Old abstract 1
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.
Background: Stroke survivors frequently experience post-stroke depression (PSD) and post-stroke anxiety (PSA), which may be underexamined by clinicians if patient mood status between discharge and follow-up is unknown. Digital monitoring may enable early identification of mood disturbances. Ecological momentary assessments (EMA) have been tested to capture mood fluctuations in patients regular environments, but no standardized procedure for monitoring PSA or PSD has been developed. Objective: Determine the feasibility and validity of EMA for evaluating subacute PSA and PSD in non-severe stroke patients. Methods: Patients with non-severe stroke discharged home responded to daily smartphone EMA questions concerning mood and activity for twelve weeks until follow-up. Questions based on symptoms of anxiety and depression were used to derive EMA Anx and EMA Dep indices, computed over five 15-day intervals. Convergent validity was assessed using follow-up Generalized Anxiety Disorder-7 (GAD-7) and Centre for Epidemiological Studies-Depression (CES-D) scores. Logistic regression models predicted PSA and PSD status at follow-up, with baseline models comprising stroke severity, age, sex, and mood status, to which EMA Anx or Dep were added. Results: Data from 118 patients were analyzed. EMA adherence was moderate, with 89 patients (75.4%) responding on 75 or more days. Correlations between EMA Anx and GAD-7 and between EMA Dep and CES-D generally strengthened at later intervals, with the average mood index generally showing the strongest associations. Adding EMA data from the third time interval (31-45 days) significantly improved model fit beyond the baseline models (Anxiety: {chi}-square = 7.08, p = 0.008, {delta}R-square = 0.060; Depression: {chi}-square = 28.0, p < 0.001, {delta}R-square = 0.256). Discussion: EMA is feasible in mild-to-moderate stroke patients and may facilitate early identification of post-stroke mood disturbances. Further analyses in more diverse populations are required to validate these findings.
Phantom limb pain (PLP) is common after amputation, yet why poor sleep becomes pain in only some individuals is unknown. We hypothesized that a regulatory response is interpretable only against the reserve sustaining it, and thus we tested whether autonomic capacity relative to demand moderates the sleep-pain relationship in 121 amputee adults. Sleep was assessed with the Pittsburgh Sleep Quality Index; PLP, residual limb pain (RLP), and phantom limb sensation (PLS) on 0-10 scales. Heart rate variability was summarized as autonomic reserve (log-transformed SDNN, RMSSD, total and high-frequency power) and autonomic drive (normalized low-frequency power). Poorer sleep was associated with greater PLP and RLP, but not PLS. No single HRV index moderated these associations, but the sleep x reserve x drive interaction did for PLP (b = -0.51, p = 0.026). Poor sleep predicted pain most strongly under high drive with reduced reserve. PLP vulnerability reflects autonomic capacity relative to demand, instead of any single HRV marker alone.
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.
Cognitive impairment is a prevalent, disabling manifestation of Long COVID, but whether cognitive rehabilitation alters neural network organization is unknown. We examined whether a 12-week cognitive rehabilitation intervention modified resting-state connectivity within the central-executive (CEN), default-mode (DMN), and salience (SN) networks, and whether connectivity changes associated with cognitive performance. Participants were adults with prior SARS-CoV-2 infection, persistent Long COVID symptoms ([≥]3 months), and objectively confirmed mild-to-moderate cognitive impairment. Of 58 participants randomized, 39 (mean age 46.4; 69% women) completed neuroimaging (19 intervention, 20 control). The 12-week intervention combined virtual cognitive rehabilitation and small-group and individual sessions with computerized cognitive training. No significant group, time, or group-by-time interaction effects were observed for within- or between-network connectivity (all P > 0.22). Exploratory analyses identified nominal associations (P < 0.05) between connectivity changes and cognition; improved processing speed associated with increased CEN-DMN connectivity, greater SN-DMN connectivity associated with worse performance across processing speed, working memory, and executive function. None survived correction for multiple comparisons. Cognitive rehabilitation was not associated with detectable changes in resting-state network connectivity in long COVID-related cognitive impairment. SN-DMN connectivity may represent a marker of reduced network segregation underlying cognitive dysfunction, warranting study in larger, multimodal trials. Trial registration: NCT05498493.
Effective screening for Parkinson disease (PD) is important for symptom management and patient recruitment into disease-modifying trials. Here, we examined the performance of the PD-RISK Index toolkit in identifying PD patients at home without supervision.
Between 2022-2024, we recruited 305 participants (ages, 40-85 years): 93 with typical PD; 66 had other neurological conditions; and 146 were healthy controls. Two versions of the toolkit were completed: An original, 69-item-long questionnaire with the 40-scent University-of-Pennsylvania-Smell-Identification-Test (UPSIT); thereafter, a simplified, 11-item-short questionnaire with a newly-developed 8-scent smell test and responses submitted online. The corresponding summary scores ( PD-RISK Indices) were calculated for each subject to evaluate diagnostic performances.
In both versions, PD patients had higher questionnaire scores and worse olfaction than healthy controls (P<0.001), as expected; scores for subjects with other neurological conditions ranked at intermediate levels. The simplified 11-item questionnaire outperformed the original version in identifying PD. The abbreviated 8-scent smell test and the UPSIT booklet performed equally well in detecting hyposmia. The simplified PD-RISK Index showed the highest diagnostic performance in identifying PD patients amongst all participants; at a value of 23 (range, 0-100, where higher scores indicate higher PD risk), we measured a sensitivity of 0.98, specificity of 0.83, and positive and negative likelihood ratios of 5.88 and 0.02, respectively. The simplified PD-RISK Index showed stable performance across sexes and disease duration.
Our study reveals that unsupervised screening for manifest PD can be effectively carried out at home using an 11-item questionnaire, 8-scent smell test and online data entry.
The plain language titleThe PD-RISK Index study: Facilitating an earlier diagnosis of adults with Parkinson disease by screening at home with a short questionnaire and a simplified smell test
Plain language summariesEffective screening for Parkinson disease (PD) is important for symptom management by healthcare workers and the recruitment of patients into disease modifying trials. We previously published a two-step model for this purpose, which has been validated using several established study cohorts. The study below represents a field-test of this model and the toolkit to implement it (i.e. a self-report questionnaire and a smell test) using a real-world setting.
Between 2022-2024, 305 participants (ages, 40-85 years) were recruited into the study: 93 with typical PD; 66 had other neurological conditions; 146 were healthy. Two versions of the toolkit were completed at-home without supervision by a healthcare worker: (1) an original, 69-item-long questionnaire and a 40-scent smell test; (2) a simplified, 11-item-short questionnaire with a newly created, 8-scent smell test. Accordingly, two versions of summary scores ( PD-RISK Index) were calculated for each subject to examine group classification. Several performance metrics were used to evaluate diagnostic performances and to suggest clinically relevant thresholds.
In both versions, PD patients had significantly higher questionnaire scores (meaning higher risk of having PD) and lower smell test scores (meaning more impaired sense of smell) than healthy controls; scores for subjects with other neurological conditions ranked at intermediate levels. The simplified questionnaire outperformed the original version in diagnostic accuracy. The abbreviated smell test performed as well as the 40-item version in identifying hyposmia. The simplified PD-RISK Index showed stable performance across sexes and disease duration.
This study shows that non-invasive and unsupervised screening for manifest PD can be effectively carried out remotely using a simple 11-item questionnaire, an abbreviated 8-scent smell test and an online data entry system, thereby generating a PD-RISK Index for each individual.
Significance of the Topic:
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. Early diagnosis and prognostication are critical in managing ALS, as they can significantly impact the quality of life for patients and their caregivers. The discovery of reliable biomarkers for ALS can provide valuable insights into disease progression and enable clinicians to develop more effective treatment strategies.
Importance:
The identification of plasma isomiRs as potential biomarkers for ALS is significant because it opens up new avenues for non-invasive monitoring of disease progression and response to treatment. IsomiRs are microRNA isoforms that are distinct from their parent microRNAs, and their presence in the plasma can be indicative of cellular stress or damage. The potential utility of isomiRs as biomarkers for neurodegenerative diseases is an area of active research, and this study contributes to our understanding of their role in ALS.
Timeliness:
The study's focus on plasma isomiRs as biomarkers for ALS is timely, given the growing interest in using liquid biopsies for disease diagnosis and monitoring. Liquid biopsies offer a non-invasive and cost-effective way to monitor disease progression and response to treatment, making them an attractive option for clinicians and researchers.
Relevance:
The study's findings are relevant to ALS research and clinical practice because they provide evidence that plasma isomiRs can be used to predict survival in ALS patients. The identified isomiR, let-7g-5p.t, has prognostic utility comparable to that of established biomarkers, such as neurofilament light chain (NfL) and miR-181. This suggests that plasma isomiRs could be used as a novel class of biomarkers for ALS, potentially refining prognostication in clinical trials and improving patient outcomes.
Items of the text and their relationships:
Usefulness for disease management or drug discovery:
The study's findings are useful for disease management and drug discovery because they:
Originality:
The study provides original information beyond the obvious because it:
Comparison with the state of art:
The study's findings are comparable to existing biomarkers for ALS, such as neurofilament light chain (NfL) and miR-181. However, the study's focus on plasma isomiRs as biomarkers for ALS is a new area of research that contributes to our understanding of the potential utility of isomiRs in neurodegenerative diseases.