Monthly Research Review – December 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 December 2021.

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

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So, what happened during December 2021?

In world news:

8th December – The Belgian death metal rock band “Omicron” announced that they would not be changing their name despite sharing it with the recent COVID variant. Apparently “all publicity is good publicity” (Source).

14th December – Two Maryland zebras that escaped from a farm in mid-August were finally returned to their herd after almost four months on the run:

14th December – On April 28th, 2021, a small NASA probe the size of a small car called the Parker Solar Probe entered extended the atmosphere of the Sun – known as the corona – and spent 5 hours there – travelling at approximately 100 miles (163 kilometers) per second. On the 14th December, NASA researchers published the first results of that fly-by (Click here to read more about this).

17th December – UK Cabinet Secretary Simon Case recused himself from his one week old role of leading an inquiry into alleged government staff parties during the 2020 lockdown, after it is reported that a similar event was also held in his own office (it would all be comical if not for the fact that these people are actually in charge).

25th December – NASA, ESA, the Canadian Space Agency and the Space Telescope Science Institute successfully launched the $10 billion James Webb Space Telescope.

31st December – the UK finished the year on a new high (remember: every time a virus infects a cell there is the opportunity for variants)

And meanwhile in the more densely populated island of Taiwan:

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

In December 2021, there were 703 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (11,668 for all of 2021). 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. UCB and Novartis partner up on inhibitors for alpha synuclein aggregation

The pharmaceutical company UCB announced that they were partnering up with another pharma company Novartis on Parkinson’s, with development of UCB0599 – a small-molecule alpha synuclein aggregation inhibitor. Alpha synuclein is a protein that accumulates (or aggregates) in certain neurons in Parkinson’s and stopping this aggregation has been viewed as a potential therapeutic approach to slowing/stopping PD. Originally developed by Neuropore Therapies, UCB0599 is currently in Phase II clinical testing. The deal also provides Novartis with an opt-in to develop the immunotherapy UCB7853 (an alpha synuclein antibody – click here to read more about this news and click here to read a SoPD post on this topic).

2. Slow-wave sleep saves synucleinopathy?

Researchers reported that sleep deprivation increased levels of alpha synuclein protein build up in the brains of genetically engineered mice. They also reported that pharmacologically increasing slow-wave sleep could reduce the alpha synuclein burden. The mechanism of action is not clear (maybe via glymphatic function & modulating protein homeostasis), but the study provides further evidence for the importance of good sleep – which is disrupted in many cases of PD (Click here to read more about this and click here to read a SoPD post on this topic).

 

3. All I want for Christmas: ‘Runner plasma’

Researchers reported that exercise-related blood plasma-based anti-inflammatory factors are transferrable, target the cerebrovasculature, & provide beneficial effects on the brains of mice. The researchers also demonstrated that many of these factors are present in humans who engage in exercise – emphasizing the need for exercise to be a component of our lives (Click here to read more about this).

 

4.  Reports of specific CAR-T cell-based therapy leading to Parkinsonisms 

Researchers report a case study of a patient with a specific type of cancer (multiple myeloma) who displayed a progressive movement disorder with features of Parkinsonism approximately 3 months after BCMA-targeting CAR-T cell therapy. “Given reports of 3 patients with grade 3 or higher parkinsonism on the Phase 2 ciltacabtagene autoleucel trial & of grade 3 parkinsonism in the idecabtagene vicleucel package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies” (Click here to read more about this and click here to read a press release).

 

5.  The publication of the terazosin pilot study results

A team of researchers at the University of Iowa have published the results of a 12-week pilot study exploring the safety and tolerability of the prostate enlargement treatment terazosin in people with Parkinson’s. Results indicate that terazosin has the desired effected of changing ATP levels in the brain & blood, and that it is safe and well tolerated (Click here to read more about this and click here to read a SoPD post on this topic).

 

Articles of general interest

  • Nice summary regarding the biotech/pharma efforts to tackle misfolding proteins in Parkinson’s (Click here to read more about this).
  • The latest version of the Parkinson’s Hope List identifies 193 projects in research phase and 178 in clinical stage, an impressive total of 371 (Click here to read more about this).
  • Cure Parkinson’s webinar on deep brain stimulation in Parkinson’s:
  • A useful update on previously reviewed Parkinson’s clinical trials from the
    Journal of Parkinson’s “Clinical Trial Highlights” team (Click here to read more about this).
  • Most neurologists spend all their time on motor symptoms. Researchers say it is time to change & summarize 7 barriers to mental health care in Parkinson’s (Click here to read more about this).
  • An interview with Prof Ray Dorsey on Ending Parkinson’s:
  • This is beautiful – a neurologist on being a dementia with Lewy body patient & a treating physician at the same time (Click here to read more about this).
  • And when you try to channel Elton John & Kenny G at the same time… & it just looks ridiculous in amongst all the other wonderful singing efforts! Merry Christmas from
    Cure Parkinson’s (Click here to read more about this):

 

Basic biology news

  • “A crystal structure of unphosphorylated Pediculus humanus corporis PINK1 resolves a previously omitted N-terminal helix revealing how unphosphorylated yet active PINK1 is oriented on mitochondria”; Activation mechanism of Parkinson’s-associated PINK1 (Click here to read more about this).
  • What am I getting Mrs SoPD for Xmas? Silk organoids! New research presents single-cell transcriptomic features of human midbrain development & dopamine neuron diversity in brain organoids (Click here to read more about this).

  • New paper uses Mendelian randomization to investigate over 3,000 genes of druggable proteins; They find 23 drug-targeting mechanisms for Parkinson’s (+ 4 repurposing opportunities & 2 drugs which may increase PD risk); “Mendelian randomization is a highly compelling, time- & cost-effective adjunct to the randomized controlled trial. They have made their code openly available for use beyond Parkinson’s research; “Our Mendelian randomization study thus provides further evidence in favour of repurposing anti-diabetic drugs for Parkinson’s” The study provides further support for a clinical trial evaluating metformin in PD (Click here to read more about this).
  • Researchers report alpha-synuclein oligomers & small nerve fiber pathology in skin could be potential biomarkers of Parkinson’s; “choice of pathology α-Synuclein marker & anatomical site influences the diagnostic performance of skin biopsy” (Click here to read more about this).
  • Preformed fibrils-injected into A53T BAC-SNCA transgenic mice = 38% reduction in dopamine neurons, apo. rotational behavior, & motor dysfunction at 2 months post-injection (Click here to read more about this).
  • New biorxiv manuscript presents label-free characterisation of amyloids & Parkinson’s-associated alpha-Synuclein polymorphs by exploiting their intrinsic fluorescence property (Click here to read more about this).
  • New research finds perillyl alcohol (a metabolite of limonene) attenuates NLRP3 inflammasome activation & rescues dopamine neurons in experimental in vitro & in vivo models of Parkinson’s (Click here to read more about this).

  • New paper reports cortical circuit dysfunction (9 months post 1x intrastriatal PFF inject.) in a mouse model of alpha-synucleinopathy; “Disturbed excitation/inhibition balance as a relevant driver of circuit dysfunction” (Click here to read more about this).
  • New RNA-sequencing study finds that the gene expression changes in idiopathic Parkinson’s & LRRK2-associated PD fibroblasts are independent of glucose concentration in vitro (Click here to read more about this).
  • Expression of Nogo-A protein in dopamine neurons of the human substantia nigra pars compacta is reduced in Parkinson’s; “While Nogo-A expression in dopaminergic neurons is higher with increasing age, the opposite is the case in PD” (Click here to read more about this).
  • New biorxiv manuscript presents functional analyses of two novel LRRK2 pathogenic variants in familial Parkinson’s (Click here to read more about this).
  • New paper reports that Parkinson’s-associated LRRK2 variants induce sequestration of Rab8a to damaged lysosomes; Regulates transferrin-mediated iron uptake in microglia; Inhibition reverses phenotype (Click here to read more about this and click here to read a press release).
  • New research finds that reduced β-catenin-dependent WNT signaling impacts dopaminergic neuron identity (in vitro) via increased expression of the transcriptional repressor, NR0B1 (Click here to read more about this).
  • Researchers from Merck present hit-to-lead optimization from their structure-guided discovery program of aminoquinazolines as brain-penetrant & selective LRRK2 inhibitors; Are they about to initiate clinical development for Parkinson’s? (Click here to read more about this).

  • New paper presents cryopreservation of induced pluripotent stem cell-derived dopamine neurospheres for clinical application; cryopreserved cells survived transplantation into a Parkinson’s model & rescued phenotype (Click here to read more about this).
  • New biorxiv manuscript shows Parkinson’s-associated Fbxo7 & PI31 affect each other’s functions in regulating both proteasomes & mitochondria; New PI31 role – adaptor for SCFFbxo7 E3 ubiquitin ligase (Click here to read more about this).
  • Researchers from Biogen identify several compounds that enhance the activity of the wildtype version of the Parkinson’s-associated protein Parkin in the presence of phospho-ubiquitin & they act as positive allosteric modulators; While they activate Parkin, these agents “fail to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. We conclude that, in the context of the cellular milieu, the therapeutic window to pharmacologically activate Parkin is very narrow” (Click here to read more about this).
  • The evolution of knowledge on genes associated with human diseases; A machine learning & cognitive computing text-mining strategy to explore how knowledge of disease-associated genes evolved over the past 30 years (Click here to read more about this).
  • New research reports that decreased dopaminergic inhibition of pyramidal neurons in anterior cingulate cortex (AAC) maintains chronic neuropathic pain (in mice); Relief of ongoing neuropathic pain depends on D1R signaling in the AAC (Click here to read more about this).

  • New biorxiv manuscript finds that DAGLB is the main 2-AG synthase in mouse nigral dopamine neurons; Sequencing links 4 DAGLB variants in 6 individuals to a form of early-onset Parkinson’s; Daglb-deficiency impairs motor learning in mice, & increase of 2-AG levels corrects (Click here to read more about this).
  • New research suggests that Parkinson’s treatment amantadine has potential against COVID-19, by inhibiting known & novel ion channels encoded by SARS-CoV-2; Currently in clinical trial: NCT04854759 (Click here to read more about this).
  • New biorxiv manuscript proposes that mouse neurons accumulate nuclear & ribosomal material of oligodendrocyte origin throughout adulthood & in response to neuroinflammation (Click here to read more about this).
  • New research reports the structure of pathological aggregated TDP-43 filaments from 2 cases of ALS with FTLD; Structurally distinct from amyloid filaments in other neurodegenerative conditions (Click here to read more about this).
  • New research presents the discovery & optimization of a novel series of competitive & central nervous system-penetrant protease-activated receptor 4 (PAR4) inhibitors; Potential for traumatic brain injury, Alzheimer’s & Parkinson’s (Click here to read more about this).
  • Ectopic expression of NeuroD1 cannot induce microglia-to-neuron conversion in mice (rather microglial cell death); Leakage suggested as reason for previous results; “Glia-to-neuron conversion by NeuroD1 should always be tested by rigid lineage tracing” (Click here to read more about this).
  • New paper reports reduced levels of GPX4 (a repressor of ferroptosis) in post-mortem spinal cord samples from sporadic & familial ALS cases & transgenic mice; GPX4 over-expression in SOD1-G93A mice delays disease onset (Click here to read more about this).

  • Interactions between SARS-CoV-2 nucleocapsid-protein & Parkinson’s-associated α-synuclein accelerate amyloid formation; Spike protein = no effect; “Microinjection of N-protein in SH-SY5Y cells disturbed the α-synuclein proteostasis & increased cell death”; In vitro data, but of interest: N-protein & α-Syn directly interact, & can lead to “the formation of complexes that contain multiple proteins & eventually amyloid fibrils” (Click here to read more about this).
  • Activity of the DNA damage detector Parp1 increases with sleep deprivation; Parp1 activity promotes sleep, chromosome dynamics, and DNA repair – implications for Parkinson’s? (Click here to read more about this).
  • New biorxiv manuscript presents structure-based discovery of small molecule inhibitors of the autocatalytic proliferation of Parkinson’s-associated alpha-synuclein aggregates (Click here to read more about this).
  • New research finds MIRO1/2 & DRP1 drive mitochondrial-derived vesicle (MDV) biogenesis & promote quality control – a mechanistic model for global GTPase-driven MDV biogenesis (Click here to read more about this).
  • New research presents data suggesting that GCH1 deficiency may unmask early, subclinical Parkinsonism & only indirectly contribute to neuronal cell death (via immune-mediated mechanisms); GTP cyclohydrolase I (GCH1) is a rate-limiting enzyme in dopamine synthesis. They find that deficiency in GCH1 (in zebrafish) impairs tyrosine hydroxylase homeostasis & activates innate immune mechanisms in the brain & provide evidence of microglial activation & phagocytic behaviour (Click here to read more about this).

  • New research finds that trophoblast glycoprotein (Tpbg) is expressed in the developing mouse ventral midbrain & remains expressed in the dopaminergic subsets of adult mouse midbrain; Genetic deletion of Tpbg = loss of dopamine neurons & axonal defects in aged mice (12-14 months – click here to read more about this).
  • Mechanistic in vitro dissection of the inhibition of Parkinson’s-associated α-synuclein fibrillation by n-acetylneuraminic acid (Click here to read more about this).
  • Researchers report AAV capsid variants with brain-wide transgene expression & decreased liver targeting after intravenous delivery in both mouse & marmoset; AAV.CAP-B10 & AAV.CAP-B22 (Click here to read more about this).
  • A systematic analysis of variants of Parkinson’s-associated PINK1 (of unknown significance) shows intact mitophagy function for most variants; “Pathogenic variants in our study could be assigned as such because of the extensive data availability, & this data was absent for most variants of uncertain significance. The presence of a missense variant in PINK1 in a Parkinson’s case does not automatically imply pathogenicty” (Click here to read more about this).
  • New report finds that pathological Parkinson’s-associated α-synuclein aggregation is mediated by glycosphingolipid chain length & the physiological state of α-syn in vivo; Reduced long-chain GSLs by 30-40% = reduced α-syn pathology (Click here to read more about this).
  • New research finds negative functional effects of the fly microbiota on the development of flies carrying a mutation in the Parkinson’s-associated Parkin gene; Parkin fly microbiota was considerably different to that of the WT control fly (Click here to read more about this).

  • New study reports Parkinson’s-associated α-synuclein aggregation in the olfactory bulb induces olfactory deficits by perturbing granule cells & granular–mitral synaptic transmission (Click here to read more about this).
  • Cadmium (toxic heavy metal) exposure profoundly modified the gut-liver axis in an Alzheimer’s mouse model (ApoE4-KI males); Increase in microbial AD biomarkers, reduction in energy supply-related pathways in gut & blood, and an increase in hepatic pathways involved in inflammation (Click here to read more about this).
  • New data indicates that “the combination of normal alpha-synuclein concentration & brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein” (Click here to read more about this).
  • By evoking a transient dopamine release & subsequently measuring the levels of dopamine metabolites in the cerebrospinal fluid & plasma, could we identify early/prodromal Parkinson’s? Preclinical research indicates it is feasible (at just 30% cell loss – click here to read more about this).
  • New research reports that Surf4 is critical for the efficient export of progranulin & prosaposin from the endoplasmic reticulum (Click here to read more about this).
  • New research indicates that mild chronic colitis can trigger Parkinsonism in LRRK2 mutant mice (via activation of the TNF-α pathway); Anti-TNF-α monoclonal antibody, adalimumab = reduced gut & neuroinflammation & improved locomotion in LRRK2 G2019S colitis mice (Click here to read more about this).

 

Disease mechanism

  • Researchers present a dopamine D3 receptor ligand (PD13R) suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of Parkinson’s; arylpiperazine pharmacophore & desirable drug-like properties (Click here to read more about this and click here for the press release).
  • Researchers report that the Parkinson’s treatment apomorphine can stabilize neurotoxic alpha-synuclein oligomers (in vitro); Apomorphine inhibits alpha-synuclein fibrillation leading to the formation of large oligomeric species (Click here to read more about this).
  • New biorxiv manuscript proposes modulation of Parkinson’s-associated alpha synuclein as a potential intervention for patients with Fabry nephropathy (Click here to read more about this).
  • New research highlights TDP-43 is a possible ligand for microglial TREM2 & that this interaction could mediate neuroprotection of microglia in TDP-43-related neurodegeneration (ALS, FTD & Alzheimers – click here to read more about this).
  • New research finds that high glucose levels can induce dopaminergic neuronal apoptotic cell death via the Fyn/mTOR/S6K pathway (in vitro & in rodents); Fyn inhibitor PP1 rescues the proapoptotic effect (Click here to read more about this).
  • New research reports that over-expressed Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) inhibited the activation of microglia, inhibited apoptosis in dopaminergic neurons, & improved the motor performance of a Parkinson’s mouse model (MPTP – click here to read more about this).

  • New research finds that dietary supplementation with docosahexaenoic acid (DHA) exerts neuroprotection of enteric dopaminergic neurons in a Parkinson’s (Thy1-αSyn) mouse model (possibly via alterations in endocannabinoid-like mediators, GLP-1 & Nrf2 – click here to read more about this).
  • Preclinical investigations of the neuroprotective effects of the GPR55 ligand VCE-006.1 in experimental models of Parkinson’s & amyotrophic lateral sclerosis (ALS – click here to read more about this).
  • New research “demonstrate that STN−GPi & STN−SNr neurons may be modulated differently by STN-DBS” in both physiological & Parkinson’s-like conditions in mice (Click here to read more about this).
  • A new preclinical study in Parkinson’s & Alzheimer’s mouse models (A53T, APPOSK, tau784, & APP23) highlights an intranasal rifampicin & resveratrol combo treatment; Medilabo RFP Inc research (Click here to read more about this and click here to read a press release).

 

Clinical research

  • Oligodendrocytes! Researchers present the myelin-weighted connectome of Parkinson’s; N=81 PD & 35 controls; ~80% of connections from the basal ganglia showed a reduced myelin content (Click here to read more about this).

  • New paper presents >41K single-nuclei transcriptomes of postmortem midbrain cells from 6 idiopathic Parkinson’s cases (vs 5 controls); CADPS2 increased + reduced TH cluster exclusively present in iPD; Oh, & oligodendrocytes reduced! (Click here to read more about this).
  • Researchers from Roche (PASADENA Investigators & Prasinezumab Study Group) report that Hoehn & Yahr stage & DAT-SPECT specific binding ratios in putamen ipsilateral to the side of motor symptom onset predicts early Parkinson’s progression (Click here to read more about this).
  • New paper finds age & disease duration were independently associated with clinical presentation, course, & progression of Parkinson’s; Age was the main predictor, but disease duration also had a strong effect (Click here to read more about this).
  • New research used PPMI imaging data from 120 de novo Parkinson’s cases (+ 157 controls) to map progression of brain atrophy over 4 years; Progression shaped by both structural & functional brain connectivity; “Atrophy was greater in regions enriched for genes related to synaptic activity & signalling. In addition, cortical regions containing relatively more oligodendrocytes & endothelial cells had reduced vulnerability 2 atrophy”; Possible biological mechanisms at play in Parkinson’s? (Click here to read more about this).
  • A curious result from a Curasen Therapeutics study in the Netherlands: Detection of clenbuterol-induced changes in heart rate using at-home recorded smartwatch data in 12 individuals with Parkinson’s (Click here to read more about this).

  • New research presents a whole-brain connectome-based model in drug-naïve Parkinson’s for predicting motor impairment; N=47 drug-naïve PD, compared in 115 drug-managed PD cases; 2 patterns of connection identified (Click here to read more about this).
  • Researchers investigating metabolic markers in 3 animal models of Parkinson’s & in 3 cohorts of de novo PD patients, have proposed a composite biomarker with a combination of 6 metabolitesexhibiting a high accuracy for de novo PD diagnosis” (Click here to read more about this).
  • New medrxiv manuscript explores diversity in Parkinson’s genetics research; Only 7 studies using a genome-wide approach were published up to 2021 including under-represented populations (Click here to read more about this).
  • New editorial explores the meaning of “vascular parkinsonism” (Click here to read more about this).
  • ParkinSong Online: protocol for a telehealth feasibility study of an online mode of delivery for a singing intervention therapeutic for people with Parkinson’s (Click here to read more about this).
  • New research metabolic profiling of plasma & CSF from 23 Parkinson’s cases, 20 PD cases with L-Dopa-induced dyskinesia, & 24 controls finds bile acid biosynthesis metabolites distinguished PD-LID (Click here to read more about this).
  • A pilot study of an automatic gait analysis pipeline for wearable sensors in Parkinson’s (Click here to read more about this).

  • A systematic literature search of the influence of cerebrovascular disease in dementia with Lewy bodies & Parkinson’s dementia finds increased severity of white matter changes on MRI, but not neuropathology, in LBD vs PD without dementia & controls (Click here to read more about this).
  • A prospective study of progression in cerebellar Multiple System Atrophy; N= 85 individuals referred for sporadic late-onset cerebellar ataxia (SLOCA); Every 6 months, SARA, UPDRS-III & SDFS scores were measured; 33 months=33 patients had probable MSA-C (Click here to read more about this).
  • Deep nasal sinus cavity microbiota dysbiosis in Parkinson’s; Could an altered deep nasal microbiota, characterized by a putative pro-inflammatory microbial community, trigger neuroinflammation in PD? (Click here to read more about this).
  • New report uses a novel model-based multi-partition clustering method applied to international, multi-center, cross-sectional study (n=402 Parkinson’s cases) & identifies 8 subtypes with motor & non-motor symptoms (Click here to read more about this).
  • Meaningful polygenic risk scores-based prognosis of Parkinson’s at an individual level is NOT feasible – the conclusion of new research based on 2 PD patient & control cohorts (Kiel PD, Luebeck PD – click here to read more about this).
  • Researchers present further evidence for α-Syn-RT-QuIC having potential as a potential early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder cases prior to conversion (Click here to read more about this).

  • Curious: “while in healthy adults, sex-related differences played a certain role in dynamic connectivity patterns, these may no longer have an effect on Parkinson’s brain connectivity as the neurodegenerative process worsens” (Click here to read more about this).
  • New research identifies cerebrospinal fluid biomarkers for parkinsonism using a proteomics approach; Validation experiments confirmed the potential of 14 CSF peptides to discriminate Parkinson’s from atypical parkinsonism (Click here to read more about this).
  • New report proposes that reward-based behaviors in Parkinson’s are regulated by ventral striatal dopamine release; Loss of inhibitory feedback (midbrain autoreceptors) may = manifestation of impulsive-compulsive behaviors (Click here to read more about this).
  • In study provides a comprehensive overview of Parkinson’s burden & its trends in the incidence, prevalence, & years lived with disabilities at the global, regional, & national levels during 1990–2019; Pronounced increasing trends of PD burden observed (Click here to read more about this).
  • New research finds an early, linear association between low plasma serotonin & high nigral iron in Parkinson’s; N=97 PD & 89 controls; “It would be interesting to explore the effects of various serotonergic agents…on regional iron content in the brain” (Click here to read more about this).

  • Medication-induced fluctuations in bradykinesia can be classified using wrist-worn accelerometry at the time scale of a single minute” – researchers present dynamic naturalistic monitoring of bradykinesia in Parkinson’s using a wrist-worn device (Click here to read more about this).
  • New research finds that strategic alterations of posture are delayed in Parkinson’s patients during deep brain stimulation (Click here to read more about this).
  • New report presents patient & caregiver outcomes from a 6-month treatment study of levodopa-carbidopa intestinal gel in advanced Parkinson’s; “Patients’ QoL improvements do not correspond with improvements in caregivers’ burden or caregivers’ QoL” (Click here to read more about this).
  • The protocol for a multicentric observational study on the technical validation of real-world monitoring of gait has been published; A Parkinson’s cohort will be part of the study (Click here to read more about this).
  • Data reveal significant associations between tyrosine decarboxylating-gene abundance, several anti-Parkinson’s medications (not levodopa), & gastrointestinal symptoms; Points toward complex interactions between anti-PD meds, GI symptoms, & gut tdc-gene abundance (Click here to read more about this).
  • New research explores differential effects of pathological beta burst dynamics between Parkinson’s phenotypes; Akinetic-rigid = greater power & longer burst durations in the high beta band than tremor-dominant during movement (Click here to read more about this).
  • New data suggests that hydrophilic (pravastatin, rosuvastatin), but not lipophilic, statins may be associated with faster Parkinson’s progression – using PD Biomarker Program data (Click here to read more about this).

  • New cerebrospinal fluid-based study reports that lactate levels in Parkinson’s correlates with both clinical disease progression & neurodegeneration biomarkers, such as tau proteins & dopamine (no sig. diff. in t-tau, p-tau & DOPAC concentrations – click here to read more about this).
  • Old Parkinson’s trial, new data: A targeted proteomic biomarker study of “blood samples from the DATATOP trial was able to distinguish responder status with an accuracy (AUC) of 91% for the primary endpoint while it was 100% across secondary endpoints” (Click here to read more about this).
  • New research presents laser capture microdissection data from post-mortem human substantia nigra samples (early & late Parkinson’s cases + Lewy body disease + controls); distinct transcript. profiles for differential duration of PD (Click here to read more about this).
  • Cognitive influences in Parkinson’s – assessed in 103 patients & 81 care partners in an Australian cohort; Mild cognitive impairment in caregivers is an important consideration for the management of PD (Click here to read more about this).
  • A large cohort study (PD=3,879 vs 2,931 controls) from a Chinese mainland population explores the association between lysosomal storage disorder genes & Parkinson’s, & confirms the importance of lysosomal mechanisms in PD pathogenesis (Click here to read more about this).
  • New research highlights the existence of abnormal network integrity & disrupted functional connectivity in Parkinson’s with probable rapid eye movement sleep behavior disorder (RBD); Associated with impaired visuoperceptual functions (Click here to read more about this).

  • A longitudinal follow-up study using a national health screening database in South Korea indicates that the presence of osteoporosis may increase the likelihood of developing Parkinson’s or Alzheimer’s in adults aged ≥40 years (Click here to read more about this).
  • A case study of a 27 year old man carrying a PARK7/DJ‐1 variant; Developed bilateral hand tremor, impaired dexterity, & less intelligible speech by 5 years of age; Possibly youngest age at onset for DJ1-associated Parkinsonims reported (Click here to read more about this).
  • Multi-omic insights into Parkinson’s: From genetic associations to functional mechanisms; New research provides complete PD GWAS cell-type & tissue enrichment summary statistics from multiple studies in a standardized format (Click here to read more about this).
  • The results of the Cognition & Obstructive sleep apnea in Parkinson’s, Effect of Positive Airway Pressure therapy (COPE-PAP) study – another example of pandemic adaptation for a clinical trial; Telephone receiver administration of the MoCA & cognitive test is feasible (Click here to read more about this).
  • In addition to the known resistance against amyloid-β deposition, the larger gray matter volumes in key brain regions may confer APOE ε2 homozygotes additional protection against Alzheimer’s-related cognitive decline“; MRI study, n = 223 (Click here to read more about this).
  • A cautionary tale suggesting “that “natural” does not always mean “safe””; A 58-y-old woman falls ill after ingestion of 5 raw seeds of Mucuna pruriens on Reunion Island; Mucuna pruriens are sometimes used to treat Parkinson’s due to high levodopa levels (Click here to read more about this).

  • The Parkinson’s MED Collaborative Group report that “patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists” in an open-label randomised clinical trial; N=500 PD (Click here to read more about this).
  • Deep brain stimulation in the subthalamic nuclei alters postural alignment & adaptation in Parkinson’s; “DBS in the STN can significantly improve body position in PD although the effects are not completely reversed” (Click here to read more about this).
  • New medrxiv manuscript explores PPMI data & suggests “a role of serum uric acid as a marker of neuroprotection, in a certain subgroup of pre-motor patients exhibiting exclusively non motor features (hyposmia or RBD)” (Click here to read more about this).
  • Movement-related EEG signatures associated with freezing of gait in Parkinson’s; Abnormalities in different motor cortical areas could be used for FOG detection (Click here to read more about this).
  • An evaluation of the discrepancies between self-report vs clinician examination in early Parkinson’s finds self-reported motor-related impairments reflect not only motor symptoms but also other self-reported non-motor measures (Click here to read more about this).
  • New study suggests that diabetes, along with white matter hyperintensities, may have a significant role in the development of motor symptoms in vascular Parkinsonism; both had independent impacts on motor symptoms (Click here to read more about this).

  • Certain pre-surgical personality dimensions are apparently significantly associated with quality of life (QoL) amelioration & discrepancy between motor state & QoL changes after sub-thalamic nuclei deep brain stimulation in Parkinson’s (Click here to read more about this).
  • Using IQVIA data & retrospective cohort study design, researchers report an association between osteoarthritis & the incidence of Parkinson’s in the UK (2000-2016; N=260,224; HR = 1.82, 95% CI: 1.63–2.02); Incidence=1.2% (vs 0.6% – click here to read more about this).
  • New study provides Class III evidence that patients with Parkinson’s have more variability within blood oxygenation (Hb02) signals during usual-walking, compared to healthy controls, but not during dual-task walking (Click here to read more about this).
  • Identifying comorbidities & lifestyle factors contributing to the cognitive profile of early Parkinson’s from the COPPADIS Study Group; Hypertension, diabetes & dyslipidemia was significantly higher in cognitively impaired cases (Click here to read more about this).
  • Could early treatment with amantadine delay L-dopa-induced dyskinesia onset more than treatment with other symptomatic agents (anticholinergics or MAO-B inhibitors)? New data from a hospital-based retrospective cohort study from Taiwan suggests ‘yes’ (Click here to read more about this).

 

New clinical trials

  • New study registered exploring virtual reality augmented bicycling (wearing a head mounted display); 35 participants will be recruited, and the study is scheduled to finish in Sept 2022 (Click here to read more about this).
  • AbbVie is collaborating on a new study that was registered to investigate a telemonitoring tool for Parkinson’s; 450 participants will be recruited and assessments will take place at baseline, 1 year and 2 years (Click here to read more about this).

 

Clinical trial news

  • Publication of the Park-in-Shape trial results; A double-blind randomized study; 130 Parkinson’s patients – assigned (1:1 ratio) to aerobic exercise or stretching (active control) interventions for 6 months; Results: “Aerobic exercise, but not stretching, led to increased functional connectivity of the anterior putamen with the sensorimotor cortex relative to the posterior putamen. Behaviorally, aerobic exercise also improved cognitive control” (Click here to read more about this).
  • Alterity Therapeutics announces that the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) has authorized their Phase 2 clinical trial for ATH434 in Multiple System Atrophy (MSA – a condition similar to Parkinson’s – click here to read more about this).

  • The results of the Phase 2 safety/efficacy, randomized, placebo-controlled trial of Mevidalen (selective PAM of dopamine D1 receptor) in Lewy Body Dementia; N = 344 randomly assigned (1:1:1:1) to daily doses of 10, 30, or 75 mg; Improves motor symptoms (Click here to read more about this).
  • New clinical trial protocol for a Phase 2a placebo-controlled, double-blind randomised controlled trial of sodium selenate for progressive supranuclear palsy; 70 participants will be treated for 1 year; 1st endpoint=imaging (Click here to read more about this).
  • The safety, pharmacokinetics, & pharmacodynamics results of the Sanofi MOVES-PD venglustat trial in 29 individuals with GBA-associated Parkinson’s have been published; This is Part 1 of the randomized, double-blinded, placebo-controlled study (Click here to read more about this).

  • New medrxiv manuscript reports that a Japanese pilot study of 21 people with ALS found that the Parkinson’s treatment ropinirole (24 weeks + open-label active extension) is safe/tolerable, & there were indications of feasibility for larger trial (Click here to read more about this).
  • European Medicines Agency refused the marketing authorisation for Aduhelm/Aducanumab; “The company that applied for authorisation, Biogen Netherlands BV, may ask for re-examination within 15 days of receiving the opinion” (Click here to read more about this).

  • Following this news, Biogen cut the price of Aduhelm by approximately half to $28,200. And they also announced cost-reduction measures for 2022 that could result in annual savings of about $500 million (Click here to read more about this).
  • And that news was followed by strange reports that Biogen had approached Samsung BioLogics about potentially acquiring a control position in Biogen valuing the company at more than $42 billion (Click here to read more about this). This news was later reported to not be true, but it would appear that Biogen is seeking an aquirer (Click here to read more about this).

 

Conferences/lectures

  • The next Michael J Fox webinar will be on “Diet, exercise and other strategies for living well as you age“. It will be held on the Thursday 20th January at 12:00pm ET (Click here to learn more about this).
  • Yours truly is looking forward to talking with the No Silver Bullet group at 7.30 pm (UK) on Monday 10th January; I will be discussing my main Parkinson’s research takeaways from 2021 & the PD research results I will be looking out for in 2022 (Click here to read more about this).

  • Interesting podcast from ‘Stimulating Brains‘, interviewing Prof Hagai Bergman about his new book (“The Hidden Life of the Basal Ganglia”) and about a life in academia (Click here to read more about this).
  • Save the date! Grand Challenges in Parkinson’s Disease returns in September 2022. This annual symposium brings together scientists, clinicians and people with Parkinson’s to explore the latest in Parkinson’s translational research (Click here to read more about this).

 

Other news

  • Major new 5 year, £30M collaboration between GlaxoSmithKline & University of Oxford aims to deepen understanding of complex diseases such as Alzheimer’s & Parkinson’s, & increase drug discovery – “The Oxford-GSK Institute of Molecular & Computational Medicine” (Click here to read more about this).

  • KeifeRx completes $6million in series A financing to support its “pipeline of optimized tyrosine kinase inhibitors targeting neurodegenerative” conditions like Parkinson’s & Alzheimer’s (Click here to read more about this).
  • Interesting summary of 2021 research highlights for Parkinson’s UK; £8.3 million towards research in 2021 – including £6 million on virtual biotech companies – focused on Parkinson’s (Click here to read more about this).

 

Review articles/videos

  • A useful short review on blood-based biomarkers for Alzheimer’s (Click here to learn more about this).
  • A useful review on kynurenic acid in neurodegenerative disorders – including a section on Parkinson’s – highlights the delicate balancing act of this pathway & asks the question “unique neuroprotection or double-edged sword“? (Click here to learn more about this).
  • For the folks always asking about keto diet research in Parkinson’s, there is a short section in this review on the evidence (& controversies) for neuroprotection by ketogenic diets; Consequences of long-term strict adherenc gets discussed; “Additional studies should determine whether modified KDs, which are less restrictive & may be easier to adopt, would also have beneficial effects for the conditions described above including investigation of improving quality of life in the aging population” (Click here to learn more about this).

  • A fairly comprehensive review of the research surrounding pharmacological modulation of Nrf2/HO-1 signaling pathway as a therapeutic target for Parkinson’s (Click here to learn more about this).
  • “Reprogramming Stars”: A cell reprogramming approach for Parkinson’s – An interview with Dr. Malin Parmar (Click here to read more about this).
  • New review explores new molecules & new approaches being proposed as potential disease-modifying therapy of alpha-synucleinopathies, like Parkinson’s (Click here to learn more about this).
  • Aptamers are molecular-recognition agents comprising single-stranded DNA or RNA oligonucleotides that similar to antibodies, bind specifically to diverse targets” Looking for a useful introduction to how aptamers can target amyloidogenic proteins? (Click here to learn more about this).
  • A new review on the neurotrophic factor cerebral dopamine neurotrophic factor (CDNF); How it protects & repairs dopamine neurons by novel mechanism; Also covers MANF & GDNF (Click here to learn more about this).
  • The IMI European Lead Factory is a wonderful thing – democratizing access to high-throughput drug screening; A short commentary on the project (Click here to learn more about this).

  • New review on the signaling of PINK1 in neurodegenerative conditions like Parkinson’s; “Primary roles of PINK1 in protein homoeostasis, mitophagy & apoptosis are highly dependent on processing and subcellular context” (Click here to learn more about this).
  • A great perspective on the motor & non-motor circuit issues in early Parkinson’s; “A silent motor period during which initial compensation takes place at the dopaminergic nigrostriatal projection itself” (Click here to learn more about this).
  • Tools, tactics & objectives to interrogate cellular roles of O-GlcNAc in disease; “Discovery & structural validation of O-GlcNAc reader proteins is an untapped area for drug design in disease” (Click here to learn more about this).
  • There is an urgent need for refined methods to test these putative medicines in clinical trials“; Trials for neurodegenerative diseases: time to innovate (Click here to learn more about this).
  • A nice short review of efforts to activate GDNF/RET signaling as a potential treatment for Parkinson’s (Click here to learn more about this).

  • A nice ‘profiles of women in science’ on Prof Malu Tansey – “Be brave & do difficult things. Don’t settle for the easy stuff. Don’t be intimidated by the competition”; “It’s important to show up, it’s important to be a role model” (Click here to learn more about this).
  • New viewpoint addresses the challenges of clinical research for freezing of gait in Parkinson’s (Click here to learn more about this).
  • New review explores the possible roles of alpha synuclein & microbiome changes in the gut in Parkinson’s; Also considers if & how the changes interact & contribute to the disease process + symptoms (Click here to learn more about this).
  • Interesting perspective from attendees of the “Biomanufacturing in Space Symposium”, spelling out the opportunities for biomanufacturing in low Earth orbit for regenerative medicine (Click here to learn more about this).
  • A new review explores current knowledge about electron transport chain + OXPHOS & their relationships with Parkinson’s; It also looks at how PD-associated genes may be involved (their influences on each ETC complex – click here to learn more about this).

  • New review explores mitochondrial phenotypes in Parkinson’s, with a focus on human iPSC-derived dopamine neurons; “The precise role of mitochondrial perturbations in the vulnerability of dopamine neurons in PD remains undetermined” (Click here to learn more about this).
  • Environmental triggers of Parkinson’s – Implications of the Braak & dual-hit hypotheses; “Prodromal research represents an unprecedented opportunity for identifying the environmental triggers & effect modifiers of PD” (Click here to learn more about this).
  • In 2021, Alim-Louis Benabid – French-Algerian neurosurgeon – was awarded the 42nd Honda Prize for his contributions that led to the development of deep brain stimulation for Parkinson’s – this is a nice short summary (Click here to learn more about this).

 

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

And there it is, just some of the highlights from December 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 2022!!!

All of the material on this website is licensed under a
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You can do whatever you like with it!


EDITOR’S NOTE: The author of this post is an employee of Cure Parkinson’s, 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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