Molecular biomarkers for vascular cognitive impairment and dementia

Hosoki, Satoshi; Hansra, Gurpreet K.; Jayasena, Tharusha; Poljak, Anne; Mather, Karen A.; Catts, Vibeke S.; Rust, Ruslan; Sagare, Abhay; Kovacic, Jason C.; Brodtmann, Amy; Wallin, Anders; Zlokovic, Berislav V.; Ihara, Masafumi; Sachdev, Perminder S.

doi:10.1038/s41582-023-00884-1

Cited by 38 publications

(20 citation statements)

References 232 publications

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“…Interestingly, despite the limited number of studies evaluating biomarkers derived from general EVs for differentiating persons with AD from persons with VCID, our analysis revealed the highest diagnostic accuracy ( Figure 6A-C ) in comparison to all other analyses, with moderate heterogeneity ( Table 2 ). Although many efforts have been ongoing to identify molecular and neuroimaging biomarkers [12, 164, 165], studies focusing on biomarkers derived from EV are scarce. This suggests that researchers should invest further efforts in investigating biomarkers derived from general EVs for this comparison.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Taha

2024

Preprint

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“…These increased levels could signify endothelial dysfunction in patients with VCI, suggesting a breach in the integrity of the BBB. The compromise of the BBB leads to oxidative stress, the invasion of cells, and the infiltration of inflammatory agents, along with the penetration of neurotoxic substances from the blood [ 47 ]. These blood-derived neurotoxic substances include thrombin, low-density lipoprotein (LDL) cholesterol, albumin, fibrinogen, and plasminogen [ 43 ].…”

Section: Pathophysiological Mechanisms Of Vcimentioning

confidence: 99%

“…Disruption in the connection between neurons and their extracellular matrix render hippocampal neurons more susceptible to cell death, thereby worsening neurological damage [ 79 ]. Therefore, coagulation factors can serve as potential biomarkers for endothelial dysfunction, offering insights into the early diagnosis and prevention of cerebral SVD and VCI [ 47 ].…”

Section: Pathophysiological Mechanisms Of Vcimentioning

confidence: 99%

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

Fan,

Xiao,

Zhang

2024

Vaccines

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Vascular cognitive impairment (VCI) encompasses a wide range of cognitive disorders stemming from cerebrovascular issues, such as strokes or small vessel disease. These conditions often pose challenges to traditional diagnostic approaches due to their multifactorial nature and varied clinical presentations. Recently, next-generation sequencing (NGS) technologies have provided detailed analyses of long non-coding RNAs (lncRNAs) in the molecular pathobiology of VCI. These new findings help with molecular-based diagnostics and treatments of VCI. Within this realm, the concept of immune modulation, especially through specific vaccinations, emerges as a promising therapeutic strategy in VCI mitigation. In this review, we comprehensively elucidate the function of lncRNAs in VCI, emphasizing the advanced understanding of VCI’s molecular underpinnings made possible through NGS technologies. Significant focus is placed on the immune system’s role in VCI, particularly the neuroinflammatory processes which are consequential to cerebrovascular abnormalities. We believe that lncRNAs participate in regulating these immunological pathways, potentially guiding the development of vaccines targeting VCI. In this context, we propose a novel perspective: using knowledge about lncRNA profiles and functions to guide vaccine development, we can potentially exploit the body’s immune response to mitigate or prevent VCI. This approach has the potential to revolutionize VCI management by introducing targeted immunization strategies informed by molecular signatures, a concept that remains largely unexplored in current research endeavors. In addition, we summarize current progress and propose future directions, advocating for robust, interdisciplinary studies to validate the potential intersections between lncRNA landscapes, VCI pathology, and immunology. This review aims to spur innovative research and promote the development of lncRNA-informed vaccine strategies as proactive interventions against the cognitive consequences of VCI.

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“…Vascular cognitive disorders (VCD), also referred to as vascular cognitive impairment (VCI) or sometimes vascular cognitive impairment and dementia (VCID), are the second most common cause of dementia after Alzheimer's disease (AD), affecting at least 7.2 million people worldwide [1] . VCD represent a heterogeneous group of disorders with multiple pathogenetic mechanisms, with the fundamental characteristic attributable to brain injury arising from cerebrovascular disorders that affect the small and large vessels of the brain [2] . One important mechanism is the breakdown of the blood brain barrier (BBB) owing to the disruption of the neurovascular unit (NVU), a mechanism shared between VCD and neurodegenerative disorders [3] .…”

Section: Introductionmentioning

confidence: 99%

Fluid biomarkers of the neurovascular unit in cerebrovascular disease and vascular cognitive disorders: A systematic review and meta-analysis

Hansra,

Jayasena,

Hosoki

et al. 2024

Cerebral Circulation - Cognition and Behavior

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Molecular biomarkers for vascular cognitive impairment and dementia

Cited by 38 publications

References 232 publications

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Extracellular Vesicles for Alzheimer’s Disease and Dementia Diagnosis

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

Fluid biomarkers of the neurovascular unit in cerebrovascular disease and vascular cognitive disorders: A systematic review and meta-analysis

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