The discovery that brain cells release extracellular vesicles (EVs) and a portion of these enter the bloodstream offers the potential of monitoring changes occurring in the brain by isolating EVs from venous blood. For instance, while the levels of Aβ42 in CSF change early in AD, measurement of Aβ42 in plasma has not proved as useful ( Janelidze et al., 2016). Unlike CSF, the contents of blood are influenced by many organs and therefore changes in blood analytes are often not sensitive to minor changes that occur in brain.
Measurement of a blood-based analyte would be ideal since blood collection is widely accepted by patients and can be done almost anywhere. Thus, there is a pressing need for less costly and intrusive, and more widely available biomarkers that can replace or supplement current CSF and PET markers ( Bateman et al., 2019). Assessment of markers in CSF is more amendable for general use, but CSF sampling remains unpopular with patients. But PET imaging is expensive and is restricted to use in certain geographies. Specifically, measurement of tau and Aβ in CSF, or quantitation of amyloid or tangle pathology by PET imaging, can be used to identify mild cognitive impairment (MCI), a frequent precursor of AD ( Jack et al., 2013 Bao et al., 2017), and use of these markers is now common in clinical research ( Blennow et al., 2012 Jack et al., 2013). Advances in brain imaging and the development of robust immunoassays to measure tau and amyloid β-protein (Aβ) in cerebrospinal fluid (CSF) have greatly aided diagnosis ( Blennow et al., 2012).
Symptom onset is insidious and even in sophisticated centers clinical diagnosis is imperfect ( Salloway et al., 2014 Monsell et al., 2015). Our results suggest that measurement of miR-132 and miR-212 in neural EVs should be further investigated as a diagnostic aid for AD and as a potential theragnostic.Īlzheimer’s disease is a devastating disorder for which there is no cure or effective treatment. Moreover, when we measured the levels of a related miRNA, miR-212, we found that this miRNA was also decreased in neural EVs from AD patients compared to controls. ROC analysis indicated that measurement of miR-132-3p in neurally-derived plasma EVs showed good sensitivity and specificity to diagnose AD, but did not effectively separate individuals with AD-MCI from controls. Thereafter, we focused on the four miRNAs that showed group differences and measured their content in neurally derived blood EVs isolated from 63 subjects: 16 patients with early stage dementia and a CSF Aβ42+ tau profile consistent with AD, 16 individuals with mild cognitive impairment (MCI) and an AD CSF profile, and 31 cognitively intact controls with normal CSF Aβ42+ tau levels. Analysis of hits in brain extracts from 11 AD, 7 HPCs and 9 controls revealed a similar fold difference in these six miRNAs, with three showing statistically significant group differences and one with a strong trend toward group differences. Twelve miRNAs were altered by >1.5-fold in AD compared to controls, and six of these were also changed compared to HPCs. To this end, we employed high-content miRNA arrays to search for differences in miRNAs in RNA pools from brain tissue of AD ( n = 5), high pathological control (HPC) ( n = 5), or cognitively intact pathology-free controls ( n = 5). Since the levels of certain micro-RNAs (miRNAs) have been reported to be altered in Alzheimer’s disease (AD) brain, we sought to assess miRNA dysregulation in AD brain tissue and to determine if these changes were reflected in neural EVs isolated from blood of subjects with AD. These findings raise the possibility that brain-derived EV’s present in blood can be used to monitor disease processes occurring in the cerebrum. It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from brain into blood.