Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson’s disease

Frontiers in Neurology, Journal Year: 2024, Volume and Issue: 15

Published: May 1, 2024

Background Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson’s disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms PD. Objective This study aimed to detect p-α-syn characteristic rare PD CHCHD2 or RAB39B mutations. Moreover, this also describe peripheral prion-like activity patients, and acquire whether the cutaneous synucleinopathy characteristics are consistent central neuropathologies. Methods We performed four skin biopsy samples from distal leg (DL) proximal neck (C7) 161 participants, including mutations, two 16 PRKN 14 LRRK2 five GBA 100 iPD 20 healthy controls. detected using immunofluorescence staining a seeding amplification assay (SAA). A systematic literature review was conducted, involving 64 biopsies 205 autopsies synucleinopathy. Results P-α-syn deposited nerves , mutations but not those There were no significant differences location rate α-syn-positive deposits between patients. Peripheral appears well represent brain PD, especially autosomal dominant (AD-PD). α-synuclein SAA analysis mutation revealed activity. Conclusion nerves, staining, may serve as accurate for future.

Language: Английский

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Comparison of disease progression between brain-predominant Parkinson's disease versus Parkinson's disease with body-involvement phenotypes

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 174, P. 105883 - 105883

Published: Oct. 5, 2022

Recently, new disease phenotyping has been proposed based on the origin site of α-synuclein pathology in Parkinson's (PD). In addition, a great deal evidences suggested parallel degeneration central nervous system and peripheral PD. The myocardial uptake pattern 123I-meta-iodobenzylguanidine can be surrogate imaging biomarker for involvement This study aimed to compare clinical progression between brain-predominant PD (br-PD) with body-involvement (bo-PD) phenotypes according onset cardiac sympathetic denervation (CSD); bo-PD group was defined as having early CSD br-PD phenotype those without initial but later developed subsequent scans (the delayed CSD). Clinical chracteristics, dopamine transporter activity, non-motor manifestations were compared groups. Motor symptoms cognitive functions at follow-up tests [3.1 (±1.4) years interval] included 29 103 patients. Symptoms rapid-eye-movement sleep behavior disorder, excessive daytime sleepiness, constipation, orthostatic hypotension more frequent than group. Unified Disease Rating Scale part III score higher increased steeply during period patients Although general status not much different groups follow-up, each showed statistically domain profiles patterns. results demonstrated that had severe steeper motor deterioration group, which indicated there may pathological involvements systems

Language: Английский

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Cardiac sympathetic “morbidity” might reflect the neurobiology of early Parkinson’s disease

Journal of Neurology, Journal Year: 2023, Volume and Issue: 271(2), P. 944 - 954

Published: Oct. 21, 2023

Language: Английский

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Targeting the Gut–Brain Axis with Fecal Microbiota Transplantation: Considerations on a Potential Novel Treatment for Parkinson's Disease

Movement Disorders Clinical Practice, Journal Year: 2022, Volume and Issue: 10(S2)

Published: Nov. 11, 2022

The bidirectional communication between the gut and central nervous system (CNS) has been identified as "gut–brain axis." Gastrointestinal symptoms occur in up to 80% of patients with Parkinson's disease (PD) can precede onset motor by more than 20 years.1, 2 Lewy bodies α-synuclein pathology are found 67% enteric (ENS) vagus nerve biopsies PD compared only 26% controls, even years before symptoms.3, 4 Evidence for increased intestinal inflammation permeability is present also newly diagnosed, untreated mouse models PD. Inflammation-induced oxidative stress be substrate misfolding aggregation gut.5, 6 misfolded could then reach brain via nerve, demonstrated some animal models,3, 7-10 truncal vagotomy might reduce risk PD,11 although evidence supporting this finding still inconsistent. All suggests that a prominent role pathogenesis progression may triggered gut. One most accredited hypotheses on so-called "dual–hit Braak hypothesis.3, 12 This postulates sporadic microbial products olfactory neurons mucosal neurons, alternatively or simultaneously. Following this, "body-first/brain-first" hypothesis13 proposed distinct phenotypes: one starting gut, successively involving substantia nigra ("body-first"), amygdala bulb, following later ("brain-first"). These other similar theories based pathological distribution have widely criticized, from Other pathological, clinical, neuroimaging observations point large variety spread process across patients14-16; hypothetically, different microbiota makeup factors underlying variety, opening avenues new treatment strategies. Healthy individuals host 400 >2000 bacterial species tract, addition archaea, viruses, yeasts. composition established first life remains relatively stable adult life, it influenced such diet, stress, inflammation, medications. produces vitamins, short-chain fatty acids (SCFAs), enzymes, neurotransmitters dopamine, acetylcholine, serotonin. It influences immune regulation play development diseases. A recent meta-analysis 10 microbiome data sets confirmed significantly controls displays relative abundance proinflammatory, scarcity anti-inflammatory, species, less SCFA producers.17 Specific taxa associated incidence severity constipation.18-20 proinflammatory activity Proteobacteria represent main cause barrier damage resulting permeability. Studies confirm determinant induce pathology, neuroinflammation, phenotype.21 Modifying mice decrease abnormalities gastrointestinal symptoms.21, 22 Recently, 2-hydroxypyridine, molecule correlated archeal Methanobrevibacter smithii, was shown promote exacerbate PD-related striatal degeneration transgenic mouse.23 aforementioned strongly supports correlation specific pathophysiology Although indicate causative, insufficient available exclude mere consequential role. Another tyrosine decarboxylases (TDCs) decarboxylate levodopa (l-dopa) dopamine without being inhibited carbidopa. By altering l-dopa levels blood, TDCs thus possibly influence response fluctuations.24, 25 There strategies modify composition, ranging dietary interventions26 supplements, antibiotics, genetically engineered microorganisms.27 antibiotics target bacteria, exerting an antiapoptotic, antioxidant action result neuroprotection.28 Treatments prebiotics, probiotics, symbiotics application small molecules foster growth bacteria producing anti-inflammatory action. Unfortunately, methods probiotics studies lack original make difficult draw definitive conclusions, meta-analysis, currently underway, provide information.29 potential beneficial not consistently supported clinical observations, which attributed incomplete temporary alteration microbiota. drastic strategy fecal transplantation (FMT). FMT implies administration solution matter healthy donor aim replacing recipient's metabolic activities.30, 31 approved indication multiple recurrent severe Clostridioides difficile infections (CDI), proven safe effective.31 Based consequent hypotheses, tempting speculate modifying affect pathophysiology. reduction agents their ENS therefore CNS. reflected slowing progression, especially when intervention would performed at early stage. If that, least cases, originates presymptomatic subjects delay prevent trigger onset. low-hanging fruit improve metabolism absorption acting TDC-producing better effect l-dopa–mediated complications. Finally, additional benefit restoration normal defecation pattern. Several preliminary neurological disorders,32 including PD,33-36 published, study protocols exploring registered.37 So far, total 33 cases reported, all studied open-label fashion.33-36 reported presented characteristics were evaluated ways variable follow-up periods. Also, pretransplant strategies, methodology, route varied among centers. In majority results show subjective objective improvement nonmotor symptoms, sleep, anxiety, depression, extents durations. particular, constipation almost constant finding. need viewed critically considering evaluations standardized blinded, leaving room placebo effect. Mild adverse effects related procedure 20% 40% include mild abdominal pain diarrhea.38 However, 0% 5% events aspiration pneumonia, septicemia, systemic inflammatory syndrome, upper hemorrhage.38-40 Interestingly, long-term largely unknown, safety,41 registers evaluate outcomes ongoing (NCT03325855). Little known about undergoing indications CDI. Patients probably effects, excluding dysphagia who incur higher aspiration. Among few published 1 patient episodes vasovagal presyncope needing hospital admission.35 transient reported.34, 36 aspect considered population theoretically radical replacement deterioration altered response, depending Therefore, storage patients' own feces purpose autologous rescue should always considered. complex treatment, variability Some these my turn out crucial importance important choice. Surely donors rigorously screened centers guarantee safety procedure. stage what ideal transplanted effective many clear differences metabolome minimal number constantly replicated cohorts great complexity growing products, experimental will ultimately help define desirable FMT, microbiota–host interactions addition, often young volunteers, no effort made identify future neurodegenerative disorders. Ideally, undergo themselves monitor Different collecting, transporting, processing, storing use. Each steps introduce alterations potentially its efficacy impair comparability studies. routes (gastroscopy, colonoscopy, capsules) linked profile but transplant when, example, flora duodenum gastroscopy. pretreatment preparation receiver impact result. Currently, prescribe (usually vancomycin) and/or apply bowel lavage increase engraftment. per se inducing changes albeit short term. unknown parameter duration induced changes; hypothesized CDI both induction maintenance treatments case progressive disease. Last least, produce groups. Factors genetic predisposition, duration, age critical. Similarly, relevant select presence maybe pattern l-dopa, selecting those very high dosages conversely reporting dyskinesia dosage. gut–brain axis gaining increasing attention scientific community organizations, unusual manifest strong trust microbiota-modifying For reason, take initiative follow restrictions use food supplements ready invasive if offered. course, literature gives ground enthusiasm justifies designing pilot trials further explore benefits. danger blindly hype give our false hopes push them toward inefficacious detrimental. At stage, responsibility clinicians researchers test controlled settings remain critical encouraging reports caution expected benefits risks authors wish thank K. Vendrik, MD, Liz Terveer, PhD, V.O. Chernova, Gut-Brain Team Leiden University Medical Center support advice. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: Writing First Draft, Review Critique. M.F.C.: 1A, 1B, 1C, 2A J.J.v.H.: 2B E.J.K.: Ethical Compliance Statement: approval institutional review board necessary work, nor informed consent. We we read Journal's position issues involved ethical publication affirm work consistent guidelines. Funding Sources Conflicts Interest: conflicts interest work. No funding received Financial Disclosures Previous Months: J.J.v.H. grants AbbVie research Centre Human Drug Research. E.J.K. unrestricted grant Vedanta. M.F.C. past year: advisory memberships Medtronic (fees institution) AbbVie, independent consultancy educational institution), speaking fees European Continuing Training (ECMT) Education (CME activity) Boston Scientific institution).

Language: Английский

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The definition of precision medicine in neurodegenerative disorders and the one disease-many diseases tension

Handbook of clinical neurology, Journal Year: 2023, Volume and Issue: unknown, P. 3 - 20

Published: Jan. 1, 2023

Language: Английский

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