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

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

Oculomotor dysfunction in idiopathic and LRRK2-parkinson's disease and at-risk individuals

Background: Video-oculography constitutes a highly-sensitive method of characterizing ocular movements, which could detect subtle premotor changes and contribute to the early diagnosis of Parkinson's disease (PD). Objective: To investigate potential oculomotor differences between idiopathic PD (iPD) and PD associated with the G2019S variant of LRRK2 (L2PD), as well as to evaluate oculomotor function in asymptomatic carriers of the G2019S variant of LRRK2. Methods: The study enrolled 129 subjects: 30 PD (16 iPD, 14 L2PD), 23 asymptomatic carriers, 13 non-carrier relatives of L2PD patients, and 63 unrelated HCs. The video-oculographic evaluation included fixation, prosaccade, antisaccade, and memory saccade tests. Results: We did not find significant differences between iPD and L2PD. Compared to controls, PD patients displayed widespread oculomotor deficits including larger microsaccades, hypometric vertical prosaccades, increased latencies in all tests, and lower percentages of successful antisaccades and memory saccades. Non-carrier relatives showed oculomotor changes with parkinsonian features, such as fixation instability and hypometric vertical saccades. Asymptomatic carriers shared multiple similarities with PD, including signs of unstable fixation and hypometric vertical prosaccades; however, they were able to reach percentages of successful antisaccade and memory saccades similar to controls, although at the expense of longer latencies. Classification accuracy of significant oculomotor parameters to differentiate asymptomatic carriers from HCs ranged from 0.68 to 0.74, with BCEA, a marker of global fixation instability, being the parameter with the greatest classification accuracy. Conclusions: iPD and LRRK2-G2019S PD patients do not seem to display a differential oculomotor profile. Several oculomotor changes in asymptomatic carriers of LRRK2 mutations could be considered premotor biomarkers

Diagnostic accuracy of plasma p-tau217 for detecting pathological cerebrospinal fluid changes in cognitively unimpaired subjects using the lumipulse platform

Background: Plasma biomarkers of Alzheimer's disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, determined either by cerebrospinal fluid (CSF) or positron emission tomography. However, it is essential to measure them in an accurate and fully automated way in order to apply them in clinical practice. Objectives: To evaluate the diagnostic performance of the fully-automated Lumipulse plasma p-tau217 assay in preclinical AD. Design: Cross-sectional analyses from a prospective cohort. Setting: A population-based study. Participants: Volunteers over 55 years without cognitive impairment or contraindications for complementary tests. Measurements: Plasma p-tau217 was measured with the fully-automated Lumipulse assay, as well as CSF Abeta40, Abeta42, p-taul81, and t-tau levels. We correlated plasma p-tau217 with CSF Abeta40, Abeta42 and p-tau181, and assessed the differences in plasma p-tau217 according to CSF amyloid status (A-/+), AD status (AD+ being those subjects A+T+ and AD- the rest) and ATN group. We performed ROC curves and measured the areas under the curve (AUC) using CSF amyloid as result, and both p-tau217 and ApoE4 status as predictor. Results: We screened 209 cognitively unimpaired volunteers with a mean age 64 years (60-69) and 30.2% of ApoE4 carriers. Plasma p-tau217 correlated significantly with CSF Abeta42/Abeta40 (Rho=-0.51; p-value<0.001) and p-tau181 (r=0.59; p-value<0.001). Its levels were significantly higher in A+ subjects (0.26 pg/ml) compared with A- (0.12 pg/ml; p-value<0.001); and along ATN groups. It predicts CSF amyloid pathology with an AUC of 0.85. Conclusions: Plasma p-tau217 measured using the Lumipulse platform shows promise as an accurate biomarker of preclinical AD pathology

Early microglial and astrocyte reactivity in preclinical Alzheimer's disease

Introduction: The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear. Methods: We assessed changes in microglial and astrocytic biomarkers in a well-characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events. Results: Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Ab42/40. CSF sTREM2 directly influenced CSF phosphorylated tau-181 (p-tau181) and neurogranin, and correlated with CSF S100 calcium-binding protein beta (S100b). CSF chitinase-3-like protein 1 (YKL-40) mediated the association between CSF p-tau181 and total tau (t-tau), whereas CSF S100b and neurofilament light showed mutual influence. Discussion: Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL-40 and S100b contribute to the progression of downstream neurodegenerative changes

LAM test: a new cognitive marker for early detection in preclinical Alzheimer's disease

Background: With the arrival of disease-modifying treatments, it is mandatory to find new cognitive markers that are sensitive to Alzheimer's disease (AD) pathology in preclinical stages. Objective: To determine the utility of a newly developed Learning and Associative Memory face test: LAM test. This study examined the relationship between AD cerebrospinal fluid (CSF) biomarkers and performance on LAM test, and assessed its potential clinical applicability to detect subtle changes in cognitively healthy subjects at risk for AD. Methods: We studied eighty cognitively healthy volunteers from the Valdecilla cohort. 61% were women and the mean age was 67.34 years (±6.416). All participants underwent a lumbar puncture for determination of CSF biomarkers and an extensive neuropsychological assessment, including performance on learning and associative memory indices of the LAM-test after 30 min and after 1 week, and two classic word lists to assess verbal episodic memory: the Rey Auditory Verbal Learning Test (RAVLT) and the Free and Cued Selective Reminding Test (FCSRT). We analyzed cognitive performance according to amyloid status (A+ versus A-) and to ATN model (A-T-N-; A+T-N-; A+T+N-/A+T+N+). Results: Performance on the LAM-test was significantly correlated with CSF Aβ ratio. A+ participants performed worse on both learning (mean difference = 2.19, p = 0.002) and memory LAM measures than A- (mean difference = 2.19, p = 0.004). A decline in performance was observed along the Alzheimer's continuum, with significant differences between ATN groups. Conclusions: Our findings suggest that LAM test could be a useful tool for the early detection of subjects within the AD continuum, outperforming classical memory tests.This study was made possible thanks to donations from Germán González, Unidos por un Reto, Trail Nocturno de Cicero, La Trasmerana, Primer Memorial Ángel Negrete and Siemens

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

Plasma Phosphorylated Tau 231 Increases at One-Year Intervals in Cognitively Unimpaired Subjects

Background: Plasma biomarkers of Alzheimer's disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid