Thursday, August 1, 2019

Near-ubiquitous presence of a vancomycin-resistant Enterococcus faecium ST117/CT71/ van B –clone in the Rhine-Main metropolitan area of Germany | Antimicrobial Resistance & Infection Control | Full Text

Near-ubiquitous presence of a vancomycin-resistant Enterococcus faecium ST117/CT71/ van B –clone in the Rhine-Main metropolitan area of Germany | Antimicrobial Resistance & Infection Control | Full Text



Antimicrobial Resistance & Infection Control

Near-ubiquitous presence of a vancomycin-resistant Enterococcus faecium ST117/CT71/vanB –clone in the Rhine-Main metropolitan area of Germany

Abstract

Whole-genome sequencing analysis of Vancomycin-resistant Enterococcus faeciumisolates from the Frankfurt metropolitan region revealed that 78/94 isolates were MLST type ST117, cgMLST complex type CT71 with a common vanB chromosomal insertion site. This indicates circulation of a single VRE clone in a catchment area of 5,000-km2 with 3 million inhabitants.

Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer’s Coordinating Center Uniform Data Set | Alzheimer's Research & Therapy | Full Text

Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer’s Coordinating Center Uniform Data Set | Alzheimer's Research & Therapy | Full Text

Alzheimer's Research & Therapy



Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer’s Coordinating Center Uniform Data Set

Abstract

Background

Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer’s disease, particularly in the early disease stages. This study leveraged the National Alzheimer’s Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition.

Methods

The sample included 465 participants from the National Alzheimer’s Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer’s Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer’s disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD.

Results

Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ε4, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (p < 0.01), Digit Symbol Coding (p < 0.01), Logical Memory Immediate Recall (p = 0.02), Trail Making A (p < 0.01), and Semantic Fluency (p < 0.01). White matter hyperintensities predicted increases in Clinical Dementia Rating Sum of Boxes (p < 0.01) and Geriatric Depression Scale-15 scores (p = 0.01). Effect sizes were comparable to total brain and hippocampal volume. White matter hyperintensities did not predict diagnostic conversion. All effects also remained after including individuals with non-AD suspected etiologies for those who converted to MCI or dementia.

Conclusions

In this baseline cognitively normal sample, greater white matter hyperintensities were associated with accelerated cognitive, neuropsychiatric, and functional decline independent of traditional risk factors and MRI biomarkers for Alzheimer’s disease.

Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study | Alzheimer's Research & Therapy | Full Text

Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study | Alzheimer's Research & Therapy | Full Text

Alzheimer's Research & Therapy

Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study

Abstract

Background

Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer’s disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers.

Methods

We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers.

Results

Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 yearsconfirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181.

Conclusions

Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.

Tau and atrophy: domain-specific relationships with cognition | Alzheimer's Research & Therapy | Full Text

Tau and atrophy: domain-specific relationships with cognition | Alzheimer's Research & Therapy | Full Text

Alzheimer's Research & Therapy



Tau and atrophy: domain-specific relationships with cognition

Abstract

Background

Late-onset Alzheimer’s disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness.

Methods

We analyzed data from 131 amyloid-β positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer’s Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores.

Results

FTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition.

Conclusions

Our findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness.

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau | Alzheimer's Research & Therapy | Full Text

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau | Alzheimer's Research & Therapy | Full Text

Alzheimer's Research & Therapy



Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau

Abstract

Background

Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer’s disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study.

Methods

Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings.

Results

Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex − 53%, p < 0.001; hippocampus − 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001).

Conclusion

Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.

A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington’s disease patients | Acta Neuropathologica Communications | Full Text

A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington’s disease patients | Acta Neuropathologica Communications | Full Text

Acta Neuropathologica Communications

A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington’s disease patients

Abstract

Huntington’s disease (HD) is a progressive neurodegenerative disease. Involuntary movements, cognitive impairment and psychiatric disturbance are the major clinical manifestations, and gradual atrophy and selective neuronal loss in the striatum and cerebral cortex are the pathologic hallmarks. HD is caused by expanded CAG trinucleotide repeats at the N-terminus of IT15 that encodes the huntingtin (HTT) protein, though the molecular mechanisms through which the mutant HTT (mHTT) exerts toxic effects remain obscure. Members of the caspase family, including caspase-2 (Casp2), play an important role in HD pathogenesis. Genetic ablation of Casp2 ameliorates cognitive and motor deficits of HD mice, though the molecular targets of Casp2 are still unclear. It is well established that the microtubule-associated protein tau potentiates cognitive dysfunction in a variety of neurodegenerative disorders, including HD. Our recent study indicates that Casp2-catalyzed tau cleavage at aspartate 314 (tau 2N4R isoform numbering system) mediates synaptotoxicity, cognitive deficits and neurodegeneration in cellular and mouse models of frontotemporal dementia; further, levels of Δtau314, the soluble, N-terminal cleavage product, are elevated in individuals with mild cognitive impairment and Alzheimer’s disease, compared with cognitively normal individuals. Here, we identified the presence of Δtau314 proteins in the striatum (caudate nucleus) and prefrontal cortex (Brodmann’s area 8/9) of human subjects, and showed that in both structures, levels of Casp2 and Δtau314 proteins correlate well, and both proteins are higher in HD patients than non-HD individuals. Our findings advance our understanding of the contribution of Casp2-mediated Δtau314 production to HD pathogenesis.

Establishing a prognostic threshold for total copy number variation within adult IDH -mutant grade II/III astrocytomas | Acta Neuropathologica Communications | Full Text

Establishing a prognostic threshold for total copy number variation within adult IDH -mutant grade II/III astrocytomas | Acta Neuropathologica Communications | Full Text



Acta Neuropathologica Communications

Establishing a prognostic threshold for total copy number variation within adult IDH-mutant grade II/III astrocytomas

Prior to the 2016 WHO update, adult astrocytomas were graded exclusively by histologic features, where grade III anaplastic astrocytomas were separated from grade II diffuse infiltrating astrocytomas on the basis of mitotic figures, and glioblastomas (GBM; grade IV) were defined based on the presence of microvascular proliferation and/or tumor necrosis [9]. With the establishment of the 2016 WHO Classification of Tumours of the Central Nervous System guidelines, adult astrocytomas have been segregated into IDH-wildtype and IDH-mutant groups due to the significant prognostic advantage conferred by the presence of an IDH1 or IDH2 mutation [914]. Since this update, much work has been done to establish additional prognostic factors in both IDH-wildtype and IDH-mutant astrocytomas to further subclassify these groups and to aid in the understanding of the underlying biology [1,2,35].