Search

Background: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients., Objective: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression., Methods: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers., Results: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction)., Conclusion: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

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 (Aβ42) 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 ɛ4-specific cerebrospinal fluid (CSF) Aβ42/P-tau cut-offs 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 Aβ42/P-tau status, time, and CSF Aβ42/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.

Background: Amyloid-β (Aβ) and [18F]FDG PET are established as amyloid pathology and neuronal injury biomarkers. Early after administration Aβ PET images have the potential to replace [18F]FDG PET images allowing dual biomarker delivery by the administration of a single tracer. For [18F]FDG PET data, a correlation with cognitive performance is known., Objective: The aim of this study was to investigate whether early after administration [11C]PiB PET data also correlate with cognitive performance., Methods: The early after administration [11C]PiB PET data of 31 patients with cognitive impairment were evaluated. CERAD subtests were summarized to five cognitive domains. The resulting z scores were correlated with the PET data on a voxel- and VOI-based approach. Additional subgroup analyses (MCI versus dementia, Aβ-positive versus Aβ-negative subjects) were performed., Results: Significant correlations between cognitive performance and early after administration [11C]PiB PET data were found between left temporo-parietal SUVR and language domain, bilateral occipital as well as left temporal SUVR and executive function, left pre- and postcentral SUVRs, and visuospatial abilities. For the episodic and immediate memory domains, the analysis at the high significance level did not show any correlated cluster, however, the exploratory analysis did., Conclusion: Our study revealed correlations between deficits in different cognitive domains and regional early after administration [11C]PiB PET data similar to those known from [18F]FDG PET studies. Thus, our data support the assumption that early [11C]PiB PET data have a potential as neuronal injury biomarker. Head-to-head double-tracer studies of larger cohorts are needed to confirm this assumption.

Background: Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates., Objective: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers., Methods: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed., Results: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006)., Conclusion: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.

Background: Biomarkers of neuronal injury and amyloid pathology play a pivotal role in the diagnosis of Alzheimer's disease (AD). The degree of AD biomarker congruence is still unclear in clinical practice., Objective: Diagnosis of AD with regard to the congruence of the clinical diagnosis and different biomarkers., Methods: In this prospective cross-sectional observational study, 54 patients with mild cognitive impairment or dementia due to AD or not due to AD were investigated. Biomarkers of neuronal injury were medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) and tau concentration in the cerebrospinal fluid (CSF). CSF Aβ(1-42) and amyloid-targeting positron emission tomography (PET) were considered as biomarkers of amyloid pathology., Results: Forty cases were diagnosed as AD and 14 cases were diagnosed as non-AD based on clinical and routine MRI assessment. AD cases had higher MTA scores, higher levels of CSF tau and lower levels of CSF Aβ(1- 42), and higher amyloid load on PET compared to the non-AD group. In the AD group, completely consistently pathological biomarkers were found in 32.5% , non-pathological in 5% . In 62.5% the findings were inconsistent. Congruence of biomarkers was 67.5% for neuronal injury and for amyloid dysfunction, respectively. In two patients, clinical diagnosis switched to non-AD due to completely consistent non-pathological biomarker findings. The criteria of the international working group were met in 75.0% ., Conclusion: Surprisingly, the number of completely congruent biomarkers was relatively low. Interpretation of AD biomarkers is complicated by multiple biomarker constellations. However, the level of biomarker consistency required to reliably diagnose AD remains uncertain.

The revised NIA-AA diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD make use of amyloid pathology and neurodegeneration biomarkers which increase the diagnostic confidence in the majority of patients. However, in daily praxis, cases with conflicting biomarker constellations occur. A MCI subject underwent neuropsychological testing supplemented by FDG and amyloid PET/MRI as well as CSF sampling. In this subject, the biomarkers of Aβ deposition were negative. [18F]FDG PET, however, showed an AD-typical hypometabolism. Further studies are required to determine frequency and relevance of cases with neurodegeneration-first biomarker constellations to improve our understanding on pathogenesis and diagnosis of AD.