Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers (original) (raw)
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Journal of Alzheimer's Disease
The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-A 1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-A provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows 1 Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.
Journal of Alzheimer's Disease, 2019
Background: Assessment of human brain atrophy in temporal regions using magnetic resonance imaging (MRI), resting state functional MRI connectivity in the left parietal cortex, and limbic electroencephalographic (rsEEG) rhythms as well as plasma amyloid peptide 42 (A 42) has shown that each is a promising biomarker of disease progression in amnestic mild cognitive impairment (aMCI) patients with prodromal Alzheimer's disease (AD). However, the value of their combined use is unknown. Objective: To evaluate the association with cognitive decline and the effect on sample size calculation when using a biomarker composite matrix in prodromal AD clinical trials. Methods: Multicenter longitudinal study with follow-up of 2 years or until development of incident dementia. APOE 4specific cerebrospinal fluid (CSF) A 42 /P-tau cutoffs were used to identify aMCI with prodromal AD. Linear mixed models were performed 1) with repeated matrix values and time as factors to explain the longitudinal changes in ADAS-cog13, 2) with CSF A 42 /P-tau status, time, and CSF A 42 /P-tau status × time interaction as factors to explain the longitudinal changes in matrix measures, and 3) to compute sample size estimation for a trial implemented with the selected matrices. Results: The best composite matrix included the MRI volumes of hippocampal dentate gyrus and lateral ventricle. This matrix showed the best sensitivity to track disease progression and required a sample size 31% lower than that of the best individual biomarker (i.e., volume of hippocampal dentate gyrus). Conclusion: Optimal matrices improved the statistical power to track disease development and to measure clinical progression in the short-term period. This might contribute to optimize the design of future clinical trials in MCI.
BMJ open, 2013
To assess the incremental value of MRI and cerebrospinal fluid (CSF) analysis after a short memory test for predicting progression to Alzheimer's disease from a pragmatic clinical perspective. Diagnostic accuracy study in a multicentre prospective cohort study. Alzheimer Disease Neuroimaging Initiative participants with complete data on neuropsychological assessment, MRI of the brain and CSF analysis. Patients with mild cognitive impairment (MCI; n=181) were included. Mean follow-up was 38.9 months (range 5.5-75.9). Diagnostic accuracy of individual instruments and incremental value of entorhinal cortex volume on MRI and p-τ/Aβ ration in CSF after administration of Rey's Auditory Verbal Learning Memory Test are calculated and expressed as the 'Net Reclassification Improvement' (NRI), which is the change in the percentage of individuals that are correctly diagnosed as Alzheimer or non-Alzheimer case. Tested in isolation, a short memory test, MRI and CSF all substantia...
Alzheimer's research & therapy, 2017
The progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1-42 (Aβ42), amyloid-beta1-40 (Aβ40) levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia. We used 115 complete datasets from MCI patients of the "Dementia Competence Network", a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndrome...
Journal of internal medicine, 2016
In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid β peptide 1-42 (Aβ42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. Prodromal AD was found in 55 aMCI patients define...
Journal of Alzheimer's disease : JAD, 2018
It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as "positive" (i.e., "prodromal AD" n = 76) or "negative" (n = 52) based on a diagnostic cut-off of Aβ42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42, Aβ40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the "positive" (i.e., prodromal AD) and "negative...
Archives of Neurology, 2009
Objective-Cerebrospinal fluid (CSF) levels of Aβ peptide 1-42 (Aβ 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer's disease (AD). We hypothesized that these biomarkers might predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT). Design-Retrospective analysis of CSF biomarkers and clinical data. Setting-An academic Alzheimer's Disease Research Center. Participants-Research volunteers in a longitudinal study of aging and cognition. Participants (n=49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All participants had at least one follow-up assessment (mean years of follow-up = 3.5 ± 1.8 years). Main outcome measures-Baseline CSF levels of Aβ 42 , Aβ 40 , tau and tau phosphorylated at threonine 181 (ptau 181), rate of dementia progression as measured by CDR-sum of boxes (CDR-SB) and by psychometric performance, Results-The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Aβ 42 , with higher tau or ptau 181 , or high tau/Aβ 42 ratio. For example, the annual change in CDR-SB was 1.1 for the lowest two tertiles of Aβ 42 values and 0.3 for the highest tertile of Aβ 42 values. Conclusions-In individuals with very mild DAT, lower CSF Aβ 42 , high tau or ptau 181 , or a high tau/Aβ 42 ratio quantitatively predict more rapid progression of cognitive deficits and dementia. CSF biomarkers may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.
Conflicting cerebrospinal fluid biomarkers and progression to dementia due to Alzheimer’s disease
Alzheimer's Research & Therapy, 2016
Background: According to new diagnostic guidelines for Alzheimer's disease (AD), biomarkers enable estimation of the individual likelihood of underlying AD pathophysiology and the associated risk of progression to AD dementia for patients with mild cognitive impairment (MCI). Nonetheless, how conflicting biomarker constellations affect the progression risk is still elusive. The present study explored the impact of different cerebrospinal fluid (CSF) biomarker constellations on the progression risk of MCI patients. Methods: A multicentre cohort of 469 patients with MCI and available CSF biomarker results and clinical follow-up data was considered. Biomarker values were categorized as positive for AD, negative or borderline. Progression risk differences between patients with different constellations of total Tau (t-Tau), phosphorylated Tau at threonine 181 (p-Tau) and amyloid-beta 1-42 (Aβ 42) were studied. Group comparison analyses and Cox regression models were employed. Results: Patients with all biomarkers positive for AD (N = 145) had the highest hazard for progression to dementia due to AD, whilst patients with no positive biomarkers (N = 111) had the lowest. The risk of patients with only abnormal p-Tau and/or t-Tau (N = 49) or with positive Aβ 42 in combination with positive t-Tau or p-Tau (N = 119) is significantly lower than that of patients with all biomarkers positive. Conclusions: The risk of progression to dementia due to AD differs between patients with different CSF biomarker constellations.
2010
Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition, we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-β (Aβ)1−42 and tau in CSF had the best predictive accuracy for AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6-32.4). Aβ1−42, total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma levels of Aβ1−40, Aβ1−42, the ratio Aβ1−42/Aβ1−40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Aβ1−42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Aβ1−42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia.