A Statement of the MDS on Biological Definition, Staging, and Classification of Parkinson's Disease

Movement Disorders, Journal Year: 2023, Volume and Issue: 39(2), P. 259 - 266

Published: Dec. 13, 2023

Language: Английский

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Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 91, P. 102044 - 102044

Published: Aug. 28, 2023

According to the Geroscience concept that organismal aging and age-associated diseases share same basic molecular mechanisms, identification of biomarkers age can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) is becoming paramount importance. These will be in fact at higher lower) risk for many different diseases, including cardiovascular neurodegeneration, cancer, etc. In turn, patients suffering from these are healthy age-matched individuals. Many correlate with have been described so far. The aim present review discuss usefulness some (especially soluble, circulating ones) order identify frail patients, possibly before appearance clinical symptoms, well diseases. An overview selected discussed this regard, particular we focus on related metabolic stress response, inflammation, cell death (in neurodegeneration), all phenomena connected inflammaging (chronic, low-grade, inflammation). second part review, next-generation markers such extracellular vesicles cargos, epigenetic gut microbiota composition, discussed. Since recent progresses omics techniques allowed an exponential increase production laboratory data also field age, making it difficult extract biological meaning huge mass available data, Artificial Intelligence (AI) approaches increasingly important strategy extracting knowledge raw providing practitioners actionable information treat patients.

Language: Английский

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Defining Parkinson’s Disease: Past and Future

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(s2), P. S257 - S271

Published: March 15, 2024

Parkinson’s disease (PD) is the second most common still relentlessly progressive neurodegenerative disorder with a long period in which pathophysiological process already spreading but cardinal motor symptoms are not present. This review outlines major developments and milestones our understanding of PD that have shaped way we define this disorder. Past criteria definitions been based on clinical manifestations enabling diagnosis only later symptomatic stages. Nevertheless, advancing knowledge pathophysiology aim early detection, shift diagnostic paradigm being advocated towards biological definition similar to other disorders including Alzheimer’s Huntington’s disease, ultimate goal an earlier, course modifying therapy. We summarize pillars possible approach vivo detection neuronal α-synuclein aggregation, neurodegeneration genetics outline their application different contexts use frame definition.

Language: Английский

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Pesticides and the Microbiome-Gut-Brain Axis: Convergent Pathways in the Pathogenesis of Parkinson’s Disease

Journal of Parkinson s Disease, Journal Year: 2023, Volume and Issue: 13(7), P. 1079 - 1106

Published: Oct. 31, 2023

The increasing global burden of Parkinson’s disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and likely driven in part by lifestyle changes environmental factors. Pesticides are well recognized risk factors for PD, supported both epidemiological experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. microbiome-gut-brain axis has gained much attention recent years considered be a significant contributor driver pathogenesis. In this narrative review, we first focus on how pesticides microbiome may influence initiation progression independently, describing pesticide-related central peripheral neurotoxicity microbiome-related local systemic due dysbiosis microbial metabolites. We then depict bidirectional interplay between context synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations pesticide availability, metabolism toxicity, complex pesticide-microbiome-host interactions inflammatory metabolic pathways, insulin resistance other mechanisms. An overview unknowns follows, role pesticide-microbiome proposed body-/brain-first phenotypes complexity exposures gene-environment discussed. final deals possible further steps translation, consisting recommendations future use research as an outline promising preventive/therapeutic approaches targeted strengthening or restoring healthy gut microbiome, closing summary gaps perspectives field.

Language: Английский

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Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women

Translational Psychiatry, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 16, 2023

Abstract Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences brain ventricular volumes, secondary endpoint. Dramatic volume-dependent/volume increase correlations were observed 52-week-placebo-treated females ( r = 0.74, P 2.36 –9 ), whereas davunetide-treated (like males) revealed such effects. Assessment primary endpoints, by the Rating Scale (PSPRS) and markedly more so Schwab England Activities Daily Living (SEADL) scale, showed significantly faster deterioration females, starting at week 13 0.01, correlating with most other endpoints 52). Twice daily davunetide treatments slowed female disease progression significant protection according to SEADL scale early 39 weeks 0.008), well bulbar limb motor domains considered PSPRS, including speaking swallowing difficulties caused damage, fine skills, respectably 0.01), weeks. Furthermore, trial, exploratory Geriatric Depression (GDS) correlated placebo group davunetide-mediated females. Female-specific volume corresponded Together slower seen men, results reveal sex-based efficacy differences, demonstrating neuroprotective disease-modifying impact treatment for patients.

Language: Английский

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Refining the clinical diagnosis of Parkinson's disease

Parkinsonism & Related Disorders, Journal Year: 2024, Volume and Issue: 122, P. 106041 - 106041

Published: Feb. 10, 2024

Language: Английский

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The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson’s therapeutics

Brain, Journal Year: 2024, Volume and Issue: 147(8), P. 2610 - 2620

Published: March 1, 2024

Abstract Parkinson’s disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in substantia nigra. However, precise molecular aetiology still unclear. Several cellular pathways have been linked disease, including autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, mechanistic link between GBA1, gene encodes lysosomal β-glucocerebrosidase (GCase), lies interplay GCase functions lysosome mitochondria. mutations alter mitochondria-lysosome contact sites. In lysosome, reduced activity leads glycosphingolipid build-up, disrupting function autophagy, thereby triggering accumulation. Additionally, aggregates reduce activity, creating self-perpetuating cycle dysfunction can also be imported into mitochondria, where it promotes integrity complex I. Thus, impair its normal increase oxidative stress compartment dopamine oxidized. turn, accumulation oxidized adducts further impairs second dysfunction. The state triggered by induce DNA damage which, cause cell death. this review, we highlight pivotal role pathogenesis discuss promising examples GCase-based therapeutics, such as enzyme replacement therapies, small molecule chaperones substrate reduction among others, potential therapeutic interventions.

Language: Английский

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Genetic mutations in Parkinson’s disease: screening of a selected population from North-Eastern Italy

Neurological Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: July 22, 2024

Abstract Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder with multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5–10% cases are monogenic. This study aims to define bases clinical features in cohort patients from Northeastern Italy, peculiar geographical area previously not included screenings. Methods Using an NGS multigenic panel, 218 were tested based on age at onset, family history development atypical features. Results A total 133 found 103 patients. Monogenic was diagnosed 43 (20% cohort); 28 (12.8%) carried mutations GBA1 , 10 LRRK2 (4.6%) 5 PRKN (2.3%). In 17% defect remained uncertain interpretation. The selection criterion “age onset < 55 years” significant predictor positive test (OR 3.8, p 0.0037). showed more severe symptoms higher burden motor non-motor complications compared negative (dyskinesias OR 3, sleep disturbances 2.8, cognitive deficits 3.6; 0.05), greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, 0.03). Conclusions Applying simple criteria for testing allows probability identify monogenic better allocate resources. process critical widen understanding mechanisms individuation potentially benefitting future disease-modifying therapies.

Language: Английский

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Prasinezumab: A Bayesian Perspective on Its Efficacy

Movement Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Parkinson's disease (PD) is a progressive neurodegenerative disorder featuring aberrant aggregation of α-synuclein (a presynaptic protein implicated in physiological synaptic vesicle trafficking and neurotransmitter release) as critical modulator the disease.1, 2 This notion has been further substantiated by discovery autosomal dominant variants PD associated with mutation or triplication gene SNCA (PARK1 PARK4, respectively).3 In PD, undergoes conformational changes (Fig. 1), leading to formation insoluble fibrils intracellular inclusions known Lewy bodies.4 One pathogenic theories postulates that these aggregates propagate prion-like manner, spreading throughout brain pattern correlates progression.5-8 Although link between anomalies established, modalities this association are still unclear. A revised approach considering both loss function (monomeric) protein9 gain abnormal could play role.10, 11 On one hand, oligomers exhibit toxic properties disrupt cellular homeostasis, impair mitochondrial function, induce oxidative stress, neuroinflammation, dysfunction, ultimately neuronal dysfunction death.10 other it also hypothesized (synucleinopenia)9 may consistently affect pathophysiology. Due its main localization at terminals, regulates release dynamics. Thus, transmission. Because predominantly expressed dopaminergic neurons, dysregulate signaling pathways.12 Furthermore, involved degradation pathways, including ubiquitin-proteasome system autophagy-lysosomal pathway.13 According model, defective favor accumulation misfolded proteins aggregates, characteristic pathology, thereby generating mixed neuropathology.14 α-Synuclein interacts mitochondria, influencing dynamics function. bioenergetics quality-control mechanisms, impairment stress.15 Moreover, linked neuroprotection against excitotoxicity.16 Therefore, compromise resilience stressors, making neurons more susceptible degeneration. Several technical issues challenge role α-synuclein. For instance, overexpression due multiplication does not necessarily lead toxicity. High levels better outcomes some studies.9 Preclinical studies knocked-out mice produced no substantial adverse effects. were fertile showed normal neurodevelopment. However, motor responses observed.17 The propagation spreads questioned. It should be underlined passive, active, process controlled thermodynamic principles. Oligomers indicated agents, but their real elusive because most experimental settings use supersaturated which presence transient, they usually revert monomers rather than forming fibers. challenges idea can persist long enough exert toxicity.9 evidence challenged gain-of-function hypothesis suggested into bodies protective mechanism process. recent development disease-modifying therapies (DMTs) for turning point. DMTs targeting crucial confirm "proteinopathy hypothesis," whereas negative results successfully Popperian "falsification element" (or least demonstrate matter far complex mere function; see Fig. 1). complicating factor currently, there precise biomarkers assessment therapy-related challenging assess short time span clinical trials. Currently, DMT approved use. More importantly, regarded disease, even though fits construct syndrome.18 That point worthwhile implies realization homogeneous cohorts Prasinezumab (PRX002) monoclonal immunoglobulin G1 antibody designed selectively target soluble aggregated forms α-synuclein, such fibrils, while sparing physiological, protein19 (see Supporting Information Data S1 [Preclinical Studies on section] preclinical studies). 2022, PASADENA phase trial20 assessed efficacy prasinezumab patients early-stage PD. disappointing.20 Participants randomly assigned receive either placebo compound (1500 4500 mg) every 4 weeks 52 weeks. primary outcome measured Movement Disorder Society–revised Unified Disease Rating Scale (MDS-UPDRS) scores, secondary assessing dopamine transporter via single-photon emission computed tomography. Among 316 participants, MDS-UPDRS scores did differ when comparing treatment groups.20 Overall, significantly progression compared placebo, optimism faded. Nonetheless, new post hoc analysis was carried out recently published.21 study might slow predefined subpopulations PD.21 original meet endpoint (changes Parts I + II III scores),20 subset rapidly progressing patients,21 drug-treated participants less worsening signs (MDS-UPDRS Part III). ongoing PADOVA (NCT04777331) investigates impact methodological limitations must accounted for, longer trials required observe effects slowly populations. trial raised many questions about drug's numerical effect specific (ie, fast phenotypes). lack significant overall raises concerns robustness findings. First, distinction "diffuse malignant" "nondiffuse phenotypes made retrospectively data driven, have introduced retrospective selection bias.21 identification baseline those "more rapid" problematic, conflates features outcomes. rapid limited observation carry time-window bias and, acknowledged authors study,21 reflect different sensitivity "signal-to-noise ratio" clinician's greater change scales, amplification perception, vice versa). prescription monoamine oxidase B inhibitors depend factors, prescriber's preferences. Lastly, action counter pathophysiological event occurs relatively early course.19 drug rapidity worsening, higher degree deposition, somehow confusing. we used Bayesian test effectiveness treatment. provides angle interpreting offers elements constructive debate. equation helps calculate BF independent groups t based frequent statistic. null ( H 0 $$ {H}_0 ) assumes population means two equal. assumptions underpin method: observations random samples, dependent variable normally distributed within each population, variances equal values similar). F 01 B{F}_{01} take infinity. When < 1 B{F}_{01}<1 , favors alternative {H}_1 ); > B{F}_{01}>1 supports ). Importantly, allows full comparison hypotheses, modeling "what look like an effect." strength depends how from is. Jeffreys (1939) proposed conventional thresholds: 3 1/3 considered favoring over other. Anything interpreted weak anecdotal evidence. example, if = 6 B{F}_{01}=6 suggests six times likely terms posterior probabilities, translates 86% probability (calculated P 7 {P}_{01}=\frac{B{F}_{01}}{B{F}_{01}+1}=\frac{6}{7} ), leaving 14% All analyses performed using JASP software.22 tested check S1, Methods: Bayes Factor section). employed examine symptoms signs. We testing. inherently comparative: weighs support model another. BFs do so fully conditioning observed data. Otherwise, value hypothetical extreme sample. Such practice violates likelihood principle inconsistent paradoxical conclusions. quantify hypothesis. framework, special status attached hypotheses under test; assesses model's predictive performance expresses preference accurate forecasts. fact substantive importance. interest predict absence across varying set conditions. Quantifying important learn whether provide absence. Specifically, possible three discrete categories: (1) effect), (2) (3) neither nor . Instead, cannot measure Finally, affected sampling plan, is, intention collected. irrelevance follows principle, collected ambiguous, unknown, absent. advantages available classical done Based findings shown first table source article21 (Table obtained out. Table 2. column indicates major clinically relevant difference treated groups. applies without progression. 50% near only data-driven subphenotype diffuse malignant subgroup. safely assessed. robust, depicted Figure 2, shows variation priori changes; instead, increase same Additional described (Additional Analyses section) results. Ultimately, consistent trial, reach end conclusion, exploratory generates benefits prespecified subgroups faster resulted supporting related anti–α-synuclein unknown mechanisms protein. Incorporation analyzing number strategies future trials, adaptive designs allow real-time decision-making optimizing parameters.23 framework probabilistic quantifies uncertainty effects, informing decisions stakeholders modifications stopping expansion allocation ratios.24 hierarchical models enable individual variability responses, providing groundwork personalized strategies.25 Beyond statistical issues, additional discussing unsuccessful attempts pertains disconnect therapeutic envisioned "clean sanitized" difficult offered real-world settings. As discussed Brett K. Beaulieu-Jones et al,26 research populations studied among actively recruited individuals who often earlier diagnoses comply follow-ups. contrast, populations, diagnosed later life combination bias, multiple-hit comorbidity, late access care, intrinsic differences.26 highlighted collection. mode gathering (actively vs. passively recorded) introduces biases carefully design analyses, affecting validity Somehow, mirrors Alzheimer's field multiple single protein, amyloid, generated modest substantially failing intervention.27 regard, novel insights promoting reconceptualization itself "synucleinopathy", heterogeneous arising convergence pathological processes giving variety manifestations. Most likely, "there Disease,"28 our collective efforts focus dissecting convergent divergent act inside outside central nervous system. Research project: A. Conception, B. Organization, C. Execution; Statistical analysis: Design, Execution, Review critique; Manuscript: Writing draft, critique. MR: 1A, 1B, 1C, 2C, 3A, 3B. TC: 2A, 2B, DC: SLS: Open publishing facilitated Universita degli Studi Gabriele d'Annunzio Chieti Pescara, part Wiley - CRUI-CARE agreement. S.L.S. supported funding Italian Department Health (RF-2013–02358785 NET-2011-02346784-1), AIRAlzh Onlus (ANCC-COOP), Association—Part Cloud: Translational Funding (18PTC-19-602325) Association—GAAIN Exploration Evaluate Novel Queries (GEENA-Q-19-596282). corresponding author upon reasonable request. S1. Information. Please note: publisher responsible content functionality any information supplied authors. Any queries (other missing content) directed article.

Language: Английский

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Investigating Neurodegenerative Diseases From Alzheimer's to Parkinson's

Advances in medical education, research, and ethics (AMERE) book series, Journal Year: 2025, Volume and Issue: unknown, P. 399 - 436

Published: Jan. 10, 2025

The neurological disorders that include Parkinson's and Alzheimer's are among the most serious threats to world health because of their crippling effects on mental physical abilities. It is essential comprehend common mechanisms such as inflammation misfolded proteins. Molecular cellular biology approaches, in conjunction with sophisticated imaging modalities PET MRI, provide insights into course disease. beta-amyloid tau proteins main targets research, immunotherapies newly developed diagnostics appear be promising. Deep brain stimulation dopamine-based therapy continue mainstays disease treatment, while neuroprotective medications try delay illness's progression. Limited disease-modifying treatments ethical issues present challenges. Utilising AI, gene editing, regenerative medicine future directions. urgent need for more research solve puzzles surrounding neurodegenerative create efficient emphasised this chapter.

Language: Английский

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