TREM2 Gene Compound Heterozygosity in Neurodegenerative Disorders.

BACKGROUND: Homozygous variants of the TREM2 and TYROBP genes have been shown to be causative for multiple bone cysts and neurodegeneration leading to progressive dementia (NHD, Nasu-Hakola disease). OBJECTIVE: To determine if biallelic variants of these genes and/or oligogenic inheritance could be responsible for a wider spectrum of neurodegenerative conditions. METHODS: We analyzed 52 genes associated with neurodegenerative disorders using targeted next generation sequencing in a selected group of 29 patients (n = 14 Alzheimer's disease, n = 8 frontotemporal dementia, n = 7 amyotrophic lateral sclerosis) carrying diverse already determined rare variants in exon 2 of TREM2. Molecular modeling was used to get an insight into the potential effects of the mutation. RESULTS: We identified a novel mutation c.401_406delinsTCTAT; p.(Asp134Valfs*55) in exon 3 of TREM2 in an Alzheimer's disease patient also carrying the p.Arg62His TREM2 variant. Molecular modeling revealed that the identified mutation prevents anchoring of the TREM2 protein in the membrane, leaving the core of the Ig-like domain intact. CONCLUSION: Our results expand the spectrum of neurodegenerative diseases, where the carriers of biallelic mutations in TREM2 have been described for Alzheimer's disease, and highlight the impact of variant burden in other genes on phenotypic heterogeneity.

MMP-9, TIMP-1 and S100B protein as markers of ischemic stroke in patients after carotid artery endarterectomy.

Ischemic stroke is the main cause of permanent disability in adult patients. No commonly accepted method were discovered to predict stroke before the first symptoms. Activation of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMP) and S100B protein may be observe in patients with symptomatic carotid artery stenosis. Hemorrhagic transformation of ischemic stroke may be associated with changes in MMP, TIMP and S100B. AIM: The aim of this study was to determine if MMP-9, TIMP-1 and S-100B protein may markers of forthcoming ischemic stroke in patients undergoing carotid endarterectomy. MATERIALS AND METHODS: Blood samples were taken and an analysis of circulating proteins (MMP-9, TIMP-1, S100B) 73 subsequent patients with carotid artery stenosis ≥70% (33 asymptomatic and 40 symptomatic), who were referred for potential revascularization. RESULTS: A statistically significant difference was found between MMP- 9 levels in patients with ischemic stroke compared to patients with asymptomatic carotid stenosis after endarterectomy. Also, average TIMP-1 levels in patients with ischemic stroke and stenosis ≥70% were statistically significantly higher than the average levels in patients after endarterectomy. In terms of S-100B, a higher mean value was observed in patients with stroke than in endarterectomy group. No statistical differences were found in the levels of that proteins in the hemorrhagic transformation of ischemic stroke. CONCLUSIONS: Increased levels of MMP-9, TIMP-1 and S-100B in patients with ischemic stroke compared to patients with asymptomatic carotid stenosis after endarterectomy showed that abovementioned proteins may be a good predictive factor of ischemic stroke in patients undergoing carotid endarterectomy.

Differences in acute ischaemic stroke care in Poland: analysis of claims database of National Health Fund in 2017.

Selected and basic indicators of acute ischaemic stroke care in Poland are reported cross-regionally based on the analysis of claims data of the National Health Fund (NFZ) in 2017, the most reliable source of healthcare funding in the country, being a single public payer. For research purposes, a selection algorithm based on the diagnosis coded as I63 according to the International Classification of Diseases (ICD-10) was used to identify all ischaemic stroke patients in the claims database provided by the NFZ. Stroke units and other centres providing treatment for acute ischaemic stroke patients were examined. The analysis showed marked differences between provinces in terms of stroke unit treatment availability. The crude and standardised rates of acute ischaemic stroke admissions to stroke units varied between provinces. Moreover, substantial differences were observed for the thrombolysis implementation rate, access to rehabilitation, hospital stay and early prognosis. As the leading cause of disability and the second leading cause of death in developed countries, stroke requires a well-organised, evidence-based healthcare system provided for both acute treatment and rehabilitation. Continuous monitoring of healthcare is crucial to identify weaknesses and areas for improvement.

Brain Functional Reserve in the Context of Neuroplasticity after Stroke.

Stroke is the second cause of death and more importantly first cause of disability in people over 40 years of age. Current therapeutic management of ischemic stroke does not provide fully satisfactory outcomes. Stroke management has significantly changed since the time when there were opened modern stroke units with early motor and speech rehabilitation in hospitals. In recent decades, researchers searched for biomarkers of ischemic stroke and neuroplasticity in order to determine effective diagnostics, prognostic assessment, and therapy. Complex background of events following ischemic episode hinders successful design of effective therapeutic strategies. So far, studies have proven that regeneration after stroke and recovery of lost functions may be assigned to neuronal plasticity understood as ability of brain to reorganize and rebuild as an effect of changed environmental conditions. As many neuronal processes influencing neuroplasticity depend on expression of particular genes and genetic diversity possibly influencing its effectiveness, knowledge on their mechanisms is necessary to understand this process. Epigenetic mechanisms occurring after stroke was briefly discussed in this paper including several mechanisms such as synaptic plasticity; neuro-, glio-, and angiogenesis processes; and growth of axon.

MMP-9 and/or TIMP as predictors of ischaemic stroke in patients with symptomatic and asymptomatic atherosclerotic stenosis of carotid artery treated by stenting or endarterectomy - A review.

We still lack an optimal tool to predict ischaemic stroke in patients with symptomatic and asymptomatic carotid stenosis (CS). It has already been shown that patients at increased risk of ischaemic stroke can be identified based on the elevated plasma levels of metalloproteinases (MMPs) and reduced activity tissue inhibitor of metalloproteinase (TIMP). There are few studies presenting the role of MMP-9 and TIMP in ischaemic stroke both in patients with symptomatic and asymptomatic CS treated with stenting or endarterectomy, however we have not found any published review summarizing the role of abovementioned markers. MEDLINE was accessed via Pub Med, and searched for published studies that analyzed MMP-9 and TIMP levels in patients with asymptomatic and symptomatic internal carotid stenosis and/or examined these parameters as potential risk markers for ischaemic stroke. A total of 13 articles documenting the outcomes of patients with symptomatic or asymptomatic carotid stenosis treated by carotid stenting or endarterectomy, were analyzed. Statistically significant differences in the levels of MMP-9 and/or TIMP in patients with symptomatic and asymptomatic CS have been reported. Also the concentrations of MMP-9 and TIMP in CS patients subjected to stenting or endarterectomy were higher than in baseline group. Moreover higher levels of MMP-9 and decreased TIMP was reported to be associated with the risk of restenosis. This systematic review shows that available evidence regarding the dynamics of MMP-9 and TIMP levels may be a predictor of cerebrovascular events in both symptomatic and asymptomatic carotid stenosis in patients treated with stenting or endarterectomy.

Hypermethylation of TRIM59 and KLF14 Influences Cell Death Signaling in Familial Alzheimer's Disease.

Epigenetic mechanisms play an important role in the development and progression of various neurodegenerative diseases. Abnormal methylation of numerous genes responsible for regulation of transcription, DNA replication, and apoptosis has been linked to Alzheimer's disease (AD) pathology. We have recently performed whole transcriptome profiling of familial early-onset Alzheimer's disease (fEOAD) patient-derived fibroblasts. On this basis, we demonstrated a strong dysregulation of cell cycle checkpoints and DNA damage response (DDR) in both fibroblasts and reprogrammed neurons. Here, we show that the aging-correlated hypermethylation of KLF14 and TRIM59 genes associates with abnormalities in DNA repair and cell cycle control in fEOAD. Based on the resulting transcriptome networks, we found that the hypermethylation of KLF14 might be associated with epigenetic regulation of the chromatin organization and mRNA processing followed by hypermethylation of TRIM59 likely associated with the G2/M cell cycle phase and p53 role in DNA repair with BRCA1 protein as the key player. We propose that the hypermethylation of KLF14 could constitute a superior epigenetic mechanism for TRIM59 hypermethylation. The methylation status of both genes affects genome stability and might contribute to proapoptotic signaling in AD. Since this study combines data obtained from various tissues from AD patients, it reinforces the view that the genetic methylation status in the blood may be a valuable predictor of molecular processes occurring in affected tissues. Further research is necessary to define a detailed role of TRIM59 and KLF4 in neurodegeneration of neurons.

Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease.

The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-ß. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-ß pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Radiological Evaluation of Strategic Structures in Patients with Mild Cognitive Impairment and Early Alzheimer's Disease.

BACKGROUND: The aim of the study was to evaluate the diagnostic value of two measurement techniques in patients with cognitive impairment - automated volumetry of the hippocampus, entorhinal cortex, parahippocampal gyrus, posterior cingulate gyrus, cortex of the temporal lobes and corpus callosum, and fractional anisotropy (FA) index measurement of the corpus callosum using diffusion tensor imaging. MATERIAL/METHODS: A total number of 96 patients underwent magnetic resonance imaging study of the brain - 33 healthy controls (HC), 33 patients with diagnosed mild cognitive impairment (MCI) and 30 patients with Alzheimer's disease (AD) in early stage. The severity of the dementia was evaluated with neuropsychological test battery. The volumetric measurements were performed automatically using FreeSurfer imaging software. The measurements of FA index were performed manually using ROI (region of interest) tool. RESULTS: The volumetric measurement of the temporal lobe cortex had the highest correct classification rate (68.7%), whereas the lowest was achieved with FA index measurement of the corpus callosum (51%). The highest sensitivity and specificity in discriminating between the patients with MCI vs. early AD was achieved with the volumetric measurement of the corpus callosum - the values were 73% and 71%, respectively, and the correct classification rate was 72%. The highest sensitivity and specificity in discriminating between HC and the patients with early AD was achieved with the volumetric measurement of the entorhinal cortex - the values were 94% and 100%, respectively, and the correct classification rate was 97%. The highest sensitivity and specificity in discriminating between HC and the patients with MCI was achieved with the volumetric measurement of the temporal lobe cortex - the values were 90% and 93%, respectively, and the correct classification rate was 92%. CONCLUSIONS: The diagnostic value varied depending on the measurement technique. The volumetric measurement of the atrophy proved to be the best imaging biomarker, which allowed the distinction between the groups of patients. The volumetric assessment of the corpus callosum proved to be a useful tool in discriminating between the patients with MCI vs. early AD.

Predicting the conversion of mild cognitive impairment to Alzheimer's disease based on the volumetric measurements of the selected brain structures in magnetic resonance imaging.

INTRODUCTION: Mild cognitive impairment (MCI) is defined as abnormal cognitive state, but does not meet the criteria for the diagnosis of dementia. According to the new guidelines Alzheimer's disease (AD) involves not only dementia's phase but also predementia phase which is asymptomatic and pathological process in the brain is already present. For this reason it is very important to determine the suitability of markers which should be positive before onset of the first symptoms. One of these biomarkers is a structural magnetic resonance imaging with hippocampal volumetric assessment. The aim of this study was to investigate the usefulness of structural brain magnetic resonance imaging with volumetric assessment of the hippocampus and entorhinal cortex, posterior cingulate gyrus, parahippocampal gyrus, temporal gyri: superior, medial and inferior, to predict the conversion of MCI to AD. MATERIAL AND METHODS: Magnetic resonance imaging of brain was performed at the baseline visit in 101 patients diagnosed with MCI. Clinic follow-ups were scheduled after 6.12 and 24 months. RESULTS: Amongst 101 patients with MCI, 17 (16.8%) converted into AD within two years of observation. All measured volumes were lower in converters than non-converters. Discriminant analysis was conducted and sensitivity for MCI conversion to AD was 64.7%, specificity 96.4%. 91% of patients were correctly classified (converter or non-converter). CONCLUSIONS: Volumetric measurements may help clinicians to predict MCI conversion to AD but due to low sensitivity it cannot be use separately. The study group requires further observation.