Rate of abnormalities in quantitative MR neuroimaging of persons with chronic traumatic brain injury.

BACKGROUND: Mild traumatic brain injury (mTBI) can result in lasting brain damage that is often too subtle to detect by qualitative visual inspection on conventional MR imaging. Although a number of FDA-cleared MR neuroimaging tools have demonstrated changes associated with mTBI, they are still under-utilized in clinical practice. METHODS: We investigated a group of 65 individuals with predominantly mTBI (60 mTBI, 48 due to motor-vehicle collision, mean age 47 ± 13 years, 27 men and 38 women) with MR neuroimaging performed in a median of 37 months post-injury. We evaluated abnormalities in brain volumetry including analysis of left-right asymmetry by quantitative volumetric analysis, cerebral perfusion by pseudo-continuous arterial spin labeling (PCASL), white matter microstructure by diffusion tensor imaging (DTI), and neurometabolites via magnetic resonance spectroscopy (MRS). RESULTS: All participants demonstrated atrophy in at least one lobar structure or increased lateral ventricular volume. The globus pallidi and cerebellar grey matter were most likely to demonstrate atrophy and asymmetry. Perfusion imaging revealed significant reductions of cerebral blood flow in both occipital and right frontoparietal regions. Diffusion abnormalities were relatively less common though a subset analysis of participants with higher resolution DTI demonstrated additional abnormalities. All participants showed abnormal levels on at least one brain metabolite, most commonly in choline and N-acetylaspartate. CONCLUSION: We demonstrate the presence of coup-contrecoup perfusion injury patterns, widespread atrophy, regional brain volume asymmetry, and metabolic aberrations as sensitive markers of chronic mTBI sequelae. Our findings expand the historic focus on quantitative imaging of mTBI with DTI by highlighting the complementary importance of volumetry, arterial spin labeling perfusion and magnetic resonance spectroscopy neurometabolite analyses in the evaluation of chronic mTBI.

T1 and FLAIR signal intensities are related to tau pathology in dominantly inherited Alzheimer disease.

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (µ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-µ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-µ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.

Alzheimer Disease Pathology and Neurodegeneration in Midlife Obesity: A Pilot Study.

Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a pro-inflammatory state, the two mechanisms involved in AD pathology. We assessed the association of obesity, MRI-determined abdominal adipose tissue volumes, and insulin resistance with PET-determined amyloid and tau uptake in default mode network areas, and MRI-determined brain volume and cortical thickness in AD cortical signature in the cognitively normal midlife population. Thirty-two middle-aged (age: 51.27±6.12 years, 15 males, body mass index (BMI): 32.28±6.39 kg/m2) cognitively normal participants, underwent bloodwork, brain and abdominal MRI, and amyloid and tau PET scan. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi-automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer was used to automatically segment brain regions using a probabilistic atlas. PET scans were acquired using [11C]PiB and AV-1451 tracers and were analyzed using PET unified pipeline. The association of brain volumes, cortical thicknesses, and PiB and AV-1451 standardized uptake value ratios (SUVRs) with BMI, VAT/SAT ratio, and insulin resistance were assessed using Spearman's partial correlation. VAT/SAT ratio was associated significantly with PiB SUVRs in the right precuneus cortex (p=0.034) overall, controlling for sex. This association was significant only in males (p=0.044), not females (p=0.166). Higher VAT/SAT ratio and PiB SUVRs in the right precuneus cortex were associated with lower cortical thickness in AD-signature areas predominantly including bilateral temporal cortices, parahippocampal, medial orbitofrontal, and cingulate cortices, with age and sex as covariates. Also, higher BMI and insulin resistance were associated with lower cortical thickness in bilateral temporal poles. In midlife cognitively normal adults, we demonstrated higher amyloid pathology in the right precuneus cortex in individuals with a higher VAT/SAT ratio, a marker of visceral obesity, along with a lower cortical thickness in AD-signature areas associated with higher visceral obesity, insulin resistance, and amyloid pathology.

Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN).

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Twelve Weeks of Intermittent Caloric Restriction Diet Mitigates Neuroinflammation in Midlife Individuals with Multiple Sclerosis: A Pilot Study with Implications for Prevention of Alzheimer's Disease.

BACKGROUND: Multiple sclerosis (MS) is a prototype neuroinflammatory disorder with increasingly recognized role for neurodegeneration. Most first-line treatments cannot prevent the progression of neurodegeneration and the resultant disability. Interventions can improve symptoms of MS and might provide insights into the underlying pathology. OBJECTIVE: To investigate the effect of intermittent caloric restriction on neuroimaging markers of MS. METHODS: We randomized ten participants with relapsing remitting MS to either a 12-week intermittent calorie restriction (iCR) diet (n = 5) or control (n = 5). Cortical thickness and volumes were measured through FreeSurfer, cortical perfusion was measured by arterial spin labeling and neuroinflammation through diffusion basis spectrum imaging. RESULTS: After 12 weeks of iCR, brain volume increased in the left superior and inferior parietal gyri (p: 0.050 and 0.049, respectively) and the banks of the superior temporal sulcus (p: 0.01). Similarly in the iCR group, cortical thickness improved in the bilateral medial orbitofrontal gyri (p: 0.04 and 0.05 in right and left, respectively), the left superior temporal gyrus (p: 0.03), and the frontal pole (p: 0.008) among others. Cerebral perfusion decreased in the bilateral fusiform gyri (p: 0.047 and 0.02 in right and left, respectively) and increased in the bilateral deep anterior white matter (p: 0.03 and 0.013 in right and left, respectively). Neuroinflammation, demonstrated through hindered and restricted water fractions (HF and RF), decreased in the left optic tract (HF p: 0.02), and the right extreme capsule (RF p: 0.007 and HF p: 0.003). CONCLUSION: These pilot data suggest therapeutic effects of iCR in improving cortical volume and thickness and mitigating neuroinflammation in midlife adults with MS.

Functional Magnetic Resonance Spectroscopy of Lactate in Alzheimer Disease: A Comprehensive Review of Alzheimer Disease Pathology and the Role of Lactate.

ABSTRACT: Functional 1H magnetic resonance spectroscopy (fMRS) is a derivative of dynamic MRS imaging. This modality links physiologic metabolic responses with available activity and measures absolute or relative concentrations of various metabolites. According to clinical evidence, the mitochondrial glycolysis pathway is disrupted in many nervous system disorders, especially Alzheimer disease, resulting in the activation of anaerobic glycolysis and an increased rate of lactate production. Our study evaluates fMRS with J-editing as a cutting-edge technique to detect lactate in Alzheimer disease. In this modality, functional activation is highlighted by signal subtractions of lipids and macromolecules, which yields a much higher signal-to-noise ratio and enables better detection of trace levels of lactate compared with other modalities. However, until now, clinical evidence is not conclusive regarding the widespread use of this diagnostic method. The complex machinery of cellular and noncellular modulators in lactate metabolism has obscured the potential roles fMRS imaging can have in dementia diagnosis. Recent developments in MRI imaging such as the advent of 7 Tesla machines and new image reconstruction methods, coupled with a renewed interest in the molecular and cellular basis of Alzheimer disease, have reinvigorated the drive to establish new clinical options for the early detection of Alzheimer disease. Based on the latter, lactate has the potential to be investigated as a novel diagnostic and prognostic marker for Alzheimer disease.

Phase 1 Evaluation of 11C-CS1P1 to Assess Safety and Dosimetry in Human Participants.

This study evaluated the safety, dosimetry, and characteristics of 3-((2-fluoro-4-(5-(2'-methyl-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl-11C)amino)propanoic acid (11C-CS1P1), a radiotracer targeting sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1). S1PR1 is of clinical interest because of its role in multiple sclerosis (and other conditions), with an expanding class of S1PR modulators approved for relapsing multiple sclerosis. 11C-CS1P1 binds S1PR1 with high specificity and has shown promise in animal models of inflammatory diseases. Methods: 11C-CS1P1 was injected into 5 male and 6 female healthy participants. Ten participants were imaged with PET using a multipass whole-body continuous-bed-motion acquisition, and one had dedicated head and neck PET and MRI. Participants were continuously monitored for safety events. Organ time-activity curve data were collected, integrated, and normalized to the injected activity. Organ radiation doses and effective dose were computed using the adult male and female models in OLINDA, version 2.2. SUV images were evaluated for qualitative biodistribution. Results: No adverse events were observed after the dose, including no bradycardia. The liver was the critical organ from dosimetry analysis (mean ± SD: female, 23.12 ± 5.19 µSv/MBq; male, 21.06 ± 1.63 µSv/MBq). The whole-body effective dose (as defined by International Commission on Radiological Protection publication 103) was 4.18 ± 0.30 µSv/MBq in women and 3.54 ± 0.14 µSv/MBq in men. Using a maximum delivered dose of 740 MBq (20 mCi), the effective dose for women would be 3.1 mSv (0.31 rem), with a liver dose of 17.1 mSv (1.7 rem); the effective dose for men would be 2.6 mSv (0.26 rem), with a liver dose of 15.6 mSv (1.56 rem). Brain uptake was seen predominantly in gray matter and correlated with regional S1PR1 RNA expression (r = 0.84). Conclusion: These results support the safety of 11C-CS1P1 for evaluation of inflammation in human clinical populations. Dosimetry permits repeated measures in the same participants. Brain uptake correlates well with known target topography.

Decoupling of regional neural activity and inter-regional functional connectivity in Alzheimer's disease: a simultaneous PET/MR study.

PURPOSE: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are characterized by both aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). However, the effect of AD/MCI on the coupling between regional neural activity (measured by regional fluorodeoxyglucose imaging (rFDG)) and inter-regional FC (measured by resting-state functional magnetic resonance imaging (rs-fMRI)) is poorly understood. METHODS: We scanned 19 patients with MCI, 33 patients with AD, and 26 healthy individuals by simultaneous FDG-PET/rs-fMRI and assessed rFDG and inter-regional FC metrics (i.e., clustering coefficient and degree centrality). Next, we examined the potential moderating effect of disease status (MCI or AD) on the link between rFDG and inter-regional FC metrics using hierarchical moderated multiple regression analysis. We also tested this effect by considering interaction between disease status and inter-regional FC metrics, as well as interaction between disease status and rFDG. RESULTS: Our findings revealed that both rFDG and inter-regional FC metrics were disrupted in MCI and AD. Moreover, AD altered the relationship between rFDG and inter-regional FC metrics. In particular, we found that AD moderated the effect of inter-regional FC metrics of the caudate, parahippocampal gyrus, angular gyrus, supramarginal gyrus, frontal pole, inferior temporal gyrus, middle frontal, lateral occipital, supramarginal gyrus, precuneus, and thalamus on predicting their rFDG. On the other hand, AD moderated the effect of rFDG of the parietal operculum on predicting its inter-regional FC metric. CONCLUSION: Our findings demonstrated that AD decoupled the link between regional neural activity and functional segregation and global connectivity across particular brain regions.

Intracranial internal carotid artery calcification is not predictive of future cognitive decline.

BACKGROUND: Intracranial internal carotid artery (ICA) calcification is a common incidental finding in non-contrast head CT. We evaluated the predictive value of ICAC (ICAC) for future risk of cognitive decline and compared the results with conventional imaging biomarkers of dementia. METHODS: In a retrospective observational cohort, we included 230 participants with a PET-CT scan within 18 months of a baseline clinical assessment and longitudinal imaging assessments. Intracranial ICAC was quantified on baseline CT scans using the Agatson calcium score, and the association between baseline ICA calcium scores and the risk of conversion from a CDR of zero in baseline to a persistent CDR > 0 at any follow-up visit, as well as longitudinal changes in cognitive scores, were evaluated through linear and mixed regression models. We also evaluated the association of conventional imaging biomarkers of dementia with longitudinal changes in cognitive scores and a potential indirect effect of ICAC on cognition through these biomarkers. RESULTS: Baseline ICA calcium score could not distinguish participants who converted to CDR > 0. ICA calcium score was also unable to predict longitudinal changes in cognitive scores, imaging biomarkers of small vessel disease such as white matter hyperintensities (WMH) volume, or AD such as hippocampal volume, AD cortical signature thickness, and amyloid burden. Severity of intracranial ICAC increased with age and in men. Higher WMH volume and amyloid burden as well as lower hippocampal volume and AD cortical signature thickness at baseline predicted lower Mini-Mental State Exam scores at longitudinal follow-up. Baseline ICAC was indirectly associated with longitudinal cognitive decline, fully mediated through WMH volume. CONCLUSIONS: In elderly and preclinical AD populations, atherosclerosis of large intracranial vessels as demonstrated through ICAC is not directly associated with a future risk of cognitive impairment, or progression of imaging biomarkers of AD or small vessel disease.

Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity.

BACKGROUND: Obesity is an increasingly recognized modifiable risk factor for Alzheimer's disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. OBJECTIVE: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. METHODS: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. RESULTS: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. CONCLUSION: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

Edge Density Imaging Identifies White Matter Biomarkers of Late-Life Obesity and Cognition.

Alzheimer disease (AD) and obesity are related to disruptions in the white matter (WM) connectome. We examined the link between the WM connectome and obesity and AD through edge-density imaging/index (EDI), a tractography-based method that characterizes the anatomical embedding of tractography connections. A total of 60 participants, 30 known to convert from normal cognition or mild-cognitive impairment to AD within a minimum of 24 months of follow up, were selected from the Alzheimer disease Neuroimaging Initiative (ADNI). Diffusion-weighted MR images from the baseline scans were used to extract fractional anisotropy (FA) and EDI maps that were subsequently averaged using deterministic WM tractography based on the Desikan-Killiany atlas. Multiple linear and logistic regression analysis were used to identify the weighted sum of tract-specific FA or EDI indices that maximized correlation to body-mass-index (BMI) or conversion to AD. Participants from the Open Access Series of Imaging Studies (OASIS) were used as an independent validation for the BMI findings. The edge-density rich, periventricular, commissural and projection fibers were among the most important WM tracts linking BMI to FA as well as to EDI. WM fibers that contributed significantly to the regression model related to BMI overlapped with those that predicted conversion; specifically in the frontopontine, corticostriatal, and optic radiation pathways. These results were replicated by testing the tract-specific coefficients found using ADNI in the OASIS-4 dataset. WM mapping with EDI enables identification of an abnormal connectome implicated in both obesity and conversion to AD.

Wiskott-Aldrich syndrome with possible congenital Cytomegalovirus infection: A diagnostic dilemma.

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder, characterized by thrombocytopenia, eczema and recurrent infections. We report a 4-month-old boy who presented with respiratory distress, petechiae, organomegaly and eczema. He was admitted to the paediatric intensive care unit because of severe respiratory distress due to Cytomegalovirus (CMV) infection. As peripheral blood smear showed microthrombocytopenia, Sanger gene sequencing was performed, which confirmed the diagnosis of WAS. This rare combination of possible congenital CMV infection in the background of WAS, misled the initial diagnosis.

Modification of Glial Cell Activation through Dendritic Cell Vaccination: Promises for Treatment of Neurodegenerative Diseases.

Accumulation of misfolded tau, amyloid ß (Aß), and alpha-synuclein (α-syn) proteins is the fundamental contributor to many neurodegenerative diseases, namely Parkinson's (PD) and AD. Such protein aggregations trigger activation of immune mechanisms in neuronal and glial, mainly M1-type microglia cells, leading to release of pro-inflammatory mediators, and subsequent neuronal dysfunction and apoptosis. Despite the described neurotoxic features for glial cells, recruitment of peripheral leukocytes to the brain and their conversion to neuroprotective M2-type microglia can mitigate neurodegeneration by clearing extracellular protein accumulations or residues. Based on these observations, it was speculated that Dendritic cell (DC)-based vaccination, by making use of DCs as natural adjuvants, could be used for treatment of neurodegenerative disorders. DCs potentiated by disease-specific antigens can also enhance T helper 2 (Th2)-specific immune response and by production of specific antibodies contribute to clearance of intracellular aggregations, as well as enhancing regulatory T cell response. Thus, enhancement of immune response by DC vaccine therapy can potentially augment glial polarization into the neuroprotective phenotype, enhance antibody production, and at the same time balance neuronal cells' repair, renewal, and protection. The characteristic feature of this method of treatment is to maintain the equilibrium in the immune response rather than targeting a single mediator in the disease and their application in other neurodegenerative diseases should be addressed. However, the safety of these methods should be investigated by clinical trials.

Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR).

We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK-), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

The effect of insomnia on development of Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia and a neurodegenerative disorder characterized by memory deficits especially forgetting recent information, recall ability impairment, and loss of time tracking, problem-solving, language, and recognition difficulties. AD is also a globally important health issue but despite all scientific efforts, the treatment of AD is still a challenge. Sleep has important roles in learning and memory consolidation. Studies have shown that sleep deprivation (SD) and insomnia are associated with the pathogenesis of Alzheimer's disease and may have an impact on the symptoms and development. Thus, sleep disorders have decisive effects on AD; this association deserves more attention in research, diagnostics, and treatment, and knowing this relation also can help to prevent AD through screening and proper management of sleep disorders. This study aimed to show the potential role of SD and insomnia in the pathogenesis and progression of AD.

Intact microstructure of the right corticostriatal pathway predicts creative ability in healthy adults.

INTRODUCTION: Creativity is one of the most complex functions of the human brain. The corticostriatal pathways have been implicated in creative thinking, yet few studies have addressed the microstructural underpinnings of creative ability, especially those related to the corticostriatal dopaminergic circuitry. We hypothesized that performance in creativity tests can be predicted based on diffusion metrics of the corticostriatal pathways and basal ganglia. METHODS: A total of 37 healthy adults were included. Neuropsychological tests of creativity, including the alternative uses task (AUT), test of creative imagery abilities (TCIA), remote associates test (RAT), and creative achievement questionnaire (CAQ), as well as diffusion MRI data were acquired for each participant. RESULTS: We demonstrated an independent effect of TCIA originality and TCIA transformativeness subscores, and RAT score in predicting the mean diffusivity (MD), mean axial diffusivity (AD), mean fractional anisotropy (FA), and mean generalized FA of the right corticostriatal pathway. We also observed independent effects of AUT elaboration subscore in predicting the AD of the right substantia nigra, and radial diffusivity (RD) of the right globus pallidus. CONCLUSION: Our results put a further spin on the "creative right brain" notion and question the presence of high-creative and low-creative networks in the brain.

International Efforts to Save Healthcare Personnel during COVID-19.

Coronavirus disease 2019 (COVID-19) pandemic is a global challenge. Several governments of the world have decided to take drastic actions in order to combat the spread of the disease, including the closing of air, maritime and land borders, as an extreme measure of isolation of each country/region. However, such measures had not prevented the disease from spreading globally; as COVID-19 has already spread in almost all countries. This virus's main victims are the healthcare personnel (HCP), who are physically and psychologically affected. The HCP serves as the first line of defense against this pandemic, what if we faced a significant loss in their number? And what if our HCP was going through a deep dark depression? The condition would be terrifying not only for now but also in the future. This raises the need for an intensified International collaboration, that mainly supports the HCP. We are throwing by challenging moments, and it is clear that social distancing, cooperation, hygiene awareness and abide by the recommendation and help of all governments, as well as obtaining the support of international organizations could be an excellent tool for preventing an increase in the number of cases, principally in countries and regions were COVID-19 is in the early stage of the epidemic. However, this is not the final solution for the current pandemic. An intensified global program, which mainly supports the HCP, then considers the other aspects of the COVID19 pandemic might bring this pandemic to a peaceful end.

Pathogenesis and promising therapeutics of Alzheimer disease through eIF2α pathway and correspondent kinases.

Eukaryotic initiation factor 2 (eIF2α) pathway is overactivated in Alzheimer disease and is probably associated with synaptic and memory deficiencies. EIF2α protein is principally in charge of the regulation of protein synthesis in eukaryotic cells. Four kinases responsible for eIF2α phosphorylation at ser-51 are: General control non-derepressible-2 kinase (GCN2), double-stranded RNA-activated protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and heme-regulated inhibitor kinase (HRI) are the four kinases. They lead to reduced levels of general translation and paradoxical increase of stress-responsive mRNAs expression including the B-secretase (BACE1) and the transcriptional modulator activating transcription factor 4 (ATF4), which in turn accelerates the beta-amyloidogenesis, tau phosphorylation, proapoptotic pathway induction and autophagy elements formation leading to the main pathological hallmarks of AD. Findings suggest that genetic or pharmacological inhibition of correspondent kinases can restore memory and prevent neurodegeneration. This implies that inhibition of eIF2α phosphorylation through respondent kinases is indeed a feasible prospect of clinical application. This review discusses recent therapeutic approaches targeting eIF2α pathway and provides an overview of the links between correspondent kinases overactivation with neurodegeneration in AD.

Gene Expression and Levels of TGF-B in PBMC Is Associated with Severity of Symptoms in Chronic Heart Failure.

BACKGROUND: TGF-ß1 is known to promote cardiac remodeling and fibrosis during Congestive Heart Failure (CHF). In this study, an attempt was made to investigate expression of Transforming Growth Factor beta1 (TGF-ß1) and relative expansion or contraction of regulatory T-cell (Tregs) population in peripheral blood of patients with Chronic Heart Failure (CHF). METHODS: Real-time PCR assay was used to investigate expression and post-stimulation levels of TGF-ß1 in cell culture supernatant of Peripheral Blood Mononuclear Cells (PBMC) of 42 patients with CHF and 42 controls. Flow cytometry was used to identify relative counts of CD4+CD25+FoxP3+ Tregs. RESULTS: PBMCs in patients with CHF expressed higher levels of TGF-ß1 compared to controls. Post-stimulation levels of TGF-ß1 expression were significantly higher in New York Heart Association (NYHA) functional class IV patients compared to stage I patients. Tregs were significantly expanded in PBMC in CHF, while the CD4+ helper T-cells were unchanged. Treg expansion was more significant in NYHA functional class I patients compared to class IV patients. CONCLUSION: Expansion of Treg population in CHF provides an extrinsic source for TGF-ß1 production to induce reactive fibrosis and cardiac remodeling. Relative decrease in Treg population at advanced stages of CHF is indicative of a loss of regulatory characteristics in these cells and unopposed proinflammatory milieu.