FV 3 Analysis of cerebrospinal fluid (CSF) biomarkers to predict risk of clinical decline and progression to dementia in patients with mild cognitive impairment and mild cognitive symptoms

Abstract Introduction Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD). Methods Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Results Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI:1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20%(6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Conclusion Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. Future investigation should clarify directionality of this association and potential utility of circadian-based interventions in the mitigation of AD progression. Support N/A

Download Full-text

Influence of APOE Genotype on Alzheimer’s Disease CSF Biomarkers in a Spanish Population

BioMed Research International ◽

10.1155/2016/1390620 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

J. A. Monge-Argilés ◽

R. Gasparini-Berenguer ◽

M. Gutierrez-Agulló ◽

C. Muñoz-Ruiz ◽

J. Sánchez-Payá ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apoe Genotype ◽

Amnestic Mild Cognitive Impairment ◽

Spanish Population ◽

Csf Biomarkers ◽

Csf Levels

Objectives. To evaluate the association between apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers and to study the influence of APOE genotype on the development of AD in a Spanish population.Material and Methods. The study comprised 29 amnestic mild cognitive impairment (MCI) patients and 27 control subjects. Using ELISA methodology, CSF biomarkers and tau/Aβratios were obtained. ANOVA and adjusted odds ratios were calculated.Results. We observed the effect of APOE genotype and age on CSF AD variables. The progression to AD was more clearly influenced by CSF AD variables than by age or APOE status.Conclusions. APOE status influences CSF AD variables. However, the presence of APOEε4 does not appear to be a deterministic factor for the development of AD, because CSF variables have a greater influence on progression to the disease. These results confirm previous observations and, to our knowledge, are the first published in a Spanish population.

Download Full-text

Cerebrospinal Fluid Biomarkers and Prediction of Conversion in Patients with Mild Cognitive Impairment: 4-Year Follow-Up in a Routine Clinical Setting

The Scientific World JOURNAL ◽

10.1100/tsw.2009.106 ◽

2009 ◽

Vol 9 ◽

pp. 961-966 ◽

Cited By ~ 19

Author(s):

Alessia Lanari ◽

Lucilla Parnetti

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Clinical Setting ◽

Cognitive Disorders ◽

Correct Prediction ◽

Csf Biomarkers ◽

Routine Clinical Setting ◽

T Tau

Mild cognitive impairment (MCI) is a very common syndrome in elderly people, with a high risk of conversion to dementia. Several investigations have shown the usefulness of cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau [T-tau], and phosphorylated tau [P-tau]) in predicting the progression to Alzheimer's disease (AD). We report a 4-year follow-up of MCI patients who underwent CSF evaluation for biomarker assessment, in order to further evaluate the usefulness of CSF analysis in predicting the conversion to dementia in a routine clinical setting. We identified 55 patients with MCI among the consecutive patients, referred from 2001 to 2003 to our Memory Clinic for cognitive disorders, who underwent a complete diagnostic assessment, including lumbar puncture (n = 273). At the end of the follow-up, 31 MCI patients (56%) did not progress to dementia (stable MCI), while 24 (44%) developed a dementia condition. At baseline, the mean levels of CSF Aβ42, T-tau, and P-tau were significantly altered in MCI patients who were converting to dementia with respect to those with stable MCI. All MCI patients with the three altered CSF biomarkers developed dementia within 1 year. Among the stable MCI patients, none showed all three pathological values and only one subject had the pathological value of P-tau. Early diagnosis of dementia and, specifically, a correct prediction of MCI outcome represent a primary goal. To this respect, the role of CSF biomarkers seems to be crucial in a routine clinical setting.

Download Full-text

Use of Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Risk in Mild Cognitive Impairment and Subjective Cognitive Decline in Routine Clinical Care in Germany

Journal of Alzheimer s Disease ◽

10.3233/jad-200794 ◽

2020 ◽

Vol 78 (3) ◽

pp. 1137-1148

Author(s):

Claudia Bartels ◽

Anna Kögel ◽

Mark Schweda ◽

Jens Wiltfang ◽

Michael Pentzek ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Clinical Care ◽

Subjective Cognitive Decline ◽

Csf Biomarkers ◽

Routine Clinical Care ◽

Biomarker Analysis ◽

Csf Biomarker

Background: The National Institute of Aging and Alzheimer’s Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals and memory clinics) in Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42, tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p = 0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed.

Download Full-text

Statistically Derived Subtypes and Associations with Cerebrospinal Fluid and Genetic Biomarkers in Mild Cognitive Impairment: A Latent Profile Analysis

Journal of the International Neuropsychological Society ◽

10.1017/s135561771700039x ◽

2017 ◽

Vol 23 (7) ◽

pp. 564-576 ◽

Cited By ~ 22

Author(s):

Joel S. Eppig ◽

Emily C. Edmonds ◽

Laura Campbell ◽

Mark Sanderson-Cimino ◽

Lisa Delano-Wood ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Latent Profile Analysis ◽

Profile Analysis ◽

Diagnostic Methods ◽

Csf Biomarkers ◽

Latent Profile

AbstractObjectives: Research demonstrates heterogeneous neuropsychological profiles among individuals with mild cognitive impairment (MCI). However, few studies have included visuoconstructional ability or used latent mixture modeling to statistically identify MCI subtypes. Therefore, we examined whether unique neuropsychological MCI profiles could be ascertained using latent profile analysis (LPA), and subsequently investigated cerebrospinal fluid (CSF) biomarkers, genotype, and longitudinal clinical outcomes between the empirically derived classes. Methods: A total of 806 participants diagnosed by means of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) MCI criteria received a comprehensive neuropsychological battery assessing visuoconstructional ability, language, attention/executive function, and episodic memory. Test scores were adjusted for demographic characteristics using standardized regression coefficients based on “robust” normal control performance (n=260). Calculated Z-scores were subsequently used in the LPA, and CSF-derived biomarkers, genotype, and longitudinal clinical outcome were evaluated between the LPA-derived MCI classes. Results: Statistical fit indices suggested a 3-class model was the optimal LPA solution. The three-class LPA consisted of a mixed impairment MCI class (n=106), an amnestic MCI class (n=455), and an LPA-derived normal class (n=245). Additionally, the amnestic and mixed classes were more likely to be apolipoprotein e4+ and have worse Alzheimer’s disease CSF biomarkers than LPA-derived normal subjects. Conclusions: Our study supports significant heterogeneity in MCI neuropsychological profiles using LPA and extends prior work (Edmonds et al., 2015) by demonstrating a lower rate of progression in the approximately one-third of ADNI MCI individuals who may represent “false-positive” diagnoses. Our results underscore the importance of using sensitive, actuarial methods for diagnosing MCI, as current diagnostic methods may be over-inclusive. (JINS, 2017, 23, 564–576)

Download Full-text

Biological Features of Reversion from Mild Cognitive Impairment to Normal Cognition: A Study of Cerebrospinal Fluid Markers and Brain Volume

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-200229 ◽

2021 ◽

Vol 5 (1) ◽

pp. 179-186

Author(s):

Kamyar Moradi ◽

Shahriar Faghani ◽

AmirHussein Abdolalizadeh ◽

Mohammadreza Khomeijani-Farahani ◽

Amir Ashraf-Ganjouei ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Brain Atrophy ◽

Significant Proportion ◽

Tau Proteins ◽

Csf Biomarkers ◽

Atrophy Rate ◽

The Difference ◽

Normal Cognition

Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. Although a significant proportion of the population with MCI experience reversion to normal cognition, it is still poorly understood. Objective: This study was designed to extend the present evidence regarding the difference between stable and reverting MCI by including whole brain atrophy measures as possible parameters involved. Methods: 405 patients diagnosed with MCI at baseline were selected. After one-year follow-up period, 337 patients (83.2%) were categorized as stable MCI and 68 patients (16.8%) reverted to cognitively normal status (reversion group). Several baseline biomarkers including cerebrospinal fluid (CSF) biomarkers of AD, including Aβ42, t-tau, and p-tau and MRI-based atrophy measurements were compared. Results: Participants with stable MCI demonstrated greater brain atrophy as well as lower Aβ and higher tau proteins in the CSF. The atrophy rate was found to be associated with CSF biomarkers merely in the stable group, after adjustment for confounding variables. Conclusion: These findings provide novel evidence regarding the biological perspective of the reversion phenomenon in individuals with MCI.

Download Full-text

Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer’s Disease in Amnestic Mild Cognitive Impairment

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000496920 ◽

2019 ◽

Vol 9 (1) ◽

pp. 100-113 ◽

Cited By ~ 5

Author(s):

Jung Eun Park ◽

Kyu Yeong Choi ◽

Byeong C. Kim ◽

Seong-Min Choi ◽

Min-Kyung Song ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Tau Protein ◽

Amnestic Mild Cognitive Impairment ◽

Csf Biomarkers ◽

Cutoff Values ◽

Prodromal Ad ◽

T Tau

Background/Aims: Disease-modifying therapy for Alzheimer’s disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD. Methods: We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Positron emission tomography was performed using florbetaben as a probe. We analyzed the concentration of Aβ1–42, total tau protein (t-Tau), and tau protein phosphorylated at threonine 181 (p-Tau181) in CSF with INNOTEST enzyme-linked immunosorbent assay. Results: For the detection of prodromal AD in patients with aMCI, the cutoff values of CSF Aβ1–42, t-Tau, and p-Tau181 were 749.5 pg/mL, 225.6 pg/mL, and 43.5 pg/mL, respectively. To discriminate prodromal AD in patients with aMCI, the t-Tau/Aβ1–42 and p-Tau181/Aβ1–42 ratios defined cutoff values at 0.298 and 0.059, respectively. Conclusions: CSF biomarkers are very useful tools for the differential diagnosis of prodromal AD in aMCI patients. The concentration of CSF biomarkers is well correlated with the stages of the AD spectrum.

Download Full-text

O4-11-01: RELATIONSHIP BETWEEN CEREBROSPINAL FLUID (CSF) BIOMARKERS AND COGNITIVE PERFORMANCE OF PATIENTS WITH MILD COGNITIVE IMPAIRMENT (MCI) AFTER LONG-TERM TREATMENT WITH CHF5074

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.04.445 ◽

2014 ◽

Vol 10 ◽

pp. P273-P273 ◽

Cited By ~ 1

Author(s):

Bruno Pietro Imbimbo ◽

Mercedes Fernandez ◽

Luciana Giardino ◽

Laura Calzà ◽

Daniel Chain ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Performance ◽

Term Treatment ◽

Csf Biomarkers ◽

Long Term Treatment

Download Full-text

What is the clinical impact of cerebrospinal fluid biomarkers on final diagnosis and management in patients with mild cognitive impairment in clinical practice? Results from a nation-wide prospective survey in France

BMJ Open ◽

10.1136/bmjopen-2018-026380 ◽

2019 ◽

Vol 9 (5) ◽

pp. e026380 ◽

Cited By ~ 5

Author(s):

Emmanuel Cognat ◽

François Mouton Liger ◽

Anne-Cécile Troussière ◽

David Wallon ◽

Julien Dumurgier ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Clinical Practice ◽

Mild Cognitive Impairment ◽

Final Diagnosis ◽

National Database ◽

Csf Biomarkers ◽

Prospective Survey ◽

Memory Clinics ◽

The Impact

ObjectivesNew diagnostic criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics.DesignWe performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey.Setting29 secondary and tertiary memory clinics in France.ParticipantsClinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP.Primary and secondary outcome measuresAssessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine.Results977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4).ConclusionThis nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.

Download Full-text