Soluble Biomarkers of Cerebrovascular Pathologies

Foley, Kate E.; Wilcock, Donna M.

doi:10.1161/strokeaha.123.044172

Cited by 4 publications

(2 citation statements)

References 111 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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“…Nonetheless, we used conventional radiology tools that can inform clinical evaluation by establishing normative expectations for the measured pathologies for an individual given their age. Future work will include the identification, validation, and incorporation of biofluidic measures of vascular function 47 , 48 and comparison to autopsy data that could provide more mechanistic context for the radiological markers studied here. Conclusions about temporal ordering of the emergence of radiological abnormalities were derived with methods that are similar to those used in studies of autosomal dominant AD 49 , 50 .…”

Section: Discussionmentioning

confidence: 99%

Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome

Lao,

Edwards,

Flores-Aguilar

et al. 2024

Sci Rep

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Adults with Down syndrome have a genetic form of Alzheimer’s disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25–72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

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