Agitation in Dementia: Relation to Core Cerebrospinal Fluid Biomarker Levels

Bloniecki, Victor; Aarsland, Dag; Cummings, Jeffrey L.; Blennow, Kaj; Freund‐Levi, Yvonne

doi:10.1159/000363500

Cited by 35 publications

(22 citation statements)

References 33 publications

(46 reference statements)

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“…For our secondary objective, we tested whether CSF markers may predict the course of NPS and found some indications that the course of some specific neuropsychiatric symptoms was associated with baseline CSF markers. We recently reported that Tau-mediated pathology was associated with increased agitation in AD [11]. In this study, low Aβ 1–42 at baseline was associated with improvement of irritability during treatment.…”

Section: Discussionsupporting

confidence: 48%

“…Pre-analytic and analytic procedures have been described in detail elsewhere [11]. In brief, T-tau concentration in CSF was determined using a sandwich ELISA (Innotest hTAU-Ag, Innogenetics, Gent, Belgium) [22].…”

Section: Methodsmentioning

confidence: 99%

“…We recently showed that agitation was associated with high levels of T-Tau and P-Tau [11]. However, we are not aware of previous studies of the association between CSF markers and the course of NPS.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Risperidone and Galantamine Treatment on Alzheimer’s Disease Biomarker Levels in Cerebrospinal Fluid

Bloniecki

Aarsland

Blennow

et al. 2017

JAD

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Background Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behaviour and cognition, but few studies have investigated their effect on Alzheimer biomarkers in cerebrospinal fluid (CSF). Aim This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of biomarkers T-Tau, P-Tau, Aβ1–42, and Aβ40/42-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS. Methods 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n=44) or risperidone (n=39) treatment. CSF samples were collected at baseline and after 12 weeks. Results Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1–42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1–42, Aβ42/40 and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1–42 levels in patients treated with risperidone were significantly decreased at follow up, showing a 8% (40 pg/mL) reduction as compared with baseline (p=0.03). Conclusions Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The Alzheimer CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

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Section: Discussionsupporting

confidence: 48%

Section: Methodsmentioning

confidence: 99%

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Effects of Risperidone and Galantamine Treatment on Alzheimer’s Disease Biomarker Levels in Cerebrospinal Fluid

Bloniecki

Aarsland

Blennow

et al. 2017

JAD

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“…Furthermore, the measurement usually reflects only the state at the time point (snapshot) the sample was obtained and different pathological situations show a distinct secretion pattern. Most importantly, in the majority of clinical evaluations, more than one biomarker needs to be available to support the interpretation of the activation state and clinical course [3] . Profiling these soluble factors is an important part in routine diagnostics for intensive care units and as a safety and exploratory parameter in clinical studies to obtain the current stage of the immune response after infections, vaccination or therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Validation of novel multiplex technologies

Akyüz¹

2017

Adv Precis Med

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Cytokine and chemokine levels in body fluid provide information of altered conditions in patients. The parallel analysis of multiple factors, such as cytokines, from small sample sizes is an interesting approach for the assessment of in vivo activation signatures and functionality after ex vivo stimulation. One interesting application is for therapy monitoringsuch as safety data, pharmacodynamics, evidences for mode-of-action and side effects-which is particularly useful for accompanying early phase clinical trials. There are different platforms for multiplex analyses of ligands available. An assay validation of three different platforms for simultaneous quantification of cytokines (Luminex Bio-Plex ® 200, Meso Scale Discovery ® and Ella ® ) was performed in this study. The comparison of multiplex platforms, which use different ways of achieving parallel measurements of biomarkers, reveal the performance strengths and weaknesses. We showed examples of in-house assessments of intra-and inter-assay variations, determination of the range and recovery of classical immunological serum markers and discussed advantages and disadvantages of these three platforms in relation to the question addressed. All the platforms show low intra-assay variances. The Luminex platform shows a high inter-assay variance for the majority of parameters, whereas the MSD and Ella platforms show low inter-assay variances.

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“…Emerging evidence on the neurobiological substrates of agitation in AD has led to investigation of repositioned and novel therapeutics for these NPS in dementia as an alternative to antipsychotics [1,5]. Central synaptic or circuit disconnections in frontal-subcortical and corticocortical networks, dysfunction in ascending monoaminergic systems involving serotonin, norepinephrine, or dopamine neurons, glutamate-mediated excitatory neurotoxicity, tau-mediated pathology, and inflammatory mediators may have a role for the development of NPS in AD [1,5,9,[35][36][37][38]. These CNS dysfunctions may occur concurrently and mediate synergistically NPS onset.…”

Section: Current and Alternative Pharmacological Approaches To The Trmentioning

confidence: 99%

Progresses in treating agitation: a major clinical challenge in Alzheimer’s disease

Panza

Solfrizzi

Seripa

et al. 2015

Expert Opinion on Pharmacotherapy

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Notwithstanding the renewed interest for the pharmacological treatment of agitation in AD, progresses have been limited. A small number and, sometimes methodologically questionable, randomized controlled trials (RCTs) have produced disappointing results. However, recently completed RCTs on novel or repositioned drugs (mibampator, dextromethorphan/quinidine, cannabinoids, and citalopram) showed some promise in treating agitation in AD, but still with safety concerns. Further evidence will come from ongoing Phase II and III trials on promising novel drugs for treating these distressing symptoms in patients with AD and dementia.

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Agitation in Dementia: Relation to Core Cerebrospinal Fluid Biomarker Levels

Cited by 35 publications

References 33 publications

Effects of Risperidone and Galantamine Treatment on Alzheimer’s Disease Biomarker Levels in Cerebrospinal Fluid

Effects of Risperidone and Galantamine Treatment on Alzheimer’s Disease Biomarker Levels in Cerebrospinal Fluid

Validation of novel multiplex technologies

Progresses in treating agitation: a major clinical challenge in Alzheimer’s disease

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