Características neuropsicológicas de pacientes con Enfermedad de Parkinson y portadores asintomáticos de la mutación R1441G en el gen LRRK2

238 p.El objetivo de esta tesis es conocer la afectación cognitiva asociada a la mutación LRRK2 R1441G tanto en pacientes con EP, como en portadores asintomáticos de la misma y la posible correlación de esta afectación con el estado dopaminérgico en los portadores asintomáticos. Para ello se ha realizado una valoración clínica y neuropsicológica de pacientes con EP asociada a mutaciones R1441G y G2019S y EP idiopática, y a familiares asintomáticos. Además, se ha realizado una prueba de imagen DaTSCAN (123I-FP-CIT SPECT) en los familiares asintomáticos. Se ha encontrado que la cognición global es similar en los EP-R1441G, EP-G2019S y EP-i, y que los rendimientos en el subtest de memoria se asocian con el UPSIT, la edad y los años de escolaridad. Así mismo, no hay diferencias en cognición, depresión y ansiedad entre EP-R1441G y EP-i emparejados por características clínicas, si bien se observó una menor prevalencia de EP-Demencia en los R1441G. Los familiares asintomáticos portadores-R1441G y no-portadores no difieren en características clínicas ni neuropsicológicas. Los portadores R1441G con TCREM, rinden peor en función visuoespacial y atención comparados con los portadores sin TCREM, cuya significación desaparece tras el ajuste estadístico. Los portadores R1441G tienen una mayor denervación dopaminérgica nigroestriatal en DaTSCAN, aunque este déficit sólo fue significativo en el putamen tras el ajuste estadístico. La condición de portador-R441G y tener un peor rendimiento en tests cronometrados predicen significativamente la disminución de la captación del DAT en el putamen y caudado más bajo, explicando aproximadamente el 70% y el 50% de su varianza respectivamente

Cerebrospinal Fluid 7-Ketocholesterol Level is Associated with Amyloid-β42 and White Matter Microstructure in Cognitively Healthy Adults

Background: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. Objective:We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals. Methods: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. Results: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). Conclusion: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

Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data

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

Características neuropsicológicas de pacientes con Enfermedad de Parkinson y portadores asintomáticos de la mutación R1441G en el gen LRRK2

238 p.El objetivo de esta tesis es conocer la afectación cognitiva asociada a la mutación LRRK2 R1441G tanto en pacientes con EP, como en portadores asintomáticos de la misma y la posible correlación de esta afectación con el estado dopaminérgico en los portadores asintomáticos. Para ello se ha realizado una valoración clínica y neuropsicológica de pacientes con EP asociada a mutaciones R1441G y G2019S y EP idiopática, y a familiares asintomáticos. Además, se ha realizado una prueba de imagen DaTSCAN (123I-FP-CIT SPECT) en los familiares asintomáticos. Se ha encontrado que la cognición global es similar en los EP-R1441G, EP-G2019S y EP-i, y que los rendimientos en el subtest de memoria se asocian con el UPSIT, la edad y los años de escolaridad. Así mismo, no hay diferencias en cognición, depresión y ansiedad entre EP-R1441G y EP-i emparejados por características clínicas, si bien se observó una menor prevalencia de EP-Demencia en los R1441G. Los familiares asintomáticos portadores-R1441G y no-portadores no difieren en características clínicas ni neuropsicológicas. Los portadores R1441G con TCREM, rinden peor en función visuoespacial y atención comparados con los portadores sin TCREM, cuya significación desaparece tras el ajuste estadístico. Los portadores R1441G tienen una mayor denervación dopaminérgica nigroestriatal en DaTSCAN, aunque este déficit sólo fue significativo en el putamen tras el ajuste estadístico. La condición de portador-R441G y tener un peor rendimiento en tests cronometrados predicen significativamente la disminución de la captación del DAT en el putamen y caudado más bajo, explicando aproximadamente el 70% y el 50% de su varianza respectivamente

Data from: Increased CAIDE dementia risk, cognition, CSF biomarkers and vascular burden in healthy adults

Objective: To investigate the cognitive profile of healthy individuals with increased CAIDE dementia risk score, and to explore whether this association is related to vascular burden and CSF biomarkers of amyloidosis and neurodegeneration. Method: Cognitively normal participants (mean age = 57.6 years) from the Gipuzkoa Alzheimer Project study were classified as having high risk (HR, n = 82) or low risk (LR, n = 293) for dementia according to a CAIDE score cut off of 9. Cognitive composites were compared between groups. We explored the role of APOE genotype, MRI white matter hyperintensities (WMH) and CSF (n = 218) levels of amyloid-β1-42 (Aβ1-42), total tau (t-tau) and phosphorylated tau (p-tau) in the association between CAIDE and cognition conducting generalized linear models. Results: HR participants obtained lower scores on executive function (EF) (p = .001) and visual perception and construction (VPC) (p < .001) composites. EFc was associated with CAIDEp-tau (p = .001), CAIDEt-tau (p = .001) and WMH (p = .003). VPCc was associated with APOE (p = .001), Aβ1-42 (p = .004), the interaction APOEAβ1-42 (p = .003), and WMH (p = .004). Performance on global memory was associated with Aβ1-42 (p = .006), APOE (p = .008), and their interaction (p = .006). Analyses were adjusted for age, education, sex, premorbid intelligence and stress. Conclusion: Healthy participants at increased dementia risk, based on CAIDE scores, show lower performance in executive function and visual perception and construction. This difference is related to APOE, WMH and Alzheimer’s biomarkers

Unlocking Preclinical Alzheimer’s: A Multi-Year Label-Free In Vitro Raman Spectroscopy Study Empowered by Chemometrics

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.This work was funded by the Basque Government (Ref. KK-2022/00001) and supported by grant CEX2020-001038-M funded by MICIU/AEI/10.13039/501100011033

Supplementary tables Ecay-Torres

These supplemetary tables contain the results of the intermediate generalized linear models needed to select the variables of the finals models shown in the manuscript

Down Syndrome—Basque Alzheimer Initiative (DS-BAI): Clinic-Biological Cohort

Background: 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. Methods: 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. Results: 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. Conclusion: Specific health plans for DS and conducting clinical and translational research on the challenges of aging, including AD, are necessary and feasible

e-References_Clinical and neuropsychological tests

The appendix includes the clinical and neuropsychological references list used in the GAP project