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Tau pathology: predictive diagnostics, targeted preventive and personalized medicine and application of advanced research in medical practice.

ABSTRACT: Microtubules are key cytoskeletal elements found in all eukaryotic cells. The microtubule shaft is composed of the heterodimer protein, tubulin and decorated with multiple microtubule associated protein, regulating microtubule function. Tau (tubulin associated unit) or MAPT (microtubule associated protein tau), among the first microtubule associated proteins to be identified, was implicated in microtubule initiation as well as assembly, with increased expression in neurons and specific association with axonal microtubules. Alzheimer's disease (AD) is the most prevalent tauopathy, exhibiting tau-neurofibrillary tangles associated with cognitive dysfunction. AD is also characterized by ?-amyloid plaques. An abundance of tau inclusions, in the absence of ?-amyloid deposits, can be found in Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and other diseases, collectively described as tauopathies. The increase in tau pathology in AD correlates with the associated cognitive decline. The current manuscript touches on the variability as well as common denominators of the various tau pathologies coupled to new approaches/current innovation in treatment of tauopathies in favor of advanced technologies in predictive diagnostics, targeted preventive and personalized medicine (PPPM).

SUBMITTER: Gozes I

PROVIDER: S-EPMC3405325 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Tau pathology: predictive diagnostics, targeted preventive and personalized medicine and application of advanced research in medical practice.

Gozes Illana I

The EPMA journal 20100612 2

Microtubules are key cytoskeletal elements found in all eukaryotic cells. The microtubule shaft is composed of the heterodimer protein, tubulin and decorated with multiple microtubule associated protein, regulating microtubule function. Tau (tubulin associated unit) or MAPT (microtubule associated protein tau), among the first microtubule associated proteins to be identified, was implicated in microtubule initiation as well as assembly, with increased expression in neurons and specific associati ...[more]

PMID: 23199066

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Project description:BackgroundQuantification of motor performance has a promising role in personalized medicine by diagnosing and monitoring, e.g. neurodegenerative diseases or health problems related to aging. New motion assessment technologies can evolve into patient-centered eHealth applications on a global scale to support personalized healthcare as well as treatment of disease. However, uncertainty remains on the limits of generalizability of such data, which is relevant specifically for preventive or predictive applications, using normative datasets to screen for incipient disease manifestations or indicators of individual risks.ObjectiveThis study explored differences between healthy German and Japanese adults in the performance of a short set of six motor tests.MethodsSix motor tasks related to gait and balance were recorded with a validated 3D camera system. Twenty-five healthy adults from Chiba, Japan, participated in this study and were matched for age, sex, and BMI to a sample of 25 healthy adults from Berlin, Germany. Recordings used the same technical setup and standard instructions and were supervised by the same experienced operator. Differences in motor performance were analyzed using multiple linear regressions models, adjusted for differences in body stature.ResultsFrom 23 presented parameters, five showed group-related differences after adjustment for height and weight (R 2 between .19 and .46, p<.05). Japanese adults transitioned faster between sitting and standing and used a smaller range of hand motion. In stepping-in-place, cadence was similar in both groups, but Japanese adults showed higher knee movement amplitudes. Body height was identified as relevant confounder (standardized beta >.5) for performance of short comfortable and maximum speed walks. For results of posturography, regression models did not reveal effects of group or body stature.ConclusionsOur results support the existence of a population-specific bias in motor function patterns in young healthy adults. This needs to be considered when motor function is assessed and used for clinical decisions, especially for personalized predictive and preventive medical purposes. The bias affected only the performance of specific items and parameters and is not fully explained by population-specific ethnic differences in body stature. It may be partially explained as cultural bias related to motor habits. Observed effects were small but are expected to be larger in a non-controlled cross-cultural application of motion assessment technologies with relevance for related algorithms that are being developed and used for data processing. In sum, the interpretation of individual data should be related to appropriate population-specific or even better personalized normative values to yield its full potential and avoid misinterpretation.Supplementary informationThe online version contains supplementary material available at 10.1007/s13167-021-00236-3.

Project description:BackgroundThe premise of disease-related phenotypes is the definition of the counterpart normality in medical sciences. Contrary to clinical practices that can be carefully planned according to clinical needs, heterogeneity and uncontrollability is the essence of humans in carrying out health studies. Full characterization of consistent phenotypes that define the general population is the basis to individual difference normalization in personalized medicine. Self-claimed normal status may not represent health because asymptomatic subjects may carry chronic diseases at their early stage, such as cancer, diabetes mellitus and atherosclerosis. Currently, treatments for non-communicable chronic diseases (NCD) are implemented after disease onset, which is a very much delayed approach from the perspective of predictive, preventive and personalized medicine (PPPM). A NCD pandemic will develop and be accompanied by increased global economic burden for healthcare systems throughout both developed and developing countries. This paper examples the characterization of the suboptimal health status (SHS) which represents a new PPPM challenge in a population with ambiguous health complaints such as general weakness, unexplained medical syndrome (UMS), chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS) and chronic fatigue immune dysfunction syndrome (CFIDS).MethodsWe applied clinical informatic approaches and developed a questionnaire-suboptimal health status questionnaire-25 (SHSQ-25) for measuring SHS. The validity and reliability of this approach were evaluated in a small pilot study and then in a cross-sectional study of 3,405 participants in China.ResultsWe found a correlation between SHS and systolic blood pressure, diastolic blood pressure, plasma glucose, total cholesterol and high-density lipoprotein (HDL) cholesterol among men, and a correlation between SHS and systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides and HDL cholesterol among women.ConclusionsThe SHSQ-25 is a self-rated questionnaire of perceived health complaints, which can be used as a new instrument for PPPM. An ongoing longitudinal SHS cohort survey (China Sub-optimal Health Cohort Study, COACS) consisting of 50,000 participants will provide a powerful health trial to use SHSQ-25 for its application to PPPM through patient stratification and therapy monitoring using innovative technologies of predictive diagnostics and prognosis: an effort of paradigm shift from reactive to predictive medicine.

Project description:RelevanceLung cancer is the most common malignant tumor with high morbidity (11.6% of the total diagnosed cancer cases) and mortality (18.4% of the total cancer deaths), and its 5-year survival rate is very low (20%). Clarification of any molecular events and the discovery of effective biomarkers will offer increasing promise for lung canner management. N6-methyladenosine (m6A) modification is one of the important RNA modifications that are closely associated with lung cancer, and are tightly regulated by m6A regulators. Elucidation of pathology-specific m6A regulators will directly contribute to lung cancer medical services in the context of predictive, preventive, and personalized medicine (PPPM).PurposeTo investigate pathology-specific regulators of m6A RNA modifications in lung cancer and further inspect the m6A regulator gene signature as useful tools for PPPM in lung cancers.MethodsThe gene expression data of 19 m6A regulators (m6A-methyltransferases-ZC3H13, KIAA1429, RBM15/15B, WTAP, and METTL3/14; demethylases-FTO and ALKBH5; and m6A-binding proteins-HNRNPC, YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPA2B1) and clinical data of 1013 lung cancer patients [511 lung adenocarcinoma (LUAD) and 502 lung squamous carcinoma (LUSC)] and 109 controls (Con) were obtained from the TCGA database. Quantitative real-time PCR (qRT-PCR) was used to verify m6A regulators in lung cancer cell lines. Protein-protein interaction (PPI), gene co-expression, survival analysis, and heatmap were used to analyze these m6A regulators in this set of lung cancer clinical data. Lasso regression was used to optimize the pathology-specific m6A regulator gene signature. Gene set enrichment analysis (GSEA) was used to reveal the functional characteristics of m6A regulators.ResultsThose 19 m6A regulator profiling was significantly differentially expressed in lung cancer tissues relative to control tissues, which was also verified in lung cancer cell lines. Those m6A regulators interacted mutually, and those regulator-based sample clusters were correlated with clinical traits, including survival status, gender, tobacco smoking history, primary disease, and pathologic stage. Further, lasso regression based on the 19 m6A regulators optimized and identified a three-m6A-regulator signature (KIAA1429, METTL3, and IGF2BP1) as independent prognostic factor, which classified 1013 lung cancer patients into high-risk and low-risk groups according to median value (0.84) of the lasso regression risk scores. This three-m6A-regulator signature profiling was significantly related to lung cancer overall survival, cancer status, and the above-described clinical traits. Further, GSEA revealed that KIAA1429, METTL3, and IGF2BP1 were significantly related to multiple biological behaviors, including proliferation, apoptosis, metastasis, energy metabolism, drug resistance, and recurrence, and that KIAA1429 and IGF2BP1 had potential target genes, including E2F3, WTAP, CCND1, CDK4, EGR2, YBX1, and TLX, which were associated with cancers.ConclusionThis study provided the first view of the pathology-specific regulators of m6A RNA modification in lung cancers and identified the three-m6A-regulator signature (KIAA1429, METTL3, and IGF2BP1) as an independent prognostic model to classify lung cancers into high- and low-risk groups for patient stratification, prognostic assessment, and personalized treatment toward PPPM in lung cancers.

Project description:BackgroundSeveral ocular factors have been identified for primary angle-closure glaucoma (PACG), such as a small cornea, elevated intraocular pressure (IOP), shallow anterior chamber, and short axial length (AL). However, the relationship between the severity of PACG and various ocular parameters [IOP, anterior chamber depth, AL, central corneal thickness] is not fully understood.MethodsA 7-year cross-sectional study. A total of 2254 eyes of 1312 PACG patients (females = 856 [1479 eyes] and males = 456 [775 eyes]) were included. A detailed eye examination was performed. The participants were categorized into gender subgroups followed by subdivision into three different severity groups according to their mean deviation (MD) of the visual fields results as follows: mild (MD ≤ 6 dB), moderate (MD 6-12 dB), and severe (MD > 12 dB) PACG. The associations of ocular biometry with severity of PACG were analyzed using paired Student's t test, multivariate linear regression, and logistic regression analysis.ResultsThere was a significant positive correlation between the MD and AL in the female subgroup (B = 0.663, p = 0.001, 95%CI = 1.070 to 1.255) but not in the male subgroup. Increased AL levels (mild [OR = 1], moderate [OR = 1.047, p = 0.062, 95%CI = 0.947 to 2.462], and severe [OR = 1.274, p < 0.001, 95%CI = 1.114 to 1.457]) were only associated with the severity of PACG in females. Paired Student's t tests showed that the long AL female eyes have a higher MD value than in the short AL female eyes (mean difference = 3.09, t = 6.846, p < 0.001) in the same subjects, but not in the male subgroup (p = 0.648).ConclusionsThe AL was positively and significantly related to the severity of PACG in female but not male subjects. This finding refers to the PACG pathogenesis and suggests the use of AL assessment in glaucoma monitoring, diagnosis, and progression. This may contribute to further development of personalized strategies in preventive medicine.

Project description:ObjectivesSuboptimal health status (SHS), a reversible borderline condition between optimal health status and disease, has been recognized as a main risk factor for non-communicable diseases (NCDs). From the standpoint of predictive, preventive, and personalized medicine (PPPM/3PM), the early detection of SHS provides a window of opportunity for targeted prevention and personalized treatment of NCDs. Considering that immunoglobulin G (IgG) N-glycosylation levels are associated with NCDs, it can be speculated that IgG N-glycomic alteration might occur at the SHS stage.MethodsA case-control study was performed and it consisted of 124 SHS individuals and 124 age-, gender-, and body mass index-matched healthy controls. The IgG N-glycan profiles of 248 plasma samples were analyzed by ultra-performance liquid chromatography instrument.ResultsAfter adjustment for potential confounders (i.e., age, levels of education, physical activity, family income, depression score, fasting plasma glucose, and low-density lipoprotein cholesterol), SHS was significantly associated with 16 IgG N-glycan traits at 5% false discovery rate, reflecting decreased galactosylation and fucosylation with bisecting GlcNAc, as well as increased agalactosylation and fucosylation without bisecting GlcNAc. Canonical correlation analysis showed that glycan peak (GP) 20, GP9, and GP12 tended to be significantly associated with the 5 domains (fatigue, the cardiovascular system, the digestive system, the immune system, and mental status) of SHS. The logistic regression model including IgG N-glycans was of moderate performance in tenfold cross-validation, achieving an average area under the receiver operating characteristic curves of 0.703 (95% confidence interval: 0.637-0.768).ConclusionsThe present findings indicated that SHS-related alteration of IgG N-glycans could be identified at the early onset of SHS, suggesting that IgG N-glycan profiles might be potential biomarker of SHS. The altered SHS-related IgG N-glycans are instrumental for SHS management, which could provide a window opportunity for PPPM in advanced treatment of NCDs and shed light on future studies investigating the pathogenesis of progression from SHS to NCDs.Supplementary informationThe online version contains supplementary material available at 10.1007/s13167-022-00278-1.

Project description:AimsCoronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19.MethodsClinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. "Gene Score" and "Drug Score" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs.ResultsOur results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient.ConclusionWe recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management.Supplementary informationThe online version contains supplementary material available at 10.1007/s13167-021-00247-0.

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Tau pathology: predictive diagnostics, targeted preventive and personalized medicine and application of advanced research in medical practice.

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Tau pathology: predictive diagnostics, targeted preventive and personalized medicine and application of advanced research in medical practice.

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