PET and P300 Relationships in Early Alzheimer\u27s Disease

The P300 (P3) wave of the auditory brain event-related potential was investigated in patients with probable Alzheimer\u27s disease to determine whether P300 latency discriminated these patients from controls and whether prolonged P300 latency correlated with rates of brain glucose metabolism as measured by Positron Emission Tomography. P300 latency was prolonged by more than 1.5 standard deviations from age expectancy in 14 of 18 patients, but none of 17 controls. In these subjects P300 latency was shown to be inversely correlated with relative metabolic rates of parietal and, to a lesser extent, temporal and frontal association areas, but not with subcortical areas

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial

Background: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer’s disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. Methods: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. Discussion: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer’s disease

Multimodal analysis in normal aging, mild cognitive impairment, and Alzheimer's disease: group differentiation, baseline cognition, and prediction of future cognitive decline

Thesis (Ph.D.)--Boston UniversityAlzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset that makes it difficult to distinguish from normal aging. It begins with an impairment of memory that develops into amnestic mild cognitive impairment (aMCI) and later to dementia as deficits become apparent in other cognitive domains. Effective biomarkers that differentiate normal aging, MCI, and AD and predict future cognitive decline are needed. Potential biomarkers have been studied in isolation, but their impact when combined is not understood. The goal of this project is to determine the optimal combination of CSF biomarkers, MRI morphometry, FDG PET metabolism, and neuropsychological test scores to differentiate between normal aging subjects and those with MCI and AD. This study addresses: 1) the optimal normalization region and partial volume correction method to quantify FDG PET analysis, 2) the effects of adjusting MRI-based cortical thickness measures for differences in gray/white matter tissue contrast in normal aging and disease, 3) whether multimodal multivariate stepwise logistic regression models can predict group membership, and 4) whether multimodal multivariate stepwise linear regression models can determine which imaging and CSF biomarker variables best predict future cognitive decline. The results indicate that normalizing FDG PET to the cerebellum along with using a gray matter mask for partial volume correction provides optimal prediction. In contrast, age-associated changes in gray/white matter intensity ratio did not differentiate between the groups and only slightly improved the efficacy of cortical thickness as a biomarker. MRI morphometry of the gray matter and neuropsychological test scores were better able to discriminate between the groups than FDG PET or CSF biomarker concentrations. Combining all modalities significantly improved the index of discrimination, especially at the earliest stages of the disease. MRI gray matter morphometry variables were more highly associated with baseline cognitive function and best predicted future cognitive decline compared to other variables. Overall these findings demonstrate that a multimodal approach using MRI morphometry, FDG PET metabolism, neuropsychological test scores, and CSF biomarkers provides significantly better discrimination than any modality alone. Hence, the variables important for discriminating between the groups may be candidates for biomarkers in human clinical interventional trials

Multivariate and Univariate Neuroimaging Biomarkers of Alzheimer's Disease

We performed univariate and multivariate discriminant analysis of FDG-PET scans to evaluate their ability to identify Alzheimer's disease (AD). FDG-PET scans came from two sources: 17 AD patients and 33 healthy elderly controls were scanned at the University of Michigan; 102 early AD patients and 20 healthy elderly controls were scanned at the Technical University of Munich, Germany. We selected a derivation sample of 20 AD patients and 20 healthy controls matched on age with the remainder divided into 5 replication samples. The sensitivity and specificity of diagnostic AD-markers and threshold criteria from the derivation sample were determined in the replication samples. Although both univariate and multivariate analyses produced markers with high classification accuracy in the derivation sample, the multivariate marker's diagnostic performance in the replication samples was superior. Further, supplementary analysis showed its performance to be unaffected by the loss of key regions. Multivariate measures of AD utilize the covariance structure of imaging data and provide complementary, clinically relevant information that may be superior to univariate measures

Longitudinal brain metabolic changes from amnestic mild cognitive impairment to Alzheimer's disease.

International audienceA sensitive marker for monitoring progression of early Alzheimer's disease would help to develop and test new therapeutic strategies. The present study is aimed at investigating brain metabolism changes over time, as a potential monitoring marker, in patients with amnestic mild cognitive impairment, according to their clinical outcome (converters or non-converters), and in relation to their cognitive decline. Seventeen amnestic mild cognitive impairment patients underwent magnetic resonance imaging and 18FDG-positron emission tomography scans both at inclusion and 18 months later. Baseline and follow-up positron emission tomography data were corrected for partial volume effects and spatially normalized using magnetic resonance imaging data, scaled to the vermis and compared using SPM2. 'PET-PAC' maps reflecting metabolic per cent annual changes were created for correlation analyses with cognitive decline. In the whole sample, the greatest metabolic decrease concerned the posterior cingulate-precuneus area. Converters had significantly greater metabolic decrease than non-converters in two ventro-medial prefrontal areas, the subgenual (BA25) and anterior cingulate (BA24/32). PET-PAC in BA25 and BA24/32 combined allowed complete between-group discrimination. BA25 PET-PAC significantly correlated with both cognitive decline and PET-PAC in the hippocampal region and temporal pole, while BA24/32 PET-PAC correlated with posterior cingulate PET-PAC. Finally, the metabolic change in BA8/9/10 was inversely related to that in BA25 and showed relative increase with cognitive decline, suggesting that compensatory processes may occur in this dorso-medial prefrontal region. The observed ventro-medial prefrontal disruption is likely to reflect disconnection from the hippocampus, both indirectly through the cingulum bundle and posterior cingulate cortex for BA24/32, and directly through the uncinate fasciculus for BA25. Altogether, our findings emphasize the potential of 18FDG-positron emission tomography for monitoring early Alzheimer's disease progression