BACKGROUND: Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain.
PURPOSE: To summarize evidence on the effects of prescription drugs and supplements for CATD treatment.
DATA SOURCES: Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies.
STUDY SELECTION: English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD).
DATA EXTRACTION: Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy.
DATA SYNTHESIS: Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, -0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes.
LIMITATION: Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials.
CONCLUSION: Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).
OBJECTIVE: To summarize evidence on: (1) the accuracy of brief cognitive tests for identifying clinical Alzheimer’s-type dementia (CATD) in individuals with suspected cognitive impairment; (2) the accuracy of biomarkers for identifying Alzheimer’s disease (AD) in individuals with dementia; and (3) the benefits and harms of prescription drugs and supplements for cognition, function, and behavioral and psychological symptoms of dementia (BPSD) in patients with CATD.
DATA SOURCES: Electronic bibliographic databases to March 2019, ClinicalTrials.gov, systematic review bibliographies.
REVIEW METHODS: Cognitive test accuracy studies must have used explicit CATD diagnostic criteria and a non-CATD control group. Biomarker accuracy studies must have used neuropathologic criteria to define AD cases and non-AD controls. All treatment trials must have enrolled participants with CATD; those evaluating BPSD enrolled individuals with CATD and BPSD. Minimum trial duration was 2 weeks for agitation, aggression, psychosis, and disinhibited sexual behavior, and 24 weeks for other outcomes. Two reviewers rated risk of bias (ROB) and strength of evidence. One reviewer extracted data; a second checked accuracy. We analyzed English-language studies with low or medium ROB.
RESULTS: We analyzed 56 unique studies on the accuracy of brief cognitive tests for CATD, 24 on accuracy of biomarkers for AD (15 brain imaging, nine cerebrospinal fluid [CSF] testing), and 67 trials of CATD treatment (54 reporting cognition or function, 13 reporting BPSD). Multiple brief cognitive tests were highly sensitive and specific (≥0.8) for distinguishing CATD from normal cognition, but less so for distinguishing mild CATD from normal cognition or CATD from mild cognitive impairment (MCI). Based on few studies, compared with clinical evaluation alone, amyloid positron emission tomography (PET), fluorodeoxyglucose (FDG)-PET, and combinations of CSF tests added to clinical evaluation may improve accuracy for distinguishing AD from non-AD dementia. Regardless of CATD severity, cholinesterase-inhibitors produced small improvements in cognition and function compared with placebo but may increase serious adverse events and withdrawals due to adverse events. For moderate to severe CATD, memantine plus a cholinesterase inhibitor slightly improved global change and inconsistently improved cognition, but not function, compared with a cholinesterase inhibitor alone. Evidence was mostly insufficient about the effects of prescription drugs and supplements on agitation, aggression, psychosis, or disinhibited sexual behavior.
CONCLUSIONS: Brief cognitive tests accurately distinguished CATD from normal cognition, but were less accurate distinguishing smaller clinical differences. Whether biomarkers improve diagnostic accuracy when added to clinical evaluation needs further verification, but potential benefits of testing are limited by lack of effective treatments for AD and non-AD dementias. Cholinesterase-inhibitors slightly outperformed placebo for cognition and function, but evidence of whether any drug treatments improved BPSD was largely insufficient.
ANTECEDENTES: Omega-3 los ácidos grasos poliinsaturados (omega-3 PUFAs) a partir de fuentes vegetales y de pescado se consideran comúnmente como una alternativa no médica prometedora para mejorar las funciones del cerebro y retrasar la progresión de la demencia. Esta suposición se basa principalmente en los resultados de los estudios preclínicos y la investigación epidemiológica. Resultantes modelos explicativos apuntan al papel PUFAs omega-3 desempeñan en el desarrollo y la integridad de las neuronas del cerebro, su efecto antioxidante protector sobre las membranas celulares y los posibles mecanismos neuroquímicos relacionados directamente con la patología de Alzheimer específica. La investigación epidemiológica también encontró evidencia de la desnutrición en las personas con demencia. Teniendo en cuenta esto y el hecho de que los omega-3 PUFA no pueden ser sintetizados por los seres humanos, omega-3 PUFAs podría ser una opción de tratamiento prometedor para la demencia.
Evaluar la eficacia y seguridad de los suplementos de ácidos grasos poliinsaturados omega-3 (PUFA) para el tratamiento de las personas con demencia.
Métodos de búsqueda: Se realizaron búsquedas en el Registro Especializado del Grupo Cochrane de Demencia y Trastornos Cognitivos (ALOIS), MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov y la Organización Mundial de la Salud (OMS) portal / ICTRP el 10 de diciembre de 2015. Se estableció contacto con los fabricantes de suplementos de omega-3 y examinaron las listas de referencias de los artículos señal y se incluyeron artículos.
Criterios de selección: Se incluyeron ensayos controlados aleatorios (ECA) en los que AGPI omega-3 en forma de suplementos o dietas enriquecidas fueron administrados a las personas con la enfermedad de Alzheimer (EA), demencia vascular (DV), la demencia con cuerpos de Lewy (DCL), demencia de la enfermedad de Parkinson (PDD) o la demencia frontotemporal (DFT).
Recopilación y análisis de datos: Las medidas de resultado primarias de interés fueron los cambios en las funciones cognitivas globales y específicos, el rendimiento funcional, gravedad de la demencia y los efectos adversos. Dos autores de la revisión seleccionaron de forma independiente los estudios, extrajeron los datos y evaluaron la calidad de los ensayos de acuerdo con el Manual Cochrane para las Revisiones Sistemáticas de Intervenciones. Hemos evaluado la calidad de las pruebas utilizando el sistema GRADE. Hemos recibido datos no publicados de los autores del ensayo y se recoge información de los efectos adversos de los artículos publicados. Hemos llevado a cabo meta-análisis para las medidas de resultado disponibles a los seis meses.
Resultados principales: Se incluyeron tres ensayos comparables aleatorios, controlados con placebo que investigan los suplementos de ácidos grasos omega-3 PUFA en 632 participantes con Alzheimer de leve a moderada durante seis, 12 y 18 meses. No se encontraron estudios que investigan otros tipos de demencia. Todos los ensayos eran de alta calidad metodológica. La calidad general de las pruebas para la mayoría de los resultados era alta.No hubo evidencia de un beneficio de PUFAs omega-3 en la función cognitiva cuando se mide a seis meses con la Escala de Evaluación de la Enfermedad de Alzheimer - subescala cognitiva (diferencia de medias estandarizada (DME) -0,02, 95% intervalo de confianza (IC) del -0,19-,15 ; 566 participantes; 3 estudios, evidencia de alta calidad) o Mini-Mental State Examination (diferencia de medias (DM) 0,18; IC del 95% -1.05 a la 1,41; 202 participantes, 2 estudios, pruebas de alta calidad) o sobre las actividades de la vida diaria ( DME -0,02; IC del 95%: -0,19 a 0,16; 544 participantes, 2 estudios, pruebas de alta calidad). También hubo ningún efecto a los seis meses de tratamiento en la gravedad de la demencia medida con el Clinical Dementia Rating - Suma de las cajas (DM -0,00; IC del 95% -0.58 a la 0,57; 542 participantes, 2 estudios, pruebas de alta calidad) o en la calidad de vida medida con la escala de calidad de vida en la Enfermedad de Alzheimer (DM -0,10; IC del 95% -1.28 a la 1,08; 322 participantes; 1 estudio; pruebas de alta calidad). No hubo diferencias a los seis meses sobre la salud mental medido con la valoración de la depresión de Montgomery-Asberg (DM -0,10; IC del 95%: -0,74 a la: 0.54; 178 participantes: 1 estudio, calidad de evidencia alta) o el Inventario Neuropsiquiátrico (DME 0,10 , IC del 95%: -0,07 a la 0,27; 543 participantes, 2 estudios, calidad de evidencia alta). Un estudio muy pequeño mostró un beneficio para los PUFAs omega-3 en las actividades instrumentales de la vida diaria después de 12 meses de tratamiento (DM -3,50; IC del 95%: -4,30 a -2,70; 22 participantes; pruebas de calidad moderada). Los estudios incluidos no midieron la función cognitiva específica. Los estudios no informaron eventos adversos también. Dos estudios indicaron que todos los eventos adversos fueron leves y que no difieren en frecuencia global entre los omega-3 PUFA y el grupo placebo. Los datos de un estudio no mostró diferencias entre los grupos en la frecuencia de eventos adversos (riesgo relativo (RR) 1,02; IC del 95%: 0,95 a 1,10; 402 participantes; 1 estudio; pruebas de calidad moderada) o cualquier evento adverso grave (RR 1.05, 95 % IC 0,78 a la 1,41; 402 participantes; 1 estudio, pruebas de alta calidad) a los 18 meses de tratamiento.
Conclusiones de los autores No se encontraron pruebas convincentes de la eficacia de los suplementos de ácidos grasos omega-3 PUFA en el tratamiento de Alzheimer de leve a moderada. Este resultado fue consistente para todos los resultados relevantes para las personas con demencia. Los efectos adversos de PUFAs omega-3 parecen ser bajos, pero en base a la evidencia sintetizada en esta revisión, no puede hacer una declaración final sobre la tolerabilidad. Los efectos sobre otras poblaciones no están claros.
Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain.
PURPOSE:
To summarize evidence on the effects of prescription drugs and supplements for CATD treatment.
DATA SOURCES:
Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies.
STUDY SELECTION:
English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD).
DATA EXTRACTION:
Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy.
DATA SYNTHESIS:
Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, -0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes.
LIMITATION:
Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials.
CONCLUSION:
Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes.
