La apatía en la demencia frontotemporal y la enfermedad de Alzheimer: estudio clínico y de neuroimagen funcional

La apatía es uno de los síndromes neuropsiquiátricos más frecuentes e invalidantes de las demencias, y puede presentarse en cualquier estadio de la enfermedad. La presencia de la apatía en enfermedades neurodegenerativas se ha relacionado con una mayor morbilidad y un peor pronóstico, y con una mayor carga de estrés para el cuidador. Recientemente, se han propuesto unos criterios clínicos para el diagnóstico de apatía en la enfermedad de Alzheimer (EA) y otros trastornos neuropsiquiátricos. De acuerdo con la clasificación original de Marin, estos criterios se organizan en torno a tres dominios y resaltan la necesidad de una evaluación multidimensional de la apatía. Actualmente, la literatura existente acepta que se pueden distinguir tres subtipos o dimensiones de la apatía, asociados a disfunción de diferentes circuitos neurales: apatía cognitiva, apatía emocional y apatía por disfunción en la autoactivación. En castellano, tan sólo existen dos escalas validadas en demencias que evalúen la apatía desde un punto de vista multidimensional: la Lillés Apathy Rating Scale (LARS) y la Apathy Scale for Institutionalized Patients with Dementia Nursing Home version (APADEM-NH). La escala APADEM-NH está diseñada para evaluar la apatía en pacientes institucionalizados con EA mediante la entrevista a un cuidador profesional, por lo que no es válida para pacientes ambulatorios. La LARS consta de nueve dominios o subescalas (“Productividad diaria”, “Aficiones”, “Tomar la iniciativa”, “Búsqueda de novedades”, “Motivación”, “Respuesta emocional”, “Preocupación”, “Vida social” y “Autoconsciencia”), que pueden combinarse para calcular cuatro dimensiones de la apatía: “Curiosidad intelectual”, “Emoción”, “Iniciativa de acción” y “Autoconsciencia”. La versión en castellano de la LARS ha sido recientemente validada por nuestro grupo en una cohorte de pacientes con demencia, mostrando excelentes propiedades psicométricas..

A Novel Assessment and Profiling of Multidimensional Apathy in Alzheimer's Disease

BACKGROUND: Apathy is a complex multidimensional syndrome frequently reported in Alzheimer's disease (AD) and is associated with impaired awareness. Here we present a psychometrically robust method to profile apathy in AD.  OBJECTIVES: To determine the validity and reliability of a multidimensional apathy measure, the Dimensional Apathy Scale (DAS), and explore the apathy subtype profile and its associations in AD.  METHODS: 102 people with AD and 55 healthy controls were recruited. Participants completed the DAS, the Apathy Evaluation Scale (AES), Geriatric Depression Short form (GDS-15), and Lawton Instrumental Activities of Daily Living (LIADL). Psychometric properties of the DAS were determined. AD-Control comparison was performed to explore group differences on the DAS. Latent Class Analysis (LCA) was used to explore the profile of apathy in AD.  RESULTS: The DAS had a good to excellent Cronbach's standardized alpha (self-rated = 0.85, informant/carer-rated = 0.93) and good convergent and divergent validity against standard apathy (AES) and depression (GDS-15) measures. Group comparison showed people with AD were significantly higher for all apathy subtypes than controls (p < 0.001), and lacking in awareness over all apathy subtype deficits. LCA showed three distinct AD subgroups, with 42.2% in the Executive-Initiation apathy, 28.4% in the Global apathy, and 29.4% in the Minimal apathy group.  CONCLUSIONS: The DAS is a psychometrically robust method of assessing multidimensional apathy in AD. The apathy profiles in AD are heterogeneous, with additional specific impairments relating to awareness dependent on apathy subtype

Influence of physiological variables and comorbidities on plasma Aβ40, Aβ42, and p-tau181 levels in cognitively unimpaired individuals

Plasma biomarkers for Alzheimer's disease (AD) are a promising tool that may help in early diagnosis. However, their levels may be influenced by physiological parameters and comorbidities that should be considered before they can be used at the population level. For this purpose, we assessed the influences of different comorbidities on AD plasma markers in 208 cognitively unimpaired subjects. We analyzed both plasma and cerebrospinal fluid levels of Aβ40, Aβ42, and p-tau181 using the fully automated Lumipulse platform. The relationships between the different plasma markers and physiological variables were studied using linear regression models. The mean differences in plasma markers according to comorbidity groups were also studied. The glomerular filtration rate showed an influence on plasma Aβ40 and Aβ42 levels but not on the Aβ42/Aβ40 ratio. The amyloid ratio was significantly lower in diabetic and hypertensive subjects, and the mean p-tau181 levels were higher in hypertensive subjects. The glomerular filtration rate may have an inverse relationship on plasma Aβ40 and Aβ42 levels but not on the amyloid ratio, suggesting that the latter is a more stable marker to use in the general population. Cardiovascular risk factors might have a long-term effect on the amyloid ratio and plasma levels of p-tau181.Funding: This research received no external funding. Acknowledgments: This study was made possible thanks to donations from Germán González, Unidos por un Reto, Trail Nocturno de Cicero, La Trasmerana, and Primer Memorial Ángel Negrete. We would like to thank the participants of the Valdecilla Cohort for their selfless help and collaboration with research on neurodegenerative diseases. We would like to particularly acknowledge the patients and the Biobank Valdecilla (PT20/00067) in the Spanish Biobank Network for their collaboration

The experience of children with parents diagnosed with young onset dementia: A systematic literature review

Background: Young onset dementia (YOD) may develop rapidly, and affect those who have dependent children. Currently, there remains a lack of understanding of the impact on children living with a parent with YOD. Aim: The aim of this systematic literature review is to explore published literature in order to understand the impact on children living with a parent with YOD. Methods: A systematic search of the following databases: Medline; PsychINFO; CINAHL and Scopus for literature published from 1/1/2013 to 31/12/2018. Results: Three major themes were identified, firstly coping encompassed two sub-themes of avoiding the situation and being empowered. Secondly, change encompassed two sub-themes of change of personality and change of family role, and lastly loss. Conclusion: There remains a need to raise awareness and develop support services for children of parents with YOD. Community nurses are the best place healthcare professionals to identify and support the needs of both the person with YOD and their children

How predictive are temporal lobe changes of underlying TDP-43 pathology in the ALS-FTD continuum?

Detection of underling proteinopathies is becoming increasingly important across neurodegenerative conditions due to upcoming disease intervention trials. In this review, we explored how temporal lobe changes in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) can potentially predict underlying TDP-43 pathology subtypes in FTD. To date, emphasis has been given to frontal lobe changes in the study of the cognitive and behavioural impairments in both syndromes but an increasing number of pathological, imaging and neuropsychological studies suggest how temporal lobe changes could critically affect the cognition and behaviour of these conditions. In this current article, we reviewed pathological, imaging as well as clinical/neuropsychological findings of temporal involvement in the ALS-FTD continuum, how they relate to temporal lobe changes and the underlying TDP-43 pathology in FTD. Findings across studies show that TDP-43 pathology occurs and coincides in many structures in ALS and FTD, but especially in the temporal lobes. In particular, anterior and medial temporal lobes atrophy is consistently found in ALS and FTD. In addition, memory and language impairment as well as emotional and Theory of Mind (ToM) processing deficits that are characteristics of the two diseases are highly correlated to temporal lobe dysfunction. We conclude by showing that temporal lobe changes due to TDP-43 type B might be particular predictive of TDP-43 type B pathology in behavioural variant FTD (bvFTD), which clearly needs to be investigated further in the future

Lewy Body Dementias: A Coin with Two Sides?

Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on α-synuclein markers

Demencia frontotemporal variante conductual: aproximación clínica y terapéutica

Resumen: Introducción: La variante conductual de la demencia frontotemporal (DFT vc) es el síndrome clínico más frecuente de las demencias frontotemporales (DFT) y se caracteriza por una alteración progresiva de la personalidad y la conducta. En las últimas 2 décadas, los avances en biología molecular y genética han contribuido a un mayor conocimiento de esta entidad, que puede ser el modo de presentación de diferentes enfermedades neurodegenerativas. Desarrollo: Se revisan los principales aspectos epidemiológicos, clínicos, diagnósticos y terapéuticos de la DFT vc. La mayoría de los casos son esporádicos, iniciándose en torno a los 58 años de media. Los criterios diagnósticos vigentes establecen 3 niveles de certeza diagnóstica: posible, probable y definitivo. El diagnóstico clínico se basa en la anamnesis detallada de familiares, complementada con la realización de test neuropsicológicos dirigidos. Hasta la fecha, los tratamientos empleados son solo sintomáticos y de eficacia controvertida. Se están diseñando fármacos dirigidos contra dianas moleculares específicas implicadas en la patogenia de las degeneraciones lobares frontotemporales. Conclusiones: La DFT vc es una causa frecuente de demencia. Se trata de un síndrome amplio, heterogéneo desde el punto de vista histopatológico y biomolecular. La definición de subtipos clínicos y la identificación de biomarcadores podrían ayudar a predecir la afección subyacente, lo que junto con el desarrollo de fármacos dirigidos contra dianas moleculares ofrece nuevas posibilidades terapéuticas. Abstract: Introduction: Behavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. Development: We reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. Conclusions: BvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities. Palabras clave: Demencia frontotemporal variante conductual, Degeneración lobar frontotemporal, Clínica, Diagnóstico, Criterios diagnósticos, Tratamiento, Keywords: Behavioural variant frontotemporal dementia, Frontotemporal lobar degeneration, Clinical aspects, Diagnosis, Diagnostic criteria, Treatmen

Biomarkers: a new approach to behavioural variant frontotemporal dementia

Introduction: Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. Development: We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. Conclusions: BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities. Resumen: Introducción: Las degeneraciones lobares frontotemporales (DLFT) son un grupo de patologías moleculares que se definen en función de la proteína acumulada en el sistema nervioso central. La demencia frontotemporal variante conductual (DFT vc) es el síndrome clínico de presentación más frecuente. Los avances realizados en los últimos años han contribuido a un mayor conocimiento de esta entidad, que puede ser el modo de presentación de diferentes enfermedades neurodegenerativas. Desarrollo: Se revisa la correlación entre clínica, patología y genética de las DLFT, en especial de la DFT vc, así como los principales biomarcadores de la enfermedad. La anatomía patológica de la DFT vc es muy variada, sin mostrar asociación significativa con ningún subtipo histopatológico concreto. Entre los biomarcadores disponibles, destacan la neuroimagen anatómica y funcional, los biomarcadores analíticos y la genética. Se están diseñando fármacos dirigidos contra dianas moleculares concretas implicadas en la patogenia de las DLFT. Conclusiones: La DFT vc es una causa frecuente de demencia. De entre todas las variantes clínicas de las DLFT, es en la que resulta más difícil establecer una relación clínico-patológica. El uso de biomarcadores puede ayudar a predecir la anatomía patológica subyacente, lo que junto al desarrollo de fármacos ligando-específicos ofrece nuevas posibilidades terapéuticas. Keywords: Behavioural variant frontotemporal dementia, Frontotemporal lobar degeneration, Biomarker, TDP-43, Tau, Genetics, Palabras clave: Demencia frontotemporal variante conductual, Degeneración lobar frontotemporal, Biomarcador, TDP-43, Tau, Genétic

Behavioural variant frontotemporal dementia: Clinical and therapeutic approaches

Introduction: Behavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. Development: We reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. Conclusions: BvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities. Resumen: Introducción: La variante conductual de la demencia frontotemporal (DFT vc) es el síndrome clínico más frecuente de las demencias frontotemporales (DFT) y se caracteriza por una alteración progresiva de la personalidad y la conducta. En las últimas 2 décadas, los avances en biología molecular y genética han contribuido a un mayor conocimiento de esta entidad, que puede ser el modo de presentación de diferentes enfermedades neurodegenerativas. Desarrollo: Se revisan los principales aspectos epidemiológicos, clínicos, diagnósticos y terapéuticos de la DFT vc. La mayoría de los casos son esporádicos, iniciándose en torno a los 58 años de media. Los criterios diagnósticos vigentes establecen 3 niveles de certeza diagnóstica: posible, probable y definitivo. El diagnóstico clínico se basa en la anamnesis detallada de familiares, complementada con la realización de test neuropsicológicos dirigidos. Hasta la fecha, los tratamientos empleados son solo sintomáticos y de eficacia controvertida. Se están diseñando fármacos dirigidos contra dianas moleculares específicas implicadas en la patogenia de las degeneraciones lobares frontotemporales. Conclusiones: La DFT vc es una causa frecuente de demencia. Se trata de un síndrome amplio, heterogéneo desde el punto de vista histopatológico y biomolecular. La definición de subtipos clínicos y la identificación de biomarcadores podrían ayudar a predecir la afección subyacente, lo que junto con el desarrollo de fármacos dirigidos contra dianas moleculares ofrece nuevas posibilidades terapéuticas. Keywords: Behavioural variant frontotemporal dementia, Frontotemporal lobar degeneration, Clinical aspects, Diagnosis, Diagnostic criteria, Treatment, Palabras clave: Demencia frontotemporal variante conductual, Degeneración lobar frontotemporal, Clínica, Diagnóstico, Criterios diagnósticos, Tratamient

Demencia frontotemporal variante conductual: biomarcadores, una aproximación a la enfermedad

Resumen: Introducción: Las degeneraciones lobares frontotemporales (DLFT) son un grupo de patologías moleculares que se definen en función de la proteína acumulada en el sistema nervioso central. La demencia frontotemporal variante conductual (DFT vc) es el síndrome clínico de presentación más frecuente. Los avances realizados en los últimos años han contribuido a un mayor conocimiento de esta entidad, que puede ser el modo de presentación de diferentes enfermedades neurodegenerativas. Desarrollo: Se revisa la correlación entre clínica, patología y genética de las DLFT, en especial de la DFT vc, así como los principales biomarcadores de la enfermedad. La anatomía patológica de la DFT vc es muy variada, sin mostrar asociación significativa con ningún subtipo histopatológico concreto. Entre los biomarcadores disponibles, destacan la neuroimagen anatómica y funcional, los biomarcadores analíticos y la genética. Se están diseñando fármacos dirigidos contra dianas moleculares concretas implicadas en la patogenia de las DLFT. Conclusiones: La DFT vc es una causa frecuente de demencia. De entre todas las variantes clínicas de las DLFT, es en la que resulta más difícil establecer una relación clínico-patológica. El uso de biomarcadores puede ayudar a predecir la anatomía patológica subyacente, lo que junto al desarrollo de fármacos ligando-específicos ofrece nuevas posibilidades terapéuticas. Abstract: Introduction: Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. Development: We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. Conclusions: BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities. Palabras clave: Demencia frontotemporal variante conductual, Degeneración lobar frontotemporal, Biomarcador, TDP-43, Tau, Genética, Keywords: Behavioural variant frontotemporal dementia, Frontotemporal lobar degeneration, Biomarker, TDP-43, Tau, Genetic