6.5 (0.1) vol% hydrogen gas in 2 L/min of mixed air or placebo air 2 x 1hr per day for 16 weeks; Results: safe, but no beneficial effects (Click here to read more about this).
- The results from the COPPADIS cohort at 2-year follow-up study identifies worsening sleep problems & neuropsychiatric symptoms as significant independent predictors of non-motor symptoms progression in Parkinson’s (Click here to read more about this).
- Improvements reported in clinical signs of Parkinson’s using photobiomodulation in a proof-of-concept unblinded pilot study (n=12; 12-week treatment of transcranial, intranasal, neck & abdominal PBM – click here to read more about this).
- A new medrxiv manuscript presents the results of a randomized crossover trial of short (30µs) versus conventional (60µs) pulse width deep brain stimulation in Parkinson’s; Results: no difference (Click here to read more about this).
- Per-oral image guided gastrojejunostomy insertion allows for effective long-term delivery of levodopa-carbidopa intestinal gel in Parkinson’s patients, & new study of 32 patients indicates that it is safe & useful (Click here to read more about this).
- Just keep dancing! Longitudinal (out to 3 yrs) assessment of 32 people with Parkinson’s who took part in once-per-week dance class shows limited motor progression (compared to reference PD cohort data); Similar results for non-motor features (Click here to read more about this and click here to read the press release).
- A report of an uncontrolled pilot study (6 cases) of fecal microbiota transplantation in Parkinson’s; The treatment was safe out to 6 months, reports of some improvements in PD symptoms (including constipation) – unblinded study though (Click here to read more about this).
- International Stem Cell Corporation announces completion of their Phase 1 clinical trial evaluating safety of their cell transplantation candidate, ISC-hpNSC for the treatment of Parkinson’s; N=12 participants; No adverse events at 12 months (Click here to read more about this).
- “Genetic markers and the progression of Parkinson’s” is the topic of the next Cure Parkinson’s/Van Andel/Journal of Parkinson’s webinar series (Click here to learn more about this).
- Parkinson’s UK have their 2021 PAR-CON virtual research conference lined up for October (Click here to learn more about this).
- Really looking forward to the NECTAR 2021 meeting in Edinburgh in November. Really impressive line up of speakers/presenters – everyone in the field basically (Click here and here to learn more about this). There is also a public event exploring clinical trial participation (Click here to learn more about this).
- Biotech firm Alector & big pharma GSK announce a global collaboration in immuno-neurology for 2 clinical stage first-in-class monoclonal sortilin antibodies for neurodegenerative conditions, including Parkinson’s, FTD, ALS & Alzheimer’s (Click here to read more about this).
- Muna Therapeutics launched with 60 million euro; Microglial targets for neurodegenerative conditions, like Alzheimer’s & Parkinson’s (Click here and here to read more about this).
- Ipsen has entered an exclusive worldwide licensing agreement with IRLAB Therapeutics aimed at developing & commercializing mid-stage D3-receptor antagonist mesdopetam for Parkinson’s; Ipsen is initiating Phase III preparatory activities (Click here and here to read more about this).
- Coave Therapeutics closes €33 million ($39 million) Series B financing to develop its gene therapy pipeline & next-gen AAV vectors; Preclinical development includes CTx-GBA1 for Parkinson’s & Gaucher disease (Click here to read more about this).
- California Governor Newsom has signed a funding bill including $8.4M over 4 years to renew funding for the “California Parkinson’s Disease Registry” (CPDR) & to expand it to other neurodegenerative conditions. Supported by the Michael J Fox Foundation (Click here to read more about this).
- Massachusetts Governor Baker has signed an act establishing a Massachusetts Parkinson’s Registry. This registry will now allow for the collection of information on the incidence of the Parkinson’s in Massachusetts (Click here to read more about this).
- NRG Therapeutics (a Parkinson’s UK supported biotech) has been awarded a $500K grant from the Michael J Fox Foundation to progress Parkinson’s programme, focused on 2nd generation inhibitors of mitochondrial permeability transition pores (Click here to read more about this).
- “Nearly 28% of 13,874 completed trials in the EU Clinical Trials Register (EUCTR) on 1 July had not posted their results”…”Public research hospitals & universities, not drugmakers, are responsible for the vast majority of the lapses” (Click here to read more about this).
- Daewoong Pharmaceutical & Hanall Biopharma have invested in NurrOn Pharmaceuticals‘ Series A round; Candidate drug targets the orphan nuclear receptor Nurr1 as a novel therapy for Parkinson’s; IND & clinical trials in the 1st half of 2022 (Click here to read more about this).
- Inhibikase Therapeutics announced US FDA clearance to begin a Phase 1b extension study to evaluate IkT-148009 in Parkinson’s patients (Click here to read more about this).
- The blood-brain barrier is no longer a barrier to drug development? Denali Therapeutics announces positive “interim” data from Phase 1/2 study with ETV:IDS (DNL310) in patients with the lysosomal storage disease Hunter Syndrome (MPS II); Based on these data, Denali is accelerating efforts to initiate a pivotal Phase 2/3 study in 1H 2022 (Click here to read more about this).
- “While almost 90% of neurologists are moderately or highly aware of Aduhelm [Aducanumab], only 3% have written prescriptions so far”; “Only about one fourth (27%) plan to prescribe the drug in the next few months” – neurologists are slow to warm to Biogen’s controversial Alzheimer’s drug (Click here to read more about this).
- The US FDA has granted BlueRock Therapeutics (& pharmaceutical company Bayer) a fast track designation for their cell therapy candidate DA01 for advanced Parkinson’s; Phase I clinical trial is currently ongoing (Click here to read more about this). This video from Prof Lorenz Studer (co-founder of Bluerock) outlines cell based approaches to treating Parkinson’s (thanks Deepak!):
- Genetics of Parkinson’s & implications for clinical practice; “While it is possible to provide some information to individual patients regarding risk of disease & prognosis, the range of predictions creates uncertainty”; “Whereas the treatment implications for different forms of monogenic diabetes have driven genetic testing into clinical practice, this is not yet the case for routine Parkinson’s care, although examples of this are beginning to emerge” (Click here to read more about this).
- New review on gene therapy (or gene editing more specifically) for neurodegenerative conditions like Parkinson’s: Clinical potential & directions (Click here to read more about this).
- A very thorough review of Parkinson’s-associated LRRK2 recruitment, activity, & function in organelles (Click here to read more about this).
- A useful review of the emerging role of circular RNAs in Alzheimer’s & Parkinson’s (Click here to read more about this).
- A new overview discussing “the different methods to generate induced neurons of a generic type & of different subtypes, with a particular focus on induced dopaminergic neurons generated from human fibroblasts” (Click here to read more about this).
- Everything you need to know about inflammasomes as therapeutic targets in human diseases, like Parkinson’s. Covers a lot (history, therapeutic strategies, etc – click here to read more about this).
- A very useful primer on Parkinson’s-associated cognitive impairment (Click here to read more about this).
- A review article explores the biology & pathobiology of glutamatergic, cholinergic, & dopaminergic signaling in the aging brain, with lots of discussion about Parkinson’s (Click here to read more about this).
- Short section on Parkinson’s, but useful review of N-Acetylcysteine in lots of other medical conditions; “an old drug with new tricks” (Click here to read more about this).
- Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function & calcium signaling – a useful review that involves a good section on Parkinson’s (Click here to read more about this).
- New review suggests the contribution of the gut in Parkinson’s is significant; “Initial pathogenesis in the gut may proceed the development of prodromal PD subtypes”; Lots of bases covered, a very thorough read (Click here to read more about this).
- Researchers from the US FDA present a prospective approach to identify meaningful & relevant benefits, risks, & other considerations that may be used for clinical trial design & quantitative patient preference studies in Parkinson’s (Click here to read more about this).
- Have you ever considered the implications of oral health disorders in Parkinson’s? This new review article is enlightening (Click here to read more about this).
- A short review/perspective on nutritional ketosis research in Parkinson’s – preclinical work, a useful literature review of clinical studies, & discussion of unanswered questions (Click here to read more about this).
- “Population-based studies provide unique design advantages for studying pre-diagnostic Parkinson’s, but they remain relatively sparse. It is therefore pivotal that population-based studies join forces. Data sharing is essential…” (Click here to read more about this).
- Interesting review article trying to find consensus (& highlight the knowledge gaps) around alpha-synuclein research – attempting to outline multipronged strategies ultimately aimed at novel therapies for Parkinson’s (Click here to read more about this).
- It is amazing how much we actually do know about the Parkinson’s-associated protein alpha synuclein. A new review provides “an all-inclusive trip around its structure, influencing factors & applied techniques” (Click here to read more about this).
- “Antagonistic pleiotropy theory posits that adaptive evolutionary changes, which facilitate reproduction & individual fitness early in life, can enhance detrimental aging-related processes” – researchers are reassessing neurodegenerative conditions; They present “a conceptual framework suggesting that the pleiotropic roles of genes in infections & host–pathogen interactions should be considered when studying neurological illnesses”, like Parkinson’s (Click here to read more about this).
- A very thorough overview/review of potential biomarkers for the conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder; Future clinical trials for prodromal Parkinson’s may depend on this ongoing research (Click here to read more about this).
- Are microbial infections a risk factor for neurodegenerative conditions, like Parkinson’s? (Click here to read more about this).
- A new review explores a novel NAD signaling mechanism in axon degeneration & its relationship to innate immunity (Click here to read more about this).
- A timely review of how PARK genes may link mitochondrial dysfunction & alpha-synuclein pathology in sporadic Parkinson’s (Click here to read more about this).
- Useful new review on targeting of lysosomal pathway genes for disease modification in Parkinson’s: New insights from cellular & animal models (Click here to read more about this).
- New review on the mitoprotective effects of Centella asiatica (L.) Urb.: Anti-inflammatory & neuroprotective opportunities in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
- A useful overview of the newly US FDA-approved catechol-O-methyl transferase (COMT) inhibitor, opicapone; “once daily dosing of opicapone simplifies the dosing regimen for Parkinson’s patients with minimal adverse effects” (Click here to read more about this).
* * * * * * * * * * * *
And there it is, just some of the highlights from July 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 August!!! (Christmas is coming)
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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.
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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.