# # # # 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 January 2022. The post is divided into 10 parts based on the type of research: Top 6 pieces of Parkinson’s news Articles of general interest Basic biology Disease mechanism Clinical research New clinical trials Clinical trial news Conferences/lectures Other news Review articles/videos # # # #

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So, what happened during January 2022?

In world news:

January 7th – COVID-19 pandemic: The number of COVID-19 cases exceeds 300 million worldwide.

January 10th – The first successful heart transplant from a pig to a human patient is reported.

January 11th to 13th – A rare rotating ice disk formation (300+ feet wide) developed on the Presumpscot River in Maine (USA) and someone thought it deserved to be on the news (and its own Twitter account).

January 15th – A large eruption of ‘Hunga Tonga’ – a submarine volcano in Tonga – triggered tsunami warnings in Australia, Canada, Chile, Fiji, Japan, New Zealand, Samoa, and the United States.

January 26th – An electronically tagged Arctic hare’s dash across northern Canada had researchers scratching their heads. The animal covered a total of 388 kilometers in 49 days – which is the longest such journey among hares and is changing how scientists think about tundra ecology.

 

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

In January 2022, there were 1,073 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (compared to 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 6 pieces of Parkinson’s news

1. The Enterin clinical trial results:

Researchers at the biotech company Enterin & collaborators reported that α-Synuclein is required for the induction of peritonitis & immune responses. They reported that endogenous α-Synuclein is required for the induction of peritonitis (inflammation of the tissue in the peritoneum of the gut) by bacterial proteoglycan (in mice). α-Synuclein is generated & secreted at the sites of inflammation, & it promotes phenotypic & functional maturation of dendritic cells. “α-Synuclein is required for the development of a normal inflammatory response to bacterial peptidoglycan introduced into the peritoneal cavity as well as antigen-specific & T cell responses following intraperitoneal immunization“; The authors report that “neural cells are the sources of α-Synuclein required for immune competence“, & they suggest that their data “supports the hypothesis that α-Synuclein accumulates within the nervous system of Parkinson’s individuals because of an inflammatory/immune response” (Click here to read more about this, click here to read the press release, & click here for a good write up on this research from Science Magazine).

2. Are we Enterin a new age? – Part 2.

In January, Enterin also announced the results of their Phase 2b randomized, placebo-controlled, double-blind KARMET study of ENT-01 (a derivative of squalamine) involving 150 individuals with Parkinson’s. Following a 2-week baseline, participants were stratified to high dose or low dose depending on baseline constipation severity & randomized to receive ENT-01 or placebo. A 25-day treatment period was followed by a 2 week phase when all participants were placed on placebo before a 4-week wash-out (Click here to read more details about this study). The results indicate that ENT-01 is safe & well tolerated – the adverse events were primarily gastro in nature – similar to the RASMET study results. The main result of the KARMET study: Primary endpoint (change in complete spontaneous bowel movement from baseline to the end of the 3-week treatment period) was met – bowel movement was significantly better in the treatment group compared to placebo – and all bowel-related secondary endpoints improved. Interestingly, there was a reduction in levels of psychosis (as measured by SAPS-PD) during 3 week study period, & effect persisted out to 6 weeks post termination of treatment (small numbers in this result, but a definite trend is present). No announcements on future study plans beyond “More details on future plans will be announced in coming weeks” (Click here to read more about this and click here to view a relay of the press announcement).

 

3. LRRK2, Luma and Lighthouse

Denali Therapeutics have announced some of their plans for their LRRK2 inhibitor program for Parkinson’s with Biogen. Two studies are planned (“LIGHTHOUSE” and “LUMA”) & some details were shared in the company’s “expected key milestones for 2022”; “The LIGHTHOUSE Study is a global Phase 3 trial expected to enroll approximately 400 Parkinson’s participants with LRRK2 mutations“. The treatment period will be at least 96 weeks for this study and the primary endpoint will be change in MDS-UPDRS from baseline. “The LUMA Study is a global Phase 2b trial expected to enroll approximately 640 participants with Parkinson’s who do not carry a LRRK2 mutation & is designed to potentially support registration of BIIB122“. The minimum treatment period for the LUMA study will be 48 weeks and like the LIGHTHOUSE study the primary endpoint will be change in MDS-UPDRS from baseline (Click here to read more about this and click here to read a SoPD post on this topic).

 

4. Big change in small chains

Two new research papers report associations between fecal & plasma levels of short-chain fatty acids with gut microbiota and clinical severity in Parkinson’s. In the first study, 96 individuals with PD & 85 controls were involved. The PD cases presented decreased fecal but increased plasma concentrations of acetate, propionate, & butyrate which correlated with MDS-UPDRS part III scores (Click here to read more about this study). And a second independent report found a similar short-chain fatty acid result: Serum propionic acid, butyric acid & caproic acid were increased, while heptanoic acid was decreased in Parkinson’s vs controls (n=50 & 50). Propionic acid levels were correlated with motor scores (Click here to read more about this study). Could gut microbial-derived short-chain fatty acids potentially affect Parkinson’s symptoms (via the blood circulation)? The authors ask if supplementation “of propionic acid could improve the motor symptoms & mental functions of PD patients”

5. Exercise!

A new observational cohort study of 237 early Parkinson’s patients found maintenance of high regular physical activity levels & exercise habits was associated with better clinical course of PD. Interestingly, each type of physical activity was associated with different effects (Click here to read more about this & click here to read the press release).

 

6. Cell transplantation in the Copper state?

Sounds like some interesting developments are afoot at the Biodesign Institute at Arizona State University – the Michael J Fox Foundation has awarded $5.2M in grants to explore 3 pioneering treatments for Parkinson’s which will be conducted at the ASU-Banner Neurodegenerative Disease Research Center. Of particular interest, one of the projects will be a clinical trial for transplanting human iPSC derived dopamine neurons into the brains of patients with early onset autosomal recessive Parkinson’s due to Parkin mutations. This project will be in collaboration with the van Andel institute and Fujifilm Cellular Dynamics (Click here to read more about this).

 

Articles of general interest

• The road ahead: 2022 – this is an annual overview of the clinical trials focused on disease modification in Parkinson’s, discussing recent events & what to look out for in 2022 (Click here to read more about this).

• A new webinar from the Michael J Fox Foundation on diet, exercise and other strategies for living well as we age (Click here to read more about this).
• A nice overview of some of the projects funded by Cure Parkinson’s in 2021, in our quest for novel therapies to slow, stop or reverse Parkinson’s (Click here to read more about this).
• A World Parkinson’s Congress blog post on “If cellular aging is a key part of Parkinson’s disease pathogenesis, how do we model it? (Click here to read more about this).
• Some wonderful science communication from Dr Stefania Giussani of the Wade Martins lab in Oxford – take 5 minutes & listen to her discussing her research:

• An interesting perspective piece on the unmet needs of women living with Parkinson’s: The gaps and the controversies (Click here to read more about this).
• A World Parkinson’s Congress blog post on drug repurposing and whether it works (Click here to read more about this).

Basic biology news

• New research employs mutagenesis studies to define the minimal region of Parkinson’s-associated PINK1 required for optimal ubiquitin phosphorylation; Defines the important role of the NTE:CTE interface (Click here to read more about this).
• Oligodendrocytes again! New medrxiv manuscript presents single-nuclei paired multiomic analysis of young, aged, & Parkinson’s post-mortem human midbrain, revealing age-associated glial changes; Analysing 69,289 high-quality nuclei from 31 individuals – 9 young donors, 8 aged donors, & 14 Parkinson’s patients, the researchers identified an oligodendrocyte subtype with a novel gene expression signature that only appears in aged individuals (termed AAODC); Comparison of AAODCs (aged vs PD) revealed that AAODC may play important roles in resistance to cellular stresses incurring in aging & PD (Click here to read more about this).

• New research reports that phosphorylation of endogenous α-synuclein induced by extracellular α-synuclein fibrils (“seeds”) initiates at the pre-synaptic region & spreads to the cell body (in vivo & in vitro – click here to read more about this).
• New biorxiv manuscript highlights the complexity of the interaction of α-Synuclein, lipid membranes, & metal ions; In addition, using peptidomimetics, a new strategy against α-Synuclein toxicity & aggregation is advanced (Click here to read more about this).
• New biorxiv manuscript finds the NAD+ precursor nicotinamide mononucleotide activates dSarm to trigger axon degeneration in Drosophila (Click here to read more about this).
• Multi-omic landscaping of human midbrains identifies disease-relevant molecular targets & pathways in advanced-stage Parkinson’s, including neuroinflammation, immune response activation, mitochondrial & synaptic dysfunction (Click here to read more about this).
• New research presents a technique called “biotinylation by antibody recognition” to label total & pathological alpha-synuclein in situ for subsequent mass spectrometry analysis. Superior immunohistological detection of Lewy pathology (Click here to read more about this).
• New biorxiv manuscript proposes relationship between inflammatory bowel diseases & the asymmetric death of dopaminergic neurons Parkinson’s; Analysis of human GI tract from IBD cases finds phosphorylated α-syn, in identical locations to PD cases; Vagotomized DSS-treated rodents exhibited phosphorylated α-syn in the gut but do not present dopaminergic cells degeneration and α-syn aggregation in the ventral mesencephalon (Click here to read more about this).

• New biorxiv manuscript finds that unconventional secretion of soluble, monomeric α-synuclein occurs via palmitoylated DNAJC5 oligomers (Click here to read more about this).
• New research identifies 518 genes subject to regulation by 76 Parkinson’s-associated SNPs across 49 tissues, that encompass 36 peripheral & 13 CNS tissues; 9 pathway/processes clusters enriched; “Discovery of the trans-eQTL-SYNJ1 connection merges observations from population level (i.e. GWAS) & familial studies, reinforcing the potential importance of SYNJ1 in Parkinson’s“; There is a retinoic acid angle (RAI14) and Cluster 7 is enriched for antigen processing & presentation (Click here to read more about this).
• New research presents a multiplexed fluorescence-based immunohistochemistry approach (up to 10 antibodies per cycle), screening up to 100 markers on human olfactory bulb from Parkinson’s & Alzheimer’s cases (Click here to read more about this).
• New biorxiv manuscript reports cognitive deficits in young adult transgenic mice carrying the Parkinson’s-associated LRRK2-G2019S variant; Cholinergic fiber density in mPFC & dorsomedial striatum sign. sparser (Click here to read more about this).
• New research presents novel engineered nanobodies specific for N-terminal region of alpha-synuclein that recognize Parkinson’s-associated Lewy-body pathology + inhibit in-vitro seeded aggregation & toxicity (Click here to read more about this).
• New research reports that mitochondrial protein Sideroflexin 3 (SFXN3) influences proteins & pathways associated with neurodegeneration; SFXN3 over-expression in fly models of Parkinson’s rescues cell loss (Click here to read more about this).

• New research presents a novel 2-factor monosynaptic TRIO tracing method for assessment of circuit integration of hESC-derived dopamine transplants; AAV-capsid MNM008 for accurate monosynaptic tracing (Click here to read more about this).
• Ageing exacerbates ribosome pausing (queueing of ribosomes during translation) leading to nascent polypeptide aggregation, & critically contributing to proteostasis impairment & systemic decline in ageing (Click here to read more about this and click here to read a related press release).
• New biorxiv manuscript offers new insights into structural basis for Parkinson’s-associated LRRK2’s binding to microtubules; LRRK1’s structure is similar, but it doesn’t interact with microtubules (Click here to read more about this).
• Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinsons “onto which pathways associated with PD pathology converge, & offers an inclusive interpretation of the phenotypic heterogeneity” (Click here to read more about this).
• New research finds depletion of Parkinson’s-associated PARK7/DJ-1 unexpectedly diminished signs of immunoaging in T-cell compartments of both human & mice at both cellular phenotypic & functional levels; Critical role for DJ-1 in immunoaging (Click here to read more about this).
• A new study presents evidence for local translation in the regulation of dopamine release from substantia nigra neuron dendrites, but not axons in mice; Next level tech & epic pics! (Click here to read more about this).

• Familial-Parkinson’s-associated α-synuclein variants, E46K & G51D, alter membrane association in opposite ways (E46K increases it, G51D decreases it); New research explores further & suggests G51D & E46K neurotoxicity can be prevented by decreasing fatty-acid unsaturation (Click here to read more about this).
• New biorxiv manuscript suggests glycation of Parkinson’s-associated alpha-synuclein perturbs the aggregation kinetics & prevents fibrilization; Glycated α-synuclein oligomers also compromise TLR2 signaling & favors NLRP3 inflammasome inflammation (Click here to read more about this).
• New review explores how VGLUT2 expression in dopamine neurons may be neuroprotective, enhancing their resilience in the context of ongoing neurodegenerative processes in Parkinson’s (Click here to read more about this).
• Neuronal phosphoprotein synapsin III (Syn III) cooperates with α-syn to regulate dopamine release & can be found in the insoluble α-syn fibrils composing Lewy bodies; Synapsin III gene silencing rescues Parkinson’s-like features in α-syn transgenic mice (Click here to read more about this).
• New research reports that PAK6 is a GTP-dependent Roc interactor able to modulate LRRK2-mediated RAB phosphorylation; Parkinson’s-associated mutations within Roc impair the ability of PAK6 to regulate LRRK2 (Click here to read more about this).
• Researchers report a previously unidentified SUMO-dependent pathway in which UPS-dependent stabilization of SENP3 upon iron chelation enhances mitochondrial targeting of Fis1 to facilitate mitophagy induction (Click here to read more about this).
• In the context of PINK1-associated Parkinson’s, new research finds ceramide accumulation negatively affects ß-oxidation, further aggravating the electron transport chain defect caused by PINK1 deficiency & results in an additional requirement for mitophagy (Click here to read more about this).

• Extraction/analysis of pathological α-syn from synucleinopathy brains finds a striking overlap between Parkinson’s & MSA insoluble proteomes; “Other fibrillization-prone protein candidates possibly cross-seeded by α-syn are neither found in PD nor MSA extracts” (Click here to read more about this).
• Researchers report that Cofilin 1 is an important regulator of the pathogenicity & transmission of pathological α-synuclein in mouse models of Parkinson’s; “It co-aggregates with α-synuclein & form more toxic aggregates” (Click here to read more about this).
• New research reports phosphorylation on serine-129 of the Parkinson’s-associated aggregate-forming protein alpha synuclein inhibits its DNA-bending properties (Click here to read more about this).
• Tyrosine hydroxylase (TH) is known as a rate-limiting enzyme in the biosynthesis of dopamine. Dopamine acts as a feedback inhibitor on TH. New research presents a structural mechanism for TH inhibition by dopamine & reactivation by Ser40 phosphorylation (Click here to read more about this).
• New research presents a method of attaching protein corona to nanoparticles allowing them to explore the interactions of Parkinson’s-associated α-synuclein & its amyloid fibril formation (Click here to read more about this).
• “Pathologic α-syn activates LRRK2 expression & kinase activity in monocytes & induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain” (Click here to read more about this).

• Aminochrome is an endogenous neurotoxin that induces mitochondrial dysfunction by inhibiting complex I. Researchers present a preclinical model of Parkinson’s based on aminochrome to help “find anti-inflammatory & neuroprotective drugs for PD” (Click here to read more about this).
• Researchers present the discovery & development of “compound 38” – an indazole-based, G2019S-selective Leucine Rich Repeat Protein Kinase 2 (LRRK2) inhibitor, with in vivo efficacy; “Our lead compound 38, shows excellent in-vitro ADME & PK properties, & in-vivo target engagement & we are continuing development of this series of highly brain penetrant G2019S-LRRK2 selective kinase inhibitors to hasten the day of precision medicines for people with Parkinson’s” (Click here to read more about this).
• New research finds aggregated α-synuclein in the Krabbe disease brain; Brain lysates from KD cases manifest high molecular weight α-synuclein species & are seed-competent (on RT-QuIC – click here to read more about this and click here to read a press release).
• A new paper reports mercury is present in neurons & oligodendrocytes in regions of the brain affected by Parkinson’s & co-localises with Lewy bodies; People without PD had a restricted uptake of mercury (Click here to read more about this).
• New biorxiv manuscript attempts to establish the predominant α-synuclein post-translational modifications in post-mortem Parkinson’s & MSA pathology (via immunohistochemistry – click here to read more about this).

• New research demonstrates how midbrain organoids mimic early embryonic neurodevelopment & recapitulate Parkinson’s-associated LRRK2-p.Gly2019Ser-associated gene expression (Click here to read more about this).
• New biorxiv manuscript reports microglial NLRP3 could be both primed & activated with SARS-CoV-2 spike glycoprotein in a NFκB & ACE2-dependent manner; They also report that “virus- & spike protein-mediated inflammasome activation in microglia was significantly enhanced in the presence of α-synuclein fibrils, which was entirely ablated by NLRP3-inhibition” (Click here to read more about this).

Disease mechanism

• New study explores the miR-132-3p/GLRX pathway on neuroinflammation & degeneration in Parkinson’s; Elevated expression of miR-132-3p & decreased expression of GLRX in PD brains & cells models; Increased miR-132-3p = activation of microglia, reversed by increased GLRX (Click here to read more about this).
• Using T cell &/or B cell deficient mice, researchers report both in vivo & in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration in models of Parkinson’s (Click here to read more about this).

• Excitatory DREADD activation of caudal glutamatergic pedunculopontine nucleus neurons normalizes otherwise severe locomotor deficit in Parkinson’s models, while targeting local GABAergic populations only leads to recovery of slow locomotion (Click here to read more about this).
• Pharmacological modulation of TRPM2 channels (with PARP inhibition) leads to neuroprotection in MPTP-rodent model of Parkinson’s (Click here to read more about this).
• New research reports Transient receptor potential melastatin 2 (TRPM2) “inhibition by AG490 is neuroprotective in the 6-OHDA model & that the TRPM2 channel may represent a potential therapeutic target for Parkinson’s” (Click here to read more about this).
• Researchers present the efficacy & immunogenicity of MultiTEP-based DNA vaccines targeting human Parkinsons-associated α-synuclein; 4 vaccines targeting 3 B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) & PV-1950D (Click here to read more about this).
• A 2-step screening method identifies α-synuclein aggregation inhibitors for Parkinson’s; FDA library of 1262 molecules, filtered down to 7; Tannic acid = >80% reduction in α-Syn aggregates without significant cytotoxicity; Validated in in vitro & C. elegans model; “Interestingly it has been reported that the oral administration of Tannic acid (TA) to an Alzheimer’s mouse model reduced Aβ deposits in the brain, although TA itself is not expected to cross the blood–brain barrier. This suggests that some metabolites of TA might remain active” (Click here to read more about this).

• Report finds that idebenone can regulate mitochondrial outer membrane proteins VDAC1 & BNIP3, activate Parkin/PINK1 mitophagy, promote degradation of damaged mitochondria, reduce dopamine neuron damage, & improve behavioral issues in mouse model of Parkinson’s (Click here to read more about this).
• New biorxiv manuscript finds mitochondrial pyruvate carrier inhibitor MSDC-0160 can attenuate neurodegeneration in a rodent (6OHDA) model of Parkinson’s; Reduced mTOR activity & neuroinflammation, plus increased ketogenesis, beta oxidation & glutamate oxidation (Click here to read more about this).
• Researchers present new preclinical data supporting the repurposing of pomalidomide as a neuroprotective drug for Parkinson’s; Efficacy in a preformed α-synuclein oligomer rodent model of PD; Agent effectively targets neuroinflammation (Click here to read more about this).
• Enteric α-synuclein impairs intestinal epithelial barrier through caspase-1-inflammasome signaling in models of Parkinson’s before brain pathology (Click here to read more about this).
• New research presents data supporting a loss-of-function association of GBA mutations in Parkinson’s & suggests that GBA-PD is more likely to develop if alpha synuclein burden is increased (Click here to read more about this).
• Researchers from Yumanity Therapeutics have published their non-clinical pharmacology studies of YTX-7739 (a clinical stage Stearoyl-CoA Desaturase inhibitor being developed for Parkinson’s – click here to read more about this).

 

Clinical research

• Analysis of samples from >10million military staff (955 of whom developed multiple sclerosis) finds that risk of Multiple sclerosis increased 32-fold after infection with EBV; NfL increased only after EBV seroconversion (Click here to read more about this & click here to read the press release).
• New research from Singapore finds that pre-diagnosis increase in healthcare utilization observed in patients supports the presence of prodromal Parkinson’s symptoms & may present an opportunity for early diagnosis (Click here to read more about this).
• New systematic pathological examination study “identified a set of signature proteins that will help to understand the pathology & etiology” of Parkinson’s dementia (N=10) & Dementia with Lewy bodies (N=9) “at the molecular level” (Click here to read more about this).
• New research explores the impact of age at onset on symptom profiles, treatment characteristics & health-related quality of life in Parkinson’s (Click here to read more about this).
• A new study suggests that people with Parkinson’s who eat three or more servings per week of foods high in flavonoids (such as tea, apples, berries and red wine) may have improved chances of living longer (Click here to read more about this and click here to read a press release associated with this study).

• New research finds a “roughly similar neurophysiological autonomic profile in non-LRRK2 Parkinson’s & LRRK2-PD”, with one or two interesting peculiarities (Click here to read more about this).
• Could biallelic expansion in RFC1 be a “rare cause of Parkinson’s”? Investigation of 569 Finnish patients with medicated parkinsonism found biallelic (AAGGG)exp in 3 non-consanguineous patients with clinically confirmed Parkinson’s disease without ataxia (Click here to read more about this).
• New report finds that peripheral neuropathy is common in Parkinson’s, & influences gait + balance parameters (as measured with mobile health-technology); “Clinicians & researchers should evaluate & consider peripheral neuropathy in the assessment of PD” (Click here to read more about this).
• New observational study explores gender differences in motor & non-motor symptoms in early Parkinson’s; Women with PD had milder motor symptoms, but had significantly higher scores of sleep disturbance (Click here to read more about this).
• Analysis of postmortem brain samples for 8 brains regions from 15 Lewy body dementia, 7 Alzheimer’s, & 6 control cases finds a correlation between β-amyloid & α-synuclein accumulation, suggesting a pathophysiologic relationship between these 2 processes (Click here to read more about this).
• New medrxiv manuscript explores genetic overlap between Parkinson’s & inflammatory bowel disease; Results highlight “a central role of host immunity and/or autoimmunity in the PD-IBD relationship” (Click here to read more about this).

• New research describes a long pre-diagnostic phase of progressive supranuclear palsy (PSP) & Parkinson’s; N=176 & 2526 respect.; Objective markers (subtle motor & cognitive signs) were evident over 7 years before diagnosis (Click here to read more about this).
• New research reports that there is more than one route to control gait & different compensation strategies seem to rely on different cortical mechanisms to achieve enhanced central motor activation in people with Parkinson’s (Click here to read more about this).
• Data driven/systematic review approach finds selected movement disorders are associated with specific anti-neuronal antibodies; “Provides a tentative approach to patients with autoimmune movement disorders” (Click here to read more about this).
• Analysis of blood from 223 Parkinson’s patients from the bioMARKers in PD (MARK-PD) study finds that serum neurofilament light chain (NfL) concentrations were higher in “postural instability/gait difficulty” cases independent of age, sex & disease duration (Click here to read more about this).
• New research reports that using a fully automatic template-based deep gray matter mapping approach, it is possible to accurately measure the tissue properties (such as volumes, iron content, & neuromelanin content) of the midbrain nuclei (Click here to read more about this).
• A systematic search of clinical trials calls for stronger consideration of “ethnicity & other issues around diversity when designing & implementing the clinical trials, not only in the Parkinson’s field but also beyond” (Click here to read more about this).
• The mortality of Parkinson’s in Italy from 1980 to 2015 (Click here to read more about this).

• New study of 163 Parkinson’s cases, 44 DLB, 30 MSA & 159 controls finds increased hexosylsphingosine concentrations in DLB & MSA cases compared to PD & controls (associated with earlier onset in DLB); Acid sphingomyelinase activity was reduced in DLB & MSA (vs PD – click here to read more about this).
• Important topic – caregiver burden & quality of life in late stage Parkinson’s from the CLaSP Consortium; “Spousal caregivers are most affected. Identifying & treating NMS…seem essential to enhance QoL for both patients & caregivers” (Click here to read more about this).
• A study of western diet & oral microbiota in Parkinson’s finds strong positive & negative correlations between specific food products & microbial taxa (59 PD & 108 controls – click here to read more about this).
• Researchers from the PArkinson’s disease COgnitive impairment Study (PACOS) suggest a potential sex-specific different role of lipids in executive functioning in Parkinson’s (Click here to read more about this).
• Analysis of circulating mononuclear phagocytes in early- & late-stage Parkinson’s finds increased CD163 & HLA-DR monocytic expression in patients with long PD duration; CCR2 & CD11b expression are associated with cognitive impairment (Click here to read more about this).
• A systematic review & a perspective on usability of virtual reality training suggests it is an effective intervention to improve the functional ability in both stroke & Parkinson’s patients (Click here to read more about this).

• New research explores the psychometric properties of clinical indicators for identification & management of advanced Parkinson’s, using data collected from device-aided therapy-naïve PD cases (Click here to read more about this).
• “Clinical decision-making is a complex process, influenced by many different factors that differ for each decision & for each individual”; A new study explores personalized decision-making in Parkinson’s, from medical professionals perspective (Click here to read more about this).
• New research explores thalamic white matter macrostructure & subnuclei volumes in Parkinson’s depression; Their results implicate the right pulvinar anterior as a relevant neural structure in PD depression (Click here to read more about this).
• Researchers find differences in immune status between individuals with early onset Parkinson’s & late onset PD; Could indicate “differences in the pathogenesis between these groups”; CD8+ T cells, NK cells, & monocytes changed (Click here to read more about this).
• New research reports bidirectional cholinergic innervation changes in 57 de novo Parkinson’s cases with & without cognitive impairment; “Posterior cortical cholinergic losses were present in all” cases (Click here to read more about this).
• 319 idiopathic/isolated REM sleep behavior disorder (iRBD) patients from 12 centers underwent a detailed assessment for potential environmental & lifestyle risk factors for phenoconversion; Follow ups: 24.2% converted after 3 yrs & 67.5% after 10 yrs (Click here to read more about this).
• New report presents the development & assessment of a new web-based tapping test for measuring distal movement in Parkinson’s (Click here to read more about this).

• A genome-wide association study & meta-analysis of common genetic variants associated with essential tremor (ET); ET affects 5% of pop. >65yrs; Now researchers (& large number of collaborators) report 5 loci associated with risk of ET (Click here to read more about this).
• Researchers report on combining skin α-syn real-time quaking-induced conversion & circulating neurofilament light chain to distinguish Multiple System Atrophy (MSA) & Parkinson’s; Small study, needs replication in larger cohorts (Click here to read more about this).
• New paper pools structural imaging data from multiple research groups into a large mega-analysis, allowing for the identification of cortical regions & networks involved in visual hallucinations associated with Parkinson’s (Click here to read more about this).
• New study finds early downregulation of hsa-miR-144-3p in the serum of drug-naïve, early cases of Parkinson’s (confirmed across a variety of analytical and experimental analyses – click here to read more about this).
• A review of clinical smartphone applications in Parkinson’s; Lots of positive opportunities, but “the variability of the applications & the need to translate complicated sensor data may hinder immediate clinical applicability” (Click here to read more about this).
• New research identifies 6 genetic variants & alterations that modulate gene regulation specifically within the heart atrial appendage as making the largest contributions to Parkinson’s risk development (Click here to read more about this).
• Researchers have uncovered a specific G2019S phospho-signature in peripheral blood cells that changes with Parkinson’s disease status & can discriminate between patients with LRRK2-G2019S PD, G2019S non-manifesting carriers, & unaffected controls (Click here to read more about this).

• A new report finds Parkinson’s is associated with increased homocysteine levels, which correlates in turn with cognitive performance & frontal cortical thinning; Could homocysteine play “a role among the multiple pathological processes”? (Click here to read more about this).
• New systematic review & meta-analysis of clinical effectiveness of self-management interventions in Parkinson’s finds “insufficient high quality RCTs in this field to show effectiveness of self-management interventions” (Click here to read more about this).
• Researchers report the identification of an early-stage Parkinson’s neuromarker using event-related potentials, brain network analytics & machine-learning (Click here to read more about this).
• New medrxiv manuscript reports circulating monocytes collected from individuals with GBA-associated Parkinson’s presented dysregulation in genes involved in alpha synuclein degradation, aging & amyloid processing (Click here to read more about this).
• Using data from 12 databases (N=367: 58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, & 128 GBA-DBS-), researchers suggest that the combined effect of Parkinson’s with GBA mutations & STN-DBS may negatively impact cognition (NOTE: Average differences are small); Using the MDRS – a standardized, 144-point mental status examination – GBA+DBS+ cases declined on average 1.49 points/year more than GBA-DBS+ individuals, & 1.71 points/year more than GBA+DBS- individuals; “We advise that DBS candidates be screened for GBA mutations” (Click here to read more about this).
• New research asks whether the probiotic bacteria in Symprove can influence bacterial composition in the microbiotas & other indicators of gut health in patients with Parkinson’s; N=3 patients to create microbiotas in an in-vitro gut model (Click here to read more about this).

• “Analysis of the evidence generated by the completed & published trials indicates that placebo controlled trials are not necessary to advance & evaluate the safety & efficacy of emerging regenerative therapies for Parkinson’s” (Click here to read more about this).
• “Holocue” – a wearable holographic cueing application for alleviating freezing of gait in Parkinson’s (Click here to read more about this).
• New research presents mendelian randomization analysis providing further support for a causal relationship between dairy intake & higher Parkinson’s risk in men (not biased by confounding or reverse causation – click here to read more about this).
• Preliminary results suggest basal ganglia dysfunction in Parkinson’s contributes to impaired modulation of sensory information & may reflect one component of a broader sensorimotor processing impairment associated with PD (Click here to read more about this).
• Curious – new study reports a significant decrease in RNA integrity number (RIN) in Alzheimer’s postmortem brain tissue compared to Parkinson’s, Huntington’s disease or control cases (Click here to read more about this).
• New report finds that heterogeneous digital biomarker integration out-performs patient self-reports in predicting Parkinson’s (Click here to read more about this).
• New study reports patients with freezing of gait fixate more on proximal areas of the ground & less on the target destination; those without=same as controls (Click here to read more about this).
• Analysis of data from the Michael J Fox foundation PPMI cohort provides trajectory analysis of orthostatic hypotension in Parkinson’s. Three basic trajectories in the cohort: 1. increasing class (N=18); 2. low-stable class (N=610); 3. high-stable class (N=32 – click here to read more about this).

New clinical trials

• New clinical trial registered involves multiple N-of-1 trials of (Intermittent) hypoxia therapy in Parkinson’s. This is called the TALISMAN-1 study, is seeking to recruit 20 participants, and is scheduled to finish in October 2022 (Click here to read more about this).
• New clinical trial registered will be exploring molecular imaging of inflammation in 24 individuals with Parkinson’s (Click here to read more about this).
• New clinical trial registered to investigate the impact of exercise in advanced Parkinson’s with Deep Brain Stimulation (Click here to read more about this).

Clinical trial news

• Results of the Phase IIa dose-escalating safety/tolerability study of Mannitol in Parkinson’s have been published (NCT03823638); Gut symptoms limited dose escalation in 1/3 participants; No improvement in sense of smell was observed in mannitol cohort (Click here to read more about this).

• One-year change in blood NfL & whole brain atrophy may be promising biomarkers of disease progression in Multiple system atrophy (MSA), but mTOR Inhibition with sirolimus had no effect on progression or biomarkers (NCT03589976 – click here to read more about this).
• Alexza Pharmaceuticals publishes results from a randomized clinical trial assessing the safety, pharmacokinetics, & efficacy during morning OFF of their agent AZ-009 (rapid-acting inhaled apomorphine) being developed for Parkinson’s (Click here to read more about this).
• The protocol for a double-blind cross-over pilot trial evaluating the safety & preliminary efficacy of long-term adaptive deep brain stimulation (aDBS) in patients with Parkinson’s has been published; N=15, 1 month assessment (NCT04681534 – click here to read more about this).

• A new paper presents the results of the EXercise in PArkinson’s disease and Neuroplasticity (EXPANd) study – a double-blind randomised controlled balance exercise trial in people with Parkinson’s; Participants were randomised to either HiBalance (n = 48) or a control group (n = 47); 10 week study; Results=no significant difference on time effect on balance performance or secondary outcomes; Contrasts with previous study (Click here to read more about this).
• Green Valley obtains IND approval from US FDA for a global Phase II 36-week, multi-center, randomized, double-blind, placebo-controlled clinical trial of sodium oligomannate (“GV-971”) in 300 early Parkinson’s, followed by a 36-week open-label extension (Click here to read more about this).

Conferences/lectures

• A recent Neurology Academy video exploring gastric issues in Parkinson’s:

 

• Management of symptoms in the complex stage of Parkinson’s:

 

Other news

• Yumanity Therapeutics reported a partial clinical hold order from the US FDA on their multi-dose clinical trials for YTX-7739 – a stearoyl-CoA desaturase inhibitor being developed for Parkinson’s; Yumanity is allowed to conduct a planned single dose trial (Click here to read more about this). Yumanity also provided an update on recent developments regarding their work on Parkinson’s, including being awarded a Michael J Fox Foundation grant, & also their partnership with Merck (Click here to read more about this).
• BlueRock therapeutics has announced the closeout of the first of 2 cohorts in their ongoing Phase 1, open-label trial of pluripotent stem cell-derived dopaminergic neurons in patients with advanced Parkinson’s (Click here to read more about this).

• BioVie announced treatment of 1st patient in Phase 2 clinical trial of NE3107 (an ERK inhibitor that selectively inhibits neuroinflammation & insulin resistance) in Parkinson’s (Click here to read more about this).
• The US FDA has given Annovis Bio guidance on specific endpoints, entry criteria, & further study parameters for two Phase 3 clinical trials of Buntanetap (ANVS401 or Posiphen) that would support a broad indication for both early & late Parkinson’s (Click here to read more about this).

• Sanofi & ABL bio entered a global license agreement (worth US$1.06B) to develop & commercialize ABL301 – a bispecific antibody targeting aggregated alpha-synuclein & Grabody-B (a BBB-penetrating shuttle targeting IGF1R) – for Parkinson’s (Click here to read more about this).
• Vaxxinity announced first Parkinson’s patient dosed in Part B of their Phase 1 clinical trial of UB-312 – a synthetic peptide vaccine targeting toxic forms of aggregated α-synuclein; Part A shows UB-312 is generally safe & well tolerated (Click here to read more about this).

• Sio Gene Therapies has announced that they intends to return the global rights for AXO-Lenti-PD to Oxford Biomedica & to cease work on their gene therapy program in Parkinson’s (Click here to read more about this).
• Cognition Therapeutics received grant funding from the Michael J Fox Foundation to support development of their Sigma-2 receptor modulators for Parkinson’s (Click here to read more about this).
• Inhibikase Therapeutics provided an update on the development of their Parkinson’s program (Click here to read more about this).

• Cantabio Pharmaceuticals has been awarded a grant from the Michael J Fox Foundation to develop novel small-molecule aggregation inhibitors of Tau protein for the treatment of Parkinson’s (Click here to read more about this).
• Interesting highlights & objectives for 2021 & 2022 (respectively) from Herantis Pharma, particularly regarding their rhCDNF (recombinant human Cerebral Dopamine Neurotrophic Factor) product for Parkinson’s (Click here to read more about this). They also announced that they expect to file for regulatory approval in Q4 2022 to start a first-in-man clinical study of HER-09 (a small molecule synthetic peptidomimetic of CDNF being developed for Parkinson’s (Click here to read more about this).

• AlzeCure Pharma gets late breaking abstract accepted for the ADPD 2022 meeting; They will be presenting data on the effect of AC-0027136 – a positive modulator of NGF/TrkA & BDNF/TrkB signaling – on mitochondrial function (Click here to read more about this).
• Iktos & South Korean biotech firm Astrogen announce a research collaboration to use artificial intelligence platform for drug design against a novel Parkinson’s target (Click here to read more about this).
• Caraway Therapeutics announces that they have received a third research grant from the Michael J Fox Foundation to continue advancement of TRPML1 agonists for GBA-associated Parkinson’s (Click here to read more about this).

• Athira Pharma announces initiation of dosing in their “SHAPE study” – a Phase 2 clinical trial of ATH-1017 (enhancer of hepatocyte growth factor (HGF) & its receptor, MET) for the treatment of Parkinson’s dementia & dementia with Lewy bodies (Click here to read more about this).
• Cortexyme has announced that they received a letter from the US FDA placing a full clinical hold on atuzaginstat’s (COR388) Investigational New Drug application; Trials for all indications (including Parkinson’s) now on hold (Click here and here to read more about this).

• Useful overview of all of the 2021 FDA approvals by modality. The diversity is impressive: ASOs, siRNAs, peptides, bi-specifics, ADCs, cell therapies, mRNA, radioligands, allosteric & orthosteric inhibitors, and more (Click here to read more about this).
• U.S. Medicare plans to cover Biogen Alzheimer’s drug Aduhelm “but will require patients to be enrolled in a clinical trial, limiting access to the treatment more than many expected” (Click here to read more about this). And in their response letter, Biogen argue that: “Alzheimer’s patients & their families deserve to have choice & access to FDA-approved treatments” (and the data supporting the approval??? Click here to read more about this).

Review articles/videos

And there it is, just some of the highlights from January 2022 – 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 February!!!

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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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