Committee on High-quality Alzheimer's Disease Studies (CHADS) consensus report.

BACKGROUND: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. METHODS: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. RESULTS: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. CONCLUSIONS: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

White matter integrity is associated with cerebrospinal fluid markers of Alzheimer's disease in normal adults.

We explored whether white matter (WM) integrity in cognitively normal (CN) older adults is associated with cerebrospinal fluid (CSF) markers of Alzheimer's disease pathology. Twenty CN older adults underwent lumbar puncture and magnetic resonance imaging within a few days of each other. Analysis of diffusion tensor imaging data involved a priori region of interest and voxelwise approaches. The region of interest results revealed a positive correlation between CSF measures of amyloid-beta (Aß(42) and Aß(42)/p-Tau(181)) and WM integrity in the fornix, a relationship which persisted after controlling for hippocampal volume and fornix volume. Lower WM integrity in the same portion of the fornix was also associated with reduced performance on the Digit Symbol test. Subsequent exploratory voxelwise analyses indicated a positive correlation between CSF Aß(42)/p-Tau(181) and WM integrity in bilateral portions of the fornix, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and in the corpus callosum and left inferior longitudinal fasciculus. Our results link lower WM microstructural integrity in CN older adults with CSF biomarkers of Alzheimer's disease and suggest that this association in the fornix may be independent of volumetric measures.

Task deactivation reductions and atrophy within parietal default mode regions are overlapping but only weakly correlated in mild cognitive impairment.

Reduced task deactivation within regions of the default mode network (DMN) has been frequently reported in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). As task deactivation reductions become increasingly used in the study of early AD states, it is important to understand their relationship to atrophy. To address this issue, the present study compared task deactivation reductions during a lexical decision task and atrophy in aMCI, using a series of parallel voxel-wise and region-wise analyses of fMRI and structural data. Our results identified multiple regions within parietal cortex as convergence areas of task deactivation and atrophy in aMCI. Relationships between parietal regions showing overlapping task deactivation reductions and atrophy in aMCI were then explored. Regression analyses demonstrated minimal correlation between task deactivation reductions and either local or global atrophy in aMCI. In addition, a logistic regression model which combined task deactivation reductions and atrophy in parietal DMN regions showed higher classificatory accuracy of aMCI than separate task deactivation or atrophy models. Results suggest that task deactivation reductions and atrophy in parietal regions provide complementary rather than redundant information in aMCI. Future longitudinal studies will be required to assess the utility of combining task deactivation reductions and atrophy in the detection of early AD.

Functional response in ventral temporal cortex differentiates mild cognitive impairment from normal aging.

This study sought to identify altered brain activation patterns in amnestic mild cognitive impairment (MCI) that could precede frank task impairment and neocortical atrophy. A high-accuracy lexical decision (LD) task was therefore employed. Both MCI and normal seniors (NS) groups completed the LD task while functional magnetic resonance imaging (fMRI) was performed. Accuracy on the LD task was high (> or =89% correct for both groups), and both groups activated a network of occipitotemporal regions and inferior frontal cortex. However, compared with the NS group, the MCI group showed reduced fMRI activation in these regions and increased activation in bilateral portions of anterior cingluate cortex. The results from a voxel-based morphometry analysis indicated that altered activations in the MCI group were not within regions of atrophy. Receiver operating characteristic curves demonstrated that reduced fMRI response in the left and right midfusiform gyri accurately discriminated MCI from NS. When activation magnitude in both fusiform gyri were included in a single logistic regression model, group classification accuracy was very high (area under the curve = 0.93). These results showed that a disrupted functional response in the ventral temporal lobe accurately distinguishes individuals with MCI from NS, a finding which may have implications for identifying seniors at risk for cognitive decline.

Age-related slowing of task switching is associated with decreased integrity of frontoparietal white matter.

A body of research has demonstrated age-related slowing on tasks that emphasize cognitive control, such as task switching. However, little is known about the neural mechanisms that contribute to this age-related slowing. To address this issue, the present study used both fMRI and DTI in combination with a standard task switching paradigm. Results from the fMRI experiment demonstrated task switching cost (switching vs. nonswitching) activations in a network of frontoparietal and striatal regions in the young group. The older group recruited a similar network of regions, but showed decreased spatial extent of activation and recruited several regions not activated in the young group. White matter (WM) ROIs bordering the cortical network showing task switching activation were then selected to explore potential relationships between task switching reaction time (RT) cost and fractional anisotropy (FA) in the same groups of participants. Results demonstrated a negative correlation between switch cost RT and FA in left frontoparietal WM in both young and older groups. In addition, age-related FA decline in the same frontoparietal WM region was found to mediate age-related increases in RT switch costs. These findings identify decreased integrity of frontoparietal WM as one mechanism contributing to age-related increases in RT switch costs.

Aging influences the neural correlates of lexical decision but not automatic semantic priming.

Human behavioral data indicate that older adults are slower to perform lexical decisions (LDs) than young adults but show similar reaction time gains when these decisions are primed semantically. The present study explored the functional neuroanatomic bases of these frequently observed behavioral findings. Young and older groups completed unprimed and primed LD tasks while functional magnetic resonance imaging (fMRI) was recorded, using a fully randomized trial design paralleling those used in behavioral research. Results from the unprimed task found that age-related slowing of LD was associated with decreased activation in perceptual extrastriate regions and increased activation in regions associated with higher level linguistic processes, including prefrontal cortex. In contrast to these age-related changes in brain activation, the older group showed a preserved pattern of fMRI decreases in inferior temporal cortex when LD was primed semantically. These findings provide evidence that older adults' LD abilities benefit from contexts that reduce the need for frontally mediated strategic processes and capitalize on the continued sensitivity of inferior temporal cortex to automatic semantic processes in aging.