Dr. José Ricardo López Contreras NEURÓLOGO

Especialista en Demencias y Trastornos del Movimiento

Estudios de Post-grado en la Especialidad de: ENFERMEDAD DE PARKINSON, TRASTORNOS DEL MOVIMIENTO Y ENFERMEDAD DE ALZHEIMER Hospital Clínico de Barcelona y Universidad de Barcelona. España

Fundador de: -ASOCIACIÓN PARKINSON DE EL SALVADOR -ASOCIACIÓN DE FAMILIARES ALZHEIMER DE EL SALVADOR

Miembro de: • International Parkinson and Movement Disorder Society (MDS) • Miembro del Comité de Educación de la Sección Panamericana de International Parkinson and Movement Disorder Society • Co-Chair of Central American Movement Disorders Work Group • Alzheimer´s Disease International • Secretario de la Confederación de Asociaciones Alzheimer de Centro América • Alzheimer Ibero América

Trabajos de Investigación: Ha publicado varios estudios de Investigación en Revistas Internacionales de Neurología: • Movement Disorder (the official Journal of the International Parkinson and Movement Disorder Society) • Revista Neurología (Revista oficial de la Sociedad Española de Neurología)

Conferencista: En Congresos Nacionales e Internacionales

Dr. José Ricardo López Contreras NEURÓLOGO

Especialista en: Demencias

y Trastornos del Movimiento

9.9millones

de casos nuevosde demencia/año

en el mundo

PERSONAS CON DEMENCIA EN EL MUNDO

64,000 El Salvador

(2019)

Deterioro de la función intelectual,

adquirido y persistente de al menos tres de las siguientes esferas de la función

mental: Lenguaje, memoria, capacidades visuo-espaciales, emoción, personalidad y cognición (abstracción, cálculo, juicio, etc.)

Condiciona interferencia en el desempeño

de las actividades sociales, laborales y de la vida cotidiana.

Metabólico o nutricional Tóxico Neoplásico Infecciosas Vascular Neurodegenerativo Otras: Hematoma subdural crónico, Hidrocefalia, TCE, depresión

Causas

DIAGNÓSTICO • Historia médica general, Neurológica, Neuroconductual,

Psiquiatrica • Toxicos, fármacos • Antecedentes Personales Familiares • Examen Físico, Neurológico y Neuropsicológico

Genetica de la enfermedad de Alzheimer:

CROMOSOMA Gen Mutaciones/Alelos Consecuencias

21 APPSingle missense mutationsDouble missense mutationTrisomy 21 (gene dosage effect)

Early-onset FADIncreased Aß production

14 PS-1 Missense mutationsSplice site mutations

Early-onset FADIncreased Aß production

1 PS-2 Missense mutations Early-onset FADIncreased Aß production

19 APOE Allele 4 Increased risk of development of

ADDecreased age at onset of AD

Encefalopatía por TDP-43 Predominantemente Límbica Relacionada con la Edad

DEMENCIA “SENIL”

DETERIORO COGNITIVO

LEVE

DEMENCIA

NORMAL

ENFERMEDAD DE ALZHEIMER FISOPATOLOGÍA.

Creciente consenso:

La producción y acumulación del

péptido beta amiloide (ßA) tiene un rol central en la

patogénesis de la enfermedad de Alzheimer.

Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease:

progress and problems on the road to therapeutics. Science 2002;297:353-6.

Jeffrey L. Cummings, M.D. Alzheimer’s Disesase N Engl J Med 2004;351:56-67.

PROTEINA PRECURSORA DE AMILOIDE Metabolismo Normal

ß-Amiloide (ß-A).

Beta Secretasa Gamma Secretasa

695-770 aa COOH NH

La Proteina Precursora de Amilodie (PPA): Ampliamente distribuida en todo el cuerpo Contiene entre 695-770 a.a.

PROTEINA PRECURSORA DE AMILOIDE Metabolismo Anormal

Suero, LCR

ßA-42 (50-100%)

Depósito: Placas PPA Alzheimer

ßA-40 ( 0-50 %)

Eliminado

The Journal of Neuroscience, June 27, 2012 • 32(26):

Normalmente es soluble y Promueve la formación de neurofilamentos

en el proceso axonal.

PROTEINA TAU

PROTEINA TAU •Normalmente es soluble. •Promueve la formación de neurofilamentos en el proceso axonal

AGREGADOS NEUROFIBRILARES

FILAMENTOS HELICOIDALES

PARES

FILAMENTOS HELICOIDALES

PARES

Placas de ß-Amiloide (“Placas Seniles”) Compuesta por:Depósito extracelular de amiloide + Proteina Tau intracelular

PRE-SINTOMATICO

Corteza Cerebral

Hipocampo

ALZHEIMER LEVE-M0DERADA

Ventriculos Ventriculos

Corteza Cerebral

Ventriculos

Hipocampo

ALZHEIMER SEVERA

Alzheimer Normal

Evolución de la enfermedad de Alzheimer

Deterioro Cogntivo Leve

Alzheimer

Normal

Normal DCL Alzheimer

DCL EA

Estadio I: Leve. •Cambios: •Memoria •Anomia.

•Orientación. •Personalidad •Habilidades

Visuo-espaciales. Estadio II: Moderado.

•Afasia. •Apraxia.

•Confusión. •Agitación. •Insomnio.

•Juicio. •Dependencia parcial en AVD.

Estadio III: Severo. •Incontinencia

•Dificultad para comer •Deterioro motor.

•Habilidades. Visuo-espaciales.

•Trast. neuropsiquiatricos •Dependencia total en AVD.

Estadio IV: Terminal •Encamamiento.

•Mutismo. •Trastorno de la deglución. •Infecciones intercurrentes.

•Cognición •Independencia

10 Años

ENFERMEDAD DE ALZHEIMER Evolución

Normalidad Demencia Severa

Functional assessment staging (FAST). Barry Reisberg. Psychopharmacol Bull 1988.

• “Personas Sanas”. • Sin síntomas subjetivos, ni objetivos de deterioro cognitivo y funcional. • Libres de cambios de carácter y comportamiento.

• “Falta de Memoria Normal para la Edad”. 65 años: 50% Dificultades subjetivas cognitivas y/o funcionales. Problemas subjetivos (inadvertidos): • Recordar nombres. • Encontrar la palabra adecuada. • Concentración. • Olvida donde deja los objetos.

• “Deterioro Cognitivo Leve”. Déficit sutiles (advertidos): 2-7 años. • Repetir preguntas. • Funciones ejecutivas. • Tareas laborales y sociales complejas. • Concentración. • Ansiedad.

• Pronóstico variable.

“Enfermedad de Alzheimer Leve” Síntomas de deterioro evidentes: 2 años. • Fallos de memoria reciente. • Desorientación parcial en tiempo. • Anómia. • Juicio conservado. Negación. • Cambios del afecto. • Dificultad AVD complejas: Cocinar, dinero. • Independiente en la comunidad.

“Enfermedad de Alzheimer Moderada”. Magnitud Síntomas: 1-5 años. • Fallos de memoria reciente y remota. • Desorientación en tiempo y lugar. • Trastornos de aprendizaje. • Olvidan hechos recientes importantes. • Anómia. Discalculia. • Elección de ropa. • Irritabilidad, agresividad, ideas paranoides. • AVD básicas: Supervizadas por cuidador. • Dependencia parcial en la comunidad.

“Enfermedad de Alzheimer Moderadamente Severa”. Déficit cognitivos severos: 2.5 años. • Desconoce hechos importantes de su vida actual y sus familiares. • Hiperactividad, agitación, alucinaciones. • Conductas inapropiadas. • Acalculia. •Trastorno expresión/comprensión verbal. •Dependiente en AVD y en la comunidad.

“Enfermedad de Alzheimer Moderadamente Severa”.

ESTADIO 6-A: Apraxia del vestir.

“Enfermedad de Alzheimer Moderadamente Severa”.

ESTADIO 6-B: Baño. Aseo bucal. ESTADIO 6-C: Lavabo.

“Enfermedad de Alzheimer Moderadamente Severa”.

ESTADIO 6-D: Incontinencia Urinaria. ESTADIO 6-E: Incontinencia Fecal.

Asistencia continua en AVD: 6 Sub-estadio. Severo Trastorno del Lenguaje. Rigidez muscular, contracturas de miembros. Sindrome de inmobilización. Complicaciones: Neumonia, Escaras.

“Enfermedad de Alzheimer Severa”.

“Enfermedad de Alzheimer Severa”. Reflejos “Primitivos”: Prensión, succión, Babinski. ESTADIO 7-A: + 6 palabras intelegibles. ESTADIO 7-B: 1 palabra inteligible. ESTADIO 7-C: Camina con ayuda. ESTADIO 7-D: Se sienta con ayuda. ESTADIO 7-E: Pierde capacidad de sonreir. Muecas. ESTADIO 7-F: No sostienen la cabeza erecta.

Tratamiento Famracológico Perspectivas a futuro

Enfermedad de Alzheimer Tratamiento. Fármacos disponibles en El Salvador

MEMANTINA 10 mg, 20 mg

13.3 /24 h

DONEPECILO

RIVASTIGMINA

Rivastigmina

GALANTAMINA

RIVASTIGMINA

Futuras alternativas de Tratamiento HIPOTESIS: Identificar Agentes que actúen sobre la cascada amiloidea para modificar el inicio y curso de la enfermedad de Alzheimer.

• Anti-Amiloideos • Anti-Oxidantes. • Anti-Inflamatorios. • Anti-Fosforilación de la Proteina Tau, • Anti-Apoptóticos • Antagonistas de Receptores NMDA.

Jeffrey L. Cummings, M.D. Alzheimer’s Disesase N Engl J Med 2004;351:56-67.

Spence JD, Viscoli CM, Inzucchi SE, et al; IRIS Investigators. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial [published online February 7, 2019]. JAMA Neurol. doi:10.1001/jamaneu- rol.2019.0079

I. J. Martins, R. Creegan

1552

Ceram ide

Palmitoyl-CoA + L-serine

Increased saturated fatty acids Cytokine induced (TNFα )

Sphingomyelin

Serine-palmitoyltransferase

Sphingomyelinase

↑ iNOS

↑ apoptosis

NFκB

↑ NO

Bcl2

Lipid Storage Excess intake Obesity

↑ lipolysis

Insulin signalling viaIRS-1, PI3-K and Akt/PKB

Figure 1. Ceramides—the toxic intermediate linking metabolic dysfunction, inflammatory cytokines and insulin resistance. When adipose tissue exceeds its storage capacity, adipokines increase inflammation which increases cera- mides. This inhibits insulin signaling further increasing lipolysis and increas- ing the release of fattyacids for ceramide synthesis. Ceramide promotes apop- tosis and the elevated saturated fatty acids inhibit the Bcl2 of anti-apoptotic proteins.

Table 1. ApoE gene frequency and disease risk [84]-[89].

Genotype Allele Frequency Disease Association APOEε2 (Cys112 Cys158) 7% ↑ and ↑ qisk foq atheqoscleqosis [81] and ↑ risk for Parkinson’s Disease [83] APOEε3 (Cys112 Arg158) 79% Considered neutral

APOEε4 (Arg112Arg158) 14% ↑ qisk foq atheqoscleqosis, AD, cognitive impaiqment, ↑hippocampal volume, fasteq progression of multiple sclerosis, cerebrovascular disease and sleep apnea [84]-[91]

key membrane-bound proteins including (amyloid precursor protein) APP, (β-site APP cleaving enzyme) BACE and γ-secretase involved in AD [24] [25]. Lipid rafts are domains within the plasma membrane bilayer consist-ing of cholesterol, glycosphingolipids and protein receptors. APP clusters in cholesterol-rich lipid rafts of neu-rons, astrocytes and microglia [92] [93]. These specialized regions compartmentalize cellular processes and act as organizing centers for assembly of signaling molecules. Rafts also influence membrane fluidity and are in-volved with membrane protein and receptor trafficking and the regulation of neurotransmitters [94].

Increased cellular ceramide levels regulate cellular cholesterol levels with effects on APP-Abeta processing [24] [25]. Aβ is produced by cleavage of APP and APP can be processed by two different pathways a non- amyloidogenic pathway by α-secretase or the amyloidogenic pathway by BACE [24] [25]. In both cases initial cleavage is followed by an additional cleavage by γ-secretase [95]-[97]. α-secretase cleaves within the Aβ domain of APP liberating a soluble APP fragment (APPsα) which precludes the formation of Aβ which has neurotrophic and neuroprotective properties [95]. The immediate precursor to Aβ is the C-terminal domain of APP called C99, which is the product of BACE cleavage of APP and has an affinity for cholesterol binding. Localisation of APP/C99 is therefore directed to the cholesterol rich rafts, where the BACE and γ-secretase are concentrated, thereby increasing amyloidogenic processing of APP [95] [98]. BACE has been shown to be stabilised by cera-mides and therefore increased ceramides may promote amyloidogenic processing of APP [99] [100]. Further-more S1P has been shown to adjust BACE activity in neurons with inhibitors of sphingosine kinase as targets for prevention of neurodegeneration in AD [101] [102].

In the brain apoE has been shown to be essential for ceramide metabolism and nerve sprouting and in these apoE knockout mice plasma lipoproteins were enriched in sphingomyelin [103] [104]. Individuals with neuro-

Health, 2014, 6, 1549-1579

Health, 2014, 6, 1549-1579 Published Online June 2014 in SciRes. http://www.scirp.org/journal/health http://dx.doi.org/10.4236/health.2014.612190

How to cite this paper: Martins, I.J. and Creegan, R. (2014) Links between Insulin Resistance, Lipoprotein Metabolism and Amyloidosis in Alzheimer’s Disease. Health, 6, 1549-1579. http://dx.doi.org/10.4236/health.2014.612190

Links between Insulin Resistance, Lipoprotein Metabolism and Amyloidosis in Alzheimer’s Disease Ian James Martins1,2,3*, Rhona Creegan1,2 1Centre of Excellence in Alzheimer’s Disease Research and Care School of Medical Sciences, Edith Cowan University, Joondalup, Australia

2School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands, Australia 3McCusker Alzheimer’s Research Foundation, Holywood Medical Centre, Nedlands, Australia Email: *i.martins@ecu.edu.au Received 23 April 2014; revised 5 June 2014; accepted 24 June 2014

Copyright © 2014 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Abstract The origins of premature brain aging and chronic disease progression are associated with athe- rogenic diets and sedentary lifestyles in Western communities. Interests in brain aging that in- volves non alcoholic fatty liver disease (NAFLD), the global stroke epidemic and neurodegenera- tion have become the focus of nutritional research. Atherogenic diets have been linked to plasma ceramide dysregulation and insulin resistance actively promoting chronic diseases and neurode- generation in developed countries. Abnormal lipid signaling as observed in chronic diseases such as hypothyroidism, obesity and diabetes is connected to stroke and neurodegenerative diseases in man. Lipids that are involved in calcium and amyloid betahomeostasis are critical to cell mem-brane stability with the maintenance of nuclear receptors and transcriptional regulators that are involved in cell chromatin structure and DNA expression. Western diets high in fat induce hyper-lipidemia, insulin resistance and other hormonal imbalances that are linked to alterations in brain calcium and lipid metabolism with susceptibility to various chronic diseases such as stroke. Nutrition and food science research identifies dietary components and lipids to prevent hyperlip-idemia and calcium dyshomeostasis connected to neuroendocrine disease by maintaining astro-cyte-neuron interactions and reversing hormonal imbalances that are closely associated with NAFLD, stroke and Alzheimer’s disease (AD) in global populations.

Keywords Nutrition, Hyperlipidemia, Ceramide, Calcium, Neuron, Astrocyte

*Corresponding author.

Health, 2014, 6, 1549-1579

I. J. Martins, R. Creegan

1558

Figure 6. Peripheral metabolic hormones and bioactive lipids regulate astro- cyte survival and oxidative stress with neuronal apoptosis.

of neurons. Lipids such as cardiolipin, anionic phospholipids and sphingolipids including ceramides not only affect astrocyte andmicroglia function but also influence neuron calcium homeostasis. Abnormal calcium ho-meostasis is linked to excitotoxicity and neuronal cell death and recent studies have shown that elevated calcium levels are linked to insulin resistance and diabetes [272]-[277]. Furthermore, metabolic disorders such as obesity and diabetes in which endocrine disturbances are present appear to promote bioactive lipid interactions affecting astrocyte function and neuron calcium homeostasis, which influences membrane function, nuclear lipids and cell receptors such as the GPCRs. Hormones binding to receptors such as the GPCRs in astrocytes result in signal transduction and are linked to a heterotrimeric G proteinwhich alters the amount of astrocytic calcium released from endoplasmic reticulum (ER)and may result in altered neuron activity (Figure 6). Abnormalities in intra-cellular neuron calcium and lipid regulation are strongly linked to ER stress that accelerate protein aggregation disorders such as occurs in non-alcoholic fatty liver disease (NAFLD), diabetes and AD [278]-[282].

Lipids such as ceramide-1-phosphate, phosphoinositides, arachidonic acid (AA), docosahexaenoic acid (DHA), DAG and prostaglandin E2 have significant effects on intracellular calcium affecting calcium dysregu-lation in the ER and mitochondria leading to cell death [283]-[286]. Polyunsaturated fatty acids such as DHA and AA may have neuroprotective effects by regulation of phospholipase A2 activity with marked effects on as-trocyte and neuronal calcium levels involved in ER stabilization in brain and peripheral cells [286]-[288]. Other bioactive lipids present in astrocyte and neuronal cell membranes such as endocannabinoids (Figure 6) and platelet activating factor (PAF) which participates in signaling cascades associated with calcium channels and calcium homeostasis may also play a role in neuroendocrine disease [289]. In diabetes, neurodegeneration and stroke [290] [291] PAF is being shown to contribute to the pathological processes by its influence on eicosanoid synthesis which participate in inflammatory and chronic neurological processes.

As previously stated obesity and diabetes lead to abnormal peripheral lipid metabolism and also involve dis-turbances in several hormones including triiodothyronine (T3), thyroxine (T4), leptin, adiponectin, and insulin [292]-[294]. In the brainhormones such as insulin, leptin, adiponectin, oxytocin, corticotropin releasing hormone (CRH) and thyroid hormones bind to extracellular receptors in astrocytes (Figure 6). Astrocytes play a central role in thyroid hormone metabolism in the brain and are responsible for uptake of thyroxine from the blood and its conversion to 3,5,3’-triiodothyronine. The supply of the biologically active form of thyroxine to neurons is important to neuron survival, neuritogenesis and synapse formation [295] [296]. Thyroid hormones, adiponectin and leptin have been shown to target the oxytocin neurons with control of body weight regulation and lipid me-tabolism [297]-[301]. Thyroid hormones have profound effects on adipokines, lipid metabolism and carbohy-drate homeostasis with alteration in plasma lipids and zinc deficiency linked to hypothyroidism [302]. Other pe-ripheral hormones such as cortisol are also associated with insulin resistance and dyslipidemia with hypotha-lamic CRH involved in its regulation and peripheral calcium homeostasis. This suggests that the existence of a complex network of hormones that regulate neuronal function involves calcium/energy homeostasis and is in-

I. J. Martins, R. Creegan

1556

Figure 5. Atherogenic diets are closely associated with oxidative stress, lipid peroxidation with the generation of second messengers that promote chronic disease progression and neurodegeneration.

lipo-protein B-100 produced in the liver and increase the cellular accumulation and secretion of free cholesterol and cholesterol esters by the liver [178]. The effects on reducing HDL are associated with an increase in CETP with abnormal transfer of cholesterol esters from HDL to LDL and VLDL [179]. Additionally the fluidity, de-termined by the fatty acid at the sn-2 of PC is a major regulator of lecithin:cholesterol acyltransferase (LCAT), which is required for the formation of mature HDL. Trans fatty acids affect membrane fluidity and reduce LCAT activity [180] with effects on abeta aggregation and on important signaling lipidsin the membrane bilayer, lipid rafts and lipoproteins that are involved in the generation of second messengers (Figure 5).

As fatty acids act as ligands for nuclear receptors (Figure 5), such as sirtuin 1 (Sirt1), peroxisome proliferator activated receptors (PPARs), liver X receptor (LXR) and SREBP, regulation of gene transcription can be altered [181]-[184], directly modulating metabolic and inflammatory responses in the periphery and brain. Sirt1 are nicotinamide (NAD+) dependent histone deacetylases which are activated by cellular stresses to enhance cellu-lar defense and repair pathways and to mediate adaptive responses to changing energy requirements. This is achieved by deacetylation and transcriptional control of numerous genes involved in lipid, glucose and Aβ me-tabolism [184]-[186]. Saturated fatty acids such as palmitic acids have been shown to inhibitSirt1 with the de-velopment of hepatic steatosis as observed in Sirt1 knockouts [187] [188]. Additionally Sirt1 has been closely linked to obesity and AD [189] and shown to regulate liver cholesterol metabolism and attenuate amyloidogenic processing of APP both in cell culture models and in transgenic mice [185] [186], suggesting a possible mecha-nistic link between saturated fatty acids, peripheral cholesterol/ceramide metabolism and AD pathology.

Brain aging associated with dyslipidemia and oxidative stress coupled with altered gene expression profiles delays DNA repair mechanisms that underlie aging, stroke [190] and neurodegeneration. The anionic glyc-erophospholipid phosphatidylserine and phosphoinositides are located in the chromatin and the regulation of chromatin structure, gene expression and transcription is determined by the nuclear lipids [191]-[194]. Inflam-mation and oxidative stress associated with hypercholesterolemia generate reactive chemical species with oxida-tion of membrane and nuclear lipids with chronic damage to DNA and RNA in astrocytes and neurons. Diets that accelerate inflammatory processes disturb the astrocyte-neuron interactions affecting neuron survival and synapse formation. Diets that stabilize neuronal membrane and nuclear lipids are important for the maintainance of astrocyte and neuron function and may slow disease processes associated with amyloidogenesis and also in-volved in neurodegeneration.

Epigenetic changes induced by alteration in nuclear lipids (Figure 5) change the expression of genes through transcription and other lipids such as diglycerides, phospholipids, cholesterol and cholesterol esters also deter-mine chromatin structure [195]-[197]. High fat high cholesterol (HFHC) diets induce oxidative stress that accel-erates lipid peroxidation of phospholipids and cardiolipin involved in nuclear stability and neuron proliferation [197]-[199] and also involved in Aβ fibrillization. Additionally, sphingomyelin is involved in chromatin assem-

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April 18, 2017; 88 (16) ARTICLEARTICLE

Physical activity and hippocampal volume inPhysical activity and hippocampal volume inmiddle-aged patients with type 1 diabetesmiddle-aged patients with type 1 diabetesKaren A. Nunley, Regina L. Leckie, Trevor J. Orchard, Tina Costacou, Howard J. Aizenstein,J. Richard Jennings, Kirk I. Erickson, Caterina Rosano

First published March 10, 2017, DOI: https:/ /doi.org/10.1212/WNL.0000000000003805

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Conclusions:Conclusions: A cross-sectional association between higher PA and largerhippocampi is already detectable by middle age for these patients with T1D, and itappears robust to chronic hyperglycemia and insulin sensitivity. Proof-of-conceptstudies should investigate whether increasing PA preserves hippocampal volume andthe mechanisms underlying the effects of PA on hippocampal volume.

GLOSSARYGLOSSARY

BMIBMI = body mass index; PAPA = physical activity; T1DT1D = type 1 diabetes;VEGFVEGF = vascular endothelial growth factor

FootnotesFootnotes

Go to Neurology.org for full disclosures. Funding information and disclosuresdeemed relevant by the authors, if any, are provided at the end of the article.

Supplemental data at Neurology.org

Received September 26, 2016.

Accepted in final form January 24, 2017.

© 2017 American Academy of Neurology

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This Issue

Original Invest igat ion

April 2018

Alina Solomon, MD, PhD1,2,3; Heidi Turunen, BM1; Tiia Ngandu, MD, PhD3,4; et al

Author Affil iat ions

JAMA Neurol . 2018;75(4):462-470. doi:10.1001/ jamaneurol .2017.4365

Quest ion Are the cognit ive benefits of a 2-year mult idomain lifestyle int ervent ion affected by

the apolipoprot ein E ε4 allele?

Findings In the Finnish Geriat ric Int ervent ion Study t o Prevent Cognit ive Impairment and Dis-

ability, a randomized clinical t rial of 1260 at-risk elderly individuals from the general popula-t ion, the cognit ive benefits of a mult idomain int ervent ion (diet , exercise, cognit ive t raining,

and vascular risk management) were not signi ficant ly different between apolipoprot ein E ε4

carriers and noncarriers (t est of int eract ion). Within-group resul ts by apolipoprot ein E ε4 car-rier status suggested beneficial effects, part icularly among carriers.

Meaning Healthy lifestyle changes may be beneficial for cognit ion in older at -risk individuals

even in the presence of apolipoprot ein E–related genet ic suscept ibil ity t o dement ia.

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Effect of the Apolipoprotein E Genotype onCognit ive Change During a Mul t idomain Lif e-style Intervent ionA Subgroup Analysis of a Randomized ClinicalTrial

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riers and noncarriers (0 .023; 95% CI, −0.021 to 0.067).

Conclusions and Relevance Healthy lifestyle changes may be beneficial for cognit ion in olderat-risk individuals even in the presence of APOE-related genet ic suscept ibil ity t o dement ia.

Whether such benefits are more pronounced in APOE ε4 carriers compared with noncarriers

should be further invest igated. The findings also emphasize the importance of early preven-t ion st rategies that target mul t iple modifiable risk factors simultaneously.

Trial Regist rat ion ClinicalTrials.gov Ident ifier: NCT01041989

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Dement ia and Cognit ive Impairment Genet ics and Genomics Geriat rics

Lifestyle Behaviors Neurogenet ics Neurology

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Novedades Registro

Mínimas intervenciones preservan o mejoran lafunción cognitiva

Podemos prevenir la expresión clínica de la demenciaEn los últ imos años la coexistencia de enfermedad vascular ycambios neurodegenerativos en los cerebros de personasafectadas de Alzheimer, han redefinido el concepto de lasdemencias. Así es que, como la enfermedad vascular y ademencia de Alzheimer comparten factores de riesgomodificables, el control de los factores de riesgo vascularespueden retrasar la expresión clínica de la demencia. Estudiosprevios han demmostrado que el 30% de las demenciaspueden ser explicada por la sumatoria de 7 factores de riesgo(hipertensión, diabetes, cigarrillo, inactividad física, obesidad,depresión y educación) y proyectaron que, retrasaren 5 añosla aparición de demencia significa disminiur en 50% laprevalencia dentro de 5 años (Lancet Neurol 2014; 13: 788–94). El estudio FINGER ( Finnish Geriatric Intervention Study toPrevent Cognitive Impairment and Disability) dirigido por la Dra.Miia Kivipetto, PhD, MD, profesora del Instituto Karolinska deSuecia y el Instituto Nacional de Salud de Helsinki, demostro

que las intervenciones multidominio pueden mejorar y/o estabilizar la función cognitiva (Lancet. 2015 Jun 6;385(9984):2255-63).

El objetivo fundamental del estudio FINGER fue realizar un programa en el que se controlaba la nutrición, actividadessociales, monitorizando y controlando los factores de riesgo metabólicos y vasculares. Mil doscientos sesenta personasentre 60 y 77 años de 6 ciudades de Finlandia, fueron randomizados en 2 grupos (intervención intensiva y otro grupocontrol) y seguidas por 2 años.

Fueron incluidas personas con un score de riesgo de demencia >6 (Lancet Neurol 2006 5;735-41). La intervención intensivaconsistía en: 7 sesiones grupales y 3 individuales de nutrición, 1 o 2 sesiones semanales de musculacion y 2 o 4 sesionessemanales de aeróbico, 9 sesiones de entrenamiento cognitivo y el monitoreo y manejo de los fa tores de riesgo vascularesy metabólicos (visitas trimestrales realizadas por enfermeras y 3 visitas médicas a lo largo del estudio).

Los resultados cognitivos fueron evaluados en base al score Z (cambio del valor medio y desvío estándar basal), sobre lacognición global (Neuropsychological test battery), función ejecutiva, velocidad de procesamiento y memoria. La situaciónbasal fue igual en ambos grupos, la edad media de los participantes fue 69.3 años, el nivel educacional fue 10 años y elMMSE promedio 26.8 puntos.

En el grupo intervención todos los resultados cognitivos fueron superiores al grupo control. La cognición global después de24 meses mejoró un 25%, la función ejecutiva 83% (p=0.039) y la velocidad de procesamiento 150% (p=0.029). Los resultadosen el dominio de la memoria no experimentaron cambios (p=ns).

El estudio pone en evidencia que pequeñas intervenciones, multidominio, conllevan importantes resultados en laprevención de las enfermedades cognitivas.

A 2 year mult idomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus controlto prevent cognit ive decline in at-risk elderly people (FINGER): a randomized controlled trial.

Miia Kivipelto et al. (Lancet. 2015 Jun 6;385(9984):2255-63)

Comunidad Médicos Institucional

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GUÍAS PARA LA REDUCCIÓN DE RIESGO DE DETERIORO COGNITIVO Y DEMENCIA

Organización Mundial de la Salud (OMS) 14-Mayo-2019

GUÍAS PARA LA REDUCCIÓN DE RIESGO DE DETERIORO COGNITIVO Y DEMENCIA

Organización Mundial de la Salud (OMS) 14-Mayo-2019

• INTERVENCIONES NUTRICIONALES

• NO CONSUMO DE TABACO • NO CONSUMO NOCIVO DE ALCOHOL • ESTIMULACIÓN COGNITIVA • CONTROL DE LA OBESIDAD • TRATAMIENTO DE LA HIPERTENSIÓN ARTERIAL • TRATAMIENTO DE LA DIABETES MELLITUS • TRATAMIENTO DE LA DISLIPIDEMIA • TRATAMIENTO DE LA DEPRESIÓN • TRATAMIENTO DE LA PÉRDIDA DE AUDICIÓN

Campaña Prevención de los Trastornos de Memoria