Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer’s Disease

Sala, Isabel; Illán-Gala, Ignacio; Alcolea, Daniel; Sánchez-Saudinós, Ma Belén; Salgado, Sergio; Morenas‐Rodríguez, Estrella; Subirana, Andrea; Videla, Laura; Clarimón, Jordi; Carmona-Iragui, María; Ribosa-Nogué, Roser; Blesa, Rafael; Fortea, Juan; Lleó, Alberto

doi:10.3233/jad-170073

Cited by 27 publications

(27 citation statements)

References 41 publications

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“…The study (IIBSP-BIO-2015-76) was approved by the local ethics committee following the ethical standards recommended by the Helsinki Declaration. All subjects were evaluated by neurologists with expertise in neurodegenerative diseases, by neuropsychologists using a previously published neuropsychological battery (12) and assessed for established AD biomarkers, namely brain amyloidosis (low CSF levels of A␤1-42 or positive amyloid PET imaging) and neurodegeneration (high CSF levels of total tau or phosphorylated tau) based on local cut-offs. These cut-offs have high specificity and sensitivity to distinguish AD dementia patients from controls (13).…”

Section: Methodsmentioning

confidence: 99%

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Lleó

Nuñez‐Llaves

Alcolea

et al. 2019

Molecular & Cellular Proteomics

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153

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A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsyntenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n ‫؍‬ 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p ‫؍‬ 0.04) in an independent cohort (n ‫؍‬ 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8fold, p < 0.04), a finding that was replicated (0.7 to 0.8fold, p < 0.05) for 6 proteins in a third cohort (n ‫؍‬ 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.

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Section: Methodsmentioning

confidence: 99%

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Lleó

Nuñez‐Llaves

Alcolea

et al. 2019

Molecular & Cellular Proteomics

Self Cite

153

151

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“…Cognitively normal control participants (n = 118) were also included in the present study. All controls had normal cognitive scores in the formal neuropsychological evaluation 23 and normal core CSF AD biomarkers (see 17 for further details of the SPIN cohort).…”

Section: Methodsmentioning

confidence: 99%

Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders

Delaby

Alcolea

Carmona-Iragui

et al. 2020

Sci Rep

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Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

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“…For the test dataset, 907 cognitively normal individuals were selected from eight cohorts of the European Medical Information Framework for Alzheimer's disease (EMIF-AD) project: Barcelona St. Pau (Alcolea et al, 2014 ; Sala et al, 2017 ), EDAR (Reijs et al, 2017 ), Gipuzkoa Alzheimer Project (GAP) (Estanga et al, 2017 ), Gothenburg MCI study (Wallin et al, 2016 ), IDIBAPS (Fortea et al, 2010 ), IMAP+ (La Joie et al, 2014 ), Leuven (Adamczuk et al, 2015 , 2016a , b ), EMIF preclinical-AD study (Demuru et al, 2017 ), and from the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study (Mueller et al, 2005 ) (Supplemental Table 1 ). Supplemental Table 2 shows an overview of the participating centers and the included number of subjects.…”

Section: Methodsmentioning

confidence: 99%

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

Bos

Vos

Jansen

et al. 2018

Front. Aging Neurosci.

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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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Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer’s Disease

Abstract: The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.

Cited by 27 publications

References 41 publications

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders

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

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