Contribution of CSF biomarkers to early-onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early‐onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid‐long form of the amyloid‐beta protein [Aβ42], total‐tau protein [T‐tau], neurofilament light chain [NfL], neurogranin [Ng], and 14‐3‐3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD

CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3

ObjectivesCARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain.MethodsIn total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC > 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis.ResultsIn total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5).ConclusionThis study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3

Early‐onset Alzheimer's disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late‐onset

Abstract Objectives Early‐ and late‐onset Alzheimer's disease (EOAD and LOAD) share the same neuropathological traits but show distinct cognitive features. We aimed to explore baseline and longitudinal outcomes of global and domain‐specific cognitive function in a well characterized cohort of patients with a biomarker‐based diagnosis. Methods In this retrospective cohort study, 195 participants were included and classified according to their age, clinical status, and CSF AD biomarker profile: 89 EOAD, 37 LOAD, 46 young healthy controls (age ≤ 65 years), and 23 old healthy controls (>65 years). All subjects underwent clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture. Results We found distinct neuropsychological profiles between EOAD and LOAD at the time of diagnosis. Both groups showed similar performances on memory and language domains, but the EOAD patients displayed worsened deficits in visual perception, praxis, and executive tasks (p < 0.05). Longitudinally, cognitive decline in EOAD was more pronounced than LOAD in the global outcomes at the expense of these non‐amnestic domains. We found that years of education significantly influenced the decline in most of the neuropsychological tests. Besides, the APOE ε4 status showed a significant effect on the decline of memory‐related tasks within the EOAD cohort (p < 0.05). Interpretation Age of onset is a main factor shaping the cognitive trajectories in AD patients, with younger age driving to a steeper decline of the non‐memory domains. Years of education are related to a transversal decline in all cognitive domains and APOE ε4 status to a specific decline in memory performance in EOAD

Systematic screening of ubiquitin/p62 aggregates in cerebellar cortex expands the neuropathological phenotype of the C9orf72 expansion mutation

The neuropathological hallmark of the C9orf72 intronic hexanucleotide expansion in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the presence of small ubiquitin/p62-positive and transactive response DNA binding protein 43 kDa (TDP-43)-negative cytoplasmic inclusions in several brain areas. The identification of this histopathological signature is highly predictive of an underlying mutation. In this study, we screened 1800 cases of the Barcelona IDIBAPS Brain Bank, independently of the clinical and final neuropathological diagnosis of the brain donor, for the presence of ubiquitin/p62-positive inclusions in the cerebellum (UPPI). Positive cases were also stained for dipeptide repeats. We identified a total of 21 donors with UPPI and in all of them the C9orf72 hexanucleotide expansion was genetically confirmed. Most donors had an FTLD or to a lesser extent ALS clinico-pathological phenotype. However, 3 cases had been previously classified as having clinically and neuropathologically Lewy body disease. Other co-existing pathologies, especially of the PART-type, were also frequently encountered. This study highlights the importance of the evaluation of ubiquitin/p62-positive cytoplasmic inclusions in all neurodegenerative diseases as a good screening method for the detection of C9orf72 expansion mutation, since this mutation is not rare and can overlap with other neurodegenerative entities