Proteomic comparison between non‐purified cerebrospinal fluid and cerebrospinal fluid‐derived extracellular vesicles from patients with Alzheimer's, Parkinson's and Lewy body dementia

Hirschberg, Yael; Valle‐Tamayo, Natalia; Dols‐Icardo, Oriol; Engelborghs, Sebastiaan; Buelens, Bart; Vandenbroucke, Roosmarijn E.; Vermeiren, Yannick; Boonen, Kurt; Mertens, Inge

doi:10.1002/jev2.12383

Cited by 12 publications

(3 citation statements)

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“…[7][8][9] A previous study also noted that LAMP1 levels were reduced in CSF of L2PD. 59 Our findings are consistent with the current understanding of the LRRK2 pathway indicating that it plays a key role in controlling the endosomal lysosomal pathway. 50,60 Beyond endolysosomal changes, we also observed changes in proteins involved in ribosomal function, protein homeostasis, and alternative splicing related to G2019S.…”

Section: Discussionsupporting

confidence: 91%

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In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s

Cortés,

Phung,

de Mena

et al. 2024

Preprint

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Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapy for LRRK2-associated Parkinson disease (L2PD) and idiopathic PD (iPD). Yet, pharmaco-dynamic readouts and progression biomarkers for disease modification clinical trials are insufficient. Employing phospho-/proteomic analyses we assessed the impact that LRRK2 activating mutations had in peripheral blood mononuclear cells (PBMCs) from a LRRK2 clinical cohort from Spain (n=174) encompassing G2019S L2PD patients (n=37), non-manifesting LRRK2 mutation carriers of G2019S, here, G2019S L2NMCs (n=27), R1441G L2PD patients (n=14), R1441G L2NMCs (n=11), iPD (n=40), and controls (n=45). We identified 207 differential proteins in G2019S L2PD compared to controls (39 up/ 168 down) and 67 in G2019S L2NMCs (10 up/ 57 down). G2019S down-regulated proteins affected the endolysosomal pathway, proteostasis and mitochondria, e.g., ATIC, RAB9A, or LAMP1. At the phospho-proteome level, we observed increases in endogenous phosphorylation levels of pSer106 RAB12 in G2019S carriers, which were validated by immunoblotting after 1 year of follow-up (n=48). Freshly collected PBMCs from 3 G2019S L2PD, 1 R1441G L2PD, 1 iPD, and 5 controls (n=10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in-vitro administration of the MLi-2 LRRK2 inhibitor. Using machine learning, we identified an 18-feature G2019S phospho-/protein signature capable of discriminating G2019S L2PD, L2NMCs, and controls with 96% accuracy that correlated with disease severity, i.e., UPDRS-III motor scoring. Our study identified pSer106 RAB12 as an endogenous biomarker in easily accessible PBMCs from G2019S carriers and suggests that phospho-/proteomic findings in human PBMCs such as pSer106 RAB12 can be deployed as a universal pharmaco-dynamic readout for L2PD, L2NMCs, and iPD. Future work may determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials.

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Section: Discussionsupporting

confidence: 91%

“…7–9 A previous study also noted that LAMP1 levels were reduced in CSF of L2PD. 59 Our findings are consistent with the current understanding of the LRRK2 pathway indicating that it plays a key role in controlling the endosomal lysosomal pathway. 50,60…”

Section: Discussionsupporting

confidence: 91%

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s

Cortés,

Phung,

de Mena

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…This initiative aims to foster informed discussions about relevant experimental parameters, to augment the rigor and clarity of EV studies, and to chart the progression of EV research. In our meta-analysis, and despite EV-TRACK being available since 2017, we noticed that only three recently published studies (4.8%) [46, 67, 73] included an EV-TRACK ID with documented methodologies. We encourage researchers to support EV-TRACK to improve standardization of EV research by promoting systematic reporting on the biology and methodology associated with EVs.…”

Section: Future Directions and Limitationsmentioning

confidence: 95%

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Taha

2024

Preprint

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Accurate differential diagnosis of dementia disorders including Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and vascular cognitive impairment and dementia (VCID), along with conditions like prodromal mild cognitive impairment (MCI) or negative controls (NCs), continues to challenge neurologists. The nuanced and sometimes shared pathophysiological features underscore the need for precision in developing disease-modifying therapies. In the pursuit of reliable antemortem biomarkers, extracellular vesicles (EVs) have emerged as a popular tool for their capacity to encapsulate disease-specific signatures, particularly in neurodegenerative and neurological disorders. To this end, we have performed a comprehensive, PRISMA-guided systematic review and meta-analysis, utilizing sophisticated statistical modeling to determine the diagnostic accuracy, explore between-study variance and heterogeneity (I2), and investigate potential publication bias using various statistical tests.Biomarkers derived from general EVs demonstrated superior diagnostic accuracy, less between-study variance, heterogeneity, and publication bias than those from speculative CNS-enriched EVs. The trim-and-fill method suggested a potential overestimation of diagnostic effectiveness for biomarkers derived from CNS-enriched EVs due to four hypothesized missing studies with low diagnostic results, but none for general EVs. Meta-regressions revealed that studies using cerebrospinal fluid or serum, involving non-fasting individuals, sampling in the afternoon, employing citrate instead of EDTA for blood collection, using thrombin for coagulation factor depletion, isolating EVs with purer methods such as combined ultracentrifugation and size-exclusion chromatography, not freezing EVs post-isolation, and quantifying miRNA biomarkers, achieved better diagnostic accuracy and less heterogeneity. The diagnostic accuracy was low in differentiating among different dementia disorders. However, the analysis for diagnosing persons with AD vs. VCID achieved the highest diagnostic accuracy, suggesting that further studies may focus on this comparison. Additionally, we highlight several limitations in the included studies and recommend the following: Implement the use of appropriate negative controls, thorough documentation of preanalytical factors, inclusion of more dementia groups beyond AD, comprehensive reporting on pharmacological treatments, consideration of racial and ethnic minority groups, adherence to ISEV guidelines, application of the A-T-N framework, detailed documentation of dementia stages, extension of studies beyond differential diagnosis, reanalysis when postmortem definitive diagnostics become available, evaluation of prodromal conversion rates, and commitment to accurate statistical modeling and data transparency. We hope that lessons learned from this comprehensive meta-analysis can be beneficial for those attempting to discover biomarkers for AD and related dementias through EVs or alternative approaches.

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Differences in Blood and Cerebrospinal Fluid Between Parkinson’s Disease and Related Diseases

Ma,

Tang,

et al. 2024

Cell Mol Neurobiol

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It is difficult to distinguish Parkinson’s disease (PD) in the early stage from those of various disorders including atypical Parkinson’s syndrome (APS), vascular parkinsonism (VP), and even essential tremor (ET), because of the overlap of symptoms. Other, more challenging problems will arise when Parkinson’s disease develops into Parkinson’s disease dementia (PDD) in the middle and late stages. At this time, the differential diagnosis of PDD and DLB becomes thorny. These complicate the diagnostic process for PD, which traditionally heavily relies on symptomatic assessment and treatment response. Recent advances have identified several biomarkers in the blood and cerebrospinal fluid (CSF), including α-synuclein, lysosomal enzymes, fatty acid-binding proteins, and neurofilament light chain, whose concentration differs in PD and the related diseases. However, not all these molecules can effectively discriminate PD from related disorders. This review advocates for a paradigm shift toward biomarker-based diagnosis to effectively distinguish between PD and similar conditions. These biomarkers may reflect the diversity that exist among different diseases and provide an effective way to accurately understand their mechanisms. This review focused on blood and CSF biomarkers of PD that may have differential diagnostic value and the related molecular measurement methods with high diagnostic performance due to emerging technologies. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10571-024-01523-z.

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Proteomic comparison between non‐purified cerebrospinal fluid and cerebrospinal fluid‐derived extracellular vesicles from patients with Alzheimer's, Parkinson's and Lewy body dementia

Cited by 12 publications

References 65 publications

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Differences in Blood and Cerebrospinal Fluid Between Parkinson’s Disease and Related Diseases

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