RESUMEN
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with complex disease etiology and pathological processes. These include formation of plaques and tangles, aberrant lipid processing, neuroinflammation, cerebrovascular dysregulation, ion channel and mitochondrial dysfunction, and oxidative stress. Disease-modifying therapies focusing on all these different facets are needed. TW001 is an oral formulation with the radical scavenger edaravone as its active ingredient, targeting oxidative stress. OBJECTIVES: This manuscript describes the trial design for Phase IIA Alzheimer Study Using oRal Edaravone (ASURE). METHODS: ASURE is a randomized, placebo-controlled, proof-of-concept study aiming to evaluate safety and target engagement following administration of TW001 in early AD patients. Patients should have a biomarker confirmed diagnosis to be included in the trial and will be treated for 90 days. The primary endpoints include safety and effect of TW001 on oxidative stress biomarkers. Exploratory endpoints focus on a panel of AD(-related) fluid-based biomarkers and EEG. In addition, a recently developed cognitive functional composite (CFC) score will measure early signs of cognitive and functional effects of TW001. RESULTS: This article outlines the design of the clinical study, no results are included. CONCLUSIONS: The ASURE trial design is discussed, with a particular focus on fluid biomarkers, EEG, and CFC as endpoints. By testing multiple measures related to pathology, pharmacodynamics, EEG as proxy for cognition, and cognitive functional scores, it is expected that small changes will be detectable in trials of shorter duration. Moreover, the wide range of endpoints allows to make well-informed decisions for designing pivotal studies later.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/psicología , Edaravona/uso terapéutico , Resultado del Tratamiento , Biomarcadores , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD. METHODS: This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics. RESULTS: To be expected early 2023 CONCLUSION: This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498650.
Asunto(s)
Enfermedad de Alzheimer , Aminoaciltransferasas , Método Doble Ciego , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: Neurofilament light in serum (sNfL) is a biomarker for axonal damage with elevated levels in many neurological disorders, including neurodegenerative dementias. Since within-group variation of sNfL is large and concentrations increase with aging, sNfL's clinical use in memory clinic practice remains to be established. The objective of the current study was to evaluate the clinical use of serum neurofilament light (sNfL), a cross-disease biomarker for axonal damage, in a tertiary memory clinic cohort. METHODS: Six neurologists completed questionnaires regarding the usefulness of sNfL (n = 5-42 questionnaires/neurologist). Patients that visited the Alzheimer Center Amsterdam for the first time between May and October 2019 (n = 109) were prospectively included in this single-center implementation study. SNfL levels were analyzed on Simoa and reported together with normal values in relation to age, as part of routine diagnostic work-up and in addition to cerebrospinal fluid (CSF) biomarker analysis. RESULTS: SNfL was perceived as useful in 53% (n = 58) of the cases. SNfL was more often perceived as useful in patients < 62 years (29/48, 60%, p = 0.05) and males (41/65, 63%, p < 0.01). Availability of CSF biomarker results at time of result discussion had no influence. We observed non-significant trends for increased perceived usefulness of sNfL for patients with the diagnosis subjective cognitive decline (64%), psychiatric disorder (71%), or uncertain diagnosis (67%). SNfL was mostly helpful to neurologists in confirming or excluding neurodegeneration. Whether sNfL was regarded as useful strongly depended on which neurologist filled out the questionnaire (ranging from 0 to 73% of useful cases/neurologist). DISCUSSION: Regardless of the availability of CSF biomarker results, sNfL was perceived as a useful tool in more than half of the evaluated cases in a tertiary memory clinic practice. Based on our results, we recommend the analysis of the biomarker sNfL to confirm or exclude neurodegeneration in patients below 62 years old and in males.
Asunto(s)
Filamentos Intermedios , Neurólogos , Biomarcadores , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos , Estudios ProspectivosRESUMEN
BACKGROUND: The behavioural variant of frontotemporal dementia (bvFTD) strongly resembles primary psychiatric disorders. Furthermore, a bvFTD mimic may occur, without neurodegenerative aetiology. AIM: To offer psychiatrist clinical tools for making or ruling out a bvFTD diagnosis. METHOD: To present the results of the first prospective cohort study on bvFTD patients and primary psychiatric patients. Results are discussed within the context of the international literature. RESULTS: Frontotemporal atrophy on imaging confirms a suspected bvFTD diagnosis. Merely fulfilling the bvFTD clinical criteria, with or without frontotemporal hypometabolism on functional imaging, may also result from primary psychiatric disorders or the bvFTD-phenocopy syndrome. A high level of stereotypy, hyperorality, a low level of depressive symptoms, impaired social cognition or absent insight increases the probability of bvFTD. Biomarker or genetic tests and follow-up are recommended. CONCLUSIONS A bvFTD diagnosis should be made multidisciplinary. Without the confirmation of atrophy or genetics, great reserve in making the diagnosis is in place and careful analyses for psychiatric aetiologies is advised.
Asunto(s)
Demencia Frontotemporal , Psiquiatría , Diagnóstico Diferencial , Demencia Frontotemporal/diagnóstico , Humanos , Neuroimagen , Pruebas Neuropsicológicas , Estudios ProspectivosRESUMEN
- Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head injuries like those seen in sports such as boxing, American football and soccer.- The clinical features of CTE are a range of cognitive, psychiatric and motor symptoms, and histopathology involves deposits of hyperphosphorylated tau protein and the presence of TAR DNA-binding protein (TDP-43) with relatively little beta-amyloid.- CTE is difficult to differentiate clinically from Alzheimer's disease, frontotemporal dementia and psychiatric disorders because of the major symptom overlap between these conditions.- The most important risk factors for developing CTE are the cumulative effect of repetitive head injuries, with or without clinical symptoms, and the duration of exposure to the repetitive injuries (the sporting career).- There is no treatment for CTE at present and the strategy must be primarily geared to prevention.- In view of the large number of people, including those in the Netherlands, who take part in sports in which head injuries may occur, research into CTE is of major societal importance.
Asunto(s)
Atletas , Encefalopatía Traumática Crónica/epidemiología , Encefalopatía Traumática Crónica/etiología , Encefalopatía Traumática Crónica/prevención & control , Humanos , Países Bajos/epidemiologíaRESUMEN
We set out to study whether single-subject gray matter (GM) networks show disturbances that are specific for Alzheimer's disease (AD; n = 90) or behavioral variant frontotemporal dementia (bvFTD; n = 59), and whether such disturbances would be related to cognitive deficits measured with mini-mental state examination and a neuropsychological battery, using subjective cognitive decline subjects as reference. AD and bvFTD patients had a lower degree, connectivity density, clustering, path length, betweenness centrality, and small world values compared with subjective cognitive decline. AD patients had a lower connectivity density than bvFTD patients (F = 5.79, p = 0.02; mean ± standard deviation bvFTD 16.10 ± 1.19%; mean ± standard deviation AD 15.64 ± 1.02%). Lasso logistic regression showed that connectivity differences between bvFTD and AD were specific to 23 anatomical areas, in terms of local GM volume, degree, and clustering. Lower clustering values and lower degree values were specifically associated with worse mini-mental state examination scores and lower performance on the neuropsychological tests. GM showed disease-specific alterations, when comparing bvFTD with AD patients, and these alterations were associated with cognitive deficits.