Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD).
We included healthy control subjects (N = 254), mild cognitive impairment (N ...= 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum.
Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages.
These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification.
Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer's disease (AD) biomarkers in mild ...cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance.
We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals.
We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7β-hydroxycholesterol (7β-OHC), amyloid-β42 (Aβ42), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults.
Higher 7-KC levels were related to lower Aβ42, indicative of greater AD pathology (p = 0.041) . Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017), genu (B = 68.64, p = 0.000), and fornix (B = 10.97, p = 0.000). Lower Aβ42 levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and Aβ42 was moderated by 7K-C (p = 0.048).
This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the Aβ42 generation process.
Dislipidemia is a risk factor for cognitive impairment. We studied the association between interindividual variability of plasma lipids and white matter (WM) microstructure, using diffusion tensor ...imaging (DTI) in 273 healthy adults. Special focus was placed on 7 regions of interest (ROI) which are structural components of cognitive neurocircuitry. We also investigated the effect of plasma lipids on cerebrospinal fluid (CSF) neurofilament light chain (NfL), an axonal degeneration marker. Low density lipoprotein (LDL) and triglyceride (TG) levels showed a negative association with axial diffusivity (AxD) in multiple regions. High density lipoproteins (HDL) showed a positive correlation. The association was independent of Apolipoprotein E (APOE) genotype, blood pressure or use of statins. LDL moderated the relation between NfL and AxD in the body of the corpus callosum (
p
= 0.041), right cingulum gyrus (p = 0.041), right fornix/stria terminalis (
p
= 0.025) and right superior longitudinal fasciculus (
p
= 0.020) and TG in the right inferior longitudinal fasciculus (
p
= 0.004) and left fornix/stria terminalis (
p
= 0.001). We conclude that plasma lipids are associated to WM microstructural changes and axonal degeneration and might represent a risk factor in the transition from healthy aging to disease.
Introduction
Amyloid plaque deposition in the brain is an early pathological change in Alzheimer's disease (AD), causing disrupted synaptic connections. Brain network disruptions in AD have been ...demonstrated with eigenvector centrality (EC), a measure that identifies central regions within networks. Carrying an apolipoprotein (APOE)‐ε4 allele is a genetic risk for AD, associated with increased amyloid deposition. We studied whether APOE‐ε4 carriership is associated with EC disruptions in cognitively normal individuals.
Methods
A total of 261 healthy middle‐aged to older adults (mean age 56.6 years) were divided into high‐risk (APOE‐ε4 carriers) and low‐risk (noncarriers) groups. EC was computed from resting‐state functional MRI data. Clusters of between‐group differences were assessed with a permutation‐based method. Correlations between cluster mean EC with brain volume, CSF biomarkers, and psychological test scores were assessed.
Results
Decreased EC in the visual cortex was associated with APOE‐ε4 carriership, a genetic risk factor for AD. EC differences were correlated with age, CSF amyloid levels, and scores on the trail‐making and 15‐object recognition tests.
Conclusion
Our findings suggest that the APOE‐ε4 genotype affects brain connectivity in regions previously found to be abnormal in AD as a sign of very early disease‐related pathology. These differences were too subtle in healthy elderly to use EC for single‐subject prediction of APOE genotype.
Decreased functional brain eigenvector centrality measured from fMRI was associated with APOE genotype, a genetic risk factor for Alzheimer's disease. Changes were found in the visual cortex, posterior cingulate, and precuneus.
Abstract Gray matter networks are disrupted in Alzheimer's disease (AD). It is unclear when these disruptions start during the development of AD. Amyloid beta 1–42 (Aβ42 ) is among the earliest ...changes in AD. We studied, in cognitively healthy adults, the relationship between Aβ42 levels in cerebrospinal fluid (CSF) and single-subject cortical gray matter network measures. Single-subject gray matter networks were extracted from structural magnetic resonance imaging scans in a sample of cognitively healthy adults (N = 185; age range 39–79, mini–mental state examination >25, N = 12 showed abnormal Aβ42 < 550 pg/mL). Degree, clustering coefficient, and path length were computed at whole brain level and for 90 anatomical areas. Associations between continuous Aβ42 CSF levels and single-subject cortical gray matter network measures were tested. Smoothing splines were used to determine whether a linear or nonlinear relationship gave a better fit to the data. Lower Aβ42 CSF levels were linearly associated at whole brain level with lower connectivity density, and nonlinearly with lower clustering values and higher path length values, which is indicative of a less-efficient network organization. These relationships were specific to medial temporal areas, precuneus, and the middle frontal gyrus (all p < 0.05). These results suggest that mostly within the normal spectrum of amyloid, lower Aβ42 levels can be related to gray matter networks disruptions.
Alzheimer's disease is a progressive neurodegenerative disorder, the early detection of which is crucial for timely intervention and enrollment in clinical trials. However, the preclinical diagnosis ...of Alzheimer's encounters difficulties with gold-standard methods. The current definitive diagnosis of Alzheimer's still relies on expensive instrumentation and post-mortem histological examinations. Here, we explore label-free Raman spectroscopy with machine learning as an alternative to preclinical Alzheimer's diagnosis. A special feature of this study is the inclusion of patient samples from different cohorts, sampled and measured in different years. To develop reliable classification models, partial least squares discriminant analysis in combination with variable selection methods identified discriminative molecules, including nucleic acids, amino acids, proteins, and carbohydrates such as taurine/hypotaurine and guanine, when applied to Raman spectra taken from dried samples of cerebrospinal fluid. The robustness of the model is remarkable, as the discriminative molecules could be identified in different cohorts and years. A unified model notably classifies preclinical Alzheimer's, which is particularly surprising because of Raman spectroscopy's high sensitivity regarding different measurement conditions. The presented results demonstrate the capability of Raman spectroscopy to detect preclinical Alzheimer's disease for the first time and offer invaluable opportunities for future clinical applications and diagnostic methods.
Down syndrome (DS) is the most common genetically determined intellectual disability. In recent decades, it has experienced an exponential increase in life expectancy, leading to a rise in ...age-related diseases, including Alzheimer's disease (AD). Specific health plans for the comprehensive care of the DS community are an unmet need, which is crucial for the early and accurate diagnosis of main medical comorbidities. We present the protocol of a newly created clinical and research cohort and its feasibility in real life.
The Down Syndrome-Basque Alzheimer Initiative (DS-BAI) is a population-based, inclusive, multidisciplinary initiative for the clinical-assistance and clinical-biological research approach to aging in DS led by the CITA-Alzheimer Foundation (Donostia, Basque Country). It aims to achieve the following: (1) provide comprehensive care for adults with DS, (2) optimize access to rigorous and quality training for socio-family and healthcare references, and (3) create a valuable multimodal clinical-biological research platform.
During the first year, 114 adults with DS joined the initiative, with 36% of them showing symptoms indicative of AD. Furthermore, adherence to training programs for healthcare professionals and families has been high, and the willingness to collaborate in basic and translational research has been encouraging.
Specific health plans for DS and conducting clinical and translational research on the challenges of aging, including AD, are necessary and feasible.
Abstract Introduction Low levels of cell-free mitochondrial DNA (mtDNA) in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients have been identified and proposed as a novel biomarker ...for the disease. The lack of validation studies of previous results prompted us to replicate this finding in a comprehensive series of patients and controls. Methods We applied droplet digital polymerase chain reaction in CSF specimens from 124 patients representing the AD spectrum and 140 neurologically healthy controls. The following pre-analytical and analytical parameters were evaluated: the effect of freeze-thaw cycles on mtDNA, the linearity of mtDNA load across serial dilutions and the mtDNA levels in the diagnostic groups. Results We found a wide range of mtDNA copies, which resulted in a high degree of overlap between groups. Although the AD group presented significantly higher mtDNA counts, the receiver-operating characteristic analysis disclosed an area under the curve of 0.715 to distinguish AD patients from controls. MtDNA was highly stable with low analytical variability. Discussion MtDNA levels in CSF show a high inter-individual variability, with great overlap within phenotypes and presents low sensitivity for AD.
We introduce a lattice independent component analysis (LICA) unsupervised scheme to functional magnetic resonance imaging (fMRI) data analysis. LICA is a non-linear alternative to independent ...component analysis (ICA), such that ICA’s statistical independent sources correspond to LICA’s lattice independent sources. In this paper, LICA uses an incremental lattice source induction algorithm (ILSIA) to induce the lattice independent sources from the input dataset. The ILSIA computes a set of Strongly Lattice Independent vectors using properties of lattice associative memories regarding Lattice Independence and Chebyshev best approximation. The lattice independent sources constitute a set of Affine Independent vectors that define a simplex covering the input data. LICA carries out data linear unmixing based on the lattice independent sources basis. Therefore, LICA is a hybrid combination of a non-linear lattice based component and a linear unmixing component. The principal advantage over ICA is that LICA does not impose any probabilistic model assumptions on the data sources. We compare LICA with ICA in two case studies. Firstly, including simulated fMRI data, LICA discovers the spatial location of meaningful sources with less ambiguity than ICA. Secondly, including real data from an auditory stimulation experiment, LICA improves over some state of the art ICA variants discovering the activation patterns detected by Statistical Parametric Mapping (SPM) on the same data.
Abstract Bilingualism as a component of cognitive reserve has been claimed to delay the onset of Alzheimer's disease (AD). However, its effect on cerebrospinal fluid (CSF) AD-biomarkers has not been ...investigated. We assessed cognitive performance and CSF AD-biomarkers, and potential moderation effect of bilingualism on the association between age, CSF AD-biomarkers, and cognition. Cognitively healthy middle-aged participants classified as monolinguals (n = 100, nCSF = 59), early (n = 81, nCSF = 55) and late bilinguals (n = 97, nCSF = 52) were evaluated. Models adjusted for confounders showed that bilinguals performed better than monolinguals on digits backwards (early-bilinguals p = 0.003), Judgment of Line Orientation (JLO) (early-bilinguals p = 0.018; late-bilinguals p = 0.004), and Trail Making Test-B (late-bilinguals p = 0.047). Early bilingualism was associated with lower CSF total-tau ( p = 0.019) and lower prevalence of preclinical AD (NIA-AA classification) ( p = 0.02). Bilingualism showed a moderation effect on the relationship between age and CSF AD-biomarkers and the relationship between age and executive function. We conclude that bilingualism contributes to cognitive reserve enhancing executive and visual-spatial functions. For the first time, this study reveals that early bilingualism is associated with more favorable CSF AD-biomarker profile.
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