Objectives
We studied a sample of cognitively unimpaired individuals, with and without subjective cognitive decline (SCD), in order to investigate accelerated long‐term forgetting (ALF) and to ...explore the relationships between objective and subjective cognitive performance and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers.
Methods
Fifty‐two individuals were included and SCD was quantified through the Subjective Cognitive Decline Questionnaire (SCD‐Q), using its validated cutoff to classify participants as Low SCD‐Q (n = 21) or High SCD‐Q (n = 31). These groups were further subdivided according to the presence or absence of abnormal levels of CSF Aβ42. Objective cognitive performance was assessed with the Ancient Farming Equipment Test (AFE‐T), a new highly‐demanding test that calls for acquisition and retention of novel object/name pairs and allows measuring ALF over a 6‐month period.
Results
The High SCD‐Q group showed a significantly higher free forgetting rate at 3 months compared to the Low SCD‐Q (F 1,44 = 4.72; p < 0.05). When stratifying by amyloid status, High SCD‐Q/Aβ+ showed a significantly lower performance than High SCD‐Q/Aβ–on the final free and cued learning scores (F 1,27 = 6.44, p < 0.05 and F 1,27 = 7.51, p < 0.05, respectively), the 1‐week free and cued recall (F 1,24 = 4.49; p < 0.05 and F 1,24 = 7.10; p < 0.01, respectively), the 1‐week cued forgetting rate (F 1,24 = 5.13; p < 0.05), and the 3‐month cued recall (F 1,24 = 4.27; p < 0.05). Linear regression analyses showed that higher SCD‐Q scores were associated with higher forgetting rates on the AFE‐T (β = −0.212; p < 0.05).
Conclusions
It is possible to detect ALF in individuals with high SCD ratings, appearing especially in those with abnormal CSF Aβ42 levels. Both in research and the clinical field, there is an increasing need of using more demanding cognitive measures, such as the AFE‐T, for identifying and tracking the earliest cognitive changes in these populations.
Key Points
We assessed accelerated long‐term forgetting (ALF) in subjective cognitive decline (SCD)
We found ALF over 3 months in individuals with high SCD ratings
Individuals with high SCD ratings and abnormal Aβ42 levels displayed higher forgetting rates
ALF might be a potential marker of subtle cognitive dysfunction in the AD continuum
OBJECTIVE:To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with ...suspected non-Alzheimer pathology (SNAP).
METHODS:We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau t-tau, phospho-tau p-tau), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging–Alzheimerʼs Association classificationstage 0, 1, 2, 3, and SNAP.
RESULTS:The median age in the whole cohort was 58.8 years (range 39.8–81.6). Participants in stages 2–3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2–3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42.
CONCLUSIONS:Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.
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.
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.
Nowadays proper detection of cognitive impairment has become a challenge for the scientific community. Alzheimer's Disease (AD), the most common cause of dementia, has a high prevalence that is ...increasing at a fast pace towards epidemic level. In the not-so-distant future this fact could have a dramatic social and economic impact. In this scenario, an early and accurate diagnosis of AD could help to decrease its effects on patients, relatives and society. Over the last decades there have been useful advances not only in classic assessment techniques, but also in novel non-invasive screening methodologies.
Among these methods, automatic analysis of speech -one of the first damaged skills in AD patients- is a natural and useful low cost tool for diagnosis.
In this paper a non-linear multi-task approach based on automatic speech analysis is presented. Three tasks with different language complexity levels are analyzed, and promising results that encourage a deeper assessment are obtained. Automatic classification was carried out by using classic Multilayer Perceptron (MLP) and Deep Learning by means of Convolutional Neural Networks (CNN) (biologically- inspired variants of MLPs) over the tasks with classic linear features, perceptual features, Castiglioni fractal dimension and Multiscale Permutation Entropy.
Finally, the most relevant features are selected by means of the non-parametric Mann- Whitney U-test.
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.
Accelerated long‐term forgetting (ALF) refers to a rapid loss of information over days or weeks despite normal acquisition/encoding. Notwithstanding its potential relevance as a presymptomatic marker ...of cognitive dysfunction, no study has addressed the relationship between ALF and Alzheimer’s disease (AD) biomarkers. We examined ALF in APOE ɛ4 carriers versus noncarriers, and its relationships with AD cerebrospinal fluid (CSF) biomarkers. We found ALF over three months in APOE ɛ4 carriers (F(1,19) = 5.60; P < 0.05; Cohen’s d = 1.08), and this performance was associated with abnormal levels of the CSF Aβ42/ptau ratio (r = −.614; P < 0.01). Our findings indicate that ALF is detectable in at‐risk individuals, and that there is a relationship between ALF and the pathophysiological processes underlying AD.
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.
GOIZ ZAINDU ("caring early" in Basque) is a pilot study to adapt the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) methodology to the Basque population ...and evaluate the feasibility and adherence to a FINGER-like multidomain intervention program. Additional aims included the assessment of efficacy on cognition and data collection to design a large efficacy trial.
GOIZ ZAINDU is a 1-year, randomized, controlled trial of a multidomain intervention in persons aged 60+ years, with Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score ≥ 6, no diagnosis of dementia, and below-than-expected performance in at least one of three cognitive screening tests. Randomization to a multidomain intervention (MD-Int) or regular health advice (RHA) was stratified by sex, age (>/≤ 75), and cognitive status (mild cognitive impairment (MCI)/normal cognition). MD-Int included cardiovascular risk factor control, nutritional counseling, physical activity, and cognitive training. The primary outcomes were retention rate and adherence to the intervention program. Exploratory cognitive outcomes included changes in the Neuropsychological Test Battery z-scores. Analyses were performed according to the intention to treat.
One hundred twenty-five participants were recruited (mean age: 75.64 (± 6.46); 58% women). The MD-Int (n = 61) and RHA (n = 64) groups were balanced in terms of their demographics and cognition. Fifty-two (85%) participants from the RHA group and 56 (88%) from the MD-Int group completed the study. More than 70% of the participants had high overall adherence to the intervention activities. The risk of cognitive decline was higher in the RHA group than in the MD-Int group in terms of executive function (p =.019) and processing speed scores (p =.026).
The GOIZ-ZAINDU study proved that the FINGER methodology is adaptable and feasible in a different socio-cultural environment. The exploratory efficacy results showed a lower risk of decline in executive function and processing speed in the intervention group. These results support the design of a large-scale efficacy trial.
GOIZ ZAINDU feasibility trial was approved and registered by the Euskadi Drug Research Ethics Committee (ID: PI2017134) on 23 January 2018. Retrospectively registered in ClinicalTrials.gov (NCT06163716) on 8 December 2023.
We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would ...improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.
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