Alexander disease is most commonly associated with macrocephaly and, on MRI, a leukoencephalopathy with frontal preponderance. The disease is caused by mutation of the GFAP gene. Clinical and MRI ...phenotypic variation have been increasingly recognized.
The authors studied seven patients with Alexander disease, diagnosed based on mutations in the GFAP gene, who presented unusual MRI findings. The authors reviewed clinical history, MRI abnormalities, and GFAP mutations.
All patients had juvenile disease onset with signs of brainstem or spinal cord dysfunction. None of the patients had a macrocephaly. The MRI abnormalities were dominated by medulla and spinal cord abnormalities, either signal abnormalities or atrophy. One patient had only minor cerebral white matter abnormalities. A peculiar finding was the presence of a kind of garland along the ventricular wall in four patients. Three patients had an unusual GFAP mutation, one of which was a duplication mutation of two amino acids, and one an insertion deletion.
Signal abnormalities or atrophy of the medulla or spinal cord on MRI are sufficient to warrant DNA analysis for Alexander disease. Ventricular garlands constitute a new sign of the disease. Unusual phenotypes of Alexander disease are found among patients with late onset and protracted disease course.
Quantitative MR imaging techniques may improve the pathologic specificity of MR imaging regarding white matter abnormalities. Our purposes were to determine whether ADC, FA, MTR, and MRS metabolites ...correlate with the degree of white matter damage in patients with X-ALD; whether differences in ADC, FA, and MTR observed in vivo are retained in fresh and formalin-fixed postmortem brain tissue; and whether the differences predict histopathology.
MRS metabolites, MTR, ADC, and FA, were determined in 7 patients with X-ALD in 3 white matter areas (NAWM, active demyelination, and complete demyelination) and were compared with values obtained in 14 controls. MTR, ADC, and FA were assessed in postmortem brains from 15 patients with X-ALD and 5 controls. Values were correlated with the degree of astrogliosis and density of myelin, axons, and cells. Equations to estimate histopathology from MR imaging parameters were calculated by linear regression analysis.
MRS showed increased mIns, Lac, and Cho and decreased tNAA in living patients with X-ALD; the values depended on the degree of demyelination. MTR, ADC, and FA values were different in postmortem than in vivo white matter, but differences related to degrees of white matter damage were retained. ADC was high and FA and MTR were low in abnormal white matter. Correlations between histopathologic findings and MR imaging parameters were strong. A combination of ADC and FA predicted pathologic parameters best.
Changes in quantitative MR imaging parameters, present in living patients and related to the severity of white matter pathology, are retained in postmortem brain tissue. MR imaging parameters predict white matter histopathologic parameters.
Human values—life goals—guide our attitudes and actions. Brands such as Patagonia, TOMS, Warby Parker, Chobani, and Nike successfully position their marketing around human values such as safety, ...harmony, seeking pleasure, or social welfare. Evidently, consumers attach importance to brands whose values align with their own values. However, the alignment of values (value congruence) and the resulting effects on (re)purchasing behavior are scarcely discussed in the marketing literature. The effects of “traits” and “functional congruence” on purchasing behavior receive considerably more attention. Since human values are conceptually distinct from personality traits, the following question is posed: What is the role of value congruence in the process of consumer brand selection compared with that of trait and functional congruence. An online survey (
N
= 1182) is conducted to study the effects of these different types of congruence on re-purchase intentions for a range of product categories. Multiple regression and mediation analyses reveal that value congruence is a significant predictor of re-purchase intentions and that it is more important than trait congruence for the categories of services and durables, but not for consumables. This study offers insights into when brand marketing should be aligned with personality traits and human values, respectively.
Arrhythmogenic cardiomyopathy (ACM) is a progressive inheritable disease which is characterized by a gradual fibro-(fatty) replacement of the myocardium. Visualization of diffuse and patchy fibrosis ...patterns is challenging using clinically applied cardiac imaging modalities (e.g., late gadolinium enhancement, LGE). During collagen synthesis and breakdown, carboxy-peptides are released into the bloodstream, specifically procollagen type-I carboxy-terminal propeptides (PICP) and collagen type-I carboxy-terminal telopeptides (ICTP). We collected the serum and EDTA blood samples and clinical data of 45 ACM patients (age 50.11 ± 15.53 years, 44% female), divided into 35 diagnosed ACM patients with a 2010 ARVC Task Force Criteria score (TFC) ≥ 4, and 10 preclinical variant carriers with a TFC < 4. PICP levels were measured using an enzyme-linked immune sorbent assay and ICTP levels with a radio immunoassay. Increased PICP/ICTP ratios suggest a higher collagen deposition. We found significantly higher PICP and PICP/ICTP levels in diagnosed patients compared to preclinical variant carriers (
< 0.036 and
< 0.027). A moderate negative correlation existed between right ventricular ejection fractions (RVEF) and the PICP/ICTP ratio (
= -0.46,
= 0.06). In addition, significant correlations with left ventricular function (LVEF
= -0.53,
= 0.03 and end-systolic volume
= 0.63,
= 0.02) were found. These findings indicate impaired contractile performance due to pro-fibrotic remodeling. Follow-up studies including a larger number of patients should be performed to substantiate our findings and the validity of those levels as potential promising biomarkers in ACM.
In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early ...treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.
Abstract
Arrhythmogenic cardiomyopathy (ACM) is a life-threatening cardiac disease caused by mutations in genes predominantly encoding for desmosomal proteins that lead to alterations in the ...molecular composition of the intercalated disc. ACM is characterized by progressive replacement of cardiomyocytes by fibrofatty tissue, ventricular dilatation, cardiac dysfunction, and heart failure but mostly dominated by the occurrence of life-threatening arrhythmias and sudden cardiac death (SCD). As SCD appears mostly in apparently healthy young individuals, there is a demand for better risk stratification of suspected ACM mutation carriers. Moreover, disease severity, progression, and outcome are highly variable in patients with ACM. In this review, we discuss the aetiology of ACM with a focus on pro-arrhythmic disease mechanisms in the early concealed phase of the disease. We summarize potential new biomarkers which might be useful for risk stratification and prediction of disease course. Finally, we explore novel therapeutic strategies to prevent arrhythmias and SCD in the early stages of ACM.
Pathogenic variants in
(
, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in
...p.Arg14del carriers. During collagen synthesis and breakdown, propeptides are released into the circulation, such as procollagen type I carboxy-terminal propeptide (PICP) and C-terminal telopeptide collagen type I (ICTP).
To investigate if PICP/ICTP levels in blood are correlative biomarkers for clinical disease severity and outcome in
p.Arg14del variant carriers.
Serum and EDTA blood samples were collected from 72
p.Arg14del carriers (age 50.5 years, 63% female) diagnosed with ACM (
= 12), DCM (
= 14), and preclinical variant carriers (
= 46). PICP levels were measured with an enzyme-linked immune sorbent assay and ICTP with a radio immuno-assay. Increased PICP/ICTP ratios suggest a higher collagen deposition. Clinical data including electrocardiographic, and imaging results were adjudicated from medical records.
No correlation between PICP/ICTP ratios and late gadolinium enhancement (LGE) was found. Moderate correlations were found between the PICP/ICTP ratio and end-diastolic/systolic volume (both
= 0.40,
= 23,
= 0.06). PICP/ICTP ratio was significantly higher in patients with T wave inversion (TWI), especially in leads V4-V6, II, III, and aVF (
< 0.022) and in patients with premature ventricular contractions (PVCs) during an exercise tolerance test (
= 0.007).
High PICP/ICTP ratios correlated with clinical parameters, such as TWI and PVCs. Given the limited size and heterogeneity of the patient group, additional studies are required to substantiate the incremental prognostic value of these fibrosis biomarkers in
p.Arg14del patients.
Congenital CYTOMEGALOVIRUS (CMV) infection and periventricular leukomalacia (PVL) both lead to static cerebral white matter lesions. In contrast to PVL, the neuropathologicAL substrate of these ...lesions in congenital CMV is not clear. By comparing changes in quantitative magnetic resonance (MR) parameters and MR spectroscopy metabolite concentrations we wanted to determine whether the nature of the white matter pathology in congenital CMV infection could be similar to the known pathology of PVL. Diffusion parameters, apparent diffusion coefficient (ADC) and fractional anisotropy (FA), magnetization transfer ratio (MTR) and MR spectroscopy concentrations were studied in white matter lesions in five patients with a congenital CMV infection and six patients with PVL. In both groups ADC values were increased, FA and MTR values were reduced, concentrations of total N-acetylaspartate and choline-containing compounds were reduced; and MYO-inositol concentrations were slightly increased. No differences were found between the two groups, suggesting that the pathology of the white matter lesions in congenital CMV infections is similar to that of PVL and also characterized by axonal losses, lack of myelin deposition due to oligodendrocytic losses, and astrogliosis. Congenital CMV infection and PVL affect the cerebral white matter in the same developmental period when immature oligodendrocytes are particularly vulnerable.
Leukoencephalopathy with vanishing white matter (VWM) is an autosomal-recessive disorder in which febrile infections may provoke major neurologic deterioration. Characteristic pathologic findings ...include cystic white matter degeneration, foamy oligodendrocytes, dysmorphic astrocytes and oligodendrocytes, oligodendrocytosis, and apoptotic losses of oligodendrocytes. VWM is caused by mutations in eukaryotic initiation factor (eIF) 2B (eIF2B). eIF2B plays an important role in the regulation of protein synthesis. Mutant eIF2B may impair the ability of cells to regulate protein synthesis in response to stress and perhaps even under normal conditions. An overload of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response (UPR), a compensatory mechanism that inhibits synthesis of new proteins and induces both prosurvival and proapoptotic signals. We have studied the activation of the UPR in VWM through the immunohistochemical expression of its upstream components PERK and phosphorylated eIF2α (eIF2αP) and combined immunohistochemical and Western blot analysis of the downstream effector proteins activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) in 4 VWM brains and 3 age-matched controls. We demonstrate activation of the UPR in glia of patients with VWM. Our findings may point to a possible explanation for the dysmorphic glia, the increased numbers of oligodendrocytes, and the apoptotic loss of oligodendrocytes in VWM.
Abstract
Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Netherlands Cardio Vascular Research Initiative (CVON) and 'Stichting ...Vriendenloterij'
Background
Arrhythmogenic cardiomyopathy (ACM) is predominantly caused by pathogenic variants in genes encoding desmosomal proteins (most often plakophilin-2). However, such variants are also found in genes encoding non-desmosomal proteins, such as phospholamban (PLN, p.Arg14del variant). Previous research showed that plakoglobin protein levels and localization in cardiac tissue of ACM patients, and p.Arg14del patients diagnosed with an ACM phenotype, are disturbed and this could be an additional tool to identify variant carriers at risk of developing ACM. Information about plakoglobin status can only be obtained via endocardial biopsies, however, this technique has major drawbacks, and therefore an alternative is needed. A promising new non-invasive tool is the use of buccal mucosa cells (BMC), as it has been reported that effects of pathogenic variants in desmosomal genes are reflected in non-cardiac tissues like BMC smears that also express those genes.
Purpose
To investigate the clinical usability of BMC as a tool to classify patients at risk of developing ACM by comparing controls with preclinical variant carriers and symptomatic ACM patients, and patients carrying the PLN p.Arg14del variant being preclinical, diagnosed with ACM or dilated cardiomyopathy (DCM).
Methods
BMC of 33 ACM patients (19 males, 28 with a PKP2 mutation), 17 PLN p.Arg14del patients (6 males, 3 diagnosed with ACM, 7 DCM and 7 preclinical carriers) and 34 controls (14 males), were collected on glass slides, fixed and labelled with anti-plakoglobin antibodies diluted 1:5.000, 1:10.000, 1:20.000 and 1:40.000, and scored for their membrane labelling.
Results
Data revealed that for each dilution, plakoglobin protein levels at the membrane were significantly reduced in BMC obtained from ACM patients (both in symptomatic patients and in preclinical variant carriers) when compared to controls. This effect was independent from age and sex of the patients. Dilutions 1:5.000 and 1:10.000 showed a moderate to strong correlation with the revised 2010 Task Force Criteria Score (TFC) which is commonly used for ACM diagnosis (rs = -0.67, n=64, p<0.0001 and rs = -0.71, n=64, p<0.0001 resp.). In contrast, plakoglobin scores of PLN p.Arg14del patients were comparable to controls (p>0.209).
Conclusion
There is a significant reduction of plakoglobin protein in BMC of ACM patients and carriers with variants predisposing to ACM, but not for patients carrying the PLN p.Arg14del variant when compared to controls. However, for clinical diagnosis of the individual ACM patient, this method is not discriminative enough to distinguish true patients from preclinical variant carriers and controls, because of high interindividual variability.
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