Detection of cortical thickness correlates of cognitive performance: Reliability across MRI scan sessions, scanners, and field strengths.

In normal humans, relationships between cognitive test performance and cortical structure have received little study, in part, because of the paucity of tools for measuring cortical structure. Computational morphometric methods have recently been developed that enable the measurement of cortical thickness from MRI data, but little data exist on their reliability. We undertook this study to evaluate the reliability of an automated cortical thickness measurement method to detect correlates of interest between thickness and cognitive task performance. Fifteen healthy older participants were scanned four times at 2-week intervals on three different scanner platforms. The four MRI data sets were initially treated independently to investigate the reliability of the spatial localization of findings from exploratory whole-cortex analyses of cortical thickness-cognitive performance correlates. Next, the first data set was used to define cortical ROIs based on the exploratory results that were then applied to the remaining three data sets to determine whether the relationships between cognitive performance and regional cortical thickness were comparable across different scanner platforms and field strengths. Verbal memory performance was associated with medial temporal cortical thickness, while visuomotor speed/set shifting was associated with lateral parietal cortical thickness. These effects were highly reliable - in terms of both spatial localization and magnitude of absolute cortical thickness measurements - across the four scan sessions. Brain-behavior relationships between regional cortical thickness and cognitive task performance can be reliably identified using an automated data analysis system, suggesting that these measures may be useful as imaging biomarkers of disease or performance ability in multicenter studies in which MRI data are pooled.

Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline.

OBJECTIVE: To use functional MRI (fMRI) to investigate whether hippocampal activation during a memory task can predict cognitive decline in individuals with mild cognitive impairment (MCI). METHODS: 25 older individuals with MCI performed a visual scene encoding task during fMRI scanning, and were followed clinically for at least 4 years after scanning. A hypothesis driven analysis of fMRI data was performed. First, fMRI data were analysed at the group level to identify the regions of the hippocampal formation that were engaged by this memory task. Parameter estimates of each subject's memory related hippocampal activation (% signal change) were extracted and were analysed with a linear regression model to determine whether hippocampal activation predicted the degree or rate of cognitive decline, as measured by change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB). RESULTS: Over 5.9 (1.2) years of follow-up after scanning, subjects varied widely in degree and rate of cognitive decline (change in CDR-SB ranged from 0 to 6, and the rate ranged from 0 to 1 CDR-SB unit/year). Greater hippocampal activation predicted greater degree and rate of subsequent cognitive decline (p<0.05). This finding was present even after controlling for baseline degree of impairment (CDR-SB), age, education and hippocampal volume, as well as gender and apolipoprotein E status. In addition, an exploratory whole brain analysis produced convergent results, demonstrating that the hippocampal formation was the only brain region where activation predicted cognitive decline. CONCLUSIONS: In individuals with MCI, greater memory task related hippocampal activation is predictive of a greater degree and rate of cognitive decline subsequent to scanning. fMRI may provide a physiological imaging biomarker useful for identifying the subgroup of MCI individuals at highest risk of cognitive decline for potential inclusion in disease modifying clinical trials.

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. .

Renal brush border membrane lipid composition in Basenji dogs with spontaneous idiopathic Fanconi syndrome.

To comprehend the renal defect underlying idiopathic Fanconi syndrome in the Basenji dog, we have focused on delineating the lipid profiles of renal brush border membranes isolated from affected and normal Basenji dogs to establish any physical or compositional changes underlying previously observed transport and membrane-fluidity changes. The lipid composition was studied with respect to total lipid, cholesterol, and phospholipid content, cholesterol to phospholipid ratio, distribution of the major phospholipid classes, and fatty acid composition. Total phospholipid of the isolated renal brush border membranes from Fanconi syndrome dogs analyzed by 31P nuclear magnetic resonance showed no difference compared with that of normal dogs. Examination of total fatty acids in both membranes using gas-liquid chromatography analysis of fatty acid methyl esters showed no difference in the mole percents of the major fatty acids. Our data suggest that changes in bulk membrane fluidity of the Fanconi syndrome dog renal brush border as measured by 1,6-diphenyl-1,3,5-hexatriene cannot be attributed to phospholipid and fatty acid compositional change. In the membranes isolated from affected dog kidney, the cholesterol content determined by gas-liquid chromatography analysis was 66 mol% higher than in membranes isolated from normal dog kidney. This correlates with the higher cholesterol to phospholipid molar ratio of 0.82 +/- 0.08 in the affected animal as compared with 0.58 +/- 0.04 in the normal. Cholesterol content and its microdomain in the membrane bilayer may be important in modulating transport functions. Increased membrane cholesterol content may affect the conformational motility of membrane transport proteins and thus affect their function.

Membrane fluidity and sodium transport by renal membranes from dogs with spontaneous idiopathic Fanconi syndrome.

To comprehend the renal defect underlying the idiopathic Fanconi syndrome in the Basenji dog, we have used isolated renal brush border membrane vesicles to examine two factors that influence membrane nonelectrolyte transport processes, sodium flux and membrane fluidity. We have found that there is no significant difference in the rate of uptake of 100 mmol/L 22Na+ and conclude that the previously observed defects in the sodium gradient-stimulated overshoot of glucose and of proline are not related to an alteration in the flux of sodium at physiological concentrations. Since carrier proteins exist in a lipid milieu, alteration in the physical state of the lipid membrane can determine transport function. Renal brush border preparations from normal and affected animals were studied by measuring fluorescence polarization to assess differences in the physical state of the membranes using the fluorescent probe, DPH, which quantitates inner core membrane fluidity. Membranes from affected dogs consistently showed a higher fluidity as measured by eta, a parameter of DPH fluorescence polarization. Since membrane fluidity is related to lipid composition, the data suggest that there may be an important alteration in the lipids in renal membranes of affected animals.

Characteristics of L-proline and sodium transport in renal brush border membranes isolated from 7-day-old and adult rats.

To explore the nature of differences in uptake by renal brush border vesicles from animals of different ages, vesicles were isolated from 7-day old and adult rats by a Mg-aggregation method. A number of criteria were compared in vesicles from the young and mature animals. The vesicles isolated from animals of both ages appear similar on electron microscopy, in response to osmotic changes, and in uptake kinetics for L-glucose. Despite these parameters which indicate no basic differences between the membranes of young and mature kidney, differences in proline and sodium handling are seen. When compared to the uptake pattern seen in vesicles from adult animals, the height of the sodium gradient-stimulated proline overshoot is diminished and sodium entry is faster in vesicles of the 7-day old rats. These are the same differences which were found in vesicles prepared by differential centrifugation from 7-day old animals. In addition, although sodium efflux was faster from vesicles of immature kidney and mirrored the faster sodium entry, proline efflux was slower. The data indicate a dissociation of proline and sodium fluxes in brush borders of the young rat kidney.