Deterioro ejecutivo en demencia fronto-temporal
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Presentada en el XXIV Congreso Peruano de Neurología 25 de Octubre de 2013 Hotel Costa Del Sol - Trujillo
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Deterioro ejecutivo en demencia fronto-temporal
- 1. Características neuropsicológicas de la demencia fronto-temporal, variante conductual «El marcado deterioro de las funciones ejecutivas» Nilton Custodio XXIV Congreso Peruano de Neurología Viernes 25 de Octubre 2013, Trujillo
- 2. Agenda • Las demencias de inicio en edad pre-senil. • El espectro de la degeneración lobar fronto-temporal (DLFT). • Pruebas cognitivas breves en DFT variante conductual. • Relativa preservación de memoria y funciones viso-espaciales. • Marcado deterioro de las funciones ejecutivas.
- 3. Agenda • Las demencias de inicio en edad pre-senil. • El espectro de la degeneración lobar fronto-temporal (DLFT). • Pruebas cognitivas breves en DFT variante conductual. • Relativa preservación de memoria y funciones viso-espaciales. • Marcado deterioro de las funciones ejecutivas.
- 4. Prevalencia de demencia de inicio en edad pre-senil Hombres: 78.2 casos por 100 000 Mujeres: 56.4 casos por 100 000 Harvey R. Dementia Research Group 1998
- 5. Distribución de tipos de demencia por grupo de edad Demencia de inicio antes de 65 Demencia de inicio después de 65 Jefferies K, Agrawal N. Adv Psychiatry Treat 2009;15:380-388
- 6. No tenemos estudios en poblaciones de menos de 65
- 7. DFT es más frecuente de lo que pensamos Lugar de estudio Zuid-Holland, Holanda (Rosso et al. 2003) Cambridgeshire, UK (Ratnavalli et al. 2002) London, UK (Harvey et al. 2003) Brescia, Italia (Borroni et al. 2010) Ibaraki, Japon (Ikejima et al. 2009) Casos (n) Definición de caso Estimado por 100,000 en 45–64 años de edad 95 % CI 55 DFTvc 4.0 2.8 – 5.7 11 DFTvc + APP 15 8.4 – 27.0 18 DFTvc 15.4 9.1 – 24.3 213 DFTvc + APP 22 17 – 27 17 DFTvc 2.0 1.3 – 3.2 Knopman D, Roberts R. J Mol Neurosc 2011;45:330-335
- 8. DFT es rara después de los 65 años de edad? 22/100,000 n=108 78/100,000 n=97 54/100,000 n=21 Borroni B, et al. J Alzheimers Dis 2010;19:111-116
- 9. Agenda • Las demencias de inicio en edad pre-senil. • El espectro de la degeneración lobar fronto-temporal (DLFT). • Pruebas cognitivas breves en DFT variante conductual. • Relativa preservación de memoria y funciones viso-espaciales. • Marcado deterioro de las funciones ejecutivas.
- 10. “Enfermedad de Pick” o “Complejo de Pick”? Enfermedad de Pick • • Europa: Diagnóstico clínico, con o sin cuerpos de Pick en la patología. América: Diagnóstico patológico, independiente de presentación clínica. Complejo de Pick DCB PSP APP DFTvc DLFT-ELA
- 11. El amplio espectro clínico de la DLFT Cambios precoces y progresivos del comportamiento y/o deterioro del lenguaje Cambios precoces y progresivos del comportamiento y/o deterioro del lenguaje Predominio de síntomas Predominio de síntomas conductuales conductuales DLFT conductual Predominio de compromiso Predominio de compromiso del lenguaje: APP del lenguaje: APP Afasia Progresiva no fluente Demencia Semántica Afasia Logopénica
- 12. Los síntomas iniciales no son reconocidos tempranamente
- 13. Los síntomas iniciales en DFTvc no afectan memoria
- 14. Los síntomas iniciales en DFTvc son similares a enfermedades psiquiátricas • Desorden bipolar • Psicosis de inicio tardío • Desorden de la personalidad • Cambios de personalidad relacionados a edad • Desorden obsesivo-compulsivo • Abuso de alcohol • Depresión atípica • Trastorno por déficit de atención/hiperactividad
- 15. The International FTD Criteria Consortium (iFTDC) Rascovsky K, et al. Brain 2011;134:2456-2477.
- 16. DFT conductual Posible A. Inicio temprano de desinhibición conductual . B. Inicio temprano de apatía o inercia. C. Inicio temprano de pérdida de simpatía o empatía. D. Inicio temprano de conducta perseverante, estereotipada o compulsiva/ritualista. E. Hiperoralidad y cambios en la dieta. F. Perfil neuropsicológico: Déficit ejecutivo con relativa preservación de las funciones de memoria y visuo-espaciales. Rascovsky K, et al. Brain 2011;134:2456-2477.
- 17. DFT conductual Probable A. Criterios para DFT posible. B. Declinación funcional significativa (reportado por el cuidador, o evidenciado por CDR, o cuestionario de actividades funcionales). C. Una de las imágenes cerebrales compatibles con DFT conductual: A. Atrofia frontal y/o temporal anterior en IRM o TC B. Hipo-perfusión o hipo-metabolismo frontal y/o temporal anterior en PET o SPECT.
- 18. IRM en DFT conductual Ravinovici GD, Miller BL. CNS Drugs 2010;24(5):375-398.
- 19. DFT conductual definitivo A. Criterios para DFT conductual probable o posible. B. Evidencia en la biopsia cerebral o post-morten. C. Presencia de mutación patogénica conocida. Criterios de exclusión de DFT conductual A. Desorden médico o SNC no degenerativo. B. Desorden conductual explicado por enfermedad psiquiátrica. C. Biomarcadores positivos para EA.
- 20. Sensibilidad y especificidad de los nuevos criterios en 156 individuos con diagnostico patológico de DFTvc Harris JM, et al. Neurology 2013;80:1881-1887
- 21. Agenda • Las demencias de inicio en edad pre-senil. • El espectro de la degeneración lobar fronto-temporal (DLFT). • Pruebas cognitivas breves en DFT variante conductual. • Relativa preservación de memoria y funciones viso-espaciales. • Marcado deterioro de las funciones ejecutivas.
- 22. MMSE incluido en Addenbrooke´s Cognitive Examination (ACE)
- 23. Utilidad del ACE en pacientes peruanos con EA y DFT: Características clínico-demográficas Controles (n=40) EA (n=40) DFT (n=18) p 68.9 (4.6) 73.0(4.2) 66.7 (3.9) ˂0.001* ‡ 23:17 26:14 8:10 0.34 Educación (años) 12.4(2.8) 11.7(2.8) 12.3(2.8) 0.46 ADAScog 3.17(2.8) 21.5(5.8) 19.0(2.4) ˂0.001* † BDI-II 4.88(2.7) 4.35(2.2) 3.00(2.3) 0.30 MMSE 29.1(0.7) 21.2(2.8) 26.7(1.5) ˂0.001* †‡ ACE 93.3(2.6) 67.8(5.0) 76.8(5.5) ˂0.001* †‡ Edad (años) Género (F:M) * Control vs EA, p ˂ 0.001 † Control vs DFT, p ˂ 0.001 ‡ EA vs DFT, p ˂ 0.001 Custodio N, et al. Vertex Rev Arg Psiquiat 2012;XXIII:165-172.
- 24. 0.00 0.25 Sensitivity 0.50 0.75 1.00 Utilidad del ACE en pacientes peruanos con EA y DFT: Análisis discriminatorios entre pacientes y controles 0.00 0.25 0.50 1-Specificity ace ROC area: 01 Reference 0.75 1.00 mmse ROC area: 0.9836 Custodio N, et al. Vertex Rev Arg Psiquiat 2012;XXIII:165-172.
- 25. Utilidad del ACE en pacientes peruanos con EA y DFT: Punto de corte para detectar demencia sugerido es 86 Controles (n=40) EA (n=40) DFT (n=18) MMSE > 27 100 % 0% 50 % ACE > 90 77.5 % 0% 0% ACE > 86* 100 % 0% 0% ACE > 80 100 % 0% 27.8 % Custodio N, et al. Vertex Rev Arg Psiquiat 2012;XXIII:165-172.
- 26. Utilidad del ACE en pacientes peruanos con EA y DFT: Evaluación de los subdominios del ACE Dominio cognitivo EA DFT p Orientación 5.75 (0.9) 8.89 (0.7) ˂ 0.001 Atención 5.98 (0.8) 5.83 (0.8) 0.52 Memoria Total 14.1 (1.7) 20.90 (3.2) ˂ 0.001 Fluencia verbal 5.45 (0.9) 4.94 (0.6) ˂ 0.001 Lenguaje 22.0 (1.7) 17.4 (0.9) ˂ 0.001 Habilidad visuo-espacial 1.33 (0.9) 2.56 (1.0) ˂ 0.001 VLOM 4.53 (0.8) 2.08 (0.1) ˂ 0.001 Custodio N, et al. Vertex Rev Arg Psiquiat 2012;XXIII:165-172.
- 27. Agenda • Las demencias de inicio en edad pre-senil. • El espectro de la degeneración lobar fronto-temporal (DLFT). • Pruebas cognitivas breves en DFT variante conductual. • Relativa preservación de memoria y funciones viso-espaciales. • Marcado deterioro de las funciones ejecutivas.
- 28. Rendimiento en atención, memoria y lenguaje en pacientes con EA, DFTvc y controles de Clínica Internacional Dominio Cognitivo Control (n=60) EA (n=60) DFTvc(n=32) p Dígitos hacia adelante 5.16 (2.4) 3.3 (1.7) 3.5 (1.2) < .001*† TMT-A (s) 41.2 (13.6) 59.4 (14.7) 69.8 (16.5) < .01*† ‡ Recuerdo inmediato 24.9 (8.6) 11.3 (3.5) 17.4 (4.7) < .001*† ‡ Recuerdo retrasado 20.6 (7.9) 7.3 (2.5) 10.6 (3.6) < .001*† ‡ Reconocimiento 16.9 (3.1) 4.9 (3.6) 13.3 (2.4) < .001*† ‡ Denominación de Boston 18.6 (0.5) 13.6 (1.6) 15.2 (1.5) < .001*† Fluencia semántica 18.5 (1.2) 11.7 (2.1) 12.3 (2.5) < .001*† Atención Memoria Lenguaje * Control vs. EA † Control vs. DFT ‡ EA vs DFT Custodio N, et al. Rev NeuroPsiquiatría 2012;75(4):120-128
- 29. Relativa preservación de la memoria episódica
- 30. Leve compromiso en memoria semántica y de trabajo
- 31. Compromiso en el registro o en la recuperación Estímulo Estímulo RECUPERACIÓN REGISTRO DEPÓSITO Control de codificación con claves Estructuras LTM Facilitar el recuerdo con claves Síndrome hipocampal Disfunción ejecutiva Déficit de atención
- 32. Agenda • Las demencias de inicio en edad pre-senil. • El espectro de la degeneración lobar fronto-temporal (DLFT). • Pruebas cognitivas breves en DFT variante conductual. • Relativa preservación de memoria y funciones viso-espaciales. • Marcado deterioro de las funciones ejecutivas.
- 33. Rendimiento en funciones viso-espaciales y ejecutivas en pacientes con EA, DFTvc y controles de Clínica Internacional Dominio Cognitivo Control (n=60) EA (n=60) DFTvc(n=32) p Copia de dibujos 10.9 (1.6) 4.6 (3.1) 8.5 (3.2) < .001*† ‡ Test de cubos (WAIS III) 11.8 (1.7) 4.5 (3.4) 6.7 (2.1) < .001*† ‡ Dígitos hacia atrás 4.8 (1.1) 3.2 (1.6) 3.9 (1.2) < .01*† Fluencia fonológica 16.4 (4.9) 12.3 (3.4) 11.3 (4.2) 0.05*† TMT-B (s) 96.6 (35.3) 145 (58.7) 178.7 (42.2) < .001*† ‡ WCST (puntaje total) 5.3 (0.6) 3.1 (1.4) 3.2 (1.3) < .01*† WCST (perseverancia) 2.1 (1.2) 4.5 (2.3) 9.5 (5.3) < .01*† ‡ Viso-espacial/Constructivo Función Ejecutiva (Clásica) * Control vs. EA † Control vs. DFT ‡ EA vs DFT Custodio N, et al. Rev NeuroPsiquiatría 2012;75(4):120-128
- 34. La corteza Pre-frontal y las funciones ejecutivas CPF Dorsolateral Núcleo Caudado Globus Pallidus Tálamo 1. Orbito-frontal 3. Ventro-medial 2. Dorso-lateral 4. Cíngulo anterior
- 35. Conclusiones • DFTvc es un tipo de demencia más frecuente de lo que sospechamos. • Atención a síntomas conductuales, con un cambio en el patrón de base. • MMSE no detecta DFTvc, intente con ACE. • La memoria no suele estar comprometida en los estadios iniciales. • Adecuada evaluación de funciones ejecutivas, incluida cognición social.
Notas del editor
- Of the five studies of the prevalence of CS-FTLD, four were from Western Europe and one was from Japan. Three of the four European studies used the 1998 diagnostic criteria (Neary et al. 1998). The London, UK, and Ibaraki, Japan studies used the original Lund– Manchester criteria (The Lund and Manchester Groups 1994) which did not explicitly recognize PPA. Three studies examined only bvFTD (Rosso et al. 2003; Harvey et al. 2003; Ikejima et al. 2009). Prevalence estimates from these three studies ranged from 2 to 15.4 per 100,000 persons in the 45–64-year-old age range. In the two studies that identified both syndromes (Ratnavalli et al. 2002; Borroni et al. 2010), the point estimates of prevalence were 15 and 22 cases per 100,000 in the 45–64-year-old age range. The incidence estimates for CS-FTLD were clustered in a tight range, but the prevalence estimates differed by a factor of 10. We believe that the low estimates of prevalence (Rosso et al. 2003; Ikejima et al. 2009) resulted from insensitive diagnostic criteria and inadequate recognition. Indeed, the studies that reported lower prevalence estimates were ones that used the older 1994 criteria (The Lund and Manchester Groups 1994). It is possible that the very high estimates of prevalence in persons over age 65 years in some studies (Borroni et al. 2010; Garre-Olmo et al. 2010) do not reflect neuropathological FTLD and therefore represent an overdiagnosis of bvFTD. Neuropathological studies typified by the large multicenter study (Rascovsky et al. 2011) simply do not support the contention that most FTLDs occur in persons over age 65. Based on the best available data, we believe that the most plausible figures are that roughly 60% of CS-FTLD occurs in the 45–64-year-old age range, and that the prevalence of CSFTLD is 15–22 per 100,000 in that age range. Because of the rarity of PPA and bvFTD, none of the studies reviewed here employed active case detection methods. Instead, they all relied on passive surveillance and case detection by medical record review. The basis for claiming that a prevalence or incidence could be calculated was that each study was able to define a geographic catchment area for their case review and claim that any case of FTLD in a resident of the catchment region that was diagnosed would have been captured by their methodology. The main threat to the validity of these observations is the accuracy of clinical diagnoses. Undercounting of cases is a distinct possibility because the clinical detection of bvFTD or PPA requires a level of expertise in behavioral neurology that is possessed by few neurologists and even fewer non-neurologists. We believe that the very low estimate of CS-FTLD prevalence from Ibaraki, Japan (Ikejima et al. 2009) reflected the use of insensitive diagnostic criteria for, and, simultaneously, a limited awareness of, the clinical syndromes of FTLD in the practitioners in Ibaraki. Overdiagnosis and misclassification of bvFTD or PPA are also possible and could occur if some of the cases that were labeled clinically as bvFTD or PPA were actually due to the pathology of Alzheimer’s disease, Lewy body disease, or cerebrovascular disease. A number of the behavioral features of bvFTD may occur in the dementia of AD or in dementia with Lewy bodies. AD pathology sometimes occurs in persons diagnosed clinically with bvFTD or PPA (Mesulam et al. 2008; Forman et al. 2006; Davies et al. 2005; Hodges et al. 2004; Knopman et al. 2005). It is not possible to estimate quantitatively the extent of under- or overdiagnosis of CS-FTLD syndromes. To resolve both misclassification problems, very large, longitudinal clinical–pathological studies would be required that were free of biases during recruitment that would compromise the estimates. Patients with dementia of any presumed etiology would have to be recruited and followed to death and autopsy confirmation of diagnosis.
- Edad 45-65: total 108; bvFTD:90, SD:3, PNFA:15 Edad 66-75: total 97; bvFTD:75, SD:7, PNFA:15 Edad 76-85: total 21; bvFTD:15, SD:3, PNFA:3 We found that in Brescia county the prevalence of FTLD is higher, accounting for 17.6 cases out of 100,000 inhabitants. It is a common form of dementia at the ages 45–65 (22/100,000 inhabitants), and its prevalence significantly increases at the ages 66– 75 (78/100,000 persons). Further, we confirmed that FTLD diagnosis needs to be considered in the older population, with the prevalence of 54/100,000 inhabitants in patients over 75 years old. It is possible that the very high estimates of prevalence in persons over age 65 years in some studies (Borroni et al. 2010; Garre-Olmo et al. 2010) do not reflect neuropathological FTLD and therefore represent an overdiagnosis of bvFTD. Neuropathological studies typified by the large multicenter study (Rascovsky et al. 2011) simply do not support the contention that most FTLDs occur in persons over age 65. To address the wide divergence of extant prevalence estimates in the younger and older age ranges, we drew on other data. First, we examined the age range of a series of autopsy-proved cases of FTLD drawn from an international consortium of centers with expertise in bvFTD (Rascovsky et al. 2011). The study set included 176 cases, of which approximately 63% had an age of onset between 45 and 64 years, 9.7% an age of onset <45 years, and 27.3% an age of onset >64 years. We also examined a clinical series of 353 patients drawn from three centers that specialized in FTLD disorders (Johnson et al. 2005). In that series, about 30% had onset after age 65 years. Using these two alternate resources together with the prevalence data from the Netherlands (Rosso et al. 2003), we therefore estimated that 10% of CS-FTLD patients were <45 years of age and 30% were over age 65 years of age at onset.
- Two usages of the term ‘Pick’s disease’ have since become commonly, but divergently, applied. Especially in German neurology, Pick’s disease has been used to designate the clinical diagnosis of a frontal dementia, with or without pathologically proven Pick bodies or Pick cells. In the American literature, by contrast, Pick’s disease has been predominantly used as a pathological diagnosis, irrespective of the clinical presentation. (For similar discussions of the history of terminology of non-Alzheimer dementias see also Poeck and Luzzatti, 1988, Hodges et al., 1998, Rossor, 2001). Given this ambiguity, some authors have dropped the term altogether and preferred terms such as frontotemporal degeneration or frontotemporal dementia with or without Pick pathology (Snowden et al., 1996). In acknowledgement of the complex interrelations with other neurodegenerative diseases such as corticobasal degeneration, the term ‘Pick complex’ has now been suggested to stress clinical, pathological, histochemical, and genetic similarities amongst these degenerative conditions (Kertesz, 1997). The importance of these issues is emphasised by the fact that these conditions are not rare: up to a quarter of all degenerative dementias diseases belong to the Pick complex (Kertesz, 1998b). Furthermore, it is worth remarking that this ‘discovery’ is not recent. As early as 1926, Onari and Spatz wrote: We hold the opinion that Pick’s disease does not belong to the extreme rarities, but that it remains often unrecognised by the clinician as well as the anatomist because not enough attention is directed to it. Pick’s disease was defined as a neurodegenerative disorder characterized by severe circumscribed lobar atrophy, marked neuronal loss and gliosis, swollen neurons and Pick bodies. However, the term Pick complex with various neuropathological substrates is also used in clinical research. Presence of globular or spherical tau-positive, argyrophilic (not with Gallyas silver staining) neuronal cytoplasmic inlcusions, called Pick bodies, in the granule cells of the dentate gyrus (DG) and pyramidal neurons of CA1 subregion of the hippocampus, temporal and/or frontal cortex characterize Pick’s disease, also called fronto temporal lobar degeneration (FTLD) with Pick bodies.
- Sagittal view of a patient with the behavioral variant of frontotemporal dementia (bvFTD); note the anterior atrophy with relative sparing of the parietal and occipital regions. The anterior corpus callosum is also thinned compared to posterior. Coronal view of patient with semantic dementia showing significant left temporal atrophy. Coronal view of patient with nonfluent variant of FTD showing significant left insular atrophy. For about 2 decades, cases of PPA were generally categorized as semantic dementia or progressive nonfluent aphasia, or in some studies as “fluent” vs “nonfluent.” However, there were a number of PPA cases that did not seem to fit a binary classification, and a third clinical variant was empirically described and termed logopenic progressive aphasia by Gorno-Tempini et al. A typical (Logopenic Aphasia) LPA patient, aged 63 years. The arrowhead shows left-lateralized atrophy in the ascending part of the Sylvian fissure.
- In the absence of definitive biomarkers, the diagnosis of bvFTD is dependent on clinical diagnostic criteria; in other words, the identification of the syndrome’s core or necessary symptoms. The publication of consensus criteria by Neary and colleagues (1998) was a major development in the field. These criteria are widely used in research and practice, but some limitations have become apparent. Among these are the ambiguity of behavioural descriptors and inflexibility in the application of criteria (i.e. the requirement that all five core features be manifest). Most importantly, a number of studies have established the relative insensitivity of these criteria in the early stages of bvFTD when disease-modifying treatments are likely to be most effective (Mendez and Perryman, 2002; Mendez et al., 2007; Rascovsky et al., 2007a; Piguet et al., 2009). Based on the empirical knowledge accumulated in the past 12 years (Mendez and Perryman, 2002; Mendez et al., 2007; Rascovsky et al., 2007a; Piguet et al., 2009), the International Behavioural Variant FTD Criteria Consortium (FTDC) developed revised guidelines for the diagnosis of bvFTD. The FTDC is comprised of 46 members with extensive experience in bvFTD. After reviewing the world literature, the FTDC developed an initial draft of the bvFTD criteria. This document was further refined over 3 years through correspondence, a web-based interactive forum and in-person meetings. In this report, we propose a revision of diagnostic and research criteria for bvFTD and provide results of an autopsy-confirmed analysis of the sensitivity of these revised diagnostic guidelines.
- Three of the following behavioural/cognitive symptoms (A–F) must be present to meet criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single or rare events. As a general guideline ‘early’ refers to symptom presentation within the first 3 years.
- All of the following symptoms (A–C) must be present to meet criteria.
- bvFTD patient shows marked atrophy throughout the medial and lateral frontal cortex and the temporal poles, with striking relative preservation of the posterior brain regions on a sagittal view.
- Criterion A and either criterion B or C must be present to meet criteria. The proposed FTDC criteria are the result of a 3-year multinational effort to develop empirically derived diagnostic criteria for bvFTD. The present study found that FTDC criteria provide greater sensitivity than previously established criteria in a multi-site sample with known FTLD pathology. Of 137 cases where sufficient clinical data were available to evaluate both FTDC and previously established 1998 criteria, known as the common sample, 118 (86%) met criteria for possible bvFTD, and 104 (76%) met criteria for probable bvFTD. In contrast, the proportion of cases meeting 1998 criteria (53%) was significantly lower. These sensitivity rates were comparable with those found in the larger sample, in which either the FTDC or 1998 criteria could be evaluated. Thus, of 176 pathology-confirmed FTLD cases, 149 (85%) met FTDC criteria for possible bvFTD, while 113/154 (75%) with functional disability and neuroimaging ratings met criteria for probable bvFTD. The increased sensitivity of FTDC criteria is thought to reflect the optimized diagnostic features, less restrictive exclusion features and crucially, a flexible structure that accommodates variation in the symptom profile at presentation. Use of FTDC criteria for bvFTD diagnosis will improve identification of the syndrome, particularly in the earliest stages when disease-modifying therapies are most likely to b effective. Comparison of FTDC and 1998 criteria The consensus criteria published by Neary and colleagues (1998) greatly advanced the field of frontotemporal degenerations, and have been widely used in research and clinical practice. In an effort to further refine criteria by incorporation of recent empirical knowledge, the FTDC developed revised guidelines for the diagnosis of bvFTD. Both the 1998 and revised FTDC criteria rely on the presence of distinct clinical features for the diagnosis of bvFTD. A major difference, however, is that the 1998 criteria require the presence of all five core diagnostic features: insidious onset and gradual progression, early decline in personal and social interpersonal conduct, emotional blunting and loss of insight. Although individual core features are common at presentation,they are not ubiquitous. In the present sample, for example, the frequency of 1998 core features at initial presentation ranged from 78% for emotional blunting, to 99% for insidious onset and gradual progression. The ambiguity in behavioural descriptions (e.g. ‘emotional blunting’, ‘regulation of personal conduct’), and the need for inferences about a patient’s cognitive or emotional state (e.g. ‘loss of insight’), also have the potential to lower interrater reliability and the ultimate validity of these items for diagnosis (Rascovsky et al., 2007b). The 1998 criteria are further restricted by a large number of exclusion features (11 exclusion features and three relative exclusion features). Of 137 cases in the common sample, 26 (19%) presented one or more exclusion features for these diagnostic guidelines. Our observations show that the presence of early severe amnesia or spatial disorientation should not be exclusionary, and elimination of these exclusions improved the sensitivity of the FTDC criteria compared with the 1998 criteria. Exclusion based solely on impaired neuropsychological memory performance can lead to underdiagnosis of bvFTD (Hornberger et al., 2010), while spatial disorientation (when applied without reference to timing) may result in erroneous rejection of the diagnosis in patients who are in the late stages of their illness. The strict, five-feature core requirement, coupled with the number and nature of exclusion features, may be responsible for the low sensitivity of 1998 criteria observed in the present study. When taking exclusion features into account, only 53% of patients met all five core features at initial presentation. Even when the number of core features was relaxed, only 72% of the patients met three of the five core features required for diagnosis. Furthermore, the three most common 1998 core features were insidious onset and gradual progression, loss of insight and impairment in regulation of personal conduct. These three features are very common in neurodegenerative diseases and may yield suboptimal discrimination when attempting to differentiate bvFTD from other forms of dementia (Ishii et al., 2009; Orfei et al., 2010; Starkstein et al., 2010). The low sensitivity of 1998 criteria found in the present study mirrors the findings in recent retrospective studies. For instance, Mendez and Perryman (2002) examined the sensitivity of 1998 criteria in a sample of 53 patients with a clinical diagnosis of bvFTD and frontal hypoperfusion on SPECT. Only a third of these patients met 1998 criteria at presentation, but this number increased to 83% at a 2-year follow-up. This low initial sensitivity was replicated by the same authors in a sample of 134 patients with a suspected diagnosis of bvFTD (Mendez et al., 2007). Another retrospective study (Piguet et al., 2009) evaluated the sensitivity of 1998 criteria in a well-characterized cohort of 45 patients with bvFTD with a 3-year follow-up (18 with confirmed FTLD pathology). Only 58% of the patients in this sample met 1998 criteria for bvFTD at presentation. In contrast to sensitivity rates reported in retrospective studies, a prospective study (Pijnenburg et al., 2008) found a much higher sensitivity of 1998 criteria for bvFTD (79%), but there was no pathological confirmation in the majority of cases. Of note, diagnostic features in the above study were ascertained by a caregiver questionnaire about the 1998 clinical features and patients were diagnosed based on 1998 criteria (with 1-year clinical follow-up as gold standard). As expected, the restrictions that lower the sensitivity of 1998 criteria also lead to increased levels of specificity. This is particularly true when attempting to discriminate bvFTD from Alzheimer’s disease or other dementing conditions. In studies with dementia comparison groups, the specificity of 1998 criteria ranged from 90 to 100% (Mendez et al., 2007; Pijnenburg et al., 2008). Sensitivity of probable behavioural variant frontotemporal dementia The designation of probable bvFTD by the FTDC criteria restricts diagnosis to patients with demonstrable functional decline and typical bvFTD anatomical findings. These criteria are particularly suited for studies where high diagnostic certainty is required (such as clinical trials). Although 86% of patients in the common sample met criteria for possible bvFTD, only 76% of cases met criteria for probable bvFTD. Patients who failed to meet criteria for probable bvFTD were significantly older (age at onset: 63 versus 56; age at initial evaluation: 67 versus 60), and all 14 cases had imaging findings inconsistent with bvFTD at presentation (e.g. no apparent lobar atrophy or significant posterior atrophy). Although disproportionate atrophy in medial frontal, orbital–insular and anterior temporal regions may help distinguish bvFTD from other conditions (Frisoni et al., 1996; Rosen et al., 2002a; Varma et al., 2002; Grossman et al., 2004; Boccardi et al., 2005; Short et al., 2005; Whitwell and Jack, 2005; Bocti et al., 2006; Perry et al., 2006; Du et al., 2007; Mendez et al., 2007; Richards et al., 2008; Schroeter et al., 2008; Seeley et al., 2008; Davies et al., 2009; Kipps et al., 2009a; Lindberg et al., 2009; Whitwell et al., 2009), this imaging pattern is not necessarily present in all cases or at very early stages of disease (Perry et al., 2006). In fact, structural imaging in the form of frontal or anterior temporal lobe atrophy has been reported in 50–64% of cases with bvFTD (Knopman et al., 2005; Mendez et al., 2007; Pijnenburg et al., 2008). Low sensitivity of structural imaging may be particularly related to age at disease onset. A recent study of pathology-confirmed FTLD cases showed that, while a majority of presenile cases (onset before 65) showed moderate to severe frontotemporal atrophy and ventricular dilation at autopsy, only 12/30 (40%) of elderly patients showed severe frontotemporal atrophy (Baborie et al., 2010). Compared with structural imaging, functional imaging changes (e.g. predominant frontotemporal hypometabolism or hypoperfusion in SPECT or PET, or perfusion changes observed with arterial spin labelling MRI) may provide additional sensitivity (Mendez et al., 2007; Hu et al., 2010), suggesting that behavioural and functional abnormalities may precede structural imaging changes in bvFTD. Of interest, there was a striking male predominance in cases that failed the imaging requirements for probable bvFTD compared with those who did (12/14 males = 0.86 versus 54/104 males). The reasons behind this gender difference are unclear, but may relate to ascertainment bias or greater reliance on imaging features to diagnose females with ambiguous behavioural profiles. Strengths and caveats The present study is the result of a multinational effort to devise empirically derived criteria for bvFTD, and represents the largest pathology-confirmed bvFTD sample reported to date. Although the study design makes our findings representative and generalizable, some caveats of the study should be kept in mind. The greatest limitation of the present study was the absence of appropriate neurological or psychiatric comparison groups to assess specificity of the FTDC criteria. In our stepwise approach to criteria development, we are pursuing the strategy of evaluating the specificity of FTDC criteria once sensitivity has been established. Validation of any diagnostic criteria is an iterative process, and we acknowledge that the FTDC criteria may require revisions in light of future specificity findings. Unfortunately, appropriate specificity studies may require a prospective design with considerable time requirements. Constructing a suitable comparison group retrospectively to estimate specificity is challenging and prone to bias for several reasons. First, the sample of pathologically proven non-FTLD cases would have to be very large. Second, it is likely that information relevant to the FTDC criteria would never have been collected in cases where FTLD was not suspected clinically. For example, information about the core behavioural symptoms characteristic of bvFTD is generally not recorded in patients with typical amnesic Alzheimer’s disease or other forms of dementia.Patients with the phenocopy syndrome also present problems. These patients are behaviourally indistinguishable from patients with true bvFTD when the 1998 criteria are applied (Hornberger et al., 2009; Kipps et al., 2009a). Phenocopy cases should be distinguishable in that they do not have functional decline or imaging changes. Given these factors, it is possible that specificity could be erroneously under or over-estimated. In order to assess specificity properly, a prospective study of a large number of unselected patients with dementia should be carried out in which the elements of the FTDC criteria are sought at the time of initial diagnosis. Ideally, such a study should have independent biomarker confirmation of the pathological diagnosis, a very considerable logistic undertaking. The use of autopsy-confirmed cases ensures that our patients had FTLD pathology, but we acknowledge that retrospective autopsy-based samples can be prone to selection bias. It should be noted, however, that most participating brain banks were associated with Alzheimer’s centres or memory clinics treating a range of degenerative conditions where autopsy is generally pursued for all types of dementia. While individuals erroneously diagnosed with a psychiatric illness may have been less likely to undergo autopsy, in our experience, it is unlikely for patients with dementia to retain a primary psychiatric diagnosis late in their disease course. Another caveat of the present study is the ascertainment of diagnostic features based on retrospective and unblinded review of records. Although raters were instructed to rate features as positive only when clearly present, a priori knowledge of the underlying pathology may have sensitized raters to features consistent with bvFTD. Conversely, some FTDC features were not known at the time of patient evaluation, so the retrospective nature of the study may have underestimated the true frequency of such diagnostic criteria (e.g. loss of sympathy or empathy). The variability of information across centres may also contribute to low frequency rates, particularly when evaluating features such as imaging and neuropsychological profiles. Prospective studies that include standardized tests, questionnaires and imaging parameters may help elucidate the utility of the revised FTDC criteria. Finally, while we relied on easily observable features with clear operational definitions, prospective studies with multiple, blinded raters with different levels of expertise will be needed to determine the reliability of the FTDC criteria.
- The study found the FTDC criteria to have good sensitivity and specificity, indicating that they are effective in distinguishing between FTLD and other pathologies during life. Predictably, there was a tradeoff between sensitivity and specificity for “probable” compared with “possible” FTD criteria, reflecting the fact that although frontotemporal changes on neuroimaging increase specificity of diagnosis of FTD, they may not invariably be present in early-stage disease. The cohort encompassed the range of FTLD pathologies, confirming that the criteria are sensitive to bvFTD associated with tau, TDP-43, and fused in sarcoma pathologies. Analysis of individual behavioral features showed differences in relative strength. Whereas emotional and dietary changes have high specificity for bvFTD, they are not invariably present, thus have proportionally lower sensitivity. By contrast, the prominence of executive over other cognitive deficits is highly sensitive. The latter finding underlines the importance of neuropsychological assessment in the evaluation of patients with FTD. Examination of false-negative and false-positive cases is instructive. Two patients, who were diagnosed clinically with FTD at their first assessment and had FTLD pathology, did not meet FTDC criteria because they endorsed only 2 behavioral/cognitive features: apathy and executive impairment. This finding exemplifies the point that criteria provide a valuable adjunct to but are not a substitute for clinical experience. The majority of false-positive “possible bvFTD” cases had AD pathology. It is recognized that AD may occasionally present as a circumscribed frontal lobe syndrome and masquerade as bvFTD.12–14. The false- positive cases included 3 such patients, 1 of whom fulfilled criteria for probable bvFTD on the grounds of circumscribed frontal atrophy on imaging. However, other false-positive cases showed additional features of memory impairment and/or mild visuospatial impairment, which are typical of AD. Indeed, those patients had been diagnosed with AD in life. The relaxation of exclusion features in the FTDC criteria compared with the 1998 criteria stems from increased awareness of the potential variability in clinical phenotype: the presence of amnesia or “parietal” features does not necessarily rule out FTLD pathology 8,10,15. Indeed, one patient in this study had amnesia but the pathology was corticobasal degeneration together with hippocampal sclerosis. Moreover, executive impairments may secondarily compromise performance on memory and perceptuospatial tests 16. Nevertheless, the present findings raise a note of caution: relaxation of exclusion criteria, particularly in relation to the presence of spatial impairment, might inadvertently increase false-positive cases. False positivity in DLB is worthy of comment. The presence of fluctuations in mental state, parkinsonism, and hallucinations normally allows differentiation of DLB from bvFTD. However, such features are not invariably present. Moreover, delusions and hallucinations may occur in a subset of patients with bvFTD, particularly those with C9ORF72 repeat expansions.17 Furthermore, the tangential line of thought typical of patients with DLB may be difficult to distinguish from the unmonitored utterances of some patients with bvFTD. Indeed, it has been surmised that there may be a subgroup of DLB patients that mimics bvFTD 18,19. In the present false-positive DLB case, mild perceptuospatial and motor features were present and the clinical diagnosis was DLB. However, relaxation of exclusion criteria meant that the patient fulfilled bvFTD criteria. The present study yielded sensitivity levels (95% and 85% for possible and probable bvFTD, respectively) that are higher than the 86% and 76% figures reported in the multicenter FTDC criteria study.11 In that study, it was noted that patients who failed to meet criteria were older and had more atypical presentations with memory impairment than other patients. The present cohort is remarkably well matched to that of the earlier study11 in terms of mean age at onset, assessment, and death. However, the SD is slightly smaller, raising the possibility that the present cohort contained fewer “outliers”of older, atypical cases. In the present study, a high rate of positive family history was recorded in both FTLD and non-FTLD groups. A positive family history was defined as the presence of dementia in 1 first-degree relative. Therefore, a positive family history may not necessarily imply an autosomal dominant pattern of inheritance in all these cases. A strength of the current study is that case material was all drawn from a single center. Patients had under gone a relatively uniform diagnostic assessment, which included a behavioral history tapping the range of behaviors associated with bvFTD. Thus, data pertaining to FTLD and non-FTLD cases are directly comparable. Ratings were performed blind both to clinical and pathologic diagnosis by “naive” raters who had no personal knowledge of the patients. An independent pilot study, involving ratings by 5 authors, served as training in the rating process and helped to establish reporting consistency. The study also has limitations. The cohort was biased toward younger-onset dementias, so may not be representative of dementias as a whole. In particular, the findings may not generalize to patients with an older age at onset. Arguably, early- onset dementias are more likely to be confused with FTD, so the comparison of “matched” FTLD and non-FTLD samples is appropriate. However, it is possible that the present cohort does not encompass the range of phenotypic presentations of bvFTD, including older “atypical” bvFTD cases. Very few patients with psychiatric or vascular disease, which can mimic bvFTD, are represented in this study. Behavioral changes in vascular dementia show greater overlap with those of bvFTD, than occurs in AD20. Such changes include alterations in affect and diet. Indeed, 2 of the 3 vascular cases in this study fulfilled FTDC criteria and were diagnosed clinically with FTD. Such findings raise the possibility that specificity of the bvFTD criteria may be overestimated. Future studies should include larger numbers of patients with vascular dementia in their cohorts. There are, conversely, also grounds for assuming that specificity may be underestimated. The study adopted a stringent procedure of treating absence of documentation of a particular behavioral feature as missing data. The majority of such instances occurred, unsurprisingly, in patients with non-FTLD pathology in whom the behavioral feature is likely to be absent. There is a need for prospective studies of sensitivity and specificity to minimize the biases caused by missing data. The present study excluded patients presenting with progressive aphasia. This was important, both to allow direct comparisons with the earlier FTDC study11 and to avoid artificially diluting sensitivity ratings due to cases who a priori would not be expected to meet FTDC criteria. Nevertheless, not all patients exhibit “pure” clinical syndromes of behavioral or language impairment. It would be valuable to ascertain the proportion of patients with progressive aphasia presentations who also fulfill criteria for FTDC. The study, for parallel reasons, excluded patients presenting with extrapyramidal syndromes of progressive supranuclear palsy and corticobasal syndrome. It is of note that there remained cases of progressive supranuclear palsy and corticobasal degeneration pathology. These cases had behavioral/cognitive rather than motor presentations and fulfilled FTDC criteria. It would be important to know the degree to which prototypical progressive supranuclear palsy and corticobasal syndromes might also fulfill behavioral/cognitive criteria for bvFTD. In conclusion, the FTDC criteria for bvFTD show encouragingly high sensitivity and specificity in an autopsy-confirmed cohort of predominantly early- onset dementia patients. Caution should be exercised in the attribution of a bvFTD diagnosis in patients with visuospatial impairment because of the risk of false-positive errors. There is a need for prospective studies involving a wider range of disorders, including vascular disease. The criteria provide the potential to explore the relationship between the distinct syndromes associated with FTLD pathologies
- El ACE evalúa seis dominios cognitivos. La puntuación máxima obtenible es 100: orientación [10], atención [8], memoria [35], fluencia verbal [14], lenguaje [28] y habilidades visuoespaciales. A su vez, permite calcular los 30 puntos del MMSE, ya que se incluyen en el cuestionario. Si comparamos ambas pruebas, mientras el MMSE asigna 3/30 puntos a la función memoria, el ACE le asigna 35/100, lo que permite evaluar el aprendizaje serial. También agrega el examen de la fluencia verbal y amplía el del lenguaje: suma 10 objetos más a la prueba de denominación, evalúa así más profundamente la lectura de palabras e incluye una prueba de comprensión más exigente. Con respecto a las funciones visuoespaciales, además de los pentágonos cruzados del MMSE, se pide al paciente el dibujo de un cubo y de un reloj. En la adaptación peruana la prueba de aprendizaje y recuerdo del nombre y la dirección fueron cambiadas por Juan Quispe, Avenida Brasil 420, Breña y Lima; y se mantuvo el número de palabras utilizadas; en la prueba de memoria semántica se realizó una adaptación cultural (Presidente del Perú, alcalde de Lima, presidente anterior y ministro de economía); en la prueba de repetición de frases también se realizó otra adaptación cultural (la mazamorra morada tiene duraznos y guindones). Finalmente, en la evaluación de las funciones visuoespaciales se solicitó que las agujas del reloj indiquen las 11:10.
- Del ACE puede extraerse un coeficiente denominado VLOM, (fluidez verbal + lenguaje) / (orientación + recuerdo diferido) diseñado para orientar la discriminación entre la DTA y DFT. Con respecto al coeficiente VLOM, nuestros resultados son similares a aquellos de la publicación de la validación Argentina (12). Si bien el VLOM puede diferenciar DTA de DFT en la presente muestra, debe tenerse en cuenta que no brinda información sobre la naturaleza de esta diferencia entre cuadros de demencia. Por lo tanto, es conveniente complementar el ACE con una herramienta de tamizaje como el INECO Frontal Screening (22) que aporte información acerca del funcionamiento ejecutivo diferencial. De hecho, el INECO Frontal Screening, ha demostrado una muy superior capacidad para detectar déficits ejecutivos que otra herramienta de screening frontal ampliamente utilizada: el Frontal Assessment Battery (FAB) (23). Evidencia de la utilidad limitada del VLOM es la falta de diferencia significativa que se observa entre los grupos en el subdominio de atención en el presente estudio. Asimismo, se aprecia que la diferencia de desempeño en la prueba de fluencia verbal, clásicamente interpretada como una medida de funcionamiento ejecutivo, no es tan marcada como en el resto de los subdominios. En la presente investigación, las diferencias más importantes entre los grupos se registraron en orientación, memoria, atención, fluencia verbal, lenguaje, y habilidades visuoespaciales. El ACE puede realizarse en un tiempo breve (entre 15 y 20 min). Comparado con el MMSE, brinda más información en memoria, denominación, funciones visuoespaciales, e incorpora además la medición de funciones ejecutivas (p. ej., fluencia verbal, prueba del reloj). Al ACE contiene en su estructura al MMSE, lo que permite que se pueda tomar en pacientes cuyas evoluciones se realizaban con ese elemento de screening, o en pacientes muy deteriorados. Si bien las muestras se homogeneizan en cuanto a edad y años de educación, se debe destacar y advertir que la población estudiada tiene como característica una escolaridad promedio de 12 años. Dicho nivel de escolaridad no es representativo de toda la población Peruana: los puntos de corte deben tomarse cuidadosamente, dado que, si bien la puntuación total del ACE no depende del sexo ni de la edad, sí lo hace con respecto a los años de educación. Para realizar una interpretación adecuada de los valores del ACE, son esenciales puntos de corte estratificados por educación.
- FTLD patients have been shown to be less impaired on measures of memory than AD patients (Beyreuther & Arendt, 2002; Clark & Trojanowski, 2000; Elfgren et al., 1994; Harciarek & Jodzio, 2005; Hodges et al., 1999; Hutchinson & Mathias, 2007; Levy & Chelune, 2007; Mathuranath et al., 2000; Pasquier et al., 2001; Perry & Hodges, 2000; Rascovsky et al., 2002; Walker et al., 2005). Moreover, they have been shown to have better delayed recall (Diehl et al., 2005; Glosser et al., 2002; Gregory et al., 1997; Hodges & Miller, 2001; Hornberger, Piguet, Graham, Nestor, & Hodges, 2010; Lindau et al., 1998; Walker et al., 2005) and recognition (Harciarek & Jodzio, 2005; Mendez et al., 1996). FTLD patients perform better on recognition than recall measures, which may be due to the preserved ability of patients to use cues (intact priming effect) (Kertesz, 2006; Kertesz et al., 2003). Pasquier et al. (2001) showed that AD and bvFTD patients differed in immediate cued recall (encoding) with AD patients performing worse, and with total recall, recognition and learning consistency more preserved in bvFTD. Perhaps the most consistent finding is the relative preservation of episodic memory in FTLD relative to other neurodegenerative patients (Harciarek & Jodzio, 2005; Hutchinson & Mathias, 2007; Kramer et al., 2003; Marra et al., 2007; Perry & Hodges, 2000). However, FTLD patients may perform worse than controls on tests of memory, which some studies have attributed to disruptive executive control processes associated with pathology in prefrontal brain regions leading to impairments in attention and active, organized strategies for encoding and retrieval (Beyreuther & Arendt, 2002; Glosser et al., 2002; Harciarek & Jodzio, 2005; Levy & Chelune, 2007; Lindau et al., 1998; Marra et al., 2007; Pasquier, 1999; Rascovsky et al., 2002).
- Los problemas de registro estan relacionados a problemas atencionales, como en ansiedad y depresion. En el sindrome hipocampal: 1. Muy pobre recuerdo libre. 2. Disminución del recuerdo total (libre + facilitado), debido a un insuficiente efecto del recuerdo facilitado con claves o procedimientos de reconocimiento. Si la facilitacion del recuerdo con claves mejora, es probablemente una afectacion de los circuitos subcortico-frontales, tipicos de las demencias no Alzheimer.
- The dorsolateral prefrontal circuit originates in Brodmann’s areas 9 and 10 on the lateral surface of the anterior frontal lobe. Neurons in these regions project to the dorsolateral head of the caudate nucleus. Fibers from this region of the caudate project to the lateral aspect of the mediodorsal GPi and rostrolateral SNr via the direct pathway. The indirect pathway sends fibers to the dorsal GPe, which in turn projects to the lateral STN; fibers from the lateral STN then terminate in the GPi-SNr complex. Output from the basal ganglia projects to parvocellular portions of the ventral anterior and mediodorsal thalamus, respectively. The mediodorsal thalamus closes the circuit by projecting back to the circuit’s origin in areas 9 and 10 of the dorsolateral frontal lobe.