The 'when' matters : evidence from memory markers in the clinical continuum of Alzheimer's disease

Objective: Cognitive assessment able to detect impairments in the early neuropathological stages of Alzheimer's disease (AD) are urgently needed. The Visual Short-Term Memory Binding Task (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) have been recommended by the Neurodegenerative Disease Working Group as promising tests to aid in the early detection of AD. In this study, we investigated their complementary value across the clinical stages of the AD continuum. Methods: 117 older adults with subjective cognitive complaint (SCC), 79 with mild cognitive impairment (MCI), 31 patients with AD dementia (ADD) and 37 cognitively unimpaired (CU) subjects, underwent assessment with the VSTMBT and the Picture version of the Spanish FCSRT. Results: After controlling for multiple comparisons, significant differences were found across groups. The VSTMBT was the only test that ‘marginally’ differentiated between CU and SCC (d = 0.47, p = 0.052). Moreover, whereas the FCSRT showed a gradient (CU = SCC) > MCI > ADD, the VSTMBT gradient was CU > SCC > (MCI = ADD) suggesting that conjunctive binding deficits assessed by the latter may be sensitive to the very early stages of the disease. Conclusions: Our results suggest that the VSTMBT and the FCSRT are sensitive to the clinical continuum of AD. Whereas the former detects changes in the early prodromal stages, the latter is more sensitive to the advanced prodromal stages of AD. These novel tests can aid in the early detection, monitor disease progression and response to treatment, and thus support drug development programs

Dopamine receptor D3 expression is altered in CD4(+) T-cells from parkinson's disease patients and its pharmacologic inhibition attenuates the motor impairment in a mouse model

Neuroinflammation constitutes a fundamental process involved in Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4(+) T-cells infiltrate the brain in PD, where they play a critical role determining the functional phenotype of microglia, thus regulating the progression of the disease. We previously demonstrated that mice bearing dopamine receptor D3 (DRD3)-deficient CD4(+) T-cells are completely refractory to neuroinflammation and consequent neurodegeneration induced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we aimed to determine whether DRD3-signalling is altered in peripheral blood CD4(+) T-cells obtained from PD patients in comparison to healthy controls (HC). Furthermore, we evaluated the therapeutic potential of targeting DRD3 confined to CD4(+) T-cells by inducing the pharmacologic antagonism or the transcriptional inhibition of DRD3-signalling in a mouse model of PD induced by the chronic administration of MPTP and probenecid (MPTPp). In vitro analyses performed in human cells showed that the frequency of peripheral blood Th1 and Th17 cells, two phenotypes favoured by DRD3-signalling, were significantly increased in PD patients. Moreover, native CD4(+) T-cells obtained from PD patients displayed a significant higher Th1 -biased differentiation in comparison with those naive CD4(+) T-cells obtained from HC. Nevertheless, DRD3 expression was selectively reduced in CD4(+) T-cells obtained from PD patients. The results obtained from in vivo experiments performed in mice show that the transference of CD4(+) T-cells treated ex vivo with the DRD3-selective antagonist PG01037 into MPTPp-mice resulted in a significant reduction of motor impairment, although without significant effect in neurodegeneration. Conversely, the transference CD4(+) T-cells transduced ex vivo with retroviral pArtículos codifying for an shRNA for DRD3 into MPTPp-mice had no effects neither in motor impairment nor in neurodegeneration. Notably, the systemic antagonism of DRD3 significantly reduced both motor impairment and neurodegeneration in MPTPp mice. Our findings show a selective alteration of DRD3-signalling in CD4(+) T-cells from PD patients and indicate that the selective DRD3-antagonism in this subset of lymphocytes exerts a therapeutic effect in parkinsonian animals dampening motor impairment

Epidemiology of chronic inflammatory demyelinating polyneuropathy in the South-Eastern area of Santiago, Chile

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated polyneuropathy. It usually has an insidious onset, progressive course and heterogeneous clinical features. As far as we know, there is no epidemiological information on CIDP in South America and the Caribbean. Our aim was to estimate the frequency of CIDP in the South-Eastern region of Santiago, where our hospital is based and the population number assigned is officially reported every year by the health authorities. Records of 581 patients registered with the diagnosis of neuropathy were found and all patients meeting the diagnostic criteria of the EFNS/PNS for definitive and possible CIDP were included. Data were collected using a data extraction protocol designed by the authors and which included demographic, clinical, laboratory and electrophysiological information. The estimated prevalence and incidence of CIDP were 2.95/100,000 and 0.46/100,000 respectively. Fifteen patients (8 men, 7 women) were classified as definitive or possible CIDP. Nine patients had typical CIDP and three also had diabetes mellitus. The prevalence and incidence rates were similar to those reported in other regions of the world. (C) 2020 Published by Elsevier Ltd

Memory markers can help trace the Alzheimer's disease continuum : evidence from the GERO cohort

Background: Cognitive assessments able to detect impairments as early as neuropathological changes that occur in neurodegenerative diseases initiate are urgently needed. The Visual Short-Term Memory Binding Test (VSTMBT) and the Free and Cued Selective Reminding Test (FCRST) have been recently recommended by the Neurodegenerative Diseases Working Group (Costa et al., 2017) as promising preclinical markers of AD. They have never been used before to assess elderlies with cognitive complain recruited from the community. Method: A total of 271 subjects (37 healthy controls (HC), 112 subjective cognitive complain (SCC), 96 mild cognitive impairment (MCI) and 26 Alzheimer's disease dementia (ADD)), recruited from Geroscience Center for Brain Health and Metabolism (GERO) Cohort and the Memory and Neuropsychiatric Clinic (CMYN), underwent assessment with the VSTMBT and the Visual Version of the FCRST (FCRST-Visual). Two memory loads were used for the VSTMBT (low and high). The ability of these tests to discriminate between groups. Result: Significant differences were found between HC, MCI and ADD using the VSTMBT and the FCRST-Visual version. Notably, the STMB was the only test that "marginally" differentiated between HC from SCC (p = 0.055). Moreover, whereas the FCRST-Visual showed a gradient (HC = SCC) > MCI > AD, the VSTMBT's gradient was HC > (SCC = MCI = ADD) suggesting that the function assessed by the latter test may be sensitive to the very early stages of the disease dropping to levels that cannot decline further. Conclusion: Our results suggest that the VSTMBT and FCSRT are sensitive to the early stages of dementia. Whereas the former detects changes in the early subjective stages, the latter is more sensitive to later objective stages of cognitive decline. The latter but not the former could help monitor disease progression. These results raise important questions about the usefulness of cognitive screening tools to detect and monitor disease progression and to separate normal and abnormal ageing trajectories. We propose the need of cognitive assessments that detect subtle differences as early as neuropathological changes occur in the brain, which will lead to the development of new "cognitive biomarkers" for dementia

Alzheimer's Disease or behavioral variant frontotemporal dementia? Review of key points toward an accurate clinical and neuropsychological diagnosis

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common neurodegenerative early-onset dementias. Despite the fact that both conditions have a very distinctive clinical pattern, they present with an overlap in their cognitive and behavioral features that may lead to misdiagnosis or delay in diagnosis. The current review intends to summarize briefly the main differences at the clinical, neuropsychological, and behavioral levels, in an attempt to suggest which aspects would facilitate an adequate diagnosis in a clinical setting, especially in Latin American and low- and middle-income countries, where the resources needed for a differential diagnosis (such as MRI or biomarkers) are not always available. A timely diagnosis of AD and FTD have significant implications for the medical management and quality of life of patients and careers

Automated text-level semantic markers of Alzheimer's disease

INTRODUCTION: Automated speech analysis has emerged as a scalable, cost-effective tool to identify persons with Alzheimer?s disease (AD). Yet, most research is undermined by low interpretability and specificity. METHODS: Combining statistical and machine learning analyses of natural speech data, we aimed to discriminate AD dementia (ADD) patients from healthy controls (HCs) based on automated measures of domains typically affected in AD: semantic granularity (coarseness of concepts) and ongoing semantic variability (conceptual closeness of successive words). To test for specificity, we replicated the analyses on Parkinson?s disease (PD) patients. RESULTS: Relative to controls, ADD (but not PD) patients exhibited significant differences in both measures. Also, these features robustly classified between ADD patients and HCs (AUC = 0.8), yielding near-chance classification between PD patients and HCs (AUC = 0.65). DISCUSSION: Automated discourse-level semantic analyses can reveal objective, interpretable, and specific markers of ADD, bridging well-established neuropsychological targets with digital assessment tools.Fil: Sanz, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Carrillo, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Slachevsky, Andrea. Universidad de Chile; ChileFil: Forno, Gonzalo. Universidad de Chile; Chile. Universidad de Barcelona; EspañaFil: Gorno Tempini, María L.. University of California; Estados UnidosFil: Villagra, Roque. Universidad de Chile; ChileFil: Ibañez, Agustin Mariano. Universidad Adolfo Ibañez; Chile. Universidad de San Andrés; Argentina. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tagliazucchi, Enzo Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: García, Adolfo Martín. Universidad de San Andrés; Argentina. Universidad Nacional de Cuyo. Facultad de Educación Elemental y Especial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

J Clin Exp Neuropsychol

Subjective Cognitive Decline (SCD) refers to a self-perceived experience of decreased cognitive function without objective signs of cognitive impairment in neuropsychological tests or daily living activities. Despite the abundance of instruments addressing SCD, there is no consensus on the methods to be used. Our study is founded on 11 questions selected due to their recurrence in most instruments. The objective was to determine which one of these questions could be used as a simple screening tool. 189 participants aged 65 and over selected from Primary Care centers in Santiago de Chile responded to these 11 questions and were evaluated with the MiniMental State Examination (MMSE), the Free and Cued Selective Reminding Test (FCSRT), the Pfeffer functional scale, and the Geriatric Depression Scale (GDS). An Item ResponseTheory (IRT) method was performed to assess the contribution of each of the 11 questions to the SCD latent trait and its discrimination ability. Based on the results of the exploratory factor analysis showing very high/low saturation of several questions on the factors, and the high residual correlation between some questions, the IRT methods led to select one question ("Do you feel like your memory has become worse?") which revealed to be the most contributive and discriminant. Participants who answered yes had a higher GDS score. There was no association with MMSE, FCSRT, and Pfeffer scores. The question "Do you feel like your memory has become worse?" may be a good proxy of SCD and could be included in routine medical checkups

Association of GST M1 null polymorphism with Parkinson's disease in a Chilean population with a strong Amerindian genetic component

We have studied the association of a null mutation of Glutathione Transferase M1 (GST M1*0/0) with Parkinson's disease (MIM 168600) in a Chilean population with a strong Amerindian genetic component. We determined the genotype in 349 patients with idiopathic Parkinson's disease (174 female and 175 male; 66.84 ± 10.7 years of age), and compared that to 611 controls (457 female and 254 male; 62 ± 13.4 years of age). A significant association of the null mutation in GST M1 with Parkinson's disease was found (p = 0.021), and the association was strongest in the earlier age range. An association of GSTM1*0/0 with Parkinson's disease supports the hypothesis that Glutathione Transferase M1 plays a role in protecting astrocytes against toxic dopamine oxidative metabolism, and most likely by preventing toxic one-electron reduction of aminochrome. © 2007 Elsevier Ireland Ltd. All rights reserved

Aging and health policies in Chile: new agendas for research

Population aging is among the most important global transformations. Compared to European and North American countries, Chile is among the countries with the fastest growth of life expectancy at birth during recent decades. The aging of Chile's population is related to the improvement of living conditions, but also entails risks that tend to be associated with a rapid economic growth accompanied by large income inequalities and a chronic deficit of basic social benefits. The rapid demographic transition towards an aged population has unfolded in a context of poor development of public policies to tackle the opportunities and needs associated with an aging society. This article provides a brief overview of current Chilean public policy on aging, with a focus on healthy aging as defined by World Health Organization. The discussion addresses core challenges to successfully achieve healthy aging in Chile.FONDAP 15150012 Conicyt/ Associative Research Program / Basal Funds Grant for Centers of Excellence FB 0003 Conicyt / Fondecyt Regular/ Fondecyt Initiation 1160940 1170010 11150355 Columbia University President's Global Innovation Fund CONICET CONICYT/FONDECYT Regular 1130920 FONCyT PICT/2012-0412 2012-1309 INECO Foundatio