Abstract:

Alzheimer´s disease (AD) is the most prevalent disorder of senile dementia mainly characterized by amyloid-beta peptide (Aβ) deposits in the brain. Cannabinoids are relevant to AD as they exert several beneficial effects in many models of this disease. Still, whether the endocannabinoid system is either up- or down-regulated in AD has not yet been fully elucidated. Thus, the aim of the present paper was to analyze endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in cerebral cortex synaptosomes incubated with Aβ oligomers or fibrils. These Aβ conformations were obtained by "aging" the 1-40 fragment of the peptide under different agitation and time conditions. A diminished availability of 2-AG resulting from a significant decrease in diacylglycerol lipase (DAGL) activity was observed in the presence of large Aβ1-40 oligomers along with synaptosomal membrane damage, as judged by transmission electron microscopy and LDH release. Conversely, a high availability of 2-AG resulting from an increase in DAGL and lysophosphatidic acid phosphohydrolase activities occurred in the presence of Aβ1-40 fibrils although synaptosomal membrane disruption was also observed. Interestingly, neither synaptosomal mitochondrial viability assayed by MTT reduction nor membrane lipid peroxidation assayed by TBARS formation measurements were altered by Aβ1-40 oligomers or fibrils. These results show a differential effect of Aβ1-40 peptide on 2-AG metabolism depending on its conformation.

Author affiliation: Pascual, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina

Author affiliation: Gaveglio, Virginia Lucía. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina

Author affiliation: Giusto, Norma Maria. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina

Author affiliation: Pasquaré, Susana Juana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina

Abstract:

The accumulation of amyloid β peptide (Aβ) in the brain of Alzheimer's disease (AD) patients begins many years before clinical onset. Such process has been proposed to be pathogenic through the toxicity of Aβ soluble oligomers leading to synaptic dysfunction, phospho-tau aggregation and neuronal loss. Yet, a massive accumulation of Aβ can be found in approximately 30% of aged individuals with preserved cognitive function. Therefore, within the frame of the "amyloid hypothesis", compensatory mechanisms and/or additional neurotoxic or protective factors need to be considered and investigated. Here we describe a modifier genetic screen in Drosophila designed to identify genes that modulate toxicity of Aβ42 in the CNS. The expression of Aβ42 led to its accumulation in the brain and a moderate impairment of negative geotaxis at 18 days post-eclosion (d.p.e) as compared with genetic or parental controls. These flies were mated with a collection of lines carrying chromosomal deletions and negative geotaxis was assessed at 5 and 18 d.p.e. Our screen is the first to take into account all of the following features, relevant to sporadic AD: (1) pan-neuronal expression of wild-type Aβ42; (2) a quantifiable complex behavior; (3) Aβ neurotoxicity associated with progressive accumulation of the peptide; and (4) improvement or worsening of climbing ability only evident in aged animals. One hundred and ninety-nine deficiency (Df) lines accounting for ~6300 genes were analyzed. Six lines, including the deletion of 52 Drosophila genes with human orthologs, significantly modified Aβ42 neurotoxicity in 18-day-old flies. So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines. PRCC encodes proline-rich protein PRCC (ppPRCC) of unknown function associated with papillary renal cell carcinoma. HPD encodes 4-hydroxyphenylpyruvate dioxygenase (HPPD), a key enzyme in tyrosine degradation whose Df causes autosomal recessive Tyrosinemia type 3, characterized by mental retardation. Interestingly, lines with a partial Df of HPD ortholog showed increased intraneuronal accumulation of Aβ42 that coincided with geotaxis impairment. These previously undetected modifiers of Aβ42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in the pathogenesis of sporadic AD.

Author affiliation: Belfiori Carrasco, Lautaro Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina

Author affiliation: Marcora, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina

Author affiliation: Bocai, Nadia Irina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina

Author affiliation: Ceriani, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina

Author affiliation: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina

Author affiliation: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina

Abstract:

Objective: To describe the Amyloid, Tau, Neurodegeneration (A/T/N) research framework classification in the Argentine-Alzheimer Neuroimaging Initiative (ADNI) cohort. Methods: 23 Mild Cognitive Impairment (MCI), 12 Alzheimer?s Disease (AD) and 14 controls were studied with the ADNI-2 protocol. Patients were categorized according to ?A? Aβ biomarkers, ?T? tau biomarker, and ?N? neurodegeneration. Results: A+/T+/N+ at baseline was found in 2/14 controls (14%), 2/10 early MCI (20%), 6/13 late MCI (46%) and 11/12 mild dementia (91%). Suspected non- AD pathophysiology (SNAP, A-/T-/N+) was found in 1/14 controls (7%), 2/10 early MCI (20%), 2/13 late MCI (15%) and 1/12 mild dementia (8%). MCI with A+/T+/N+ showed 75% (6/8) and A-/T-/N+ 50% (2/4) of conversion to dementia in two years.Conclusions: This is the first report from this region based on AD biomarkers and the new A/T/N classification. Our findings suggest that this biological classification is better for prognosis in a short time than the classical clinical one.

Author affiliation: Allegri, Ricardo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de la Costa; Colombia

Author affiliation: Pertierra, Lucia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Cohen, Gabriela. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Chrem Mendez, Patricio Alexis. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Russo, María Julieta. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Calandri, Ismael. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Bagnati, Pablo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Tapajoz Pereira de Sampaio, Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Clarens, Florencia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Campos, Jorge. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Nahas, Federico Exequiel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Surace, Ezequiel Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Vázquez, Silvia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Author affiliation: Sevlever, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Abstract:

Objective: Language is a key source of cross-cultural variability, which may have both subtle and major effects on neurocognition. However, this issue has been largely overlooked in two flourishing lines of research assessing the relationship between language-related neural systems and dementia. This paper assesses the limitations of the evidence on (i) the neuroprotective effects of bilingualism in Alzheimer´s disease and (ii) specific language deficits as markers of Parkinson´s disease. Design: First, we outline the rationale behind each line of research. Second, we review available evidence and discuss the potential impact of cross-linguistic factors. Third, we outline ideas to foster progress in both fields and, with it, in cross-cultural neuroscience at large. Results: On the one hand, studies on bilingualism suggest that sustained use of more than one language may protect against Alzheimer´s disease symptoms. On the other hand, insights from the embodied cognition framework point to syntactic and action-verb deficits as early (and even preclinical) markers of Parkinson´s disease. However, both fields share a key limitation that lies at the heart of cultural neuroscience: the issue of cross-linguistic generalizability. Conclusion: Relevant evidence for both research trends comes from only a handful of (mostly Indo-European) languages, which are far from capturing the full scope of structural and typological diversity of the linguistic landscape worldwide. This raises questions on the external validity of reported findings. Greater collaboration between linguistic typology and cognitive neuroscience seems crucial as a first step to assess the impact of transcultural differences on language-related effects across neurodegenerative diseases.

Author affiliation: Calvo Garbarino, Noelia Belén. Universidad Nacional de San Juan. Facultad de Filosofía, Humanidades y Artes; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina. Instituto de Neurología Cognitiva. Laboratorio de Psicología Experimental y Neurociencia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Ibáñez Barassi, Agustín Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Universidad Autónoma del Caribe; Colombia. Universidad Adolfo Ibañez; Chile. Australian Research Council; Australia

Author affiliation: Muñoz, Edinson. Universidad de Santiago de Chile; Chile

Author affiliation: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Universidad Nacional de Cuyo; Argentina

Abstract:

Introduction: In the present study we have elaborated a multivariate–multifactor diagnostic method for diagnosis of ischemic and nonischemic dementia, and validated it using different human populations. Our purpose was to improve dementia diagnosis by means of comprehensive neuropsychological assessment and the control of intervening variables. Methods: Data were obtained from 114 healthy volunteers to 101 patients consecutively referred for suspected dementia. On the basis of neuromorphological criteria, the patient sample was subdivided into those with ischemic lesions (IL: N = 12) and without ischemic lesions (non-IL: N = 89). The patient groups and the healthy subjects (HS) were matched according to age, education, sex ratio and handedness. A comprehensive neuropsychological battery was administered to all the participants. Results: The two patient groups differed in their Hachinski ischemic score, but not in terms of demographic variables, the Blessed rating scale, Mini Mental State, Geriatric Depression Scale, or other measures. Discriminant analysis selected fifteen neuropsychological variables from the comprehensive battery, and these were found to provide accuracy of classification in 98% of HS and 87% of the patients considered as a whole. Considering the three groups, those variables provided accuracy of classification in 98% of HS, 82% of IL patients and 82% of non-IL patients. Subtests were internally consistent (Cronbach's alpha: 0.87) and a positive association between ischemic lesions and cognitive impairment was observed when the 15 dependent variables were added. Discussion: It is possible to select a combination of cognitive tests that discriminated HS from dementia patients and, within this category, patients with and without ischemic lesions. Analysis of the 15 variables provides an improved method for diagnosis of ischemic vs. nonischemic lesion dementia in humans.

Author affiliation: Vigliecca, Nora Silvana. Universidad Nacional de Cordoba. Facultad de Filosofia y Humanidades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cordoba. Facultad de Medicina. Hospital Cordoba; Argentina

Author affiliation: Aleman, Gretel Patricia. Universidad Nacional de Cordoba. Facultad de Filosofia y Humanidades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cordoba. Facultad de Medicina. Hospital Cordoba; Argentina

Abstract:

Cholinergic deficit is regarded as an important factor responsible for Alzheimer's disease (AD) symptoms. Acetylcholinesterase (AChE) and nicotinic receptor (AChR) are two molecular targets for the treatment of this disease. We found here that methanolic extracts of Camellia sinensis exhibited anticholinesterase activity and induced AChR conformational changes. From bioguided fractionation we confirmed that caffeine was the active compound exerting such effects. It is well-known that caffeine acts as an inhibitor of AChE and here we explored the effect of caffeine on the AChR by combining single channel recordings and fluorescent measurements. From single channel recordings we observed that caffeine activated both muscle and α7 AChRs at low concentrations, and behaved as an open channel blocker which was evident at high concentrations. Fluorescent measurements were performed with the conformational sensitive probe crystal violet (CrV) and AChR rich membranes from Torpedo californica. Caffeine induced changes in the K D value of CrV in a concentration-dependent manner taking the AChR closer to a desentisized state. In the presence of α-bungarotoxin, an AChR competitive antagonist, high concentrations of caffeine increased the K D value of CrV, compatible with a competition with CrV molecules for the luminal channel. Our electrophysiological and fluorescent experiments show that caffeine has a dual effect on nicotinic receptors, behaving as an agonist and an ion channel blocker, probably through distinct AChR sites with quite different affinities. Thus, caffeine or its derivatives can be considered for the design of promising multitarget-directed drugs for AD treatment by modulation of different targets in the cholinergic pathway.

Author affiliation: Fabiani, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina

Author affiliation: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina

Author affiliation: Corradi, Jeremias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina

Author affiliation: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina

Abstract:

A dual readout autographic assay to detect acetylcholinesterase inhibitors present in complex matrices adsorbed on reversed-phase or normal-phase thin-layer chromatography plates is described. Enzyme gel entrapment with an amphiphilic copolymer was used for assay development. The effects of substrate and enzyme concentrations, pH, incubation time, and incubation temperature on the sensitivity and the detection limit of the assay were evaluated. Experimental design and response surface methodology were used to optimize conditions with a minimum number of experiments. The assay allowed the detection of 0.01% w/w of physostigmine in both a spiked Sonchus oleraceus L. extract chromatographed on normal phase and a spiked Pimenta racemosa (Mill.) J.W. Moore leaf essential oil chromatographed on reversed phase. Finally, the reversed-phase thin-layer chromatography assay was applied to reveal the presence of an inhibitor in the Cymbopogon citratus (DC.) Stapf essential oil. The developed assay is able to detect acetylcholinesterase inhibitors present in complex matrixes that were chromatographed in normal phase or reversed-phase thin-layer chromatography. The detection limit for physostigmine on both normal and reversed phase was of 1×10-4 μg. The results can be read by a change in color and/or a change in fluorescence.

Author affiliation: Ramallo, Ivana Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina

Author affiliation: García, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina

Author affiliation: Furlan, Ricardo Luis Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina

Abstract:

We study the complex formation of a peptide betaAbetaAKLVFF, previously developed by our group, with Abeta(1-42) in aqueous solution. Circular dichroism spectroscopy is used to probe the interactions between betaAbetaAKLVFF and Abeta(1-42), and to study the secondary structure of the species in solution. Thioflavin T fluorescence spectroscopy shows that the population of fibers is higher in betaAbetaAKLVFF/Abeta(1-42) mixtures compared to pure Abeta(1-42) solutions. TEM and cryo-TEM demonstrate that co-incubation of betaAbetaAKLVFF with Abeta(1-42) causes the formation of extended dense networks of branched fibrils, very different from the straight fibrils observed for Abeta(1-42) alone. Neurotoxicity assays show that although betaAbetaAKLVFF alters the fibrillization of Abeta(1-42), it does not decrease the neurotoxicity, which suggests that toxic oligomeric Abeta(1-42) species are still present in the betaAbetaAKLVFF/Abeta(1-42) mixtures. Our results show that our designed peptide binds to Abeta(1-42) and changes the amyloid fibril morphology. This is shown to not necessarily translate into reduced toxicity.

Author affiliation: Castelletto, Valeria. University of Reading. Department of Chemistry; Reino Unido

Author affiliation: Hamley, Iam W.. University of Reading. Department of Chemistry; Reino Unido. Diamond Light Source; Reino Unido

Author affiliation: Lim, Teck. University of Oxford. Department of Materials; Reino Unido

Author affiliation: de Tullio, Matias Blas. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina

Author affiliation: Castaño, Eduardo Miguel. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina

Abstract:

Deposition of amyloid-β (Aβ), the proteolytic product of the amyloid precursor protein (APP), might cause neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the direct involvement of APP in the mechanism of Aβ-induced degeneration in AD remains on debate. Here, we analyzed the interaction of APP with heterotrimeric Go protein in primary hippocampal cultures and found that Aβ deposition dramatically enhanced APP-Go protein interaction in dystrophic neurites. APP overexpression rendered neurons vulnerable to Aβ toxicity by a mechanism that required Go-Gβγ complex signaling and p38–mitogen-activated protein kinase activation. Gallein, a selective pharmacological inhibitor of Gβγ complex, inhibited Aβ-induced dendritic and axonal dystrophy, abnormal tau phosphorylation, synaptic loss, and neuronal cell death in hippocampal neurons expressing endogenous protein levels. In the 3xTg-AD mice, intrahippocampal application of gallein reversed memory impairment associated with early Aβ pathology. Our data provide further evidence for the involvement of APP/Go protein in Aβ-induced degeneration and reveal that Gβγ complex is a signaling target potentially relevant for developing therapies for halting Aβ degeneration in AD.

Author affiliation: Bignante, Elena Anahi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoda; Argentina

Author affiliation: Ponce, Nicolás Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Heredia, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Musso, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Krawczyk, Maria del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina

Author affiliation: Millán, Julieta. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina

Author affiliation: Pigino, Gustavo Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Inestrosa, Nibaldo C.. Pontificia Universidad Católica de Chile; Chile. Centro de Excelencia en Biomedicina de Magallanes; Chile

Author affiliation: Boccia, Mariano Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina

Author affiliation: Lorenzo, Alfredo Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina

Abstract:

Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up. Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD. Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF Aβ1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d-prime were predictive of progression to AD (χ2 = 38.23, df = 14, p < 0.001). Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d-prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI.

Author affiliation: Russo, María Julieta. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Campos, Jorge. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina

Author affiliation: Vázquez, Silvia. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina

Author affiliation: Sevlever, Gustavo. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Allegri, Ricardo Francisco. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina