Progression of Cognitive Impairment to Alzheimer’s Disease: Through the Lens of Salivary Extracellular Vesicles

The elusiveness encircling around the domain of cognition, its impairment, and the poor prognosis of Alzheimer’s disease has made early diagnosis a necessity. The noticeable symptoms in these conditions appear years later after the neuropathological changes occur in the brain. Exosomes, a small-sized extracellular vesicle facilitate intercellular communication of disease pathologies and their cargo can provide molecular information about its place of origin. The study titled “A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into Alzheimer’s disease” was an attempt toward understanding the role of salivary small-sized extracellular vesicular (EV’s) cargo in monitoring the progression. Outcomes of the study represent, that the salivary small-sized EV’s (ssEV’s) levels were higher in the cognitively impaired and Alzheimer’s diseased as well the differential expression of the protein in the cargo correlates well with the disease severity staging. Thus, it can help in the development of an early non-invasive screening method

Progression of Cognitive Impairment to Alzheimer’s Disease: Through the Lens of Salivary Extracellular Vesicles

The elusiveness encircling around the domain of cognition, its impairment, and the poor prognosis of Alzheimer’s disease has made early diagnosis a necessity. The noticeable symptoms in these conditions appear years later after the neuropathological changes occur in the brain. Exosomes, a small-sized extracellular vesicle facilitate intercellular communication of disease pathologies and their cargo can provide molecular information about its place of origin. The study titled “A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into Alzheimer’s disease” was an attempt toward understanding the role of salivary small-sized extracellular vesicular (EV’s) cargo in monitoring the progression. Outcomes of the study represent, that the salivary small-sized EV’s (ssEV’s) levels were higher in the cognitively impaired and Alzheimer’s diseased as well the differential expression of the protein in the cargo correlates well with the disease severity staging. Thus, it can help in the development of an early non-invasive screening method.

A qualitative study to assess the psychological experiences and coping strategies of families affected with Li-Fraumeni syndrome in the Indian population

Background: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome. Due to the high risk of occurrence of multiple cancers, families with LFS may have an overwhelming psychosocial burden. Methods: This cross-sectional study was conducted at a tertiary care center using face-to-face interviews through a grounded theory approach. Statistical analysis was done using Smith’s Interpretative Phenomenological Approach. Themes and sub-themes were extracted, and a thematic schema was developed. Results: A total of five themes were identified. The extracted themes were psychological experiences, behavioural responses, stressors, coping strategies and perceived needs. The interlay of the themes deepened the impact of LFS on the affected ones and brought into light the turmoil of emotions and difficulties that these individuals were going through in the face of the disease. Conclusions: LFS-affected individuals had a range of experiences with this rare and little-known disease. The lack of information seems to be a precursor to the denial of diagnosis. Their experience with the illness sheds light on the grey areas like guilt and helplessness that demand immediate attention. Future policies need to be developed in accordance with the identified perceived needs to potentially guide the treatment and rising needs of LFS-affected individuals

The Evolving Landscape of Exosomes in Neurodegenerative Diseases : Exosomes Characteristics and a Promising Role in Early Diagnosis

Neurodegenerative diseases (ND) remains to be one of the biggest burdens on healthcare systems and serves as a leading cause of disability and death. Alzheimer’s disease (AD) is among the most common of such disorders, followed by Parkinson’s disease (PD). The basic molecular details of disease initiation and pathology are still under research. Only recently, the role of exosomes has been linked to the initiation and progression of these neurodegenerative diseases. Exosomes are small bilipid layer enclosed extracellular vesicles, which were once considered as a cellular waste and functionless. These nano-vesicles of 30–150 nm in diameter carry specific proteins, lipids, functional mRNAs, and high amounts of non-coding RNAs (miRNAs, lncRNAs, and circRNAs). As the exosomes content is known to vary as per their originating and recipient cells, these vesicles can be utilized as a diagnostic biomarker for early disease detection. Here we review exosomes, their biogenesis, composition, and role in neurodegenerative diseases. We have also provided details for their characterization through an array of available techniques. Their updated role in neurodegenerative disease pathology is also discussed. Finally, we have shed light on a novel field of salivary exosomes as a potential candidate for early diagnosis in neurodegenerative diseases and compared the biomarkers of salivary exosomes with other blood/cerebrospinal fluid (CSF) based exosomes within these neurological ailmentsValiderad;2021;Nivå 2;2021-01-13 (johcin)</p

Mapping the inorganic and proteomic differences among different types of human teeth: A preliminary compositional insight

In recent years, studies on mineralized tissues are becoming increasingly popular not only due to the diverse mechanophysical properties of such materials but also because of the growing need to understand the intricate mechanism involved in their assembly and formation. The biochemical mechanism that results in the formation of such hierarchical structures through a well-coordinated accumulation of inorganic and organic components is termed biomineralization. Some prime examples of such tissues in the human body are teeth and bones. Our current study is an attempt to dissect the compositional details of the inorganic and organic components in four major types of human teeth using mass spectrometry-based approaches. We quantified inorganic materials using inductively coupled plasma resonance mass spectrometry (ICP-MS). Differential level of ten different elements, Iron (Fe), Cadmium (Cd), Potassium (K), Sulphur (S), Cobalt (Co), Magnesium (Mg), Manganese (Mn), Zinc (Zn), Aluminum (Al), and Copper (Cu) were quantified across different teeth types. The qualitative and quantitative details of their respective proteomic milieu revealed compositional differences. We found 152 proteins in total tooth protein extract. Differential abundance of proteins in different teeth types were also noted. Further, we were able to find out some significant protein-protein interaction (PPI) backbone through the STRING database. Since this is the first study analyzing the differential details of inorganic and organic counterparts within teeth, this report will pave new directions to the compositional understanding and development of novel in-vitro repair strategies for such biological material

Osteogenic markers in peri‐implant crevicular fluid in immediate and delayed‐loaded dental implants: A randomized controlled trial

IntroductionThe study evaluates the levels of matrix metalloprotease-8 (MMP-8), and Cathepsin-K (CatK) in peri-implant crevicular fluid (PICF) among patients with immediate loaded (IL) and delayed-loaded (DL) implants at different time points to know the inflammation and osteogenic status.MethodsThe study population consisted of two groups (n = 25, each group) with a mean age of 28.7 ± 3.5 years, and PICF was collected. MMP-8 and CatK levels were quantified through ELISA.ResultsWe observed the concentrations of inflammatory markers (MMP-8 and CatK) at three time points in the IL and DL groups. The mean concentration of MMP-8 in the IL group was 9468 ± 1230 pg/mL, 5547 ± 1088 pg/mL, and 7248 ± 1396 pg/mL at 2 weeks, 3 months, and 12 months, respectively; while in the DL group was 10 816 ± 779.7 pg/mL, 9531 ± 1245 pg/mL, and 9132 ± 1265 pg/mL at 2 weeks, 3 and 12 months, respectively. The mean concentration of Cat-K in the IL group was observed at 422.1 ± 36.46 pg/mL, 242.9 ± 25.87 pg/mL, and 469 ± 75.38 pg/mL at 2 weeks, 3, and 12 months, whereas in the DL group was 654.6 ± 152.9 pg/mL, 314.7 ± 28.29 pg/mL, and 539.8 ± 115.1 pg/mL at 2 weeks, 3 months and 12 months, respectively.ConclusionIn this study, the levels of CatK and MMP-8 levels decline at 12 months in both groups, and the IL group shows lower values compared to the DL group; however, no significant changes were observed after analyses were adjusted for multiple comparisons (p &gt; 0.025). Therefore, there is not much difference observed in the inflammation process between immediate and delayed loading. (Clinical trial identifier: CTRI/2017/09/009668).Funder: All-India Institute of Medical Sciences </p

Deciphering pancreatic neuroendocrine tumors: Unveiling through circulating small extracellular vesicles

The survival rate over a five-year period for rare pancreatic neuroendocrine tumors (PanNET) is notably lower compared to other neuroendocrine tumors due to late-stage detection, which is a consequence of the absence of suitable diagnostic markers; therefore, there exists a critical need for an early-stage biomarker-specific to PanNETs. This study introduces a novel approach, investigating the impact of small extracellular vesicles (sEV) in PanNET growth and metastasis. As proof of concept, this study shows a correlation between sEV concentration in controls and PanNET. Notably, higher sEV concentrations were observed in PanNETs than in controls (p &lt; 0.0001) with a sensitivity of 100%. Further, apparent differences were observed in the sEV concentrations between controls and grades 1 PanNET (p = 0.005). The expression of sEV markers was confirmed using CD63, TSG101, CD9, Flotillin-1, and GAD65 antibodies. Additionally, the expression of cancer marker BIRC2/cIAP1 (p = 0.002) and autophagy marker Beclin-1 (p = 0.02) were observed in plasma-derived sEVs and PanNET tissue. This study represents the first to indicate the increased secretion of sEV in PanNET patients&amp;apos; blood plasma, proposing potential function of sEV as a new biomarker for early-stage PanNET detection.Validerad;2024;Nivå 2;2024-04-16 (hanlid);Funder: Department of Science and Technology, Govt of India (EEQ/2018/000697);Full text license: CC BY</p

Circulating plasma miR-23b-3p as a biomarker target for idiopathic Parkinson's disease: comparison with small extracellular vesicle miRNA

Background: Parkinson's disease (PD) is an increasingly common neurodegenerative condition, which causes movement dysfunction and a broad range of non-motor symptoms. There is no molecular or biochemical diagnosis test for PD. The miRNAs are a class of small non-coding RNAs and are extensively studied owing to their altered expression in pathological states and facile harvesting and analysis techniques. Methods: A total of 48 samples (16 each of PD, aged-matched, and young controls) were recruited. The small extracellular vesicles (sEVs) were isolated and validated using Western blot, transmission electron microscope, and nanoparticle tracking analysis. Small RNA isolation, library preparation, and small RNA sequencing followed by differential expression and targeted prediction of miRNA were performed. The real-time PCR was performed with the targeted miRNA on PD, age-matched, and young healthy control of plasma and plasma-derived sEVs to demonstrate their potential as a diagnostic biomarker. Results: In RNA sequencing, we identified 14.89% upregulated (fold change 1.11 to 11.04, p &lt; 0.05) and 16.54% downregulated (fold change −1.04 to −7.28, p &lt; 0.05) miRNAs in PD and controls. Four differentially expressed miRNAs (miR-23b-3p, miR-29a-3p, miR-19b-3p, and miR-150-3p) were selected. The expression of miR-23b-3p was “upregulated” (p = 0.002) in plasma, whereas “downregulated” (p = 0.0284) in plasma-derived sEVs in PD than age-matched controls. The ROC analysis of miR-23b-3p revealed better AUC values in plasma (AUC = 0.8086, p = 0.0029) and plasma-derived sEVs (AUC = 0.7278, p = 0.0483) of PD and age-matched controls. Conclusion: We observed an opposite expression profile of miR-23b-3p in PD and age-matched healthy control in plasma and plasma-derived sEV fractions, where the expression of miR-23b-3p is increased in PD plasma while decreased in plasma-derived sEV fractions. We further observed the different miR-23b-3p expression profiles in young and age-matched healthy control.Validerad;2023;Nivå 2;2023-11-21 (hanlid);Funder: Indian Council of Medical Research (ICMR) (2020-1194); Department of Health Research (DHR) (R.11013/21/2021-GIA/HR); Ministry of Health and Family WelfareFull text license: CC BY</p

Fluorescence-tagged salivary small extracellular vesicles as a nanotool in early diagnosis of Parkinson’s disease

Abstract Background Parkinson’s disease is generally asymptomatic at earlier stages. At an early stage, there is an extensive progression in the neuropathological hallmarks, although, at this stage, diagnosis is not possible with currently available diagnostic methods. Therefore, the pressing need is for susceptibility risk biomarkers that can aid in better diagnosis and therapeutics as well can objectively serve to measure the endpoint of disease progression. The role of small extracellular vesicles (sEV) in the progression of neurodegenerative diseases could be potent in playing a revolutionary role in biomarker discovery. Methods In our study, the salivary sEV were efficiently isolated by chemical precipitation combined with ultrafiltration from subjects (PD = 70, healthy controls = 26, and prodromal PD = 08), followed by antibody-based validation with CD63, CD9, GAPDH, Flotillin-1, and L1CAM. Morphological characterization of the isolated sEV through transmission electron microscopy. The quantification of sEV was achieved by fluorescence (lipid-binding dye-labeled) nanoparticle tracking analysis and antibody-based (CD63 Alexa fluor 488 tagged sEV) nanoparticle tracking analysis. The total alpha-synuclein (α-synTotal) in salivary sEVs cargo was quantified by ELISA. The disease severity staging confirmation for n = 18 clinically diagnosed Parkinson’s disease patients was done by 99mTc-TRODAT-single-photon emission computed tomography. Results We observed a significant increase in total sEVs concentration in PD patients than in the healthy control (HC), where fluorescence lipid-binding dye-tagged sEV were observed to be higher in PD (p = 0.0001) than in the HC using NTA with a sensitivity of 94.34%. In the prodromal PD cases, the fluorescence lipid-binding dye-tagged sEV concentration was found to be higher (p = 0.008) than in HC. This result was validated through anti-CD63 tagged sEV (p = 0.0006) with similar sensitivity of 94.12%. We further validated our findings with the ELISA based on α-synTotal concentration in sEV, where it was observed to be higher in PD (p = 0.004) with a sensitivity of 88.24%. The caudate binding ratios in 99mTc-TRODAT-SPECT represent a positive correlation with sEV concentration (r = 0.8117 with p = 0.0112). Conclusions In this study, for the first time, we have found that the fluorescence-tagged sEV has the potential to screen the progression of disease with clinically acceptable sensitivity and can be a potent early detection method for PD. Graphical Abstrac