Synaptic, axonal damage and inflammatory cerebrospinal fluid biomarkers in neurodegenerative dementias.

INTRODUCTION: Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD). METHODS: Unicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins. RESULTS: Biomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used. DISCUSSION: Biomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied.

Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants.

Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) have a high proportion of genetically determined cases. Next-generation sequencing technologies have triggered the discovery of new mutations and genetic variants in dementia-causal genes. We performed whole-exome sequencing and selective analysis of known genes causative of EOAD and FTD in a well-characterized Spanish cohort of 103 patients (60 EOAD, 43 FTD) to find genetic variants associated to patients' phenotype. In EOAD patients, a new likely pathogenic variant in PSEN1 gene (p.G378R) was found. In FTD patients, 2 likely pathogenic variants were found, one in MAPT gene (p.P397S) and one in VCP gene (p.R159H). In our series, 2% of early-onset dementia without criteria for clinical genetic testing according to current guidelines presented a likely pathogenic mutation. We have also detected 13 additional variants of uncertain significance in causal genes, as well as rare variants in risk genes for dementia (ABCA7, SORL1, SQSTM1, and TREM2). Next-generation technologies in neurodegenerative diseases constitute a powerful tool that significantly contributes to patients' diagnosis.

Thermal Effects in the Ablation of Bovine Cortical Bone with Pulsed Laser Sources.

Lasers have advantages as bone surgical tools over mechanical methods, but two goals should be achieved to assure its use: Similar ablation rates to those obtained with mechanical tools (1 mm3/s at least) and to avoid thermal damage, a condition that can prevent proper bone healing. We present results of cow femoral bone with a 355 nm nanosecond (ns) and a 1064 nm picosecond (ps) pulsed laser sources that allow us to discuss the influence on the process of pulse duration and the selective ablation through high energy absorption (as bone highly absorbs 355 nm radiation). The treated samples were characterized by scanning electron microscopy (SEM) and Raman spectroscopy. The evaluation of the thermal effects produced in the samples shows clear differences between both laser sources: On one hand, the ns laser allows reaching high ablation rates (around 1 mm3/s); Raman spectra show no signal of bone carbonization, but unavoidable thermal effects in the form of melted and solidified material have been observed by electron microscopy in the samples treated with this laser. On the other hand, ablation without any sign of thermal effects is obtained using the ps laser, but with lower ablation rates, (around 0.15 mm3/s).

Hippocampal atrophy has limited usefulness as a diagnostic biomarker on the early onset Alzheimer's disease patients: A comparison between visual and quantitative assessment.

NIA-AA diagnostic criteria include volumetric or visual rating measures of hippocampal atrophy (HA) as a diagnostic biomarker of Alzheimer's disease (AD). We aimed to determine its utility as a diagnostic biomarker for early onset Alzheimer's disease (EOAD) by assessing Medial Temporal Atrophy (MTA) and hippocampal volume (HV) determination. MTA score and HV quantified by FreeSurfer were assessed in 140 (aged ≤65) subjects with biomarker supported diagnosis: 38 amnesic (A-EOAD), 20 non-amnesic (NA-EOAD), 30 late onset AD (LOAD), 20 fronto-temporal dementia (FTD) and 32 healthy controls (HC). The results showed that the proportion of MTA ≥ 1.5 was higher on LOAD and FTD than EOAD and HC but none of the MTA thresholds (≥1, ≥1.5 and ≥ 2) showed acceptable diagnostic accuracy. LOAD had lower HV than the other groups. A-EOAD HV was lower than NA-EOAD and HC but equal to FTD. The 6258 mm3 cut-off showed good diagnostic accuracy between A-EOAD and HC. Both tools showed a moderate inverse correlation. In conclusion, MTA has a limited diagnostic utility as an EOAD biomarker as it does not discriminate AD from FTD or HC in initial symptomatic stages. HV may discriminate A-EOAD from HC but not from FTD.

CSF microRNA Profiling in Alzheimer's Disease: a Screening and Validation Study.

MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression through post-transcriptional repression of target genes. They have been shown to be implicated in the pathophysiology of Alzheimer's disease (AD) and proposed as disease biomarkers. In the present work, we have studied the expression levels of 754 miRNAs in cerebrospinal fluid (CSF) from AD patients and control subjects. We have explored a first screening cohort (N = 20) and selected 12 miRNAs to be further tested in a second independent validation cohort (N = 69). We have found a significant upregulation of miR-222 and miR-125b in AD CSF. Of these, the association of miR-222 with AD is novel and reported here for the first time whereas upregulation of miR-125b has been previously reported in AD brain. Yet we do not find association with other miRNAs which were previously linked to AD. Our results shed light on potential underlying pathophysiological processes of AD and also point out the need for consensus procedures in CSF miRNA detection and data analysis.

Altered Blood Gene Expression of Tumor-Related Genes (PRKCB, BECN1, and CDKN2A) in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common of the neurodegenerative diseases. Recent diagnostic criteria have defined a preclinical disease phase during which neuropathological substrates are thought to be present in the brain. There is an urgent need to find measurable alterations in this phase as well as a good peripheral biomarker in the blood. We selected a cohort of 100 subjects (controls = 47; preclinical AD = 11; patients with AD = 42) and analyzed whole blood expression of 20 genes by quantitative polymerase chain reaction. The selected genes belonged to calcium signaling, senescence and autophagy, and mitochondria/oxidative stress pathways. Additionally, two genes associated with an increased risk of developing AD (clusterin (CLU) and bridging integrator 1 (BIN1)) were also analyzed. We detected significantly different gene expressions of BECN1 and PRKCB between the control and the AD groups and of CDKN2A between the control and the preclinical AD groups. Notably, these three genes are also considered tumor suppressor (CDKN2A and BECN1) or tumor promoter (PRKCB) genes. Gene-gene expression Pearson correlations were computed separately for controls and patients with AD. The significant correlations (p < 0.001) were represented in a network analysis with Cytoscape tool, which suggested an uncoupling of mitochondria-related genes in AD group. Whole blood is emerging as a valuable tissue in the study of the physiopathology of AD.