Association of Lipoprotein(a) Levels With Myocardial Infarction in Patients With Low-Attenuation Plaque.

BACKGROUND: Lipoprotein(a) (Lp[a]) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association has yet to be fully elucidated. OBJECTIVES: This multicenter study aimed to investigate whether association between Lp(a) and MI risk is reinforced by the presence of low-attenuation plaque (LAP) identified by coronary computed tomography angiography (CCTA). METHODS: In a derivation cohort, a total of 5,607 patients with stable chest pain suspected of coronary artery disease who underwent CCTA and Lp(a) measurement were prospectively enrolled. In validation cohort, 1,122 patients were retrospectively collected during the same period. High Lp(a) was defined as Lp(a) ≥50 mg/dL. The primary endpoint was a composite of time to fatal or nonfatal MI. Associations were estimated using multivariable Cox proportional hazard models. RESULTS: During a median follow-up of 8.2 years (Q1-Q3: 7.2-9.3 years), the elevated Lp(a) levels were associated with MI risk (adjusted HR [aHR]: 1.91; 95% CI: 1.46-2.49; P < 0.001). There was a significant interaction between Lp(a) and LAP (Pinteraction <0.001) in relation to MI risk. When stratified by the presence or absence of LAP, Lp(a) was associated with MI in patients with LAP (aHR: 3.03; 95% CI: 1.92-4.76; P < 0.001). Mediation analysis revealed that LAP mediated 73.3% (P < 0.001) for the relationship between Lp(a) and MI. The principal findings remained unchanged in the validation cohort. CONCLUSIONS: Elevated Lp(a) augmented the risk of MI during 8 years of follow-up, especially in patients with LAP identified by CCTA. The presence of LAP could reinforce the relationship between Lp(a) and future MI occurrence.

Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

BACKGROUND: Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. PURPOSE: To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. STUDY TYPE: Prospective. POPULATION: Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). FIELD STRENGTH/SEQUENCE: 3-T, single-shot echo-planar imaging sequence. ASSESSMENT: Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). STATISTICAL TESTS: Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. RESULTS: mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (ß = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (ß = 5.67, 95% CI 4.56, 6.97), executive function (ß = 2.34, 95% CI 1.49, 3.20), and PSMD (ß = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. DATA CONCLUSION: Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Associations of MRI-visible perivascular spaces with longitudinal cognitive decline across the Alzheimer's disease spectrum.

OBJECTIVE: To investigate the characteristics and associations of MRI-visible perivascular spaces (PVS) with clinical progression and longitudinal cognitive decline across the Alzheimer's disease spectrum. METHODS: We included 1429 participants (641 [44.86%] female) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. PVS number and grade in the centrum semiovale (CSO-PVS), basal ganglia (BG-PVS), and hippocampus (HP-PVS) were compared among the control (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) groups. PVS were tested as predictors of diagnostic progression (i.e., CN to MCI/AD or MCI to AD) and longitudinal changes in the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13), Mini-Mental State Examination (MMSE), memory (ADNI-MEM), and executive function (ADNI-EF) using multiple linear regression, linear mixed-effects, and Cox proportional hazards modeling. RESULTS: Compared with CN subjects, MCI and AD subjects had more CSO-PVS, both in number (p < 0.001) and grade (p < 0.001). However, there was no significant difference in BG-PVS and HP-PVS across the AD spectrum (p > 0.05). Individuals with moderate and frequent/severe CSO-PVS had a higher diagnostic conversion risk than individuals with no/mild CSO-PVS (log-rank p < 0.001 for all) in the combined CN and MCI group. Further Cox regression analyses revealed that moderate and frequent/severe CSO-PVS were associated with a higher risk of diagnostic conversion (HR = 2.007, 95% CI = 1.382-2.914, p < 0.001; HR = 2.676, 95% CI = 1.830-3.911, p < 0.001, respectively). A higher CSO-PVS number was associated with baseline cognitive performance and longitudinal cognitive decline in all cognitive tests (p < 0.05 for all). CONCLUSIONS: CSO-PVS were more common in MCI and AD and were associated with cognitive decline across the AD spectrum.

Enlarged perivascular spaces and white matter hyperintensities in patients with frontotemporal lobar degeneration syndromes.

Objective: The aim of this study was to investigate the distribution characteristics of enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) and their associations with disease severity across the frontotemporal lobar degeneration (FTLD) syndromes spectrum. Methods: This study included 73 controls, 39 progressive supranuclear palsy Richardson's syndrome (PSP-RS), 31 corticobasal syndrome (CBS), 47 behavioral variant frontotemporal dementia (bvFTD), 36 non-fluent variant primary progressive aphasia (nfvPPA), and 50 semantic variant primary progressive aphasia (svPPA). All subjects had brain magnetic resonance imaging (MRI) and neuropsychological tests, including progressive supranuclear palsy rating scale (PSPRS) and FTLD modified clinical dementia rating sum of boxes (FTLD-CDR). EPVS number and grade were rated on MRI in the centrum semiovale (CSO-EPVS), basal ganglia (BG-EPVS), and brain stem (BS-EPVS). Periventricular (PWMH) and deep (DWMH) were also graded on MRI. The distribution characteristics of EPVS and WMH were compared between control and disease groups. Multivariable linear regression analysis was performed to evaluate the association of EPVS and WMH with disease severity. Results: Compared with control subjects, PSP-RS and CBS had more BS-EPVS; CBS, bvFTD, and nfvPPA had less CSO-EPVS; all disease groups except CBS had higher PWMH (p < 0.05). BS-EPVS was associated with PSPRS in PSP-RS (ß = 2.395, 95% CI 0.888-3.901) and CBS (ß = 3.115, 95% CI 1.584-4.647). PWMH was associated with FTLD-CDR in bvFTD (ß = 1.823, 95% CI 0.752-2.895), nfvPPA (ß = 0.971, 95% CI 0.030-1.912), and svPPA (OR: 1.330, 95% CI 0.457-2.204). Conclusion: BS-EPVS could be a promising indicator of disease severity in PSP-RS and CBS, while PWMH could reflect the severity of bvFTD, nfvPPA, and svPPA.

MRI-Visible Perivascular Spaces Associated With Cognitive Impairment in Military Veterans With Traumatic Brain Injury Mediated by CSF P-Tau.

Objective: To investigate the association of MRI-visible perivascular spaces (PVS) with cognitive impairment in military veterans with traumatic brain injury (TBI), and whether cerebrospinal fluid (CSF) p-tau and Aß mediate this effect. Materials and Methods: We included 55 Vietnam War veterans with a history of TBI and 52 non-TBI Vietnam War veterans from the Department of Defense Alzheimer's Disease Neuroimaging Initiative (ADNI) database. All the subjects had brain MRI, CSF p-tau, Aß, and neuropsychological examinations. MRI-visible PVS number and grade were rated on MRI in the centrum semiovale (CSO-PVS) and basal ganglia (BG-PVS). Multiple linear regression was performed to assess the association between MRI-visible PVS and cognitive impairment and the interaction effect of TBI. Additionally, mediation effect of CSF biomarkers on the relationship between MRI-visible PVS and cognitive impairment was explored in TBI group. Results: Compared with military control, TBI group had higher CSO-PVS number (p = 0.001), CSF p-tau (p = 0.022) and poorer performance in verbal memory (p = 0.022). High CSO-PVS number was associated with poor verbal memory in TBI group (ß = -0.039, 95% CI -0.062, -0.016), but not in military control group (ß = 0.019, 95% CI -0.004, 0.043) (p-interaction = 0.003). Further mediation analysis revealed that CSF p-tau had a significant indirect effect (ß = -0.009, 95% CI: -0.022 -0.001, p = 0.001) and mediated 18.75% effect for the relationship between CSO-PVS and verbal memory in TBI group. Conclusion: MRI-visible CSO-PVS was more common in Vietnam War veterans with a history of TBI and was associated with poor verbal memory, mediated partially by CSF p-tau.

Subcortical nuclei in Alzheimer's disease: a volumetric and diffusion kurtosis imaging study.

Background Previous studies revealed that subcortical nuclei were harmed in the process of Alzheimer's disease (AD). Purpose To investigate the volumetric and diffusion kurtosis imaging (DKI) parameter changes of subcortical nuclei in AD and their relationship with cognitive function. Materials and Methods A total of 17 mild AD patients, 15 moderate to severe AD patients, and 16 controls underwent neuropsychological tests and magnetic resonance imaging (MRI) scans. Volume, mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) were measured in hippocampus, thalamus, caudate, putamen, pallidum, and amygdala. MRI parameters were compared. Correlation analysis was performed between subcortical nuclei volume, DKI parameters, and MMSE score. Results Significant volume reduction was seen in the left hippocampus in mild AD, and the bilateral hippocampus, thalamus, putamen, left caudate, and right amygdala in moderate to severe AD ( P < 0.05). Increased MD values were observed in the left hippocampus, left amygdala, and right caudate in mild AD, and the bilateral hippocampus and right amygdala in moderate to severe AD ( P < 0.05). Decreased MK values were observed only in the bilateral hippocampus in moderate to severe AD ( P < 0.05). No group significances were found in FA value. MMSE score was positively correlated with the volume of the bilateral hippocampus, thalamus, and putamen, and MK value of the left hippocampus ( P < 0.05). A negative correlation was found with the MD value of the bilateral hippocampus and left amygdala ( P < 0.05). Conclusion Mild AD mainly has microscopic subcortical changes revealed by increased MD value, and moderate to severe AD mainly has macroscopic subcortical changes revealed by volume reduction. MK is more sensitive in severe AD than mild AD.

Self-reported traumatic brain injury and in vivo measure of AD-vulnerable cortical thickness and AD-related biomarkers in the ADNI cohort.

In this study, we aimed to investigate whether self-reported mild traumatic brain injury (mTBI) was associated with decreased AD-vulnerable cortical thickness, and to assess the relationship between AD-vulnerable cortical thickness and AD-related biomarker in the Alzheimer's Disease Neuroimaging Initiative subjects. We identified 45 self-reported mTBI subjects, who had structural MRI, 18F-AV45 PET, and cerebrospinal fluid (CSF) data. Of them, eight subjects were normal; ten were preclinical AD; seventeen were MCI due to AD; ten were AD. Additional demographics-controlled 45 subjects were included. Cortical thickness of eight AD-vulnerable regions, mean AD-vulnerable cortical thickness, 18F-AV45 PET mean amyloid SUVR, CSF Aß42, CSF total tau (T-tau), and CSF phosphorylated tau (P-tau) were compared between mTBI and non-TBI groups. Correlational analysis was done to investigate the relationship between mean AD-vulnerable cortical thickness and mean amyloid SUVR, CSF Aß42, CSF T-Tau, CSF P-Tau. Our study revealed that preclinical AD subjects with self-reported mTBI had smaller cortical thickness in mean and three AD-vulnerable cortical regions than non-TBI subjects (P<0.05). The mean AD-vulnerable cortical thickness was correlated with CSF T-tau (r=-0.81, P=0.001). There was no statistical difference in the comparison of normal, MCI due to AD, and AD groups. Our study indicated that among individuals with preclinical AD, but not normal, MCI due to AD and AD subjects, self-reported mTBI was associated with more decreased AD-vulnerable cortical thickness which was related to CSF tau pathology, suggesting the possible early involvement of tau pathology in the decreased AD-vulnerable cortical thickness of self-reported TBI subjects.

Inhibition of endoplasmic reticulum stress by neuregulin-1 protects against myocardial ischemia/reperfusion injury.

Neuregulin-1 (NRG-1), an endogenously produced polypeptide, is the ligand of cardiomyocyte ErbB receptors, with cardiovascular protective effects. In the present study, we explored whether the cardioprotective effect of NRG-1 against I/R injury is mediated by inhibiting myocardial endoplasmic reticulum (ER) stress. In vitro, NRG-1 directly inhibited the upregulation of ER stress markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12 induced by the ER stress inducers tunicamycin or dithiothreitol in both neonatal and adult ventricular myocytes. Attenuating ErbB signals by an ErbB inhibitor AG1478 or ErbB4 knockdown and preincubation with phosphoinositide 3-kinase inhibitors all reversed the effect of NRG-1 inhibiting ER stress in cultured neonatal rat cardiomyocytes. Concurrently, cardiomyocyte ER stress and apoptosis induced by hypoxia-reoxygenation were decreased by NRG-1 treatment in vitro. Furthermore, in an in vivo rat model of myocardium ischemia/reperfusion (I/R), intravenous NRG-1 administration significantly decreased ER stress and myocardial infarct size induced by I/R. NRG-1 could protect the heart against I/R injury by inhibiting myocardial ER stress, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.

Angiotensin II Receptor Blockers and Cancer Risk: A Meta-Analysis of Randomized Controlled Trials.

Angiotensin II receptor blockers (ARB) are widely used drugs that are proven to reduce cardiovascular disease events; however, several recent meta-analyses yielded conflicting conclusions regarding the relationship between ARB and cancer incidence, especially when ARB are combined with angiotensin-converting enzyme inhibitors (ACEI).We investigated the risk of cancer associated with ARB at different background ACEI levels.Search of PubMed and EMBASE (1966 to December 17, 2015) without language restriction.Randomized, controlled trials (RCTs) had at least 12 months of follow-up data and reported cancer incidence was included.Study characteristics, quality, and risk of bias were assessed by 2 reviewers independently.Nineteen RCTs including 148,334 patients were included in this study. Random-effects model meta-analyses were used to estimate the risk ratio (RR) of cancer risk. No excessive cancer risk was observed in our analyses of ARB alone versus placebo alone without background ACEI use (risk ratio [RR] 1.08, 95% confidence interval [CI] 1.00-1.18, P = 0.05); ARB alone versus ACEI alone (RR 1.03, 95%CI 0.94-1.14, P = 0.50); ARB plus partial use of ACEI versus placebo plus partial use of ACEI (RR 0.97, 95%CI 0.90-1.04, P = 0.33); and ARB plus ACEI versus ACEI (RR 0.99, 95%CI 0.79-1.24, P = 0.95).Lack of long-term data, inadequate reporting of safety data, significant heterogeneity in underlying study populations, and treatment regimens.ARB have a neutral effect on cancer incidence in randomized trials. We observed no significant differences in cancer incidence when we compared ARB alone with placebo alone, ARB alone with ACEI alone, ARB plus partial use of ACEI with placebo plus partial use of ACEI, or ARB plus ACEI combination with ACEI.

[Intermediate and long-term follow-up evaluation of posterior dynamic lumbar stabilization in lumbar degenerative disease].

OBJECTIVE: To evaluate the intermediate and long-term follow-up effect of posterior dynamic lumbar stabilization in lumbar degenerative disease. METHODS: The clinical outcomes of 96 patients (male 51, female 45, age from 21 to 68 years, mean 41.5 years) whose follow-up time were more than 2 years with lumbar degenerative disease treated by posterior decompression with Wallis posterior dynamic lumbar stabilization implant or combined with posterior lumbar fusion from August 2007 to January 2010 were retrospectively studied, and assessed with visual analogue scale (VAS) and spinal operative standard of Chinese Medical Association. The early and long-term follow-up effect and complications associated with Wallis posterior dynamic lumbar stabilization were recorded. The height of intervertebral space at the treated level in lateral plain film were measured at preoperatively, 3 month postoperatively and last follow-up, respectively. The finds of MRI obtained at over 6 month postoperative were recorded. RESULTS: The operative procedure of Wallis posterior dynamic lumbar stabilization implant was easy and less invasive. The VAS scores were 78 ± 24, 28 ± 16 and 14 ± 12 preoperatively, 3 month postoperatively and last follow-up, respectively. The good or excellent result was 91.7% at the last follow-up. No complication related with Wallis posterior dynamic lumbar stabilization was found. The rate of patient's satisfaction with the Wallis implant operation was 95.8%. The disc height at the treated level in lateral plain film were (8.2 ± 3.7), (10.4 ± 2.6) and (10.1 ± 1.9) mm at preoperatively, 3 month postoperatively and last follow-up, respectively. There is no further degenerative change found in MRI obtained at over 6 month postoperative. MRI 1 year after Wallis procedure showed rehydration of the formerly black disc at the treated level. CONCLUSIONS: It is easy and safe to use Wallis posterior dynamic lumbar stabilization in treatment of degenerative lumbar disease, and the effect of the intermediate and long-term follow-up more than 2 years is good. The Wallis system provides an alternative for treatment of lumbar degenerative disease.