Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number of AD patients, elucidating underlying mechanisms and developing corresponding interventional strategies are necessary. Hypotheses about AD such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, and vascular hypotheses are not mutually exclusive, and all of them play a certain role in the development of AD. The amyloid cascade hypothesis is currently the most widely studied; however, other hypotheses are also gaining support. This article summarizes the recent evidence regarding major pathological hypotheses of AD and their potential interplay, as well as the strengths and weaknesses of each hypothesis and their implications for the development of effective treatments. This could stimulate further studies and promote the development of more effective therapeutic strategies for AD.

Causal Relationships of Ligamentous Injuries in the Knee on Corticospinal Tract Structure: A Mendelian Randomization Analysis.

BACKGROUND: The association between ligamentous knee injuries and corticospinal tract (CST) structure has attracted attention; however, any causal relationship remains uncertain. We performed Mendelian randomization (MR) analysis to identify the causal effects of ligamentous knee injuries on the CST. HYPOTHESIS: Ligamentous knee injuries impair CST microstructure (ie, by reducing fractional anisotropy [FA] and increasing mean diffusivity [MD]). STUDY DESIGN: MR analysis. LEVEL OF EVIDENCE: Level 2. METHODS: MR uses genetic variants as instrumental variables to infer causal relationships between exposures and outcomes. Summary data for ligamentous injuries in knee and CST structure were obtained from genome-wide association study datasets. Significant and independent (5 × 10-6; r2 < 0.001; 10,000 kb) single-nucleotide polymorphisms were extracted for MR analysis. Three methods for MR analysis were used (hypothesis-driven 1-tailed inverse variance weighted, MR-Egger, and weighted median), and sensitivity analyses were conducted to test reliability and stability. RESULTS: Results from 3 MR methods consistently demonstrated that ligamentous knee injuries increased MD of the right CST (ß, 0.063; 90% CI, 0.003-0.123; P = 0.04), and weak statistical significance suggested increased MD of the left CST (ß, 0.060; 90% CI, -0.002 to -0.121; P = 0.05). However, no significant causal relationships were observed in CST FA, and no significant pleiotropy or heterogeneity was observed. Sensitivity analysis utilizing 2-tailed tests had no significant associations between ligamentous knee injuries and changes in CST structure. CONCLUSION: There is statistically weak genetic evidence that corticospinal pathway abnormalities may evolve after ligamentous knee injuries, which manifests as abnormally organized neurites. CLINICAL RELEVANCE: Ligamentous knee injuries require attention not only to damage to the structure of the knee joint itself but also to the process of maladaptive neuroplasticity that leads to structural and functional changes of the CST; novel interventions that target the corticospinal pathway may provide subsequent treatment of ligamentous knee injuries.

Balance Error Scoring System in the assessment of chronic ankle stability: A systematic review and meta-analysis.

OBJECTIVE: Chronic ankle instability (CAI) is a common musculoskeletal injury associated with static balance deficits. The Balance Error Scoring System (BESS) is commonly used to assess static balance in individuals with CAI. However, the sensitivity of BESS in detecting balance deficits in CAI is unknown. This study compared BESS performance between people with CAI and controls and investigated which stances most effectively identified balance deficits in individuals with CAI. LITERATURE SURVEY: Seven electronic databases (Web of Science, CINAHL, Embase, PubMed, Scopus, SPORTDiscus, and Cochrane Library) were searched from July 13, 2023, to September 10, 2023, using the ankle instability and balance related terms as keywords to search original studies and perform a systematic review. METHODS: Studies that compared BESS scores between individuals with CAI and healthy controls were systematically identified. Extracted data included study characteristics, participant demographics, and assessment details. The risk of bias was assessed using the Newcastle-Ottawa Scale. The standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect sizes to compare groups for the BESS components used to assess CAI. RESULTS: Six studies met the eligibility criteria. The double-leg foam stance yielded an SMD of -0.02 (95% CI: -0.32 to 0.29), with an I2 value of 3.5%. Significant differences between groups were noted in the single foam (SMD = 0.89; 95% CI: 0.33-1.45; I2 = 78.3%) and single firm (SMD = 0.62; 95% CI: 0.14-1.10; I2 = 72.1%) performances, although both demonstrated high heterogeneity. Conversely, the tandem foam (SMD = 0.77; 95% CI: 0.51-1.02; I2 = 0.0%) and tandem firm (SMD = 0.38; 95% CI: 0.11-0.68; I2 = 23.8%) performances showed small to moderate between-group differences with considerably lower heterogeneity. CONCLUSION: This review indicates that tandem stances on foam and firm surfaces in the BESS are reliable indicators of static balance deficits in individuals with CAI.

Postural Control Deficits During Static Single-leg Stance in Chronic Ankle Instability: A Systematic Review and Meta-Analysis.

CONTEXT: Postural control deficits arising from injured ankles are central to chronic ankle instability (CAI) and its persistent symptoms. This is usually measured by recording the center of pressure (CoP) trajectory during static single-leg stance using a stable force plate. However, existing studies have produced conflicting results on whether this mode of measurement adequately reveals the postural deficits in CAI. OBJECTIVE: To determine whether postural control during static single-leg stance is impaired in CAI patients when compared with uninjured healthy controls. DATA SOURCES: Literature databases, PubMed, Embase, Web of Science, Cochrane Library, Scopus, CINAHL, and SPORTDiscus, were searched from inception to April 1, 2022, using ankle-, injury-, and posture-related terms. STUDY SELECTION: Two authors independently performed the step-by-step screening of article titles, abstracts, and full texts to select peer-reviewed studies investigating CoP trajectory during static single-leg stance using a stable force plate in CAI patients and healthy controls. A total of 13,637 studies were reviewed, and 38 studies (0.003%) met the selection criteria. STUDY DESIGN: Meta-analyses of descriptive epidemiological study. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: CoP parameters, sway directions, visual condition, and numerical data (means and standard deviations) were extracted. RESULTS: The injured ankles of CAI patients had higher standard deviations of sway amplitude in both anterior-posterior and medial-lateral directions (standardized mean difference [SMD] = 0.36 and 0.31, respectively) under conditions of open eyes than controls. Higher mean sway velocity in anterior-posterior, medial-lateral, and total directions (SMD = 0.41, 0.37, and 0.45, respectively) with closed eyes was also found. CONCLUSION: CAI patients had deficits of postural control during static single-leg stance, and these deficits were identified by the CoP trajectory. Further methodological explorations of CoP parameters and corresponding test conditions are required to enhance the sensitivity and reliability of postural deficit assessments in CAI using force plates.

Association between Neural Plasticity and Pain-Related Fear in Chronic Ankle Instability: A Structural Neuroimaging Study.

CONTEXT: Pain-related movement fear is a contributing factor to residual pain and functional deficits in chronic ankle instability (CAI), but its underlying neural mechanisms remain unclear. OBJECTIVES: We aimed to (1) delineate whether participants with CAI exhibit discernible differences in specific emotion and pain-related brain regions, compared to a healthy control (HC) cohort and (2) explore potential neural mechanisms underlying pain and fear in participants with CAI, with an emphasis on investigating possible associations with pain-related neural plasticity. DESIGN: Cross-sectional study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: 28 participants with CAI (17males and 11 females; age: 31.28±6.31 years) and 28 HCs (16 males and 12 females; age: 30.18±7.59 years). MAIN OUTCOME MEASURE(S): We analyzed T1 structural imaging data from participants and assessed their fear of movement and pain intensity using the Tampa Scale for Kinesiophobia (TSK) and the Visual Analog Scale (VAS) for pain, respectively. We compared the mean gray matter (GM) density of pain-related area between the two groups and their correlations with the TSK and VAS scores. RESULTS: In comparison with the HC group, participants with CAI showed a significant decrease in the mean GM density in the prefrontal cortex (Cohen's d = -0.808) and periaqueductal gray (Cohen's d = -0.934). In participants with CAI, the mean GM density of the prefrontal cortex (PFC) was negatively correlated with the TSK scores (r = -0.531). During intense exercise, the mean GM density of the periaqueductal gray (PAG) was negatively correlated with the VAS scores (r = -0.484). Additionally, TSK scores were positively correlated with VAS scores (r = 0.455). CONCLUSIONS: Our exploratory findings suggest that, in participants with CAI, the atrophy of the PFC and PAG may be associated with pain-related fear. Future clinical diagnosis and treatment for CAI should consider the impact of psychological barriers on functional recovery.

Clinical Features Post Anterior Cruciate Ligament Reconstruction Associated with Structural Alterations in Corticospinal Tract.

CONTEXT: Structural evidence for corticospinal tract (CST) abnormality between patients with ACLR and healthy controls, and the relationships between CST structure and clinical features of the patients (e.g., objective sensorimotor outcomes, postoperative duration) are lacking. OBJECTIVES: To investigate whether the structural features of CST 1) differ between patients with ACLR and healthy controls, and 2) were associated with clinical features in patients following ACLR. DESIGN: Cross-sectional study. SETTING: Sports medicine laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-six patients who had undergone ACLR and twenty-six healthy controls were enrolled in this cross-sectional investigation. MAIN OUTCOME MEASURE(S): Using the CST as the region of interest, we performed diffusion tensor imaging to measure the microstructure of white matter tracts. Between-group comparisons and correlation analyses with clinical features in patients with ACLR were performed. RESULTS: The patients with ACLR showed significant, moderate lower fractional anisotropy (FA, Cohen's d = -0.666, 95% CIs -1.221 to -0.104), lower axial diffusivity (AD, Cohen's d = -0.526, 95% CIs -1.077 to 0.030), and higher radial diffusivity (RD, Cohen's d = 0.514, 95% CIs -0.042 to 1.064) when compared to that of healthy controls, with the RD values being significantly correlated with the postoperative duration (r = 0.623, p < 0.001) after controlling the age, sex, and BMI in patients with ACLR. CONCLUSIONS: This study revealed that patients with ACLR have impaired integrity (lower FA values and higher RD values) in the CST contralateral to the ACLR injured limb in comparison with healthy controls. Decreased integrity (higher RD) of the CST in patients was significantly associated with longer postoperative duration, which hinted that impaired structural integrity of the CST may be a maladaptive process of neuroplasticity in ACLR.

Rehabilitation increases cortical activation during single-leg stance in patients with chronic ankle instability.

Background: Chronic ankle instability (CAI) has been considered a neurophysiological disease, having as symptoms dysfunction in somatosensory and motor system excitability. Rehabilitation has been considered an effective treatment for CAI. However, few studies have explored the effects of rehabilitation on neuroplasticity in the CAI population. Objective: The purpose of this study was to investigate the effects of rehabilitation on cortical activities for postural control in CAI patients and to find the correlation between the change in cortical activities and patient-reported outcomes (PROs). Methods: Thirteen participants with CAI (6 female, 7 male, age = 33.8 ± 7.7 years, BMI = 24.7 ± 4.9 kg/m2) received a home exercise program for about 40 min per day, four days per week and six weeks, including ankle range-of-motion exercise, muscle strengthening, and balance activities. Cortical activation, PROs and Y-balance test outcomes were assessed and compared before and after rehabilitation. Cortical activation was detected via Functional near-infrared spectroscopy (fNIRS) while the participants performed single-leg stance tasks. Results: The participants had better PROs and Y balance test outcomes after rehabilitation. Greater cortical activation was observed in the primary somatosensory cortex (S1, d = 0.66, p = 0.035), the superior temporal gyrus (STG, d = 1.06, p = 0.002) and the middle temporal gyrus (MTG, d = 0.66, p = 0.035) in CAI patients after rehabilitation. Moreover, significant positive correlations were observed between the recovery of ankle symptoms and the change of cortical activation in S1 (r = 0.74, p = 0.005) and STG (r = 0.72, p = 0.007) respectively. Conclusion: The current study reveals that six weeks of rehabilitation can cause greater cortical activation in S1, STG and MTG. This increase in cortical activation suggested a better ability to perceive somatosensory stimuli and may have a compensatory role in function improvement.

Force sense deficits in chronic ankle instability: A systematic review and meta-analysis.

OBJECTIVE: Patients with chronic ankle instability (CAI) may experience ankle force sense deficits due to mechanoreceptor injury and proprioceptive deafferentation in the affected ankles. This study aimed to systematically review the literature and investigate (1) whether patients with CAI have impaired force sense when compared with uninjured contralateral sides or healthy controls, and (2) which characteristics of CAI (e.g., any measurement of CAI symptoms, clinical questionnaires, or functional tests on the injured ankles) are correlated with force sense deficits. TYPE: Systematic review and meta-analysis. LITERATURE SURVEY: PubMed, Embase, Web of Science, Cochrane Library, Scopus, CINAHL, and SPORTDiscus were searched for ankle-related, injury-related, and force sense-related terms from inception to February 2, 2022. METHODOLOGY: The following information was extracted from included articles: demographic data, sample size, selection criteria, methodology, force reproduction test outcomes, and correlations between force sense and other characteristics of CAI. Meta-analyses were conducted for the force sense outcomes, and a narrative review was undertaken for the correlation between force sense deficits and other characteristics of CAI. SYNTHESIS: Eight studies were included. The meta-analyses revealed eversion force sense deficits of the injured ankles in absolute error (magnitude of force reproduction error) at 20% maximal voluntary isometric contractions (MVIC) (standardized mean difference [SMD] = 0.67, 95% confidence interval [CI] 0.23-1.11) and variable error (consistency of force reproduction) at 30% MVIC (SMD = 0.46, 95% CI 0.07-0.85), as compared with healthy controls. None of the included studies reported a significant correlation between these two deficits and other characteristics of CAI. CONCLUSIONS: Patients with CAI have eversion force sense deficits in the magnitude of force reproduction error at 20% MVIC and the consistency of force reproduction at 30% MVIC.

Cortical Activation During Single-Legged Stance in Patients With Chronic Ankle Instability.

CONTEXT: Chronic ankle instability (CAI) has been considered a neurophysiological condition, with dysfunctional somatosensory and motor system excitability. However, few researchers have explored the changes in cortical activation during balance tasks of patients with CAI. OBJECTIVE: To compare the cortical activity during single-legged stance among CAI, copers, and uninjured control participants and to compare dynamic balance across groups. DESIGN: Cross-sectional study. SETTING: Biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 22 participants with CAI (median [interquartile range]; age = 34.5 [11.0] years, height = 170.0 [15.8] cm, mass = 67.0 [16.2] kg), 17 copers (age = 27.0 [14.0] years, height = 170.0 [9.5] cm, mass = 66.5 [16.5] kg), and 21 uninjured control participants (age = 25.0 [10.5] years, height = 170.0 [11.0] cm, mass = 64.0 [16.5] kg). MAIN OUTCOME MEASURE(S): Participants performed single-legged stance while cortical activation was tested with functional near-infrared spectroscopy. The peak oxyhemoglobin response of the activated cortex was calculated and compared across groups. The Y-Balance test outcomes and patient-reported outcomes were assessed and compared across groups. RESULTS: The CAI group had worse Y-balance test and patient-reported outcomes than the coper and uninjured control groups. Differences in the peak oxyhemoglobin response were observed for the primary somatosensory cortex (S1; F2,57 = 4.347, P = .017, ηp2 = 0.132) and superior temporal gyrus (STG; F2,57 = 4.548, P = .015, ηp2 = 0.138). Specifically, copers demonstrated greater activation in S1 and STG than the CAI (d = 0.73, P = .034, and d = 0.69, P = .043, respectively) and uninjured control (d = 0.77, P = .036, and d = 0.88, P = .022, respectively) groups. No differences were found in the cortical activation between CAI and uninjured control participants. CONCLUSIONS: Copers displayed greater cortical activation in S1 and STG than CAI and uninjured control participants. Greater activation in S1 and STG suggested a better ability to perceive somatosensory stimuli and may represent a compensatory mechanism that allows copers to maintain good functional ability after the initial severe ankle sprain.

Do exercise therapies restore the deficits of joint position sense in patients with chronic ankle instability? A systematic review and meta-analysis.

To determine whether existing exercise therapies can restore the joint position sense (JPS) deficits of patients with chronic ankle instability (CAI) when compared with controlled non-training patients. Seven databases were searched using ankle, injury, proprioception, and exercise-therapy-related terms. Peer-reviewed human studies in English that used the absolute errors score of joint position reproduction (JPR) test to compare the JPS of injured ankles in CAI patients before and after exercise therapy and non-training controls were included and analyzed. Demographic information, sample size, description of exercise therapies, methodological details of the JPR test, and absolute error scores were extracted by two researchers independently. Meta-analysis of the differences in JPS changes (i.e., absolute errors after treatment minus the baseline) between the exercise therapies and non-training controls was performed with the weighted mean difference (WMD) and 95% confidence interval (CI). Seven studies were finally included. Meta-analyses revealed significantly higher improvements in passive JPS during inversion with, WMD â€‹= â€‹-1.54° and eversion, of, WMD â€‹= â€‹-1.80°, after exercise therapies when compared with non-training controls. However, no significant changes in the impaired side active JPS were observed with regard to inversion and eversion. Existing exercise therapies may have a positive effect on passive JPS during inversion and eversion, but do not restore the active JPS deficits of injured ankles in patients with CAI when compared with non-training controls. Updated exercise components with a longer duration that focus on active JPS with longer duration are needed to supplement the existing content of exercise therapies.

Neuroplasticity of pain processing and motor control in CAI patients: A UK Biobank study with clinical validation.

Background: Pain plays an important role in chronic ankle instability (CAI), and prolonged pain may be associated with ankle dysfunction and abnormal neuroplasticity. Purpose: To investigate the differences in resting-state functional connectivity among the pain-related brain regions and the ankle motor-related brain regions between healthy controls and patients with CAI, and explore the relationship between patients' motor function and pain. Study design: A cross-database, cross-sectional study. Methods: This study included a UK Biobank dataset of 28 patients with ankle pain and 109 healthy controls and a validation dataset of 15 patients with CAI and 15 healthy controls. All participants underwent resting-state functional magnetic resonance imaging scanning, and the functional connectivity (FC) among the pain-related brain regions and the ankle motor-related brain regions were calculated and compared between groups. The correlations between the potentially different functional connectivity and the clinical questionnaires were also explored in patients with CAI. Results: The functional connection between the cingulate motor area and insula significantly differed between groups in both the UK Biobank (p = 0.005) and clinical validation dataset (p = 0.049), which was also significantly correlated with Tegner scores (r = 0.532, p = 0.041) in patients with CAI. Conclusion: A reduced functional connection between the cingulate motor area and the insula was present in patients with CAI, which was also directly correlated with reduction in the level of patient physical activity.

Longitudinal neuroplasticity after ankle sprain in mice: A voxel-based morphometry study on 11.7T MRI.

Lateral ankle sprains (LAS) might lead to joint sensory deafferentation, which induces maladaptive neuroplasticity, especially the morphological atrophy of the cerebellar vermis. However, longitudinal evidence on the causality of injury and neural differences is still lacking. To this end, this study aimed to determine whether the morphology of the central nervous system would be altered before and after ligament transection in LAS mouse models. A total of 40 C57BL/6 mice were randomly divided among the LAS, Sham and Blank groups. We repeatedly performed the balance beam test and neural voxel-based morphometry (VBM) measurements using an 11.7 T magnetic resonance imaging before and 2 months after the surgery. The results showed that for balance outcomes, the LAS group had a significantly longer time and more slips of the balance beam tests compared with the Sham and Blank groups at 2 months after surgery, with no significant difference among the three groups before surgery. Regarding the VBM analysis, the LAS group showed significantly lower VBM values in the central lobule III of the cerebellar vermis and medial amygdalar nucleus (MEA) compared with the Sham and Blank groups after surgery, with no significant difference among the three groups before surgery. In conclusion, lateral ligament injuries might lead to morphological atrophy of the cerebellar vermis in animal models, which might pave the way for the pathological process of ankle instability after LAS.

Do External Supports Influence Proprioception in Patients With Chronic Ankle Instability?: A Systematic Review and Meta-analyses.

OBJECTIVE: Individuals with chronic ankle instability experience recurring sprains and impaired proprioception, and the effect of external support in the proprioception of injured ankles is still inconsistent in existing studies. Therefore, this study aimed to investigate whether external support could enhance the proprioception of injured ankles in patients with chronic ankle instability. DESIGN: This was a systematic review and meta-analysis. RESULTS: Eight studies from PubMed, Embase, Cochrane Library, Web of Science, SPORTDiscus, Scopus, and CINAHL were finally included after applying the exclusion criteria. Meta-analyses revealed a significantly higher joint position sense on inversion with a weighted mean difference of 1.25 degrees and plantar flexion (weighted mean difference, 1.74 degrees) and lower kinesthesia in eversion (weighted mean difference = -0.70 degrees) with the application of external support in the injured ankles of patients with chronic ankle instability. CONCLUSION: Applying external support has statistically significant negative effects on kinesthesia and a positive effect on the active joint position sense in the injured ankles of patients with chronic ankle instability. However, this study did not support the restoration of proprioception deficits as a mechanism of external support in preventing reinjuries, owing to its potentially negative effect on kinesthesia, clinically small changes in proprioception, and poor methodologic quality of existing studies.

Impaired corticospinal tract in chronic ankle instability: A diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) study at 7.0 Tesla.

OBJECTIVES: Electrophysiological studies have revealed that abnormal function of the corticospinal pathway might contribute to chronic ankle instability, but structural evidence underlying the abnormality is lacking. The purpose of this study was to quantitate microstructural differences between corticospinal tracts in patients with chronic ankle instability and healthy controls. DESIGN: Cross-sectional. METHODS: Seventeen patients with chronic ankle instability and sixteen healthy controls underwent diffusion weighted-imaging scans using an ultra-high-field 7.0 Tesla magnetic resonance imaging scanner. We focused on corticospinal tracts as a region of interest and performed classical diffusion tensor imaging and the advanced neurite orientation dispersion and density imaging outcomes that measured the microstructure of white matter tracts. Correlation analyses were also performed between the significantly different diffusion outcomes in both groups. RESULTS: The patients with chronic ankle instability showed significantly lower fractional anisotropy (p-corrected = 0.045) and higher orientation dispersion index (p-corrected = 0.033) when compared with healthy controls. These two measures were significantly correlated in the healthy controls (r = -0.56, p = 0.024) and the CAI patient group (r = -0.53, p = 0.029). CONCLUSIONS: This study revealed that the contralateral corticospinal tract of the unstable ankle in patients with chronic ankle instability exhibited impaired integrity, which was associated with abnormally organized neurites. We propose that this is a useful target for the clinical assessment of chronic ankle instability and the development of targeted neuromuscular rehabilitation.