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Neuropsychiatric syndromes have been associated with memory dysfunction and risk of and earlier onset of dementia, but how psychotropic drugs affect clinical changes in Alzheimer's disease is not entirely clear. This study aimed to assess the prospective effects of psychotropic drugs on cognitive and functional changes in Alzheimer's disease according to APOE ε4 carrier status.The study included consecutive outpatients with late-onset Alzheimer's disease (N=193) and examined score variations at 1 year on the following tests: Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, Severe Mini-Mental State Examination (SMMSE), Brazilian version of the Zarit Caregiver Burden Interview, Index of Independence in Activities of Daily Living, and Lawton's Instrumental Activities of Daily Living Scale. Analyses of score variations accounted for the use of psychotropic drugs or the number of different medications in use, as well as APOE ε4 carrier status, with significance at p0.05.For APOE ε4 noncarriers (N=90), cholinesterase inhibitors were beneficial regarding caregiver burden (p=0.030) and basic functionality (p=0.046), memantine was harmful regarding SMMSE score changes (p=0.032), second-generation antipsychotics had nonsignificant harmful effects on SMMSE score changes (p=0.070), and antiepileptic therapy (p=0.001) and the number of different medications in use (p=0.006) were harmful in terms of basic functionality. APOE ε4 carriers (N=103) did not experience any effects of isolated psychotropic drugs on clinical changes, including antidepressants.Results support the harmful prospective effects of second-generation antipsychotics and antiepileptic drugs on cognitive and functional changes in Alzheimer's disease, particularly for APOE ε4 noncarriers, whereas antidepressants may be safer options for behavioral enhancement.

Introduction: The inherited risk of late-onset Alzheimer’s disease (AD) is genetically determined. We aimed to examine associations of genetic variants of APOE and ACE with age at AD onset and with...

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF. Fil: Parra, Mario Alfredo. Universidad Autónoma del Caribe; Colombia Fil: Baez, Sandra. Universidad de los Andes; Colombia Fil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gonzalez Campo, Cecilia. Universidad de San Andrés; Argentina Fil: Santamaría García, Hernando. Pontificia Universidad Javeriana; Colombia Fil: Aprahamian, Ivan. No especifíca; Fil: Bertolucci, Paulo. Universidade Federal de Sao Paulo; Brasil Fil: Bustin, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina Fil: Camargos Bicalho, Maria Aparecida. Universidade Federal de Minas Gerais; Brasil Fil: Cano Gutierrez, Carlos. Hospital Universitario San Ignacio; Colombia Fil: Caramelli, Paulo. Universidade Federal de Minas Gerais; Brasil Fil: Chaves, Marcia L. F.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Perez Cogram, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina Fil: Beber, Bárbara Costa. Universidade Federal do Rio Grande do Sul; Brasil Fil: Court, Felipe A.. Universidad Mayor; Chile Fil: de Souza, Leonardo Cruz. Universidade Federal de Minas Gerais; Brasil Fil: Custodio, Nilton. Peruvian Institute of Neurosciences; Perú Fil: Damian, Andres. Universidad de la República; Uruguay Fil: de la Cruz, Myriam. University of California; Estados Unidos Fil: Diehl Rodriguez, Roberta. Universidade de Sao Paulo; Brasil Fil: Dozzi Brucki, Sonia Maria. Universidade de Sao Paulo; Brasil Fil: Fajersztajn, Lais. Universidade de Sao Paulo; Brasil Fil: Farías, Gonzalo A.. Universidad de Chile; Chile Fil: De Felice, Fernanda G.. Universidade Federal do Rio de Janeiro; Brasil Fil: Ferrari, Raffaele. Colegio Universitario de Londres; Reino Unido Fil: Ferreira de Oliveira, Fabricio. Universidade de Sao Paulo; Brasil Fil: Ferreira, Sergio Teixeira. Universidade Federal do Rio de Janeiro; Brasil Fil: Ferretti, Ceres. Universidade de Sao Paulo; Brasil Fil: Figueredo Balthazar, Marcio Luiz. Universidade Estadual de Campinas; Brasil Fil: Ferreira Frota, Norberto Anizio. Universidade de Fortaleza; Brasil Fil: Fuentes, Patricio. No especifíca; Fil: García, Adolfo Martín. Universidad Nacional de Cuyo; Argentina. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Garcia, Patricia J.. Cayetano Heredia University; Perú Fil: de Gobbi Porto, Fábio Henrique. Universidade de Sao Paulo; Brasil Fil: Duque Peñailillo, Lissette. Ecuadorian Dementia Association; Ecuador Fil: Engler, Henry Willy. Universidad de la República; Uruguay Fil: Maier, Irene. Universidad de Chile; Chile Fil: Mata, Ignacio F.. University of Pittsburgh; Estados Unidos Fil: González Billault, Christian. Universidad de Chile; Chile Fil: Lopez, Oscar L.. University of Pittsburgh; Estados Unidos Fil: 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 Fil: Nitrini, Ricardo. Universidade de Sao Paulo; Brasil Fil: Quiroz, Yakeel T.. Harvard Medical School; Estados Unidos Fil: Guerrero Barragan, Alejandra. Universidad de la Sabana; Colombia Fil: Huepe, David. Universidad Adolfo Ibañez; Chile Fil: Pio, Fabricio Joao. Hospital Governador Celso Ramos; Brasil Fil: Suemoto, Claudia Kimie. Universidade de Sao Paulo; Brasil Fil: Kochhann, Renata. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Kochen, Sara Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina Fil: Kumfor, Fiona. University of Western Sydney; Australia Fil: Lanata, Serggio. University of California; Estados Unidos Fil: Miller, Bruce. University of California; Estados Unidos Fil: Lessa Mansur, Leticia. Universidade de Sao Paulo; Brasil Fil: Lie Hosogi, Mirna. Universidade de Sao Paulo; Brasil Fil: Lillo, Patricia. Universidad de Chile; Chile Fil: Llibre Guerra, Jorge. University of California; Estados Unidos Fil: Lira, David. Peruvian Institute of Neurosciences; Perú Fil: Lopera, Francisco. Universidad de Antioquia; Colombia Fil: Comas, Adelina. No especifíca; Fil: Avila Funes, José Alberto. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; México Fil: Sosa, Ana Luisa. Instituto Nacional de Neurología y Neurocirugía; México Fil: Ramos, Claudia. University of California; Estados Unidos Fil: de Paula França Resende, Elisa. University of California; Estados Unidos Fil: Snyder, Heather M.. No especifíca; Fil: Tarnanas, Ioannis. University of California; Estados Unidos Fil: Yokoyama, Jenifer. University of California; Estados Unidos Fil: Llibre, Juan. Centro de Estudios de Alzheimer; Cuba Fil: Cardona Londoño, Juan Felipe. Universidad del Valle; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Possin, Kate. University of California; Estados Unidos Fil: Kosik, Kenneth. University of California; Estados Unidos Fil: Montesinos, Rosa. Peruvian Institute of Neurosciences; Perú Fil: Moguilner, Sebastian Gabriel. University of California; Estados Unidos Fil: Solis, Patricia Cristina Lourdes. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche; Argentina. Universidad de Buenos Aires; Argentina Fil: de Lucena Ferretti Rebustini, Renata Eloah. Universidade de Sao Paulo; Brasil Fil: Ramirez, Jeronimo Martin. No especifíca; Fil: Matallana, Diana. Pontificia Universidad Javeriana; Colombia Fil: Mbakile Mahlanza, Lingani. University of California; Estados Unidos Fil: Mendonça Marques Ton, Alyne. Universidade Federal do Rio de Janeiro; Brasil Fil: Melo Tavares, Ronnielly. Centro Universitario de Belo Horizonte.; Brasil Fil: Miotto, Eliane C.. Universidade de Sao Paulo; Brasil Fil: Muniz-Terrera, Graciela. University of Edinburgh; Reino Unido Fil: MuñozN evárez, Luis Arnoldo. University of California; Estados Unidos Fil: Orozco, David. Universidad Nacional del Sur; Argentina Fil: Okada de Oliveira, Maira. University of California; Estados Unidos Fil: Piguet, Olivier. University of Western Sydney; Australia Fil: Pintado Caipa, Maritza. University of California; Estados Unidos Fil: Piña Escudero, Stefanie Danielle. University of California; Estados Unidos Fil: Porcello Schilling, Lucas. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Rodrigues Palmeira, André Luiz. Hospital Ernesto Dornelles; Brasil Fil: Sanches Yassuda, Mônica. Universidade de Sao Paulo; Brasil Fil: Santacruz Escudero, Jose Manuel. Pontificia Universidad Javeriana; Colombia Fil: Serafim, Rodrigo Bernardo. Universidade Federal do Rio de Janeiro; Brasil Fil: Smid, Jerusa. Universidade de Sao Paulo; Brasil Fil: Slachevsky, Andrea. Universidad de Chile; Chile Fil: Serrano, Cecilia Mariela. No especifíca; Fil: Soto Añari, Marcio. Universidad Católica San Pablo; Perú Fil: Takada, Leonel Tadao. Universidade de Sao Paulo; Brasil Fil: Tenenholz Grinberg, Lea. Universidade de Sao Paulo; Brasil Fil: Teixeira, Antonio Lucio. Universidade Federal de Minas Gerais; Brasil Fil: Tonidandel Barbosa, Maira. Universidade Federal de Minas Gerais; Brasil Fil: Trépel, Dominic. Trinity College; Estados Unidos Fil: Ibañez, Agustin Mariano. Universidad Autónoma del Caribe; Colombia. Universidad Adolfo Ibañez; Chile. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Effects of statins over clinical changes in Alzheimer's disease (AD) are usually non-significant, but epistatic interactions between genetic variants involved in cholesterol metabolism could be important for such effects. We aimed to investigate whether LDLR single-nucleotide polymorphisms rs11669576 (LDLR8), rs5930 (LDLR10), and rs5925 (LDLR13) are associated with cognitive and functional changes in AD, while also considering APOE haplotypes and lipid-lowering treatment with lipophilic statins for stratification. Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and caregiver burden, with prospective neurotranslational correlations documented for 1 year. For 179 patients, minor allele frequencies were 0.078 for rs11669576-A (14.5% heterozygotes), 0.346 for rs5930-A (42.5% heterozygotes), and 0.444 for rs5925-C (56.4% heterozygotes), all in Hardy-Weinberg equilibrium; 134 patients had hypercholesterolemia, and 133 used lipophilic statins. Carriers of rs11669576-G had faster cognitive decline, while functional decline was slower for carriers of rs11669576-A who used lipophilic statins. APOE-ε4 carriers who also carried rs5930-AA had improved caregiver burden, while carriers of haplotypes that included rs5930-AG had worse cognitive and functional outcomes, though carriers of the A allele of rs5930 had better cognitive and functional response to lipophilic statins. APOE-ε4 non-carriers who carried rs5925-TT had slower cognitive decline, while lipophilic statins protected carriers of the other genotypes. We preliminarily conclude that reportedly protective variants of LDLR and APOE against risk of AD also slowed cognitive decline, regardless of cholesterol variations, while therapy with lipophilic statins might benefit carriers of specific genetic variants.

Background: Pharmacogenetic effects of statins on clinical changes in Alzheimer’s disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism. Objective: To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOE ɛ4 carrier status and lipid-lowering treatment with lipophilic statins. Methods: Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year. Results: Considering n = 190:142 had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOE ɛ4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOE ɛ4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G. Conclusion: Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOE ɛ4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

The field of vascular contributions to cognitive impairment and dementia (VCID) is evolving rapidly. Research in VCID encompasses topics aiming to understand, prevent, and treat the detrimental effects of vascular disease burden in the human brain. In this perspective piece, early career researchers (ECRs) in the field provide an overview of VCID, discuss past and present efforts, and highlight priorities for future research. We emphasize the following critical points as the field progresses: (a) consolidate existing neuroimaging and fluid biomarkers, and establish their utility for pharmacological and non-pharmacological interventions; (b) develop new biomarkers, and new non-clinical models that better recapitulate vascular pathologies; (c) amplify access to emerging biomarker and imaging techniques; (d) validate findings from previous investigations in diverse populations, including those at higher risk of cognitive impairment (e.g., Black, Hispanic, and Indigenous populations); and (e) conduct randomized controlled trials within diverse populations with well-characterized vascular pathologies emphasizing clinically meaningful outcomes.

Background: Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases. Objective: We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer’s disease (AD) and cognitively healthy people. Methods: Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-β (Aβ)42, Aβ40, Aβ38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOE ɛ4 carrier status. Results: Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOE ɛ4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOE ɛ4 carriers) and 27 controls (78.48±8.7 years old, four APOE ɛ4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOE ɛ4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis. Conclusion: Biomarker ratios were superior to Aβ and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOE ɛ4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB.

Background: Swallowing and feeding problems may occur with the progression of behavioral variant frontotemporal dementia (bvFTD) and can impair the anticipatory and oral preparatory phases of swallowing. Objective: To characterize swallowing problems and the feeding situation of patients with bvFTD and to correlate the swallowing problems with functionality, executive functions, cognitive and behavioral features. Methods: Consecutive outpatients with bvFTD in mild, moderate and severe dementia stages were recruited along with their caregivers. Patients and caregivers were screened with the following scales: “Mini-Mental State Examination”, “Severe Mini-Mental State Examination”, “FTLD-modified Clinical Dementia Rating”, “Neuropsychiatric Inventory”, “Frontal Assessment Battery”, “Index of Independence in Activities of Daily Living”, “Swallowing Rating Scale” and “Assessment of Feeding and Swallowing Difficulties in Dementia”. Results: Overall, thirty patients with bvFTD were included along with their caregivers. Patients with bvFTD showed feeding and swallowing difficulties such as: messy to eat, passivity, coughing and choking, difficulty with some food consistencies and with specific food. Swallowing problems in bvFTD correlated with impaired functionality (p

Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from Sao Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE e 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE e 4/e 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE e 4. Exclusively for carriers of APOE e 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.

To identify knowledge gaps regarding new‐onset agitation and impulsivity prior to onset of cognitive impairment or dementia the International Society to Advance Alzheimer's Research and Treatment Neuropsychiatric Syndromes (NPS) Professional Interest Area conducted a scoping review. Extending a series of reviews exploring the pre‐dementia risk syndrome Mild Behavioral Impairment (MBI), we focused on late‐onset agitation and impulsivity (the MBI impulse dyscontrol domain) and risk of incident cognitive decline and dementia. This scoping review of agitation and impulsivity pre‐dementia syndromes summarizes the current biomedical literature in terms of epidemiology, diagnosis and measurement, neurobiology, neuroimaging, biomarkers, course and prognosis, treatment, and ongoing clinical trials. Validations for pre‐dementia scales such as the MBI Checklist, and incorporation into longitudinal and intervention trials, are needed to better understand impulse dyscontrol as a risk factor for mild cognitive impairment and dementia.

The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS-CoV-2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently call for a coordinated action plan, including the development of inexpensive mass testing and multilevel regional coordination for dementia care and related actions. Brain health diplomacy should lead to a shared and escalated response across the region, coordinating leadership, and triangulation between governments and international multilateral networks. Fil: Ibañez, Agustin Mariano. Universidad Adolfo Ibáñez; Chile. Universidad de San Andrés; Argentina. Universidad Autónoma del Caribe; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Santamaria Garcia, Hernando. Pontificia Universidad Javeriana; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Guerrero Barragan, Alejandra. University of California; Estados Unidos Fil: Kornhuber, Alexander. University of California; Estados Unidos Fil: Mendonca Marques Ton, Alyne. Universidade Vila Velha; Brasil Fil: Slachevsky, Andrea. Universidad de Chile; Chile Fil: Teixeira, Antonio Lucio. No especifíca; Fil: Mar Meza, Beatriz Marcela. University of California; Estados Unidos Fil: Serrano, Cecilia Mariela. Unidad Asistencial "Dr. César Milstein"; Argentina Fil: Cano, Carlos. Pontificia Universidad Javeriana; Colombia Fil: Arias Gonzalez, Carolina. University of California; Estados Unidos Fil: González Billault, Christian. Universidad de Chile; Chile Fil: Butler, Christopher. University of Oxford; Reino Unido. Pontificia Universidad Católica de Chile; Chile Fil: Bustin, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt; Argentina Fil: Duran Aniotz, Claudia. Universidad Adolfo Ibañez; Chile Fil: Acosta, Daisy. Universidad Nacional Pedro Henríquez Ureña; República Dominicana Fil: Matallana, Diana L.. Pontificia Universidad Javeriana; Colombia Fil: Acosta Alvear, Diego. University of California; Estados Unidos Fil: Trépel, Dominic. No especifíca; Fil: De Paula França Resende, Elisa. University of California; Estados Unidos. Universidade Federal do Rio de Janeiro; Brasil Fil: Ferreira de Oliveira, Fabricio. Universidade Federal de Sao Paulo; Brasil Fil: Ibanez, Francisco. Universidad Nacional de San Juan; Argentina Fil: De Felice, Fernanda G.. Universidade Federal do Rio de Janeiro; Brasil Fil: Navarrete, Gorka. Universidad Adolfo Ibañez; Chile Fil: Tarnanas, Ioannis. No especifíca; Fil: Meier, Irene B.. No especifíca; Fil: Smid, Jerusa. No especifíca; Fil: Llibre-Guerra, Jorge. University of California; Estados Unidos Fil: Llibre Rodriguez, Juan J.. Universidad de Ciencias Médicas; Cuba Fil: Fajersztajn, Laís. University of California; Estados Unidos. Universidade de Sao Paulo; Brasil Fil: Tadao Takada, Leonel. Universidade de Sao Paulo; Brasil Fil: Duque, Lissette. National Commission In Bioethics; Ecuador Fil: Okada de Oliveira, Maira. Universidade de Sao Paulo; Brasil Fil: Aparecida Camargos Bicalho, Maria. Universidade Federal de Minas Gerais; Brasil Fil: Behrens, María Isabel. Universidad Nacional de San Juan; Argentina. Universidad de Chile; Chile Fil: Pintado Caipa, Maritza. University of California; Estados Unidos Fil: Parra, Mario. University of Strathclyde; Reino Unido Fil: Wilson, Maxwell Z.. University of California; Estados Unidos Fil: De La Cruz Puebla, Myriam. Universidad de Barcelona; España. University of California; Estados Unidos Fil: Custodio, Nilton. Peruvian National Institute Of Health; Perú Fil: Santibanez, Rodrigo. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; Chile Fil: Serafim, Rodrigo Bernardo. No especifíca; Fil: Melo Tavares, Ronnielly. Universidade Federal do Rio de Janeiro; Brasil Fil: Piña Escudero, Stefanie Danielle. University of California; Estados Unidos Fil: Rodriguez, Tomas Leon. Universidad de Chile; Chile Fil: Dawson, Walter. University of California; Estados Unidos Fil: Miller, Bruce L.. University of California; Estados Unidos Fil: Kosik, Kenneth. University of California; Estados Unidos

Objective Differential diagnosis between Parkinson’s disease (PD) dementia and dementia with Lewy bodies (DLB) is difficult due to common features, whereas management decisions and research endpoints depend upon knowledge of dementia severity. We aimed to assess risk factors for age at dementia onset, as well as which neuropsychiatric features are associated with pharmacotherapy and signs and symptoms of Lewy body dementia. Patients and methods Patients with PD dementia or DLB were evaluated for age at disease onset, education, sanitation, anthropometric measures, alcohol use, smoking, history of infections or head trauma with unconsciousness, family history of neurodegenerative diseases, functional independence, cognition, behavior, motor features, caregiver burden and pharmacotherapy. Results Fifty-one patients were recruited (37 with DLB, 14 with PD dementia). Cumulative alcohol use and married status were associated with earlier dementia onset, whereas history of treated systemic infections and cumulative family history of primary neurodegenerative diseases led to later dementia onset. The length of dementia was shorter only for severely impaired patients who used anti-depressants, but not for users of cholinesterase inhibitors, while no behavioral symptom was associated with dopaminergic therapy. Night-time behavior disturbances were inversely associated with sleep satisfaction, while caregiver burden was more affected by depression and motor features. Non-motor symptoms were more burdensome for patients with DLB, while in PD dementia anxiety and dysphoria occurred when motor features were less burdensome. Conclusions PD dementia and DLB are two phenotypes of the same pathological entity, differing mostly by the occurrence of parkinsonian signs. Predictors of dementia onset differ from other neurodegenerative diseases.

Sleep disorders (SD) have a complex aetiology, and socioeconomic status (SES) as determined by social class, household income, ethnicity and education plays an important role in their development. As SD are associated with cognitive impairment and mood disorders, they in turn impact SES. Socioeconomic status also influences allostatic load caused by chronic accumulation of stress throughout life. Environmental and psychological stressors have a direct effect on SD, and they are modulated by SES, in combination with comorbidities like obesity and cardiovascular disease. This review explores the recent theories about the influence of SES on the development of SD in the general population, whether or not occurring with comorbidities, and also focusses on the interplay between socioeconomic status, circadian rhythms, aging and clinical outcomes like metabolic diseases and cancer.

Background: Midlife hypertension followed by late life hypotension resulting from neurodegeneration increases amyloidogenesis and tauopathy. Methods: Consecutive outpatients with late-onset Alzheimer's disease (AD) at various stages and their respective caregivers were assessed for score variations in 1 year of tests assessing caregiver burden, functionality and cognition according to blood pressure (BP) variations and APOE haplotypes, while also taking into account differential effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, diuretics, or no antihypertensive medication on score changes. The diagnosis and treatment of arterial hypertension followed the JNC 7 report. Results: Variations in systolic BP (-11.76 ± 17.1 mm Hg), diastolic BP (-4.92 ± 10.3 mm Hg) and pulse pressure (-6.84 ± 12.6 mm Hg) were significant after 1 year (n = 191; ρ < 0.01). For APOE4+ carriers, rises in systolic or diastolic BP improved Clinical Dementia Rating Scale Sum of Boxes scores (ρ < 0.04), with marginally significant improvements in Mini-Mental State Examination scores resulting from risen systolic (ρ = 0.069) or diastolic BP (ρ = 0.079), and in basic independence only regarding risen diastolic BP (ρ = 0.055). APOE4- carriers resisted any functional or cognitive effects of BP variations. No differences were found regarding any antihypertensive class for variations in BP or any test scores, regardless of APOE haplotypes. Conclusions: Targeting mild BP elevations brings better functional and cognitive results for APOE4+ carriers with AD.

Midlife cerebrovascular risk, low cognitive reserve and APOE4+ haplotypes are risk factors for Alzheimer's disease dementia (AD). We prospectively searched for factors that might be associated with yearly changes in caregiver burden, cognition, basic and instrumental functionality in 193 consecutive outpatients with late-onset AD, namely gender, APOE haplotypes, schooling, age at AD onset, marital status, depression, cerebrovascular risk factors, serum TSH levels, cognitive and physical activities, and treatment with cholinesterase inhibitors or anti-psychotics, while also investigating associations between APOE haplotypes and patient participation in cognitive or physical activities. Higher education led to greater declines in instrumental functionality, whereas increases in body mass index were associated with rises in basic functionality and cognitive test scores. Established cerebrovascular risk factors had no independent effects over cognitive or functional change, but their combinations led to cognitive improvement, possibly related to enhanced cerebral perfusion in late life. Cholinesterase inhibitors improved caregiver burden. Enhanced instrumental functionality and steeper cognitive decline by the use of anti-psychotics might be attributed to improved behavioural symptoms and neuropsychiatric side effects, respectively. Each copy of APOE-ε4 (β=-0.102) led to cumulative decreased participation in physical activities (ρ=0.015). These results might impact public health policies and the interpretation of clinical trials for AD.

Aims Primarily, we sought to verify correlations among assessments for cognition, behaviour and functional independence in a sample of patients with dementia due to Alzheimer's disease (AD). Secondarily, impacts of education, APOE haplotypes, length of dementia, age and alcohol use over the neuropsychiatric assessment were estimated. Methods Patients with AD were assessed for demographic features, neuropsychiatric symptoms, cognitive test scores, functional impairment, caregiver burden and APOE haplotypes. Statistical comparisons were undertaken by way of Kruskal–Wallis test, linear regressions and Spearman correlations, significance at ρ Results A total of 217 patients were included. Mean schooling was 4.21±3.7 years, with significant impacts over cognitive tests. Mean age at examination was 78±6.19 years-old, significantly influencing instrumental functionality. The mean length of the dementia syndrome was 5.4±2.9 years, significantly impacting cognitive decline and functionality. Apathy was the most common behavioural symptom, negatively correlated with anxiety and delusions, and positively correlated with lifetime alcohol load. Patients with previous smoking or drinking habits were more likely to continue smoking or drinking later in life. APOE4+ haplotypes led to earlier dementia onset and significantly lower caregiver burden in mild dementia stages. Conclusions Most correlations among test results were highly significant, confirming that cognition, behaviour and functionality are usually interrelated in all stages of AD. Caregiver burden was correlated with behaviour, but not with cognition, and was lower for patients with APOE4+ haplotypes in mild dementia stages. Education is a major impact factor for cognitive performance.

Illiteracy, high cerebrovascular risk and copies of APOE-ϵ4 are risk factors for Alzheimer's disease dementia (AD). We aimed to investigate the impacts of gender, education, coronary heart disease (CHD) risk and creatinine clearance variations, body mass index (BMI) and APOE haplotypes over the rates of cognitive and functional decline of AD in one year.Consecutive outpatients with late-onset AD were assessed for gender, schooling, BMI and APOE haplotypes, variations in one year of creatinine clearance and Framingham projections of the 10-year absolute CHD risk, and prospective scores of the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Sum-of-Boxes (CDR-SOB), the Index of Independence in Activities of Daily Living (ADL) and Lawton's Scale for Instrumental Activities of Daily Living (IADL).For 191 patients, mean age at AD onset was 73.26 ± 6.4 years-old, earlier for APOE-ϵ4/ϵ4 carriers (p = 0.0039). For women, higher BMI led to improvements in CDR-SOB (β = -0.091; p = 0.037) and MMSE (β = 0.126; p = 0.017) scores, while increased creatinine clearance was associated with improvements in ADL (β = 0.028; p = 0.012) and MMSE (β = 0.043; p = 0.039) scores and higher schooling led to faster worsening of IADL (β = -0.195; p = 0.022) scores. No variables impacted cognitive or functional decline for men, whereas copies of APOE-ϵ4 and the CHD risk had no significant effects whatsoever.Higher BMI and creatinine clearance are protective regarding cognitive and functional decline for women, whereas higher cognitive reserve may lead to faster decline in instrumental functionality. APOE haplotypes affected the age at AD onset, but not cognitive or functional decline.

Sleep length and architecture are potential markers of progressive cognitive impairment, while neuropsychiatric symptoms and APOE4- haplotypes have been associated with more sleep complaints in patients with dementia due to Alzheimer's disease (AD). In this cross-sectional study, we sought to investigate which factors might be related to sleep satisfaction in patients with AD. A total of 217 consecutive patients with AD were assessed for demographic features, neuropsychiatric symptoms, cognitive decline, functional impairment for activities of daily living, caregiver burden, APOE haplotypes, self-reported sleep satisfaction and length of sleep. Statistical comparisons were conducted with significance at p0.05. Concerning sleep complaints, 179 patients (82.5%) reported satisfactory sleep, while 38 (17.5%) were unsatisfied, with no relation to age, sex, APOE haplotypes, obesity, education, marital status, alcohol consumption or smoking found. Length of sleep (p=0.011) and behavioural symptoms (p=0.009) had significant associations with sleep satisfaction. Length of sleep was positively correlated with apathy (p=0.014) and scores on the Clock Drawing Test (p=0.015), and inversely correlated with anxiety (p=0.015) and independence for instrumental activities of daily living (p=0.003). Patients who were treated with memantine (p=0.02) or anti-psychotics (p0.01) had longer duration of sleep. In conclusion, behavioural symptoms had strong associations with sleep satisfaction, which is highly correlated with length of sleep in patients with AD. Functional independence, apathy, anxiety, use of memantine or anti-psychotics, and scores on the Clock Drawing Test were significantly associated with length of sleep in this sample.

Objective In view of the mild effects of pharmacological treatment for dementia due to Alzheimer's disease (AD), the search for modifiable risk factors is an important challenge. Although risk factors for AD are widely recognized, elements that influence the time of onset of the dementia syndrome have not been comprehensively reported. We aimed to investigate which risk factors might be associated with the age at onset of AD in a sample of patients with low mean schooling from Sao Paulo, Brazil. Methods We included 210 consecutive patients with late-onset AD to investigate whether education, gender, nationality, urban living and sanitation, occupation, cognitive and physical inactivity, head trauma, depression, systemic infections, surgical interventions, cerebrovascular risk factors, family history of neurodegenerative diseases or cardiovascular diseases and apolipoprotein E gene (APOE) haplotypes might be related to the age at AD onset. Results Each copy of APOE-e4 led to onset of AD almost 2 years earlier, while depression, smoking, higher body mass index and family history of cardiovascular diseases were also highly significant. Protective factors included non-Brazilian nationality, use of a pacemaker and waist circumference. Cerebrovascular risk factors had a mild combined effect for earlier onset of AD. Conclusion APOE haplotypes, depression, nationality and cerebrovascular risk factors were the most important elements to influence the age at AD onset in this sample, whereas gender, education, occupation and physical activities had no isolated effects over the age at onset of this dementia syndrome. Copyright © 2014 John Wiley & Sons, Ltd.

Hypercholesterolemia and statin use have been unevenly associated with clinical change in Alzheimer's disease dementia. In this longitudinal study, 192 consecutive outpatients with late-onset Alzheimer's disease dementia were stratified according to APOE haplotypes, and followed for one year to investigate associations of lipid profile variations and lipophilic statin therapy with changes in cognition, caregiver burden, basic and instrumental functionality. Overall, 102 patients (53.1%) carried APOE4+ haplotypes and 90 (46.9%) carried APOE4- haplotypes; 189 patients (98.4%) used either a cholinesterase inhibitor, or Memantine, or both; 144 patients had dyslipidemias and 143 of them received statin therapy. Total cholesterol, LDL-cholesterol, Mini-Mental State Examination scores, and functional independence scores were significantly lower at the end of the follow-up, while Clinical Dementia Rating sum-of-boxes scores were higher. Exclusively for APOE4- carriers, rising LDL-cholesterol levels were associated with a trend toward improvements in the Index of Independence in Activities of Daily Living (β=0.010; ρ=0.16), whereas rising HDL-cholesterol levels were associated with lowered scores (β=-0.051; ρ=0.04). Lipophilic statin therapy had non-significant protective effects over Clinical Dementia Rating sum-of-boxes score variations only for APOE4- carriers. APOE4- haplotypes might enhance lipid availability to protect neuronal membranes, thus overcoming their supposed dysfunction in cholesterol metabolism, while APOE4+ carriers have inefficient neural repair mechanisms. In conclusion, APOE haplotypes seem to influence the protective effects of lipid profile variations for patients with Alzheimer's disease dementia, but current evidence is insufficient to propose lipid-lowering drugs as specific anti-dementia therapy.

More than 95% of right-handed individuals, as well as almost 80% of left-handed individuals, have left hemisphere dominance for language. The perisylvian networks of the dominant hemisphere tend to be the most important language systems in human brains, usually connected by bidirectional fibres originated from the superior longitudinal fascicle/arcuate fascicle system and potentially modifiable by learning. Neuroplasticity mechanisms take place to preserve neural functions after brain injuries. Language is dependent on a hierarchical interlinkage of serial and parallel processing areas in distinct brain regions considered to be elementary processing units. Whereas aphasic syndromes typically result from injuries to the dominant hemisphere, the extent of the distribution of language functions seems to be variable for each individual.Review of the literature Results: Several theories try to explain the organization of language networks in the human brain from a point of view that involves either modular or distributed processing or sometimes both. The most important evidence for each approach is discussed under the light of modern theories of organization of neural networks.Understanding the connectivity patterns of language networks may provide deeper insights into language functions, supporting evidence-based rehabilitation strategies that focus on the enhancement of language organization for patients with aphasic syndromes.

Objective: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer’s disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results: Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.

Background Few studies have described characteristics of swallowing in primary progressive aphasia (PPA) and its variants. Objective To describe and characterize swallowing and eating behaviors of patients with PPA, as well as their correlates with neuropsychiatric symptoms and patterns of communication. Methods We studied 16 patients with PPA and 16 their caregivers. PPA was subdivided in agrammatic variant (PPA-G), semantic variant (PPA-S) and logopenic variant (PPA-L). All patients and their caregivers were screened with the following scales: "Assessment of Feeding and Swallowing Difficulties in Dementia", "Neuropsychiatric Inventory", and "Functional Outcome Questionnaire for Aphasia". Results Patients with PPA-S had diverse swallowing problems such as drooling of saliva or food, multiple swallows, delayed swallow and choking, all of which correlated with anxiety, apathy and aberrant motor behavior. Patients with PPA-G and PPA-L had choking and delayed swallow, respectively. Disturbances in eating behaviors were more frequent in the group with PPA-L, and they correlated with difficulties in patterns of communication. Conclusions All variants showed swallowing difficulties and they were more frequent in PPA-S. Further studies with larger samples of patients are needed to better characterize swallowing problems and their consequences in the different variants of PPA.

Normal pressure hydrocephalus is an unusual manifestation of systemic lupus erythematosus and its pathogenesis is still unclear. We report the case of a 39-year-old white woman with systemic lupus erythematosus who developed magnetic gait, speech difficulties, progressive memory impairment, urinary incontinence and episodes of involuntary closure of the eyelids. Signs and symptoms, associated with ventriculomegaly and normal cerebrospinal fluid pressure, suggested normal pressure hydrocephalus, which as a complication of systemic lupus erythematosus believably develops due to the insidious inflammatory process that occurs in the meningeal tissues or to the vasculitis itself. Normal pressure hydrocephalus tends to develop secondary to trauma, infection or subarachnoid haemorrhage, but in 50 % of patients no aetiology is found. Shunt surgery is the only effective treatment, specifically for the gait disorder, which usually improves more than the cognitive symptoms. Since the tap-test showed a strongly positive result, a medium pressure ventriculoperitoneal shunt was inserted, further replaced by a high pressure one in view of the complications, with less than expected improvement. Subdural hematomas and empyemas developed, requiring surgery and antibiotic therapy. A new tap-test was positive, and the patient improved only after a programmable valve was finally placed. However, pressure regulation shall be continuously required, and shunt dysfunction might still develop in the long term. The few similar case reports in the literature are reviewed, confirming the rarity of this neurological complication of systemic lupus erythematosus.

Background & objectives: Neurodegeneration affects blood pressure variations, while renal function and cerebral perfusion are impaired by vascular risk factors. This study was aimed to estimate variations of measures of cardiovascular risk in Alzheimer's dementia by pharmacogenetic analyses of the effects of angiotensin-converting enzyme (ACE) inhibitors and statins. Methods: Consecutive patients were prospectively followed to study variations of creatinine clearance and blood pressure for one year, estimated by correlating the effects of ACE inhibitors with the ACE Alu I/D polymorphism and genotypes or haplotypes of rs1800764 or rs4291, and the effects of statins with LDLR (low-density lipoprotein receptor) genotypes or haplotypes of rs11669576 (exon 8) or rs5930 (exon 10), or genotypes of rs2695121 (liver X receptor β gene). Variations of the coronary heart disease (CHD) risk according to these cardiovascular measures were also explored. Results: All polymorphisms of the 193 patients were in Hardy-Weinberg equilibrium. Genetic determinants of cardiovascular effects affected the individual variability of the response to ACE inhibitors and statins. ACE inhibitors, but not statins, reduced blood pressure for all patients. ACE inhibitors protected carriers of alleles that supposedly decrease serum ACE levels (rs1800764-T, rs4291-A, Alu II) regarding creatinine clearance variations (P