Kristina M. DePeau

Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis

Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimers disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity in 52 individuals across the continuum of normal aging, mild cognitive impairment (MCI), and mild AD. Independent component analyses revealed specific memory-related networks that activated or deactivated during an associative memory paradigm. Across all subjects, hippocampal activation and parietal deactivation demonstrated a strong reciprocal relationship. Furthermore, we found evidence of a nonlinear trajectory of fMRI activation across the continuum of impairment. Less impaired MCI subjects showed paradoxical hyperactivation in the hippocampus compared with controls, whereas more impaired MCI subjects demonstrated significant hypoactivation, similar to the levels observed in the mild AD subjects. We found a remarkably parallel curve in the pattern of memory-related deactivation in medial and lateral parietal regions with greater deactivation in less-impaired MCI and loss of deactivation in more impaired MCI and mild AD subjects. Interestingly, the failure of deactivation in these regions was also associated with increased positive activity in a neocortical attentional network in MCI and AD. Our findings suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD. These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD.

Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation

The neural underpinnings of age-related memory impairment remain to be fully elucidated. Using a subsequent memory face–name functional MRI (fMRI) paradigm, young and old adults showed a similar magnitude and extent of hippocampal activation during successful associative encoding. Young adults demonstrated greater deactivation (task-induced decrease in BOLD signal) in medial parietal regions during successful compared with failed encoding, whereas old adults as a group did not demonstrate a differential pattern of deactivation between trial types. The failure of deactivation was particularly evident in old adults who performed poorly on the memory task. These low-performing old adults demonstrated greater hippocampal and prefrontal activation to achieve successful encoding trials, possibly as a compensatory response. Findings suggest that successful encoding requires the coordination of neural activity in hippocampal, prefrontal, and parietal regions, and that age-related memory impairment may be primarily related to a loss of deactivation in medial parietal regions.

Relationship of fMRI activation to clinical trial memory measures in Alzheimer disease

Background: Functional MRI (fMRI) has shown promise as a tool to characterize altered brain function in Alzheimer disease (AD) and for use in proof of concept clinical trials. FMRI studies of subjects with AD have demonstrated altered hippocampal and neocortical activation while encoding novel stimuli compared to older controls. However, the relationship between fMRI activation and performance on standardized clinical trial memory measures has not been fully investigated. Objective: To determine whether patterns of activation during an associative-memory fMRI paradigm correlate with performance on memory measures used in AD clinical trials. Methods: Twenty-nine subjects with AD underwent neuropsychological testing, including the AD Assessment Scale (ADAS-Cog), and an associative-encoding fMRI paradigm. Scores were entered as regressors in SPM2 analyses of the differential fMRI activation to novel-vs-repeated (NvR) stimuli. To account for cerebral atrophy, native-space structure-function analyses were performed with subjects’ high-resolution structural images. Results: Performance on the ADAS-Cog verbal memory component, and the ADAS-Cog total score, correlated with NvR activation in left superior temporal (p = 0.0003; r = −0.51) and left prefrontal (p = 0.00001; r = −0.63) cortices. In a subgroup with more extensive neuropsychological testing (n = 14), performance on the Free and Cued Selective Reminding Test was correlated with activation in these same regions. fMRI activation remained correlated with performance even when accounting for atrophy. Conclusions: The relationship between functional MRI (fMRI) activation and standardized memory measures supports the potential use of fMRI to investigate regional mechanisms of treatment response in clinical trials of novel therapies for Alzheimer disease. GLOSSARY: AD = Alzheimer disease; ADAS-Cog = AD Assessment Scale; EPI = echoplanar imaging sequence; FA = flip angle; FCSRT = Free and Cued Selective Reminding Test; FLAME = FMRIB’s Local Analysis of Mixed Effects; fMRI = Functional MRI; FOV = field of view; GLM = general linear model; HRF = hemodynamic response function; LFG = left fusiform gyrus; LPFC = left prefrontal cortex; LSTG = left superior temporal gyrus; MMSE = Mini-Mental State Examination; MTL = medial temporal lobe; NvR = novel-vs-repeated; ROI = region of interest; TE = echo time; TR = repetition time.

IC-P-071

who progressed to AD after follow-up period (CDR 1; 11 patients; 7 women, 4 men) and second group consisted of patients who had stable symptoms of MCI (CDR 0.5; 8 patients; 3 women, 5 men). The relationship between hippocampal volume z-score and the risk of developing AD over a two-year period of observation adjusted for age and sex interaction in logistic regression model was Rsquare 0.65; p 0.045 for left hippocampus and Rsquare 0.56; p 0.055 for right hippocampus. Conclusions: Initial hippocampal volume may influence the dynamics of cognitive decline in MCI patients over a two-year period of observation. The difference of effect between sides suggests higher sensitivity of left hippocampal volume as a predictive marker of AD. However lack of normative values of hippocampal volume mean and SD for elderly population limits calculated z-score to studied population.

IC-P-086 : Failure of hippocampal habituation in mild cognitive impairment and Alzheimer’s disease

achieve a uniform quality level for this study, the dataset was reduced to 224 subjects from 6 centers. A supervised fully connected ANN was implemented with a single layer of hidden units and 30 inputs (3 modalities, each with their respective 3x3 neighborhood and spatial information). The output comprised of four probability maps GM, WM, CSF and ARWMC, but only the ARWMC output is assessed here. Before segmentation all data were pre-processed for head motion and intensity variations. The ANN was trained with an ROI dataset drawn on 6 subjects from 4 centers. For segmentation, the optimal threshold of the ARWMC probability map was determined using the Index of Similarity describing the overlap between ANN and manual ROI’s. Here a threshold of 90% was found to be optimal. Results: From each of the 6 center the correlation coefficient between ANN and manually determined were generally high: 0.97, 0.97, 0.87, 0.88, 0.73 and 0.98. The correlation of the combined set was 0.89. The two first centers, with a correlation coefficient of 0.97, had two subjects in the training set which may explain their better performance. Deviating quality in the FLAIR image contributes to the lowest correlation in a center. In other cases a systematic bias was present in some anatomical regions (e.g. septum pellucidum, where lesion were not drawn manually) or regarding lacunar infarcts. Conclusion: In this multi-center investigation of ARWMC segmentation a high average correlation of 0.89 was found. Improvements may be gained from representing more centres in the training set. The results demonstrate the generalizability of ANN methods, and underline the importance of rigorous standardization of MRI quality in multi-center studies.