Ventricular Atrophy Research Articles

Baseline Aβ and tau markers contribute to localized patterns of brain tissue atrophy across 1223 individuals from four harmonized longitudinal datasets

AbstractBackgroundAmyloid‐β (Aβ) plaques and tau pathogenesis in the brain precede cognitive decline in the progression of Alzheimer’s dementia, yet the extent to which these measures can predict localized brain tissue atrophy has not been studied in a large, diverse population. Multisite studies offer robust statistical power with larger sample sizes but are confounded by variations in biomarker quantification across studies, including variations in MRI scanners, PET tracers, and CSF assays. Longitudinal data from N=1223 individuals from four independent AD studies were harmonized to assess localized brain tissue atrophy over 2 to 5 years. We tested for associations between volumetric changes and baseline measures of Aβ, phosphorylated tau (p‐tau), and cognitive function. Associations between atrophy and ApoE4 and diagnostic conversion were also assessed.MethodBaseline (BL) and follow‐up (FU; mean=2.3+/‐0.5 years) 3T T1‐weighted brain MRI (T1w) from ADNI3 (N=373), Prevent‐AD (N=213), HABS‐MGH (N=213), and OASIS3 (N=424) were used along with corresponding PET measures obtained from FBB, FBP or PiB tracers, and CSF measures (Figure 1A). Subject‐wise maps of volumetric brain changes were created and warped to a common template for statistical analyses (Figure 1B). Voxel‐wise mixed effects linear regressions were run to test for associations between change in brain volume and Aβ‐42 positivity (CSF / PET), CSF p‐tau‐181 positivity, ApoE4 genotype, Clinical Dementia Rating (CDR), and diagnostic conversion (i.e., cognitively normal vs decline). Fixed effects included BL age, sex, scan time interval, and PET imaging tracer type or CSF processing batch; scan site was a random effect. FDR was used for voxel‐wise multiple comparisons correction.ResultAβ and p‐tau positivity at baseline, and the ApoE4 genotype, were associated with accelerated atrophy in the temporal lobe, medial‐parietal lobe and amygdala (Figure 2). CDR and conversion were associated with ventricular expansion and atrophy in the insula, temporal lobe, hippocampus and amygdala (Figure 3).ConclusionOur multi‐study brain mapping and harmonization approaches showed how baseline PET and CSF based amyloid and tau metrics are predictive of common and localized brain atrophy across multiple studies with diverse data collection protocols and study designs.

Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation.

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity.

Alternative Venous Pathways: A Potential Key Imaging Feature for Early Diagnosis of Sturge-Weber Syndrome Type 1.

Sturge-Weber syndrome (SWS) is a rare congenital disorder characterized by cortical atrophy and calcifications on late-stage imaging. Understanding the evolution of brain lesions is crucial for effective early interventions, yet the timeline remains unclear. We aimed to evaluate early brain MRI findings and their progression longitudinally on follow-up MRI in children diagnosed with SWS. We retrospectively included all children with a confirmed diagnosis of SWS between 2009 and 2023 who had at least 2 available MRIs performed before the age of 2 years. A pediatric radiologist and a pediatric neuroradiologist evaluated all the MRI scans for pial enhancement, choroid plexus enlargement, atrophy, calcifications, a prominent subarachnoid varicose network, transmedullary veins, subependymal veins, and deep extraventricular veins. Descriptive analysis was used for demographic data and brain lesion prevalence. Cumulative incidence curves were used to show the timeline of emerging lesions. K-means clustering was used to categorize the lesions based on their prevalence at 1, 2, 3, 6, 12, 18, and 24 months after birth. Nine patients met the inclusion criteria. Median ages at the first and last MRIs were 35 days (interquartile range [IQR]: 11-123) and 294 days (IQR: 208-465), respectively. The most prevalent lesions at the first MRI were subarachnoid varicose network (88.9%) and transmedullary veins (77.8%), while prevalence of atrophy and calcifications differed most between the first and last MRIs. The results of the elbow method and K-means clustering showed that we can divide SWS lesions into 3 groups based on their timeline of emergence. The first cluster contained subarachnoid varicose network, transmedullary veins, subependymal veins, and choroid plexus enlargement. The second cluster contained deep extraventricular veins, pial enhancement, accelerated myelination, and atrophy. The last cluster contained calcifications. Our findings suggest that dilated venous channels emerge early as a compensatory mechanism, preceding atrophy and calcification. Additionally, these dilated channels precede the appearance of abnormal contrast enhancement of the pia, often termed leptomeningeal angioma. This underscores the importance of early recognition and monitoring of these initial imaging indicators in clinical practice.

Differentiating MCI from depression through verbal memory scores.

The present study aims to assess the differences between major depressive disorder (MDD) and mild cognitive impairment (MCI) in terms of verbal learning profile together with structural changes in the brain on magnetic resonance imaging (MRI) and to reveal predictive factors for MCI. Fifty-six patients with MDD and 31 MCI subjects were assessed using the Turkish Verbal Memory Processes Test (VMPT). Brain MRI was used to evaluate sulcal atrophy (SA), ventricular atrophy, periventricular white matter hyperintensity (WMH), subcortical WMH, basal ganglia infarct, medial temporal lobe atrophy, and infratentorial infarct scores based on the Modified Visual MRI Rating Scale (MVMRS). The symptoms of depression were evaluated with the Beck Depression Inventory in both groups. Demographic factors, VMPT scores, and MVMRS scores between MDD and MCI groups were compared. Also, potential predictors of MCI were analyzed by binary logistic regression analyses. The total scores of VMPT and the scores of VMPT subgroups, including immediate memory, highest learning, total learning, and delayed recall, were significantly higher in the MDD groups compared to MCI patients (Mann-Whitney U, Student's t-test, p < 0.05), indicating that higher scores were associated with better memory. The total MVMRS score and a subgroup of MVMRS, the SA score, were significantly higher in MCI patients compared to the MDD group, suggesting more atrophic changes and a higher burden of infarction in MCI patients. In our statistical analyses, impaired immediate memory (p < 0.001; OR = 6.002; 95% CI: 1.996-18.042), increased SA (p = 0.008; OR = 1.522; 95% CI: 1.118-2.073), and education (p = 0.028; OR = 0.84; 95% CI: 0.719-0.981) were significant predictive values obtained through backward Wald elimination in the binary logistic regression model for detecting MCI. Our findings suggest that VMPT may potentially represent a novel neuropsychiatric test that might be combined with MRI-based morphometric evaluation methods, such as MVMRS.

Myocardial mechanics and cardiac biomarkers in adults with severe anorexia nervosa.

Anorexia nervosa (AN) is associated with left ventricular (LV) atrophy and unexplained sudden death. Myocardial mechanics have not been well studied in adults with AN. Whether LV mass or illness duration, markers of AN severity, correlate with abnormal strain imaging is unknown. We performed a prospective study among patients hospitalized with severe AN (n = 29) [body mass index (BMI) < 14.5 kg/m2] and sex/age-matched controls (n = 16) (BMI > 18.5 kg/m2). LV ejection fraction (LVEF) was calculated via modified-biplane method and LV mass was derived using the truncated ellipsoid formula. Apical 2-, 3-, and 4-chamber images were used to generate regional strain mapping and global longitudinal strain (GLS). N-terminal brain natriuretic peptide (NT-proBNP) levels were measured and linear regression was used to determine independent predictors of strain. Mean LVEF did not differ (65% ± 6.0 vs. 62% ± 4.4, p = 0.06), but LV mass was substantially reduced (61.6 ± 16.8 vs. 97.6 ± 19.1 g, p < .0001). GLS was similar (-20.6 ± 3.8 vs. -20.9 ± 2.8, p = 0.82), however, the basal strain was worse (-18.7 ± 4.8 vs. -21.9 ± 4.1, p = 0.03). Lower LV mass was associated with worsening GLS (r = -0.40, p = 0.003), but not among controls (p = 0.89). Median (IQR) NT-proBNP (pg/ml) was higher in patients with AN [141 (59-257) vs. 35.5 (21-56.5) p = 0.0007]. Both increasing NT-proBNP and illness duration were associated with worsening strain patterns in AN (both p = .001). While LVEF and GLS did not differ, regional strain variation was noted among patients with AN. Elevated NT-proBNP may reflect increased wall tension from LV atrophy. Whether strain heterogeneity can identify patients with AN, at risk for sudden death, requires further study.

Abstract P2072: Chronic Treatment With An Androgen Receptor Antagonist Promotes Maladaptive Structural And Functional Cardiac Remodeling In Aging Male Mice

Testosterone levels decrease with age in men, while the risk for cardiovascular diseases (CVD) increases dramatically. Indeed, low circulating testosterone levels in men are associated with diseases such as heart failure. Testosterone exerts its effects via androgen receptors, which are even present in the heart. In addition, androgen receptor antagonists are used to treat prostate cancer in older men who may also have CVD. We investigated the effects of the androgen receptor antagonist flutamide on cardiac structure and function in aged mice. Twenty-month-old male C57BL/6 mice were treated with flutamide for 90 days (slow-release pellet implant; ~20mg/kg/day). In-vivo heart structure/function was assessed using echocardiography and then hearts were Langendorff-perfused to assess load-independent ventricular function ex-vivo . Androgen receptor blockade via flutamide caused maladaptive ventricular remodeling. In-vivo studies showed that flutamide-treated mouse hearts had smaller left ventricular inner diameters when compared to vehicle-treated mice ( e.g. , diastolic: 4.7 ± 0.1 vs. 4.4 ± 0.1 mm; p=0.01; n=8,7). Flutamide also caused left ventricular (LV) atrophy with thinner posterior walls (0.91 ± 0.07 vs. 0.74 ± 0.04 mm; p=0.05) and reduced LV mass when compared to vehicle controls (140 ± 12 vs. 105 ± 6 mg; p=0.03). Ex-vivo functional assessment showed a marked reduction in LV developed pressure in the flutamide-treated mice (111 ± 11 vs. 71 ± 3 mmHg; p&lt;0.01). These mice also had significantly slower rates of LV pressure rise (+dP/dT=2219 ± 263 vs. 1406 ± 95 mmHg/s; p&lt;0.01) as well as LV pressure decay (-dP/dT=-1975 ± 263 vs. -1327 ± 132 mmHg/s; p=0.04). This indicates that flutamide-treated mice had defects in both systolic and diastolic cardiac function. These results demonstrate that suppressing the effects of testosterone by blocking androgen receptors promotes maladaptive structural remodeling of the left ventricle and promotes systolic and diastolic dysfunction in hearts from aged male mice. This study suggests that chronic treatment with androgen receptor antagonists may induce cardiac dysfunction in older men, which has implications for individuals taking these medications for prostate cancer treatment.

Dissecting the role of H-2D bclass I molecule in the development of brain atrophy during Theiler’s murine encephalomyelitis virus (TMEV) infection

Abstract Brain atrophy is a common feature of many neurological diseases as diverse as Alzheimer’s disease, cerebral palsy, Huntington’s disease, multiple sclerosis, epilepsy, encephalitis, neurosyphilis, neuroAIDS, and Covid-19 infection. We have developed a murine model of brain atrophy using the Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis. In this study, we investigated the contribution of the MHC class I molecule, H-2Db, in generating an immune response associated with the onset of brain atrophy using mice with a C57BL/6 background. The H-2D bClass I molecule not only contributed to significantly more ventricular enlargement in a T2-weighted MRI at 45 d.p.i., but this ventricular enlargement correlated to CD8 T cell infiltration. To further define the cellular and molecular mechanisms of MHC class I molecules in TMEV induced brain atrophy we investigated the cell specific contribution of brain resident antigen presenting cells (APCs) in ventricular atrophy. We developed novel bi-transgenic mouse lines with tamoxifen induced conditional ablation of the H-2Db class I molecule in Cx3CR1+ brain resident myeloid cells. Cx3CR1cre+/Db Lox P mice presented with significantly less ventricular atrophy at 45 d.p.i., compared to cre- littermates along with a decrease in CD8 T cell infiltration. These results strongly imply that antigen presentation by H-2Db on myeloid cells, at least in part is responsible for the development of brain atrophy and provided insight into the molecular mechanism of this poorly understood neuropathology. NS103212, NS122174

Electrocardiogram properties and risk of covert brain infarction and other magnetic resonance imaging abnormalities in a stroke-free population.

This study aimed to investigate the association between electrocardiogram (ECG) abnormalities and silent vascular brain injury as defined by cerebral magnetic resonance imaging (MRI) in a stroke-free community-based population. A total of 5888 participants were studied from the Cardiovascular Health Study (CHS), a prospective cohort of community-living older adults. Standard 12-lead ECGs measured prior to MRI scan were used. MRI scans were conducted at years 4-6 and 10-11. The primary outcome was presence of incident covert brain infarcts (CBIs) on the 2nd MRI examination, excluding previous CBIs and stroke occurrence. Secondary outcomes included white matter, ventricular, and sulcal atrophy on the 1st MRI. Logistic and multiple linear regression models were used to assess the relationship between ECG findings and silent vascular brain injury. Left axis deviation before MRI scan was related to presence of incident CBIs (odds ratio [OR]: 1.45; 95% CI: 1.01-2.08, p=.047). A long QT interval was associated with severe white matter hyperintensity (OR: 1.36; 95% CI: 1.04-1.77, p=.024). Minor Q and QS waves with ST-T abnormalities were positively related to sulcal atrophy (β: 0.43, 95% CI: 0.06-0.81, p=.023). Our study found that ECG abnormalities were related to presence of CBIs, white matter hyperintensity, and sulcal atrophy on MRI in a stroke-free relderly population. Specifically, those with left axis deviation had an increased risk of presence of CBIs.

Interrater reliability of modified visual mrı rating scale assessing atrophy and white matter changes.

<p>Cortical atrophy and white matter changes are common findings on magnetic resonance imaging among elderly. Several visual scales have been proposed to evaluate these changes using neuroimaging. We have recently proposed a scale (Modified Visual Magnetic Resonance Rating Scale) recently which allows us to evaluate atrophy, white matter hyperintensities, basal ganglia and infratentorial infarcts together. Our aim in this study was to evaluate the interrater reliability of magnetic resonance visual assessment using this scale between two neurologists and a radiologist.&nbsp;</p>. <p>Randomly selected 30 patients in different ages who underwent brain magnetic resonance imaging between January 2014 and March 2015 were included. Axial T1, coronal T2, and axial FLAIR sequences were visually scored by two neurologists and one radiologist separately. Sulcal, ventricular and medial temporal lobe atrophy, periventricular and subcortical white matter hyperintensities, basal ganglia and infratentorial infarcts were graded according to our scale. The interrater reliability and internal consistency analysis were evaluated by using intraclass correlation coefficient and Cronbach&rsquo;s alpha tests.&nbsp;</p>. <p>The interrater agreements vary between good to excellent. The interrater correlations are moderate to excellent. Interrater correlations were excellent between two neurologists, especially on ventricular atrophy, medial temporal atrophy, basal ganglia infarcts, infratentorial infarcts. When assessing ventricular atrophy, interrater correlations between individual raters were higher than sulcal atrophy. We found good correlations between neurologists and radiologist, and excellent correlations between the two neurologists for medial temporal atrophy. We found excellent interrater correlations between neurologists and radiologist for white matter hyperintensities.</p>. <p>Our scale is a reliable tool assessing both atrophy and white matter hyperintensities with a good interrater reliability. Ventricular atrophy seems to be a more reliable marker than sulcal atrophy when assessing the atrophy on neuroimaging of a patient with memory decline. We think that the total score of the scale will also guide us in clinical practice.</p>.

Thyroid-stimulating hormone regulates cardiac function through modulating HCN2 via targeting microRNA-1a.

Previous studies have found microRNA-1 (miR-1) and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) may be involved in the pathogenesis of thyroid hormone (TH) induced cardiac hypertrophy. However, little is known about the role of miR-1 and HCN2 in thyroid stimulation hormone (TSH)-induced cardiac dysfunction. In order to investigate the molecular mechanisms of TSH induced cardiac dysfunction and the role of miR-1/HCN2 in that process, we evaluated the expression of miR-1a/HCN2 in the ventricular myocardium of hypothyroid mice and in TSH-stimulated H9c2 cardiomyocytes. Our data revealed that hypothyroidism mice had smaller hearts, ventricular muscle atrophy, and cardiac contractile dysfunction compared with euthyroid controls. The upregulation of miR-1a and downregulation of HCN2 were found in ventricular myocardium of hypothyroid mice and TSH-stimulated H9c2 cardiomyocytes, indicating that miR-1a and HCN2 may be involved in TSH-induced cardiac dysfunction. We also found that the regulation of miR-1a and HCN2 expression and HCN2 channel activity by TSH requires TSHR, while the regulation of HCN2 expression and HCN2 channel function by TSH requires miR-1a. Thus, our data revealed the potential mechanism of TSH-induced cardiac dysfunction and might shed new light on the pathological role of miR-1a/HCN2 in hypothyroid heart disease.

Exercise Training Preserves Myocardial Strain and Improves Exercise Tolerance in Doxorubicin-Induced Cardiotoxicity.

Doxorubicin causes cardiotoxicity and exercise intolerance. Pre-conditioning exercise training seems to prevent doxorubicin-induced cardiac damage. However, the effectiveness of the cardioprotective effects of exercise training concomitantly with doxorubicin treatment remains largely unknown. To determine whether low-to-moderate intensity aerobic exercise training during doxorubicin treatment would prevent cardiotoxicity and exercise intolerance, we performed exercise training concomitantly with chronic doxorubicin treatment in mice. Ventricular structure and function were accessed by echocardiography, exercise tolerance by maximal exercise test, and cardiac biology by histological and molecular techniques. Doxorubicin-induced cardiotoxicity, evidenced by impaired ventricular function, cardiac atrophy, and fibrosis. Exercise training did not preserve left ventricular ejection fraction or reduced fibrosis. However, exercise training preserved myocardial circumferential strain alleviated cardiac atrophy and restored cardiomyocyte cross-sectional area. On the other hand, exercise training exacerbated doxorubicin-induced body wasting without affecting survival. Finally, exercise training blunted doxorubicin-induced exercise intolerance. Exercise training performed during doxorubicin-based chemotherapy can be a valuable approach to attenuate cardiotoxicity.

Abstract 15784: Left Ventricular Structural Remodeling and Cardiomyopathy in Duchenne Muscular Dystrophy Carriers

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder. DMD-associated cardiomyopathy is the primary mode of premature death in the majority of male DMD patients, but the prevalence of cardiomyopathy and its clinical significance in female DMD carriers is less well characterized. Hypothesis: We hypothesized that a significant proportion of DMD carriers develop maladaptive left ventricular (LV) structural remodeling and cardiomyopathy over time. Methods: A cross-sectional study was undertaken comparing cardiac magnetic resonance imaging (cMRI) and cardiopulmonary stress test (CPX) parameters between DMD carriers and healthy age- and sex-matched controls from the Dallas Heart Study (DHS). Demographic data, cMRI parameters, and CPX parameters were collected retrospectively on 30 consecutive DMD carriers and 26 control DHS subjects. Results: Overall, DMD carriers had a significantly lower LVEF compared to DHS controls (58+8% vs 70+7%, p&lt; 0.0001). The overall prevalence of reduced LVEF in DMD carriers (defined as LVEF &lt;60%) was 63% compared to 8% in DHS controls. The volumetric variables indexed to body surface area (LVEDVi and LVESVi) were significantly higher in DMD carriers compared to control subjects (72+14 ml/m 2 vs 58+7, p&lt; 0.0001; 31+10 ml/m 2 vs 17+5, p&lt; 0.0001; respectively). LV concentricity was also significantly lower among all DMD carriers compared to DHS controls (3.10+0.65 g/mL 0.67 vs 3.73+0.79, p =0.002). LV concentricity was significantly lower in DMD carriers with reduced EF compared to controls (3.09+0.51 g/mL 0.67 vs 3.73+0.79, p = 0.012), while DMD carriers with preserved EF also had reduced concentricity compared to controls (3.12+0.86 vs 3.73+0.79, p = 0.054). Finally, peak VO 2 was lower in DMD carriers compared to DHS controls (23+6 ml/kg/min vs 25+4, p =0.076), though this difference did not reach statistical significance. Conclusions: Collectively, the data suggest that middle-aged female DMD carriers are at greater risk of developing left ventricular systolic dysfunction and cardiomyopathy associated with decreased exercise capacity. A possible mechanism driving the development of this cardiomyopathy is progressive, maladaptive left ventricular dilatation and cardiac atrophy.

Modified Visual Magnetic Resonance Scale and Neuropsychometric Corelations in Alzheimer's disease

Amaç: Alzheimer hastalığı (AH) araştırmaları için daha ileri nörogörüntüleme teknikleri geliştirilmiş olsa da, yapısal manyetik rezonans görüntüleme (MRG) AH’nin klinik tanısında önemini korumaktadır. Birçok parametreyi değerlendiren kapsamlı görsel MRG derecelendirme ölçeklerinin, hastalığın kognitif ve davranışsal görünümleriyle ilişkisi yeterince araştırılmamıştır. Bu çalışmada, Modifiye Görsel Manyetik Rezonans Derecelendirme Skalası’nın (MGMRDS) 7 alt bölümünün, AH tanısı almış hastaların demografik, kognitif ve davranışsal verileri ile korelasyonunu değerlendirmek amaçlanmıştır. Gereç ve Yöntemler: Retrospektif çalışmamıza beyin MRG ve nöropsikometrik test (NPT) verileri olan, Ruhsal Bozuklukların Tanısal ve Sayımsal Elkitabı (DSM-IV-TR) ölçütleri ile Ulusal Nörolojik ve İletişimsel Bozukluklar ve İnme Enstitüsü &amp;amp; Alzheimer Hastalığı ve İlişkili Bozukluklar Derneği (NINCDS–ADRDA) kriterleri temelinde AH tanısı almış, 50 yaş ve üzeri toplam 42 hasta dahil edildi. Beyin MRG verileri, hasta yaş, cinsiyet ve tanı verilerine kör bir nöroradyolog tarafından MGMRDS kullanılarak değerlendirildi. MGMRDS verilerinin kognitif ve davranışsal test sonuçlarıyla korelasyonu incelendi. Bulgular: Hastaların %61,9’u kadın, yaş ortalaması 75,19±9,26 (53–92) yıl idi. Ortalama eğitim süresi 5,02±4,84 (0–15) yıl, ortalama hastalık süresi 4,52±2,94 yıldı. Ortalama Mini Mental Durum Testi skoru 18,51±5,43 (4–30) iken, ortalama Klinik Demans Derecelendirmesi (KDD) skoru 1,07±0,42 (0,5–2,0) idi. Sulkal atrofi puanları uzun süreli hatırlama ve yüz tanıma ile negatif korele idi; ventriküler atrofi skorları ise öğrenme puanları, meyve–insan ve yüz tanıma değişkenleri ile ters korelasyon gösterdi. Anlık hatırlama, öğrenme puanı, kendiliğinden hatırlama, meyve–insan ve KDD değişkenleri ile mediyal temporal atrofi değişkeni arasında anlamlı ilişki gözlendi. Tartışma ve Sonuç: Beyin MRG’ye dayalı görsel derecelendirme skalaları kullanmak, demans değerlendirmelerinde tanıyı doğrulayıcı, ucuz ve pratik bir yaklaşımdır. MGMRDS, kognitif (yürütücü işlevler, bellek, dikkat, dil) verilerle de anlamlı korelasyon göstermektedir. Bu ölçeği daha geniş hasta gruplarında değişik kognitif bozukluklarda değerlendirecek çalışmalar klinik açıdan faydalı olacaktır.

Mitigation of Late Cardiac Toxicity following Radiotherapy through Abrogation of cGAS/STING-dependent Interferon (IFN)

The pathogenesis of radiation (XRT) induced cardiac toxicity remains poorly understood. We sought to identify the molecular mechanisms of late cardiac toxicity using a mouse model with goal of elucidating potential therapeutic targets. Protocols were approved by our institution’s animal care and use committee. Cardiac XRT was delivered to adult wild type C57BL/6 mice aged 8-12 weeks via a precision small animal irradiator (X-Rad 225Cx). Principal cardiac tissues were acutely harvested and enzymatically isolated into cell type specific populations and analyzed by RNAseq and quantitative RT-PCR. Subsequent studies were carried out using Cgas-/-, Tmem173-/-, Ifnar-/-, and Mavs-/- strains (Jackson Laboratories). Acutely harvested heart tissues following survival studies were examined by histopathologic evaluation. Statistical analyses were carried out using t-test with multiple comparison adjustment where appropriate, and log-rank method for survival analysis. RNAseq analysis of cardiac fibroblasts, myocytes and endothelium after cardiac XRT with 12 Gy revealed strong activation of Irf7, an interferon activating transcription factor, in fibroblasts (p < 10-78) and to a lesser degree in myocytes one month after XRT, but not in endothelial cells. GSEA analysis of all upregulated genes 28 days after XRT revealed enrichment for multiple Ifn transcription factors in fibroblasts (p < 10-21), but not in endothelium. Because radiation might elicit specific damage associated molecular pattern (DAMP) signaling, we hypothesized that this Ifn signaling resulted from cGAS/STING activation following DNA damage. Indeed, RT-PCR for Irf7 in cardiac fibroblasts from wild-type and Mavs-/- (which are deficient in RNA mediated DAMP recognition) mice showed strong activation (p < 0.001 compared to sham XRT), but Cgas-/- animals lacked this response (p = NS compared to sham XRT, p < 0.001 compared to wild-type and Mavs-/- after XRT). Cgas-/- (HR = 0.40, p = 0.034) and Tmem173-/- (HR = 0.15, p = 0.002) animals had significantly improved survival after cardiac XRT as compared to wild-type mice, while Ifnar-/- animals showed a trend for improvement as well (HR = 0.47, p = 0.094). Histopathologic analysis of cardiac tissues at time of death revealed consistent widespread atrial and ventricular mural thrombus formation and cardiomyocyte atrophy in irradiated wild-type animals, but markedly reduced in Tmem173-/- counterparts. Our system establishes a contemporary, genetically defined mouse model of XRT-induced cardiac toxicity. In doing so, we find cardiac irradiation elicits cGAS/STING- (and not MAVS-) dependent, delayed, chronic interferon activation in cardiac fibroblasts. Eliminating this signaling rescues radiation induced cardiac toxicity and improves survival. Inhibitors the cGAS/STING pathway are soon to begin early stage clinical trials and may be candidate drugs for mitigation of late cardiac toxicity following radiotherapy.

Idiopathic normal pressure hydrocephalus and Alzheimer's disease in clinical practice: comorbidity and differentiation

The idiopathic normal pressure hydrocephalus (Hakim – Adams syndrome) is characterized by the expansion of cerebrospinal cavities, which is clinically manifested by triad symptoms: cognitive impairment, impaired gait and urination. In this research the severity and modality of cognitive impairment, the pattern of gait changes and the levels of protein biomarkers of amyloidosis and neurodegeneration and neuroimaging changes was evaluated for idiopathic normal pressure hydrocephalus, Alzheimer's disease and their combination. It has been established that for patients with idiopathic normal pressure hydrocephalus the most characteristic is the dysregulatory type of disorders of higher brain functions, while for patients with a combination of Alzheimer's disease and idiopathic normal pressure hydrocephalus, mnemonic disorders are also detected. The specific changes of cerebrospinal fluid in patients with idiopathic normal pressure hydrocephalus are higher levels of amyloid beta, a decrease concentration of tau and phosphorylated tau-protein compared to patients with Alzheimer's disease. In the case of a combination of diseases (comorbidity), it was characterized by intermediate results by cerebrospinal fluid biomarkers. We also revealed patterns of transformation of moderate cognitive impairment into dementia (according to the ratio of tau/Aβ‑42 and ftau /Aβ‑42). The value of evaluating the results of magnetic resonance imaging using special techniques that evaluate both the expansion of the ventricular system and atrophy of the brain parenchyma. Comorbid patients are characterized by a combination of these processes based on the results of neuroimaging. That is why it is necessary to use complex visually analog neuroimaging scales for differential diagnosis and establishing diagnosis. Also, in the course of this work, an algorithm is proposed for mandatory clinical-neuropsychological and laboratory-instrumental examination of patients with cognitive impairment in idiopathic normal pressure hydrocephalus, Alzheimer's disease and their combination.

An analysis of the clinical and imaging features of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

Objective: To investigate the clinical features and imaging characteristics of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).Methods: Seventeen patients with MELAS diagnosed in the Affiliated Hospital of Xuzhou Medical University from July 2014 to August 2018 were enrolled in this study and their clinical manifestations, imaging and histopathological features were retrospectively analysed. We also discussed and summarised the related literature.Results: All of the 12 patients had seizures; stroke-like episodes in 12 cases; audio-visual impairment in 12 cases; headache in six cases; dysplasia in four cases; mental retardation in three cases; ataxia in two cases. On cranial magnetic resonance (MR) scans, the most common manifestations were in temporal–occipital–parietal lobe, cortical or subcortical areas as well as frontal lobe, thalamus, and basal ganglia showing long or equal T1 signals, long T2 signals, and hyperintense or iso-intense diffusion-weighted imaging (DWI) signals accompanied by ventricular enlargement and brain atrophy. MR spectroscopy showed that lactic acid peaks could be found in lesion sites, normal brain tissues, and cerebrospinal fluid. Muscle biopsy and genetic testing are the gold standard for diagnosing MELAS, muscle biopsy revealed COX-negative muscle fibres and SDH-stained red ragged fibres (RRF) under the sarcolemma. Mutations of mtDNA A3243G locus were common on gene testing. Improvement of mitochondrial function was observed after symptomatic and supportive treatment.Conclusion: MELAS should be considered for patients with epileptic seizures, headache, stroke-like episodes, extraocular palsy, cognitive decline and other clinical manifestations with the lesion located in the temporal–occipital–parietal lobe regardless of the distribution of blood vessels, and further examinations including muscle biopsy and gene testing should be performed to confirm the diagnosis.

Heterotopic Heart Transplantation as a Left Ventricular Biological Assistance: a New Two-Stage Method Proposal.

Since Barnard’s first heterotopic heart transplant in 1974, Copeland’s method has been the greatest contribution to heterotopic transplants but has the drawback of donor’s right ventricular atrophy. This new method proposes a modification in the anastomosis of the superior vena cava aiming to pre-serve donor’s right ventricular function by decompressing the pulmonary territory and reducing the pulmonary arterial pressure, as a biological ventricular assist device. Finally, a second intervention is proposed, where a “twist” is performed to place the donor’s heart in an orthotopic position after re-moval of the native heart. A pioneering research on this method received approval from the ethics committee of the Heart Institute of São Paulo. We believe that this method has the potential to im-prove quality of life in a selected group of patients.

Association of brain white matter lesions and atrophy with cognitive function in chronic kidney disease.

Cognitive impairment is common in patients with chronic kidney disease (CKD), possibly leading to poor outcomes. However, the correlation between brain structural abnormalities and cognitive impairment remains unclear. The aim of this study was to investigate the impairment of specific cognitive domains and their association with brain structural abnormalities. Patients with CKD of at least stage 3 who were not on hemodialysis were enrolled. All participants underwent comprehensive neuropsychological testing in five cognitive domains. Ventricular atrophy, sulcal atrophy, medial temporal atrophy, and white matter changes were assessed using brain magnetic resonance imaging according to standard protocols. Eighty-seven patients and 50 controls were enrolled. Patients with CKD exhibited decreased cognitive function relative to controls. Compared with patients with stage 3 CKD, those with advanced stage (stages 4 or 5) had poorer cognitive performance, more pronounced white matter hyperintensity (WMH) and more severe ventricular atrophy. Among CKD patients, executive function (β = -.23, P = .043) and attention (β = -.29, P = .004) were associated with WMH in controlled analyses. However, no cognitive impairment was associated with ventricular atrophy. Patients with CKD exhibited cognitive impairment and brain structural abnormalities including WMH and general brain atrophy. Impairment of attention and executive dysfunction were associated with WMH.

Effects of adjunct testosterone on cardiac morphology and function in advanced cancers: an ancillary analysis of a randomized controlled trial

BackgroundAdjunct testosterone therapy improves lean body mass, quality of life, and physical activity in patients with advanced cancers; however, the effects of testosterone on cardiac morphology and function are unknown. Accordingly, as an ancillary analysis of a randomized, placebo-controlled trial investigating the efficacy of testosterone supplementation on body composition in men and women with advanced cancers, we explored whether testosterone supplementation could prevent or reverse left ventricular (LV) atrophy and dysfunction.MethodsMen and women recently diagnosed with late stage (≥IIB) or recurrent head and neck or cervical cancer who were scheduled to receive standard of care chemotherapy or concurrent chemoradiation were administered an adjunct 7 week treatment of weekly intramuscular injections of either 100 mg testosterone (T, n = 1 M/5F) or placebo (P, n = 6 M/4F) in a double-blinded randomized fashion. LV morphology (wall thickness), systolic function (ejection fraction, EF), diastolic function (E/A; E’/E), arterial elastance (Ea), end-systolic elastance (Ees), and ventricular-arterial coupling (Ea/Ees) were assessed.ResultsNo significant differences were observed in LV posterior wall thickness in placebo (pre: 1.10 ± 0.1 cm; post: 1.16 ± 0.2 cm; p = 0.11) or testosterone groups (pre: 0.99 ± 0.1 cm; post: 1.14 ± 0.20 cm; p = 0.22). Compared with placebo, testosterone significantly improved LVEF (placebo: − 1.8 ± 4.3%; testosterone: + 6.2 ± 4.3%; p < 0.05), Ea (placebo: 0.0 ± 0.2 mmHg/mL; testosterone: − 0.3 ± 0.2 mmHg/mL; p < 0.05), and Ea/Ees (placebo: 0.0 ± 0.1; testosterone: − 0.2 ± 0.1; p < 0.05).ConclusionsIn patients with advanced cancers, testosterone was associated with favorable changes in left ventricular systolic function, arterial elastance, and ventricular-arterial coupling. Given the small sample size, the promising multisystem benefits of testosterone warrants further evaluation in a definitive randomized trial.Trial registrationThis study was prospectively registered on ClinicalTrials.gov (NCT00878995; date of registration: April 9, 2009).

Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study.

Centenarian studies are important sources for understanding of factors that contribute to longevity and healthy aging. Clinico-neuropathological finding is a key in identifying pathology and factors contributing to age-related cognitive decline and dementia in the oldest old. To characterize the cross-sectional relationship between neuropathologies and measures of premortem cognitive performance in centenarians. Data were acquired from 49 centenarians (≥98 years) from the Georgia Centenarian Study. Cognitive assessment from the time point closest to mortality was used (<1 year for all subjects) and scores for cognitive domains were established. Neuropathologies [cerebral atrophy, ventricular dilation, atherosclerosis, cerebral amyloid angiopathy (CAA), Lewy bodies, hippocampal sclerosis (HS), hippocampal TDP-43 proteinopathy, neuritic plaque (NP) and neurofibrillary tangle (NFT) counts, Braak staging, and National Institute on Aging-Reagan Institute (NIARI) criteria for the neuropathological diagnosis of Alzheimer's disease (AD)] were compared among subjects with different ratings of dementia. Linear regression was applied to evaluate the association between cognitive domain scores and neuropathologies. Wide ranges of AD-type neuropathological changes were observed in both non-demented and demented subjects. Neocortical NFT and Braak staging were related to clinical dementia rating. Neocortical NFT and NP, Braak and NIARI staging, cerebral and ventricular atrophy, HS, CAA, and TDP-43 proteinopathy were differentially associated with poor performance in multiple cognitive domains and activities of daily living. AD-type pathology was associated with severe dementia and poor cognition but was not the only variable that explained cognitive impairment, indicating the complexity and heterogeneity of pathophysiology of dementia in the oldest old.