Browsing by Author "Molinuevo, José Luis"

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    The characterisation of subjective cognitive decline
    (Elsevier, 2020-03) Jessen, Frank; Amariglio, Rebecca E.; Buckley, Rachel F.; van der Flier, Wiesje M.; Han, Ying; Molinuevo, José Luis; Rabin, Laura; Rentz, Dorene M.; Rodriguez-Gomez, Octavio; Saykin, Andrew J.; Sikkes, Sietske A.M.; Smart, Colette M.; Wolfsgruber, Steffen; Wagner, Michael; Medical and Molecular Genetics, School of Medicine
    A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases.
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    Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk
    (PLOS, 2022-05-26) Ali, Muhammad; Sung, Yun Ju; Wang, Fengxian; Fernández, Maria V.; Morris, John C.; Fagan, Anne M.; Blennow, Kaj; Zetterberg, Henrik; Heslegrave, Amanda; Johansson, Per M.; Svensson, Johan; Nellgård, Bengt; Lleó, Alberto; Alcolea, Daniel; Clarimon, Jordi; Rami, Lorena; Molinuevo, José Luis; Suárez-Calvet, Marc; Morenas-Rodríguez, Estrella; Kleinberger, Gernot; Haass, Christian; Ewers, Michael; Levin, Johannes; Farlow, Martin R.; Perrin, Richard J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Dominantly Inherited Alzheimer Network (DIAN); Cruchaga, Carlos; Neurology, School of Medicine
    Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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    Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease
    (Springer Nature, 2022) Milà-Alomà, Marta; Ashton, Nicholas J.; Shekari, Mahnaz; Salvadó, Gemma; Ortiz-Romero, Paula; Montoliu-Gaya, Laia; Benedet, Andrea L.; Karikari, Thomas K.; Lantero-Rodriguez, Juan; Vanmechelen, Eugeen; Day, Theresa A.; González-Escalante, Armand; Sánchez-Benavides, Gonzalo; Minguillon, Carolina; Fauria, Karine; Molinuevo, José Luis; Dage, Jeffrey L.; Zetterberg, Henrik; Gispert, Juan Domingo; Suárez-Calvet, Marc; Blennow, Kaj; Neurology, School of Medicine
    Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials.
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    Publisher Correction: Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease
    (Springer Nature, 2022) Milà-Alomà, Marta; Ashton, Nicholas J.; Shekari, Mahnaz; Salvadó, Gemma; Ortiz-Romero, Paula; Montoliu-Gaya, Laia; Benedet, Andrea L.; Karikari, Thomas K.; Lantero-Rodriguez, Juan; Vanmechelen, Eugeen; Day, Theresa A.; González-Escalante, Armand; Sánchez-Benavides, Gonzalo; Minguillon, Carolina; Fauria, Karine; Molinuevo, José Luis; Dage, Jeffrey L.; Zetterberg, Henrik; Gispert, Juan Domingo; Suárez-Calvet, Marc; Blennow, Kaj; Neurology, School of Medicine
    This corrects the article "Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease" in Nat Med, volume 28 on page 1797.
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    Subjective cognitive decline and rates of incident Alzheimer's disease and non-Alzheimer's disease dementia
    (Elsevier, 2019-03) Slot, Rosalinde E. R.; Sikkes, Sietske A. M.; Berkhof, Johannes; Brodaty, Henry; Buckley, Rachel; Cavedo, Enrica; Dardiotis, Efthimios; Guillo-Benarous, Francoise; Hampel, Harald; Kochan, Nicole A.; Lista, Simone; Luck, Tobias; Maruff, Paul; Molinuevo, José Luis; Kornhuber, Johannes; Reisberg, Barry; Riedel-Heller, Steffi G.; Risacher, Shannon L.; Roehr, Susanne; Sachdev, Perminder S.; Scarmeas, Nikolaos; Scheltens, Philip; Shulman, Melanie B.; Saykin, Andrew J.; Verfaillie, Sander C. J.; Visser, Pieter Jelle; Vos, Stephanie J. B.; Wagner, Michael; Wolfsgruber, Steffen; Jessen, Frank; Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION: In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia. METHODS: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. RESULTS: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia. DISCUSSION: SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.
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    Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies
    (IOS Press, 2015-09-24) Rabin, Laura A.; Smart, Colette M.; Crane, Paul K.; Amariglio, Rebecca E.; Berman, Lorin M.; Boada, Mercè; Buckley, Rachel F.; Chételat, Gaël; Dubois, Bruno; Ellis, Kathryn A.; Gifford, Katherine A.; Jefferson, Angela L.; Jessen, Frank; Katz, Mindy J.; Lipton, Richard B.; Luck, Tobias; Maruff, Paul; Mielke, Michelle M.; Molinuevo, José Luis; Naeem, Farnia; Perrotin, Audrey; Petersen, Ronald C.; Rami, Lorena; Reisberg, Barry; Rentz, Dorene M.; Riedel-Heller, Stefi G.; Risacher, Shannon L.; Rodriguez, Octavio; Sachdev, Perminder S.; Saykin, Andrew J.; Slavin, Melissa J.; Snitz, Beth E.; Sperling, Reisa A.; Tandetnik, Caroline; van der Flier, Wiesje M.; Wagner, Michael; Wolfsgruber, Steffen; Sikkes, Sietske A.M.; Department of Radiology and Imaging Sciences, IU School of Medicine
    Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcomes