LSB y deterioro cognitivo
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El rol de la lesión de sustancia blanca en la etiología de demencia, sobre todo demencia vascular. Prevención primaria, con adecuado manejo de hipertensión arterial es una válida opción.
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LSB y deterioro cognitivo
- 1. Rol de lesión de sustancia blanca (LSB) en el deterioro cognitivo y demencia Jornada con servicio de Neurología de Clínica Internacional 14 de abril de 2015, Lima-Perú Nilton Custodio Instituto Peruano de Neurociencias ncustodio@ipn.pe
- 2. Agenda • Incidencia y prevalencia de LSB. • Algunos aspectos en fisiopatología de LSB. • Evidencia de LSB en imágenes cerebrales. • Estudios de seguimiento longitudinal de LSB. • LSB y relación con deterioro cognitivo/demencia. • LSB como objetivo de prevención y tratamiento.
- 3. Agenda • Incidencia y prevalencia de LSB. • Algunos aspectos en fisiopatología de LSB. • Evidencia de LSB en imágenes cerebrales. • Estudios de seguimiento longitudinal de LSB. • LSB y relación con deterioro cognitivo/demencia. • LSB como objetivo de prevención y tratamiento.
- 4. Leucoaraiosis o lesión de sustancia blanca debido a enfermedad de pequeños vasos(LSB) • Leucoaraiosis: Hachinsky, 1986. Cambios en SB cerebral hemisférica debido a enfermedad de pequeños vasos. • Leucoaraiosis: Hipodensidad en TC, Hiperintensidad en T2/FLAIR. • Diversas denominaciones: – Anormalidades de sustancia blanca. – Cambios de sustancia blanca. – Hiper-intensidades de sustancia blanca (WMH). Weller RO. et al. Brain Pathology 2015;25: 63-78
- 5. Infartos lacunares y espacios peri-vasculares dilatados pueden ser confundidos con LSB Weller RO. et al. Brain Pathology 2015;25: 63-78 Espacios peri-vasculares dilatados, asociados a HIC debido a AAC
- 6. Prevalencia de infarto cerebral silente – 5.8-17.7% basado en IRM en estudios de población. – Relacionado a la edad: Estudio Framingham • 5ta y 7a década 10% • 8a década 17% • 9a década 30% – Localización de Lesión • Ganglio basal 52% • Otras áreas subcorticales 35% • Áreas corticales 11% Gorelick PB. et al. Stroke 2011;42: 2672-2713
- 7. Prevalencia de LSB depende de la población estudiada Estudio Tipo de estudio Prevalencia Helsinki Ageing Study Población de 55-85 años de edad, sin enfermedades neurológicas y psiquiátricas. 39% Austrian Stroke Prevention Study Población de 65-75 años de edad, con exclusión de diagnóstico de demencia, y con MMSE < 15. 45% Cardiovascular Health Study Basado en población, en mayores de 60 años de edad. 96% Rotterdam Scan Study Basado en población, en mayores de 60 años de edad. 95% Prins ND & Scheltens P. Nat Rev Neurol 2015;11: 157-165
- 8. Prevalencia de al menos un tipo de LSB en estudios de casos y controles y frecuencia de localización de LSB Población estudiada Prevalencia de LSB LSB en ganglios basales Demencia vascular 100% 96% Enfermedad de Alzheimer 100% 89% Demencia con cuerpos de Lewy 100% 85% Controles 92% 73% Barber R. et al. J Neurol Neurosurg Psychiatry 1999;67: 66-72
- 9. Distribución de grados de LSB en IRM en 3301 individuos del Cardiovascular Health Study (CHS) Longstreth WT Jr. Stroke 1996;27: 1272-1282
- 10. LSB es más frecuente en mujeres después de los 70 años de edad y se incrementa con la edad en el CHS Longstreth WT Jr. Stroke 1996;27: 1272-1282
- 11. Relación entre PAS y grado de LSB ajustado para 75 años de edad en el CHS Longstreth WT Jr. Stroke 1996;27: 1272-1282
- 12. Distribución de LSB según edad y sexo en pacientes con AIT y stroke de acuerdo a TC e IRM cerebral Simoni M. et al. Neurology 2012;79: 1215-1222 Aparente mayor frecuencia de LSB en mujeres según edad, se explica por mayor probabilidad de muerte prematura en hombres con LSB.
- 13. Agenda • Incidencia y prevalencia de LSB. • Algunos aspectos en fisiopatología de LSB. • Evidencia de LSB en imágenes cerebrales. • Estudios de seguimiento longitudinal de LSB. • LSB y relación con deterioro cognitivo/demencia. • LSB como objetivo de prevención y tratamiento.
- 14. Dos subtipos de enfermedad vascular cerebral generan la mayor proporción de injuria vascular cerebral Ateroesclerosis - Grandes Vasos: Dislipidemia, factores inflamatorios Arterioloesclerosis - Pequeños vasos: Hipertensión, Diabetes
- 15. La injuria vascular cerebral en grandes arterias
- 16. La injuria vascular cerebral en pequeñas arterias Infarto Completo Infarto Incompleto Oclusión Laguna Estado Lacunar Hipoperfusión Lesión Sustancia Blanca Enfermedad de Sustancia Blanca (Síndrome Binswanger)
- 17. Diversos grados de compromiso cognitivo antes de demencia vascular Desorden Cognitivo Vascular Incremento del compromiso cognitivo Cerebro en Riesgo Demencia Criterios de TCV Criterios de DV Factor Riesgo Vascular Enfermedad Vascular Cerebral Injuria Vascular Cerebral
- 18. Diversos sub-tipos de desorden cognitivo vascular Oclusión Grandes Arterias Oclusión Pequeñas Arterias Oclusión Incompleta Arterias Episodios Hipotensivos INFARTO CORTICAL INFARTOS LACUNARES LESIONES DE SUSTANCIA BLANCA Desorden Cognitivo , Demencia , Desorden no cognitivo (Depresión) ATROFIA CEREBRAL D post S DMI DVISC ESB
- 19. LSB es heterogénea, habitualmente refleja diversos grados de pérdida axonal y de mielina Prins ND & Scheltens P. Nat Rev Neurol 2015;11: 157-165 Pérdida axonal Desmielinización
- 20. Prins ND & Scheltens P. Nat Rev Neurol 2015;11: 157-165 Pérdida axonal Desmielinización LSB es heterogénea, habitualmente refleja diversos grados de pérdida axonal y de mielina
- 21. Riesgo relativo de la duración de hipertensión arterial y LSB según IRM en 2 estudios prospectivos LSB y categorías por edad Zoetermeer Study Rotterdam Study No HTA < 20 años > 20 años No HTA < 5 años > 5 años Subcortical 60-70 1.3 10.7 23.5 7.4 20.5 13.2 70-80 8.6 21.9 15.0 16.7 17.4 41.7 80-90 31.3 35.7 23.5 47.4 59.1 52.5 Total 6.6 17.6 18.9 17.4 28.1 38.3 Periventricular 60-70 1.7 5.3 20.6 5.5 15.4 9.4 70-80 22.8 20.3 31.7 14.3 17.1 31.7 80-90 58.8 57.1 29.4 47.4 43.5 51.3 Total 13.9 16.3 27.9 15.5 22.7 33.7 De Leeuw FE. et al. Brain 2002;125: 765-772 . . . .
- 22. HTA y progresión de LSB en población general Verhaaren BFJ. et al. Hypertension 2013;61: 1354-1359
- 23. Hipertensos no tratados, no controlados tienen significativamente mayor progresión de LSB Verhaaren BFJ. et al. Hypertension 2013;61: 1354-1359
- 24. Agenda • Incidencia y prevalencia de LSB. • Algunos aspectos en fisiopatología de LSB. • Evidencia de LSB en imágenes cerebrales. • Estudios de seguimiento longitudinal de LSB. • LSB y relación con deterioro cognitivo/demencia. • LSB como objetivo de prevención y tratamiento.
- 25. IRM es superior a TC para detectar LSB menores Wahlund LO. et al. Stroke 2001;32: 1318-1322
- 26. IRM en T2/FLAIR es más sensible para detectar LSB a nivel parieto-occipital e infratentorial Wahlund LO. et al. Stroke 2001;32: 1318-1322
- 27. Fazekas F. et al. AJR Am J Roentgenol 1987;149: 351-356 Escalas semi-cuantitativas en IRM válidas y confiables LSB peri-ventricular LSB profunda Discreta confluencia en “capuchón” o borde peri-ventricular delgado Focos puntiformes (lesiones únicas ≤ 9 mm) (lesiones agrupadas < 20 mm)
- 28. Escalas semi-cuantitativas en IRM válidas y confiables Fazekas F. et al. AJR Am J Roentgenol 1987;149: 351-356 LSB peri-ventricular LSB profunda Marcada confluencia en “capuchón” y borde peri-ventricular continuo grueso Confluencia de focos puntiformes (lesiones únicas 10-20 mm) (lesiones agrupadas > 20 mm)
- 29. Fazekas F. et al. AJR Am J Roentgenol 1987;149: 351-356 LSB peri-ventricular LSB profunda Marcada confluencia en “capuchón” y borde peri-ventricular continuo grueso que se extiende hacia SB profunda Extensas áreas de confluencia (áreas ≥ 20 mm) Escalas semi-cuantitativas en IRM válidas y confiables
- 30. Longstreth WT Jr. Stroke 1996;27: 1272-1282 1 2 3 4 5 6 7 8 Escala de severidad de LSB y correlato neuropsicológico
- 31. Longstreth WT Jr. Stroke 1996;27: 1272-1282 Relación entre el grado de LSB y rendimiento cognitivo
- 32. Longstreth WT Jr. Stroke 2005;36: 56-61 Variación anual en rendimiento cognitivo según LSB
- 33. Cambios relacionados a la edad en Anisotropía funcional según Tensor de Difusión (DTI) Malloy P. et al. The Clinical Neuropsychologist DOI:10.1080
- 34. Agenda • Incidencia y prevalencia de LSB. • Algunos aspectos en fisiopatología de LSB. • Evidencia de LSB en imágenes cerebrales. • Estudios de seguimiento longitudinal de LSB. • LSB y relación con deterioro cognitivo/demencia. • LSB como objetivo de prevención y tratamiento.
- 35. Progresión de LSB en relación a factores de riesgo y consecuencias cognitivas en el Rotterdam Scan Study n=668 X=71 Neuropsicología IRM cerebral 39% Progresión LSB (32% en SB subcortical) (27% en SB peri-ventricular) Seguimiento a 3 años Predictores de progresión Severidad de leucoaraiosis Edad Presión arterial Tabaquismo actual Presencia de infartos lacunares Van Dijk EJ. et al. Stroke 2008;39: 2712-2719
- 36. LSB peri-ventricular fue asociado con declinación de velocidad del procesamiento de información y cognición Van Dijk EJ. et al. Stroke 2008;39: 2712-2719
- 37. Progresión en frecuencia y efectos clínicos de LSB en Leucoaraiosis And DISability (LADIS) • Estudio multi-céntrico europeo, iniciado en 2001. • Evalúa el rol independiente de LSB para predecir discapacidad. • 639 individuos de 65 a 84 años de edad, evaluados cada 3 años. • Los individuos no tienen o tiene sólo un ítem alterado en AVD-I. • Con alguna lesión de sustancia blanca (LSB) en IRM basal. • LSB según escala de Fazekas: Leve, moderada o severa. Schmidt R. et al. Stroke 2012;43: 2643-2647
- 38. LSB según Fazekas en 633 individuos luego de 3 años del estudio LADIS Schmidt R. et al. Stroke 2012;43: 2643-2647 44 % 31 % 25 %
- 39. Progresión de LSB al tercer año de seguimiento de acuerdo al grado de LSB basal en LADIS Schmidt R. et al. Stroke 2012;43: 2643-2647 102 (57.3%) 110 (89.4%) 78 (83.9%) 290 (73.6%)
- 40. Factores de riesgo vascular y comorbilidades de acuerdo a severidad de cambios de LSB en LADIS Inzitari D. et al. BMJ 2009;339: b2477
- 41. Tasa de transición a discapacidad o muerte según severidad de cambios de LSB en LADIS Inzitari D. et al. BMJ 2009;339: b2477
- 42. Agenda • Incidencia y prevalencia de LSB. • Algunos aspectos en fisiopatología de LSB. • Evidencia de LSB en imágenes cerebrales. • Estudios de seguimiento longitudinal de LSB. • LSB y relación con deterioro cognitivo/demencia. • LSB como objetivo de prevención y tratamiento.
- 43. Meta-análisis de estudios que evalúan asociación de LSB con incidencia de demencia Debette S & Markus HS. BMJ 2010;341: c3666
- 44. LSB no correlaciona significativamente con el riesgo de deterioro cognitivo sin demencia Autor, año Población Resultados Smith EE, 2008 Americana n=67, riesgo DCL Incremento de Vol LSB: HR 3.30;95% CI 1.33 - 8.22 Debette S, 2010 Framingham Offspring Study n=1,694 Seguidos por 6 años Para DCL Vol LSB: OR 1.06; 95% CI 0.83-1.36 Incremento de Vol LSB: OR 1.26; 95% CI 0.67 - 2.39 Para DCL amnésico Vol LSB: OR 1.24; 95% CI 0.98-1.57 Incremento de Vol LSB: OR 1.67; 95% CI 0.96 - 2.93 Para DCL amnésico, edad ≥ 60 Vol LSB: OR 1.49; 95% CI 1.14-1.97 Incremento de Vol LSB: OR 2.47; 95% CI 1.31 - 4.66 Schmidt R, 2005 Austrian Stroke prevention study n=329 Seguidos por 6 años Vol LSB: β – 0.025;95% CI -0.047 a -0.004 (memoria) Vol LSB: β – 0.022;95% CI -0.043 a 0.0004 (conceptualización) Vol LSB: β – 0.035;95% CI -0.059 a -0.011 (habilidades visuoespaciales) Vol LSB: β – 0.017;95% CI -0.036 a -0.002 (atención/velocidad proceso) Chutinet A & Rost NS. Curr Treat Options Cardiovasc Med 2014;16:292
- 45. Volumen de LSB según protocolos volumétricos semi- automatizados con alto grado de precisión Smith EE. et al. Neurology 2004;63: 1606-1612
- 46. LSB es un riesgo significativo para desarrollar demencia según estudios de seguimiento longitudinal Autor, año Población Resultados Kuller LH, 2003 Cardiovascular Health Cognitive Study (480 de 3,608 evolucionan a demencia tras 8 años) LSB ≥ 3: HR 1.7;95% CI 1.36 - 2.10 (demencia total) LSB ≥ 3: HR 1.5;95% CI 1.17 – 1.99 (EA) LSB ≥ 3: HR 2.1;95% CI 1.36 – 3.11 (DV/Demencia Mixta) Prins ND, 2004 Rotterdam Scan Study (1,077 cognitivos sanos en 5 años) LSB peri-ventricular: HR 1.67;95% CI 1.25 – 2.24 Meguro K, 2007 The Osaki-Tajiri Project (204 adultos sanos y 335 con “demencia cuestionable” en seguimiento por 5 años) LSB peri-ventricular: OR 0.78; no significativo (EA) LSB profunda: OR 1.07; 1.02 (Der, Izq, no significativo) (EA) LSB peri-ventricular: OR 4.14 ; (P < 0.05) (DV) LSB profunda: OR 4.04; 3.27 (Der, Izq, P < 0.05) (DV) Debette S, 2010 Framingham Offspring Study (2013 adultos seguidos por 5.9 años) Vol LSB: HR 2.22; 95% CI 1.32-3.72 Incremento de Vol LSB: HR 3.97; 95% CI 1.10 - 14.30 Debette S, 2010 Meta-análisis LSB: HR 2.9;95% CI 1.3 – 6.3 Chutinet A & Rost NS. Curr Treat Options Cardiovasc Med 2014;16:292
- 47. Qué tipo específico de demencia se asocia con LSB? Lesión de Sustancia Blanca DEMENCIA VASCULAR DEMENCIA MIXTA ENFERMEDAD DE ALZHEIMER Lagunas Infartos Placas Neuríticas Ovillos NeuroFibrilares Enfermedad de pequeños vasos
- 48. Cabeza del Caudado Globus Pallidus Tálamo anterior y Dorso Medial Rodilla CI Centro Semioval Anterior Brazo Anterior CI Corteza Prefrontal Mayor frecuencia de localización de LSB altera el circuito PreFrontal-Subcortical
- 49. LSB asociada a “lagunas” explica síntomas frontales de demencia vascular Localización de lagunas en 1,086 casos de necropsia: • Sustancia Blanca Frontal : 35% • Putamen: 16% • Caudado: 8% • Tálamo: 8% Promedio de lagunas según Presión Arterial: • Hipertensos: 3.61 • Borderline: 2.77 • Normotensos: 1.15 Dozono K. Stroke 1991;22: 993-996
- 50. Selden NR et al . Brain 1998;121:2249–2257 BA C D E F Interrupción de vías colinérgicas por LSB o infartos
- 51. Enfermedad de pequeños vasos puede contribuir en demencia vascular y EA Hipertensión Enfermedad de vasos pequeños Lesión sustancia blanca/ infarto lacunar silente Alelo Apo E 4/ acumulación ßa Disminución transmisión colinérgica Atrofia Cerebral Formación de placa/ Hipertrofia arterial/ Vasoconstricción arterial DEMENCIA Disrregulación circulación cerebral/ Disminucion flujo sanguineo cerebral
- 52. Memoria y Función Ejecutiva en casos patológicamente definidos (n=62) Reed BR et al. Brain 2007;130:731-739 Control DVIS EA Mixto Leve compromiso de MEMORIA y EJECUTIVO en DVIS (n=11) Mayor y severo compromiso de MEMORIA que EJECUTIVO en EA (n=23) y Mixto (n=9)
- 53. Perfil neuropsicológico en casos patológicamente definidos (n=59) Grupo (n) Perfil Memoria baja (%) Perfil Ejecutivo bajo (%) Otro perfil (%) EA (21) 71 10 19 DVIS (11) 18 45 36 Mixto (9) 67 22 11 Control (18) 33 39 28 Reed BR et al. Brain 2007;130:731-739
- 54. Perfil individual en casos patológicamente definidos DVIS (n=11) Reed BR et al. Brain 2007;130:731-739 Perfil Ejecutivo Bajo Perfil Memoria Baja Otro perfil Perfil Ejecutivo Bajo en DVIS: SENSIBILIDAD = 67% ESPECIFICIDAD: 86% TASA PROBABILIDAD POSITIVA: 4.7
- 55. Agenda • Incidencia y prevalencia de LSB. • Algunos aspectos en fisiopatología de LSB. • Evidencia de LSB en imágenes cerebrales. • Estudios de seguimiento longitudinal de LSB. • LSB y relación con deterioro cognitivo/demencia. • LSB como objetivo de prevención y tratamiento.
- 56. Estrategias orientadas en la prevención de LSB
- 57. Impedir formación de LSB (Prevención Primaria) o retrasar progresión de LSB (Prevención Secundaria) Hipertensión Diabetes Colesterol LDL Cardiopatía • Síntomas neurológicos focales • Signos neurológicos focales • Infarto estratégico/múltiple • LSB confluentes • Síndrome disejecutivo u otro síndrome cognitivo • Escaso compromiso de memoria? Injuria Cerebral IsquémicaFactores de Riesgo DEMENCIA Prevención y Tratamiento Primario Prevención Secundaria Alivio Terciario
- 58. Antihipertensivos y declinacion cognitiva: Estudios longitudinales en prevención primaria Autor n Seguimiento (años) Evaluación Resultados Tzourio, 1999 1,373 4 Declinación MMSE: Caída ≥ 4 puntos Declinación cognitiva menor en hipertensos tratados vs no tratados: RR (95% CI)=1.9 (0.8-4.4) vs 4.3 (2.1-8.8) Murray, 2002 1,617 5 Screening comunidad Riesgo reducido de compromiso cognitivo en 38%: OR (95% CI)=0.62 (0.45-0.84) Korf , 2004 543 30 IRM: Atrofia hipocampo Riesgo incrementado para atrofia hipocampo en pacientes nunca tratados con antihipertensivos: OR(95% CI)=1.7 (1.12-2.65) Hanon, 2008 25,745 1/2 MMSE Reducción PA asociado con incremento de 0.8 puntos en MMSE entre las visitas basal y final (p<0.001) Nagai M et al. Am J Hypertens 2010;23:116-124
- 59. Autor n Seguimiento (años) Tipo demencia Medicación Asociación Guo, 1999 1810 3 Demencia Diurético (83%) Reducción RR (95% CI)=0.70 (0.6-1.0) Qiu , 2003 1270 6 EA AntiHTA Reducción RR (95% CI)=0.5 (0.5-0.9) Khatchaturian 2006 3308 3 EA AntiHTA Reducción RR (95% CI)=0.64 (0.41-0.98) Peila, 2006 1294 ≥ 12 Demencia EA AntiHTA HR para demencia HR (95% CI)=0.40 (0.22-0.75) HR para EA HR (95% CI)=0.35 (0.16-0.78) Lindsay, 2002 6434 5 EA AntiHTA No significativo RR (95% CI)=0.91 Morris, 2002 634 4 EA Diuréticos y BB No asociación Yasar, 2005 1092 11 EA BCC-DHP No significativo RR (95% CI)=0.30 In’tveld 2001 7046 2.2 DV EA AntiHTA Reducción para DV RR (95% CI)=0.30 (0.11-0.99) No significativo para EA RR (95% CI)=0.83 (0.49-1.93) Antihipertensivos y demencia: Estudios longitudinales en prevención primarias Nagai M et al. Am J Hypertens 2010;23:116-124
- 60. Meta-análisis de antihipertensivos que evalúan demencia incidente PROGRESS, RR Syst-Eur, RR SHEP, RR HYVET, RR Combinado (Ramdom) Cochrane Q=2.409; p=0.491Test for overall effect; p=0.045 Activo, (N/n) Placebo, (N/n) Hazard ratio (95% CI) 3051 / 193 1238 / 11 2361/ 37 1687 / 126 3054 / 217 1180 / 21 2371 / 44 1649 / 137 0.89 (0.74 – 1.07) 0.50 (0.25 – 1.02) 0.84 (0.55 – 1.30) 0.90 (0.71 – 1.13) 0.87 (0.76 – 1.00) A favor del tratamiento A favor del control 0.2 0.5 1.0 2.0 Peters R. et al. Lancet Neurol 2008;7:683-689
- 61. Porcentaje de reducción de demencia en grupos tratados en los RCTs para prevención primaria Nagai M et al. Am J Hypertens 2010;23:116-124 0 1 2 3 4 5 10 20 30 40 50 60 70 SEGUIMIENTO (años) %reduccióndedemencia SYST-EUR SCOPE SYST-EUR extensión abierta PROGRESS demencia con stroke PROGRESS terapia dual PROGRESS SHEP HYVET-COG Tratar 52 pacientes por 5 años podría evitar un caso de demencia Tratar 1000 pacientes por 5 años podría evitar 20 casos de demencia
- 62. Existe efecto de clase de anti-HTA sobre funcion cognitiva? Característica de soporte ACC IECA ARA Evidencia clínica Syst-Eur (1998) Cochrane (2002) PROGRESS (2003) Japon-Ohrui et al (2004) OSCAR (2008) PRoFESS (2008) Drogas eficaces Nitrendipino Nimodipino Perindopril Capto/Perin vs Enal /imida Eprosartan AAS+dipiridamol/clopidogrel/telmi sartan Mecanismos propuestos •Dismin. producción peroxido. •Dismin. Influjo IC masivo Ca. •Inhibe activacion citocinas . •AII inhibe liberacion de Ach. •Mejora el FSC. • Disminuye stress oxidativo. • Incrementa expresion EDI. • Activa depuracion de ß-A. Dickstein DL et al. Mt Sinai J Med 2010;77:82-102
- 63. Escasa evidencia de beneficio de estatinas en prevención primaria de demencia Autor n Estudio Población Resultados Hajjar,2002 655 O, cs Edad: 78.7±0.3 Riesgo reducido para EA: OR (95% CI)=0.37 (0.19-0.74) Zamrini,2004 3397 O, cs Pacientes con EA Riesgo reducido para EA: OR (95% CI)=0.61(0.42-0.87) Rea, 2005 2798 O, p-l Edad ≥ 65 No asociación. Zandi, 2005 5092 O, p-l Edad ≥ 65 No asociación. Green, 2006 2378 O, cs Pacientes con EA Baja probabilidad de tener EA. Rosenberg, 2008 216 O, p-l EA incidente Baja tasa anual de incremento en CDR-sum. Arvanitakis, 2008 929 O, p-l Edad: 75±0.6 No asociación. Haag, 2009 6992 O, p-l Población general Riesgo reducido para EA: HR (95% CI)=0.57 (0.37-0.90) Collins, 2002 20536 RCT-simvas FRV (40-80 a) No beneficio. Sparks, 2006 98 RCT-atorvas EA leve-moderado Mejoría significativa en cognición y memoria tras 6 meses. Trompet, 2009 5804 RCT-pravas FRV (70-82 a) No diferencia en declinación cognitiva tras 42 meses. Luzzi S. et al. J Alz Dis 2010;19:1661-1673
Notas del editor
- The term leukoaraiosis [from the Greek λευκος (leukos): white; and αραιο´ς (araios): rarefied] was coined by Hachinski et al in 1986 (Hachinski VC, Potter P, Merskey H (1986) Leuko-araiosis: an ancient term for a new problem. Can J Neurol Sci 13:533–534) to describe changes in the hemispheric cerebral white matter seen on neuroimaging: initially as areas of low attenuation on CT and subsequently as hyperintensities on T2-weighted or Fluid Attenuated Inversion Recovery (FLAIR) MRI. The term was developed to avoid ascribing a particular pathological cause to these increasingly detected imaging findings, which may reflect a range of pathological processes in different populations (eg, in younger patients may be due to leukodystrophy or inflammatory demyelination). Leukoaraiosis is common in patients with cognitive impairment including dementia as well as those with symptomatic cerebrovascular disease. Leukoaraiosis can be defined as white matter abnormality (low density on CT, hyperintensity on T2-weighted or FLAIR MRI), which may be patchy or confluent. These white matter appearances on MRI have variously been termed white matter abnormalities, white matter changes and WMH; a recent consensus group recommended the term “white matter hyperintensities of presumed vascular origin” (111). The term leukoaraiosis nevertheless has the advantage of being applicable to both CT and MRI. Here, we will mainly focus on imaging changes seen on MRI, which will be referred to as “white matter hyperintensities” (WMH).
- Izquierda: T2-weighted MRI axial image showing confluent WMH in association with extensive deep (basal ganglia) MRI-visible perivascular spaces and lacunar infarcts. Derecha: T2-weighted axial image showing MRI-visible PVS in the hemisphere white matter in a patient with CAA-related ICH. The pathological substrates of WMH include tissue rarefaction associated with loss of myelin and axons, enlarged (dilated) PVS and mild gliosis. These lesions are located in deep hemispheric white matter, typically sparing the subcortical U-fibers, and are often seen in association with vessels affected by small vessel disease including arteriolosclerosis. However, the pathological basis of WMH is heterogeneous as the basis of increased signal on T2-weighted and FLAIR MRI is simply an increase in free tissue water content, which is not specific for any particular pathological process. Furthermore, the degree of pathological heterogeneity appears to reduce as the severity of MRI-defined lesions increases from small punctate lesions to confluent WMH; the latter almost always have an ischemic appearance with myelin loss, gliosis and small areas of Infarction. Dilated PVS seen on MRI (figura de la derecha) have recently emerged as a new MRI marker of small vessel disease, as they are associated with other MRI features of small vessel disease, including lacunes and WMH. Dilated PVS have particular interest in the study of ISF dynamics as they are closely linked to the established clearance pathways for ISF and solutes along basement membranes and are enlarged in patients with conditions known to impair ISF drainage, including AD with associated CAA (Cerebral amyloid angiopathy). There is no detectable PVS around the arteries in the cerebral cortex, whereas PVS may dilate in the white matter and are thought to indicate failure of drainage of fluid and solutes from the white matter. Recent data in cohorts with intracerebral hemorrhage (ICH) (another end result of small vessel disease, but in this case causing fragility) indicate that the anatomical distribution of MRI-visible dilated PVS is linked to the underlying small vessel pathological process: in patients with lobar ICH attributed to probable CAA, severe dilatation of PVS was noted in the cerebral hemispheric white matter, while in other ICH cases (including deep ICH attributed to arteriolosclerosis-related rupture of deep basal ganglia perforating small vessels) severe dilatation of PVS was found in the basal ganglia (Figura de la izquierda). A similar topographical association of hemispheric white matter PVS with radiologically defined CAA was also noted in a memory clinic cohort, supporting this hypothesis. The clinical relevance of dilated PVS is less well established than that of WMH, with no clear association shown with cognitive function and no available prospective data on the risk of future stroke or cognitive impairment.
- Relation between systolic BP and white matter grade for men and women, adjusted for age using a mean age of 75 years. For the deciles, the upper end point is included in the subgroup but the lower is not.
- The most consistently reported histological substrates of WMHs are diffuse myelin rarefaction with sparing of the subcortical U fibres, astrogliosis, spongiosis, axonal loss, and widened perivascular spaces. However, the histopathology of WMHs is heterogeneous, as shown by correlative MRI and postmortem studies that reported tissue damage ranging from slight disentanglement of the matrix to varying degrees of myelin and axonal loss. This heterogeneity might partly explain the clinic radiological paradox—that is, the weak correlation between MRI abnormalities and clinical symptomatology—with regard to WMHs.
- Se demuestra una sólida relación entre la duración de la hipertensión y la presencia de LSB, además se demuestra que el tratamiento anti HTA efectivo puede reducir la tasa de LSB.
- The study is based on participants from the Rotterdam Study, a population-based cohort study in The Netherlands that investigates determinants of various chronic diseases among the elderly people. The original study population consisted of the general population aged 55 years and older within the Ommoord area, a suburb of Rotterdam. In 2000, the cohort was expanded with 3011 people (≥55 years) who were living in the study area and had not been included before.For this report, we used data from a random subset of the latter cohort expansion, which underwent 3 visits: visit 1 (in the year 2000), visit 2 (2005–2006), and visit 3 (2008–2010). At visits 1 and 2, blood pressure and cardiovascular determinants were assessed. At visits 2 and 3, MRI scanning was performed.2 Figure displays the design used and the timings of the various longitudinal measurements. No blood pressure measurements were available at visit 3.
- Hypertension treatment and white matter lesion (WML) progression. This figure shows the mean WML progression in mL (95% confidence interval [CI]; black bars) on top of the baseline WML volume (grey bars) for 4 blood pressure categories. Categories were defined as follows based on their mean blood pressure and medication use in the 5 years before the first scan: (1) normotensives: study participants with normal mean blood pressure and receiving no antihypertensive medication during this period (n=255); (2) controlled treated hypertensives: study participants with normal mean blood pressure and receiving antihypertensive medication during this period (n=83); (3) uncontrolled treated hypertensives: study participants with hypertensive mean blood pressure and receiving antihypertensive medication during this period (n=155); and (4) uncontrolled untreated hypertensives: study participants with hypertensive mean blood pressure and receiving no antihypertensive medication during this period (n=172). Hypertensive mean blood pressure was defined as diastolic blood pressure ≥90 mm Hg or systolic blood pressure ≥140 mm Hg. A statistically significant difference in WML progression was observed between the uncontrolled untreated hypertensives group and the uncontrolled treated hypertensives group, after adjustment for age, sex, intracranial volume, time between scans, and the baseline WML load (P<0.05). People with uncontrolled untreated hypertension had significantly more WML progression than people with uncontrolled treated hypertension (difference [95% confidence interval], 0.12 [0.00; 0.23] mL/y). The present study further establishes high blood pressure to precede WMLs and implies that hypertension treatment could reduce WML progression in the general population.
- this study shows that differences of MRI and CT in detecting ARWMC are primarily related to lesion size. MRI was superior due to its better detection of small ARWMC, whereas medium and large lesions were detected equally well by both modalities. Regional differences played a subordinate role, which is not unexpected from the predominant location of ARWMC in areas that can usually be imaged with high quality by both MRI and CT. Therefore, CT studies in combination with MRI might be used in evaluation of ARWMC in multicenter studies when attempting to address primarily more marked white matter damage. (This could also be the type of white matter damage that shows closer relation to clinical-cognitive deficits, at least in cross sectional studies). In this context, the new ARWMC rating scale may be a useful tool that demonstrates good inter rater reliability. However, for minor ARWMC, MRI appears mandatory, and it is probably also the technique needed for monitoring ARWMC progression.
- White matter changes on MRI were defined as ill-defined hyperintensities ≥ 5 mm on both T2 and PD/FLAIR images, and on CT as ill-defined and moderately hypodense areas of ≥ 5 mm. Lacunes were defined as well-defined areas of > 2 mm with attenuation (on CT) or signal characteristics (on MRI) the same as cerebrospinal fluid. If lesions with these characteristics were ≤ 2 mm, they were considered perivascular spaces, except around the anterior commissure, where perivascular spaces can be large. Changes in the basal ganglia were rated in the same way and considered white matter lesions even if located in the gray matter nuclei, which contains a small amount of white matter. We found that when using standard T2/PD images, MRI was more sensitive in detecting ARWMC in the parietooccipital and infratentorial regions of the brain. The latter region is easier to study with MRI than with CT because no bone artifacts are present. Moreover, the differences were mainly due to the ability of MRI to detect small ARWMCs. CT was as good as MRI in detecting larger lesions. This might explain why many studies have shown that ARWMC found on CT correlate better with symptoms than do the changes detected with MRI. When the FLAIR sequence was used for MRI rating, ARWMC were found significantly more often than with CT. This suggests that FLAIR may be preferable for the study of ARWMC. However, this issue will have to be addressed more extensively in a further study.
- Periventricular white matter changes (PVWMC) and deep white matter changes (DWMC) can be rated using the method originally described by Fazekas et al. For PVWMC, a rating of ‘0’ indicates no changes, ‘1’ indicates ‘caps’ or pencil-thin periventricular bands, ‘2’ indicates a smooth ‘halo’ and 3 indicates irregular periventricular changes extending into deep white matter. For DWMC ‘0’ indicates no changes, ‘1’ indicates punctate foci, ‘2’ beginning confluence of foci and ‘3’ large confluent areas.
- 1: Borde periventricular discontinuo con puntos mínimos de enfermedad subcortical 2: Borde periventricular continuo delgado con escasos parches de enfermedad subcortical 3: Borde periventricular continuo grueso con parches dispersos de enfermedad subcortical 4: Borde periventricular continuo grueso con bordes irregulares, con enfermedad subcortical leve, puede tener lesiones periventriculares confluentes mínimas 5: Confluencia periventricular leve rodeando el asta frontal y occipital 6: Confluencia periventricular moderada rodeando el cuerno frontal y occipital 7: Confluencia periventricular con moderado compromiso del centro semioval 8: Confluencia periventricular con compromiso más allá del centro semioval.
- Como podemos observar existe una fuerte correlación entre mayor severidad de lesión de SB con bajos puntajes en la evaluación cognitiva basal.
- Los 1,919 sujetos con 2 IRM realizados en un lapso de 5 años, el 28% mostró empeoramiento de lesiones de SB. Aquellos con empeoramiento de lesiones de SB, experimentaron mayor declinación en 3MS y en el Test de sustitución de digitos y simbolos (p<0.001). Los predictores independientes de empeoramiento de lesiones de SB incluye tabaquismo e infarto en el scan inicial.
- Note the differences in the thickness of the genu and splenium on representative slices through the lateral ventricles. FA was measured in the genu and white matter anterior to the frontal horns of the lateral ventricles. Studies using DTI scalar parameters have demonstrated age-related reductions in white matter anisotropy, increases in diffusivity, and decreased intravoxel coherence with a tendency toward greater effects in anterior vs. posterior regions.
- Background and Purpose—Cerebral white matter lesions and lacunar infarcts are small vessel disease-related lesions, which are associated with cognitive decline and dementia. We aimed to assess the relationship between risk factors, effect modifiers, and progression of these lesions. Furthermore, we studied the cognitive consequences of lesion progression. Methods—Six hundred sixty-eight people, aged 60 to 90 years, underwent repeated MRI scanning and neuropsychological testing within 3-year follow-up. We rated incident lacunar infarcts and change in periventricular and subcortical white matter lesion severity with a semi-quantitative scale. We assessed the relationships between age, sex, baseline lesion load, risk factors, lesion progression, and change in cognitive function by multivariate regression analyses and additional stratified analyses. Results—Baseline lesion load, higher age, high blood pressure, and current smoking were independently associated with progression of white matter lesions. Women had more marked progression of subcortical white matter lesions and incident lacunar infarcts compared with men. Carotid atherosclerosis was associated with incident lacunar infarcts. Higher blood pressure did not contribute to lesion progression in people with already severe lesions at baseline nor in the very old. Lesion progression was associated with a paralleled decline in general cognitive function and in particular with a decreased information processing speed. Conclusions—Higher age, female sex, cigarette smoking, elevated blood pressure, and baseline lesion load were associated with small vessel disease progression. Age and baseline lesion load influenced the risk relations with blood pressure. Progression of small vessel disease was related to a paralleled decline in cognitive function.
- The observation that WML progression and incident lacunar infarct do not only predict cognitive decline, but also parallel it over time, even stronger suggests that these lesions play a causative role. The relationship between progression of small vessel disease and change in cognitive function is complex. A different kind of co-occurring lesion at a different anatomic location interacts in affecting different cognitive domains. Despite this complexity, the relationship between periventricular WML progression and decrease in psychomotor speed seems robust given the comparable results in the Cardiovascular Health Study and the PROSPER trial cohort. Our finding that memory performance improved at the second examination may be explained by a learning effect that does not effect psychomotor speed tests. Because WML progression is strongest in the oldest people and in those with already severe lesions at baseline, it seems to be a chronic disorder that accelerates over time. We hypothesize that at time of this acceleration, the effect of traditional treatable risk factors attenuates and factors like inflammation and chronic hypoperfusion take over. Future studies aimed to slow cognitive decline by prevention of cerebral small vessel disease-related brain damage should evaluate the effect of rigorous treatment of high blood pressure, taking into account the potential weak or even negative effect in the very old and in those already at a severe stage of small vessel disease.
- Data were collected as part of the multicenter, multinational LADIS study. The rationale and design of LADIS have been described elsewhere. In short, 639 elderly subjects were enrolled in a hospital-based setting. Included subjects had to be between age 65 and 84 years, had to show WML on MRI of any degree, had no or only mild disability on the instrumental activities of daily living scale, had a knowledgeable informant, and signed an informed consent. Exclusion criteria were: likelihood of dropping out because of the presence of severe illnesses (eg, cardiac, hepatic, renal failure), cancer, or other relevant systemic diseases; severe unrelated neurological diseases; leukoencephalopathy of nonvascular origin (immunologic, demyelinating, metabolic, toxic, infectious); severe psychiatric disorders; inability to provide informed consent; and inability or refusal to undergo cerebral MRI. Subjects were selected and stratified for WML severity according to the categorization of the modified Fazekas scale into 3 severity classes. The cohort was followed-up for 3 years. Reasons for dropouts during the observational period were death for 43, withdrawal of consent for 73, and refusal to undergo follow-up examination or second MRI scan in 73 subjects. In 1 center (47 individuals), funding was lacking for rescanning. Moreover, scans from 7 participants were excluded because of absent fluid attenuation inversion recovery images or inappropriate slice positioning, and in 2 subjects WML progression could not be evaluated because of bilateral infarctions. The current study cohort thus consists of those 394 study participants who underwent a baseline and 3-year follow-up scan that could be evaluated for WML progression. Their mean age was 73.1 +/- 5.0 years. There were 210 (53.3%) women and 184 (46.7%) men. As described previously, subjects who underwent a follow-up MRI were younger, had higher education, higher diastolic blood pressure, lower total cholesterol, higher low-density lipoprotein, triglyceride, and glucose levels than subjects who were not scanned at follow-up. We also reported elsewhere that baseline MRI characteristics were comparable between the groups with and without follow-up MRI.
- Results are given for the total sample and subsets with different WML grades at baseline. Any progression was seen in 290 (73.6%) of the 394 study participants. One hundred two (57.3%) participants with punctate WML, 110 (89.4%) with early confluent WML, and 78 (83.9%) with confluent WML at baseline showed WML progression after 3 years (P< 0.0001). Baseline WML grade influenced the magnitude of future WML progression. A change of ≥ 4 grades on the RPS was present in only 12 (6.7%) individuals with punctate WML, whereas this was seen in 32 (26.0%) subjects with early confluent and 29 (31.2%) with confluent abnormalities (P< 0.0001).
- In three groups compared by clinical and functional features at entry, we found that older age, history of arterial hypertension, stroke, falls in the past year, complaint of gait disturbances, and visual problems were all more common among patients with the severe grade.
- Over a mean follow-up period of 2.42 years (SD 0.97, median 2.94 years), 242 (38.2%, mean age 75.4 (SD 4.8), 44.2% men) of the 633 patients reached the study end point. Table 5 shows the frequency of the composite primary outcome (transition to disability or death) and of individual outcomes. Patients with severe age related changes in white matter had a worse prognosis; about 60% had become disabled or had died at the end of the follow-up. The rate (per 100 person years at risk) of transition from independence in instrumental activities of daily living activities to disability or death was 10.5 (95% confidence interval 8.2 to 12.8), 15.1 (11.6 to 18.6), and 29.5 (23.5 to 35.5) for patients in the mild, moderate, and severe Fazekas scale group, respectively. Survival analysis carried out for each of the Fazekas scale grades or volume fifths (fig 2) showed that the probability of surviving free of disability or death decreased with the increasing severity of changes in white matter (Kaplan-Meier log rank test P<0.001 for either grading).
- Incident dementia overall Three population based studies and 11 studies in high risk populations examined the relation between white matter hyper-intensities and incident dementia overall. Meta-analyzing the three population based studies yielded a significant association of white matter hyper-intensities with the occurrence of all types of dementia (2.9, 1.3 to 6.3, P=0.008; fig 3). Six of the 11 studies done in high risk populations could be included in the meta-analysis, yielding no significant association of white matter hyper-intensities with incident dementia (1.4, 0.9 to 2.3, P=0.14). Four of these six studies included patients with mild cognitive impairment: meta-analysing these separately also did not yield any significant association (1.1, 0.8 to 1.6, P=0.46). Five studies in high risk populations could not be included in the meta-analysis, three because white matter hyper-intensities were studied continuously only, and two because the authors reported the absence of association without indicating numbers. None of them identified a significant association of white matter hyper-intensities with incident dementia. Not all quality criteria were satisfied for several of the studies. When combining data from population based studies and high risk populations the risk of dementia associated with white matter hyper-intensities was increased overall (1.9, 1.3 to 2.8, P=0.002). Various potential mechanisms could account for the association of white matter hyperintensities with dementia. Firstly, subcortical neural networks could be damaged directly. Consistent with this hypothesis is the predominant association with decline in executive functions (believed to depend on cortical-subcortical circuits passing through the white matter), which could be disrupted by damage to white matter. Secondly, white matter hyperintensities could interact with pathological changes related to Alzheimer’s disease and thereby accelerate their clinical expression, or vice versa. Thirdly, white matter hyperintensities could be a confounder reflecting the association of vascular risk factors or of concomitant ischaemic damage to the cortex with dementia. Several studies have adjusted for vascular risk factors, for prevalent or incident stroke, or for concomitant magnetic resonance imaging defined brain infarcts, and found similar results, suggesting that vascular risk factors are unlikely to be a major mechanism, although undetected cortical microinfarcts cannot be excluded. Finally, reverse causation through amyloid angiopathy or wallerian degeneration as a result of cortical atrophy has been hypothesised. However, data from the Austrian Stroke Prevention Study suggest that progression of lesions in white matter precedes loss in parenchymal volume in elderly people without dementia, implying that this reverse causation is unlikely to play a predominant role. The finding that white matter hyperintensities were associated with an increased risk of dementia and Alzheimer’s disease mainly in healthy populations and not in high risk patients who are already cognitively impaired, needs to be interpreted cautiously. Studies in high risk populations were carried out in small samples and had several methodological flaws. If this lesser association in higher risk and cognitively impaired populations is confirmed, however, it could suggest that once the neurodegenerative lesions become clinically evident, the effect of white matter lesions may be less important. As has been suggested by others, the presence of white matter hyperintensities may increase the risk that an individual will develop mild cognitive impairment or have declining performances on cognitive tests but may not be enough to facilitate progression from mild cognitive impairment to dementia, the latter being overwhelmingly driven by neurodegenerative lesions. An exception could be the rare cases of pure vascular dementia, where diffuse white matter hyperintensities could be important also at later stages of cognitive decline and conversion. Effect of progression of white matter hyperintensities: Only three studies have assessed the impact of progression of white matter hyperintensities on incident stroke and dementia, suggesting a significant association of increasing progression of white matter hyperintensities with these outcomes. Progression of white matter hyperintensities has been more widely studied in association with cognitive decline, with increasing progression predicting a more rapid decline in global cognitive performance and executive function.
- Many population based studies evaluated the association between leukoaraiosis and the risk of cognitive impairment. Some studies used the severity of WMH at baseline but many assessed the progression of WMH longitudinally. A study in 67 American participants with normal cognition found that high baseline WMHv was related to the risk of progression to mild cognitive impairment (MCI) (HR 3.3; 95%CI 1.33–8.2, p= 0.01). However, the Framingham Offspring Study which followed up 1,694 persons for a mean duration of 6.2 years showed that the severity of WMHv did not correlate with the risk of all MCI or amnestic MCI. Similarly, the Austrian Stroke Prevention Study followed 329 participants for 6 years and demonstrated that WMHv progression was associated with cognitive decline in some domains, including memory, conceptualization, and visuopractical skills. However, changes in WMHV were not related to cognitive decline after adjustment for brain volume.
- The link between severity of leukoaraiosis and risk of dementia has been examined in a number of large prospective, population based studies, including the Cardiovascular Health Cognitive Study, in which 480 of 3,608 persons developed dementia in up to 8 years of follow-up. This study found that extensive WMH grade at study baseline was a significant risk factor for dementia (HR 1.8) and Alzheimer’s disease (AD). [29] The Rotterdam Scan Study demonstrated that WML, predominantly in the periventricular region, independently increased the risk of dementia in 1,077 cognitively intact participants at 5.2 years (HR 1.67; 95%CI 1.25–2.24). [30] Similarly, the Osaki-Tajiri Project in Japan followed 204 healthy adults and 335 participants with questionable dementia for 5 years and showed that WML was a predictor for progression to vascular dementia (VaD). [31] The Framingham Offspring Study (n=2,013) reported that severity of WMHv was significantly associated with an increased risk of dementia (HR 2.22; 95% CI 1.32–3.72 for WMHv, HR 3.97; 95% CI 1.10–14.3 for extensive WMHv) in a mean follow-up of 5.9 years. [19] Finally, a metaanalysis of three population based studies confirmed a significant association between WMH and the risk of all types dementia (HR 2.9; 95%CI 1.3–6.3, p=0.008).
- Together with epidemiological studies linking mid-life and accumulating vascular risk factors to the severity of WMH in later life, these studies help establish that WMH represent brain pathology that is somehow age-dependent and reflective accumulating “subclinical” vascular disease. There is little evidence that WMH burden decreases once the pathology has begun. Thus, for all intents and purposes, we treat WMH severity as a marker of pathology that tends to emerge later in life. Given the consistently-observed association between WMH and clinical AD, the determination of how the two are related remains critical. There are at least three non-mutually exclusive possibilities. First, WMH represent a second, independent pathological “hit” that lowers diagnostic threshold for AD or contributes additively to disease presentation. In this scenario, WMH are simply due to perfusion or general vascular abnormalities and reflect ischemic change in the brain and do not promote AD-related pathology (or vice versa). Second, the pathology underlying WMH may be heterogeneous as a function of regional distribution and may interact with or reflect primary AD pathology. In this scenario, measured pathology in areas identified radiologically as WMH may vary across location and diagnosis and WMH (or their etiological factors) may interact mechanistically with AD pathology. Third, WMH and AD may be related to each other epiphenomenologically through their shared association with some third set of factors. We have been pursuing the first two possibilities by systematically examining the mediators of WMH and how WMH and markers of AD pathology may interact.
- Equivocal results from cross-sectional studies have contributed to a long debate on whether WMHs on MRI are truly related to cognitive decline and dementia.Results from prospective studies have provided clear evidence that small vessel disease, including WMHs, causes cognitive decline, and that WMHs are particularly related to reductions in information processing speed and executive dysfunction, consistent with prevailing subcortical damage. Small vessel disease can interrupt prefrontal subcortical loops directly, or might indirectly lead to cognitive decline through incident stroke. Damage to neurotransmitter systems, in particular the cholinergic system, could also account for the cognitive sequelae of WMHs.Vascular risk factors, such as hypertension, diabetes and hyperhomocysteinaemia, may be related to cognitive impairment through other mechanisms.
- PROGRESS: Perindopril Protection Against Recurrent Stroke Study 6105 sujetos con AIT o stroke previo recibieron un inhibidor de la enzima convertidora de angiotensina (IECA), perindopril con posible adicion de diuretico, indapamida vs placebo. Syst-Eur: Systolic Hypertension in Europe 2418 hipertensos sistolicos recibieron un bloqueador de canales de calcio (BCC), nitrendipino con adicion posible de un IECA (enalapril), diuretico (hidroclorotiazida), o ambos vs placebo. SHEP: Systolic Hypertension in the Elderly Program 4736 hipertensos sistolicos de edad promedio 72 anos recibieron un diuretico, clortalidona con posible adicion de beta-bloqueador (atenolol), o bloqueador del sistema nervioso simpatico (reserpina) vs placebo. HYVET: Hypertension in the Very Elderly Trial 3336 hipertensos (PAS: 160-200, PAD<110 mmHg) mayores de 80 anos de edad, recibieron un diuretico, indapamida con posible adicion de un IECA (perindopril) vs placebo.
- The Study on Cognition and Prognosis in the Elderly (SCOPE), which included 4,964 hypertensive patients over 70 years old without dementia, assessed the effect of a stepwise treatment for hypertension angiotensin-receptor blockers (candesartan ± hydrochlorothiazide) compared to placebo on cognitive function or dementia after a follow-up period of 3.7 years.
- Syst-Eur: Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, BabeanubS, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R (1998) Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 35, 1347-1351. Cochrane: Lopez-Arrieta JM, Birks J (2002) Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev, CD000147, suggested a positive effect of nimodipine in AD patients to slow cognitive decline compared to placebo in short-term trials, but no data were available for studies with longer follow-ups. PROGRESS: Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, Chalmers J; PROGRESS Collaborative Group (2003) Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 163, 1069-1075. Ohrui T, Matsui T, Yamaya M, Arai H, Ebihara S, Maruyama M, Sasaki H (2004) Angiotensin-converting enzyme inhibitors and incidence of Alzheimer's disease in Japan.J Am Geriatr Soc 52,649-50. OSCAR: Hanon O, Berrou JP, Negre-Pages L, Goch JH, Nádházi Z, Petrella R, Sedefdjian A, Sévenier F, Shlyakhto EV, Pathak A (2008) Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: primary results of the Observational Study on Cognitive function And Systolic Blood Pressure Reduction open-label study. J Hypertens 26, 1642-1650. PRoFESS: Diener HC, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voigt T, Weber M, Yoon BW; Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group (2008) Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 7, 875-884.