Old abstract 5
Feedforward control is impaired after stroke, but whether practice improves it in the chronic stage remains unclear. In fast single-joint movements, feedforward control scales initial acceleration to movement amplitude. Feedback-error-learning theory predicts that fast practice should promote recalibration. We tested whether speed-emphasized reach training improved this scaling in the more-affected arm. Thirty-six individuals with mild-to-moderate chronic stroke completed 2,080 reaches over four sessions emphasizing Speed (n = 17) or Accuracy (n = 19). At baseline, 3 days, and 1 month after training, participants performed single-joint elbow movements of three amplitudes without online visual feedback. The slope relating initial peak acceleration to target amplitude quantified feedforward scaling. At baseline, scaling was reduced on the more-affected side for extension ({Delta}{beta} = -17.1 {+/-} 3.5 s-{superscript 2}, P < 0.001) and flexion ({Delta}{beta} = -21.9 {+/-} 3.2 s-{superscript 2}, P < 0.001). Speed training increased flexion scaling at 3 days ({Delta}{beta} = 14.7 {+/-} 3.6 s-{superscript 2}, P = 0.00029), with 14 of 17 participants improving. The group-by-session interaction showed a greater increase after Speed than Accuracy training ({Delta}{beta} = 14.13 {+/-} 4.9 s-{superscript 2}, P = 0.0053). Scaling declined by 1 month (P = 0.02); no training-related changes occurred for extension. Peak acceleration occurred within 100 ms. Time to peak velocity, an index of pulse width, showed no group-specific training effect. Thus, speed-emphasized training produced a short-term improvement in early flexion acceleration scaling that transferred to an untrained single-joint task and was consistent with improved feedforward control. Transfer primarily reflected acceleration pulse-height rather than pulse-width modulation.
Significance of the Topic
The topic of this text revolves around understanding the molecular mechanisms underlying the genetic risks associated with Alzheimer's disease (Alzheimer's disease) conferred by the Apolipoprotein E (APOE) gene. Specifically, it explores the role of the 4 and 2 alleles of the APOE gene in modulating Alzheimer's disease pathology. The significance of this topic lies in its potential to shed light on the underlying biology of Alzheimer's disease, a complex and multifactorial disease.
Importance
Alzheimer's disease is a devastating and debilitating neurodegenerative disorder that affects millions of people worldwide. Understanding the genetic and molecular mechanisms underlying Alzheimer's disease is crucial for developing effective therapeutic strategies and preventing or slowing disease progression. The APOE gene has been associated with Alzheimer's disease risk, with the 4 allele being a well-established risk factor.
However, the underlying molecular mechanisms remain poorly characterized, making this research area highly important and timely.
Timeliness
The text is timely as it addresses a critical knowledge gap in the field of Alzheimer's disease research. Recent advances in proteomics and genomics have enabled researchers to systematically profile APOE-associated proteomic alterations in human samples, providing new insights into the molecular mechanisms underlying Alzheimer's disease. The text leverages these advances to investigate the role of the APOE 4 and 2 alleles in Alzheimer's disease pathology, making it a timely contribution to the field.
Relevance
The text has significant relevance to Alzheimer's disease research, as it provides novel insights into the molecular mechanisms underlying APOE-driven Alzheimer's disease pathology. The findings have implications for the development of therapeutic strategies for early intervention and potentially for the identification of new targets for Alzheimer's disease treatment.
Furthermore, the text highlights the importance of considering the APOE 4 and 2 alleles as distinct risk factors for Alzheimer's disease, rather than just focusing on the 4 allele.
Analysis of the Text
The text presents a comprehensive analysis of APOE-associated proteomic alterations across five cohorts, using a range of proteomics platforms and samples, including plasma and cerebrospinal fluid (cerebrospinal fluid). The study uses systematic profiling to identify a comprehensive APOE-protein network and applies mediation modeling to classify genotype-related signals as upstream mediators, downstream consequences, or APOE-specific changes. The text then leverages cerebrospinal fluid beta-amyloid (A ) biomarker data to improve temporal resolution and isolate early, A -independent proteomic programs.
The findings of the text are significant, as they provide novel insights into the molecular mechanisms underlying APOE-driven Alzheimer's disease pathology. The study identifies allele-specific, temporally structured proteomic signatures that precede Alzheimer's disease pathology, offering potential therapeutic targets for early intervention. The text highlights the importance of considering the APOE 4 and 2 alleles as distinct risk factors for Alzheimer's disease and underscores the challenges in reproducibility associated with proteomics studies.
Usefulness for Disease Management and Drug Discovery
The text provides valuable insights for Alzheimer's disease disease management and drug discovery, as it highlights the potential therapeutic targets for early intervention. The identification of allele-specific, temporally structured proteomic signatures offers a new perspective on Alzheimer's disease pathology and provides a starting point for the development of novel therapeutic strategies. The text also underscores the importance of considering individual variability in APOE genotype as a critical factor in Alzheimer's disease risk, which may inform personalized medicine approaches.
Original Information Beyond the Obvious
While the text presents novel insights into the molecular mechanisms underlying APOE-driven Alzheimer's disease pathology, it does not break new ground in terms of fundamental understanding.
However, the systematic profiling and mediation modeling approaches used in the study provide a comprehensive and nuanced understanding of APOE-associated proteomic alterations, which is a significant advance in the field. The text highlights the challenges associated with reproducibility in proteomics studies, emphasizing the need for careful consideration of sample size, platform choice, and data analysis methods.
Overall, the text provides a comprehensive and insightful analysis of APOE-associated proteomic alterations in human samples, highlighting the importance of considering individual variability in APOE genotype as a critical factor in Alzheimer's disease risk. The findings offer novel insights into the molecular mechanisms underlying APOE-driven Alzheimer's disease pathology and provide potential therapeutic targets for early intervention.
Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimers disease prognosis, diagnosis and monitoring. Here, we show that a blood-based immunoassay for an endogenously-cleaved "eMTBR-tau" fragment of tau protein is strongly associated with autopsy-diagnosed Alzheimer neuropathologic change (ADNC) and predominantly reflects the burden and anatomical progression of tangle pathology but not amyloid plaque load despite being most elevated in amyloid-positive symptomatic individuals. Plasma eMTBR-tau was significantly more accurate than plasma p-tau217 in classifying Braak staging and ADNC statuses at autopsy. Importantly, neuropathologic classification by plasma eMTBR-tau remained high (AUC=0.91-0.95) even when increasing intervals between blood collection and death up to a decade, while maintaining superior sensitivity and specificity over p-tau217. Higher baseline plasma eMTBR-tau was associated with worse cognition cross-sectionally and longitudinally predicted faster worsening. These results were replicated in a living cohort with in vivo tangle and plaque neuroimaging. Plasma eMTBR-tau concordance with tau neuroimaging was up to 94%, suggesting surrogacy. Together, plasma eMTBR-tau captures biological signatures of Braak staging and ADNC over a prolonged pre-mortem window, highlighting potential for early disease detection, biological staging, prognosis and therapeutic development.
Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimers disease prognosis, diagnosis and monitoring. Here, we show that a blood-based immunoassay for an endogenously-cleaved "eMTBR-tau" fragment of tau protein is strongly associated with autopsy-diagnosed Alzheimer neuropathologic change (ADNC) and predominantly reflects the burden and anatomical progression of tangle pathology but not amyloid plaque load despite being most elevated in amyloid-positive symptomatic individuals. Plasma eMTBR-tau was significantly more accurate than plasma p-tau217 in classifying Braak staging and ADNC statuses at autopsy. Importantly, neuropathologic classification by plasma eMTBR-tau remained high (AUC=0.91-0.95) even when increasing intervals between blood collection and death up to a decade, while maintaining superior sensitivity and specificity over p-tau217. Higher baseline plasma eMTBR-tau was associated with worse cognition cross-sectionally and longitudinally predicted faster worsening. These results were replicated in a living cohort with in vivo tangle and plaque neuroimaging. Plasma eMTBR-tau concordance with tau neuroimaging was up to 94%, suggesting surrogacy. Together, plasma eMTBR-tau captures biological signatures of Braak staging and ADNC over a prolonged pre-mortem window, highlighting potential for early disease detection, biological staging, prognosis and therapeutic development.
Significance, Importance, Timeliness, and Relevance:
The topic of this text revolves around the genetic connection between TAS2R38, a taste receptor implicated in innate immunity, and Alzheimer's disease (AD). The significance of this research lies in its potential to aid in the development of new treatments or repurpose existing ones for AD management. This is crucial as AD remains a leading cause of dementia worldwide, with limited treatment options available.
The importance of this study is twofold: it explores a novel relationship between a taste receptor and AD risk, which could lead to new therapeutic targets. The timeliness of this research is also evident, given the growing understanding of the role of genetics in disease susceptibility and the increasing emphasis on precision medicine.
In terms of relevance, the study leverages existing databases (ADNI and ROSMAP) and utilizes established methodologies (linear mixed-effects models and RNA-seq analysis), making it a valuable contribution to the field of AD research.
Relationship between items in the text:
Usefulness for disease management or drug discovery:
This study suggests that TAS2R38 haplotypes could guide precision drug repurposing strategies for AD. Specifically, the identification of MGAM as a novel drug target with existing FDA-approved inhibitors (Acarbose and Miglitol) provides a valuable lead for future research.
Originality:
While the study builds upon existing knowledge in the field, it presents novel connections between TAS2R38, MGAM, and AD pathology. The identification of MGAM as a potential therapeutic target is a notable finding, as it suggests a new avenue for AD treatment.
Comparison to the state of the art:
This study contributes to our understanding of the genetic and molecular mechanisms underlying AD susceptibility. However, it should be noted that the sample sizes used in this study are relatively small compared to other AD research studies.
In conclusion, this study provides a valuable addition to the growing body of evidence on the genetic and molecular mechanisms of AD. The identification of MGAM as a potential therapeutic target with existing FDA-approved inhibitors holds promise for future research and potential clinical applications.