Gene E Alexander

PMID: 10768555;Abstract:

Alzheimer's disease is associated with reductions in resting-state brain metabolism, as measured by PET, progressing with dementia severity. The purpose of this study was to see to what extent brain regions with reduced resting-state metabolic rates in Alzheimer patients could be activated by a passive audiovisual stimulation test and to compare the result with activation in age-matched healthy volunteers. The extent of activation in Alzheimer's disease is considered to reflect the integrity of synaptic function, or inherent viability, and the potential responsiveness of the Alzheimer brain to drug therapy. Methods: Regional cerebral metabolic rates for glucose (rCMR(gic), in mg/100 g tissue/min) were measured in the resting state (eyes and ears covered) and during passive audiovisual stimulation (watching a movie) in 15 otherwise healthy Alzheimer patients of differing dementia severity (Mattis Dementia Rating Scale score, 23-128) and in 14 age- matched healthy volunteers (score, 141 ± 3) using PET with 2 sequential injections of FDG. Results: In the volunteers, audiovisual stimulation caused significant rCMR(glc) increases in visual and auditory cortical areas but significant decreases in frontal areas. In the mildly demented patients, rCMR(glc) responses were within 2 SDs of the mean in volunteers. However, the magnitude of the rCMR(glc) responses during stimulation declined significantly with dementia severity in the right occipitotemporal, right and left occipital association, and left calcarine cortical regions. Conclusion: Functional brain responsiveness, evaluated by a passive audiovisual stimulation paradigm with PET, is within normal limits in mildly demented Alzheimer patients but fails with worsening dementia severity. Declining responsiveness may account for the limited success of neurotransmitter replacement therapy in Alzheimer patients with moderate-to-severe dementia.

PMID: 8540589;Abstract:

Objective: Visual-processing abnormalities commonly contribute to typical Alzheimer's disease symptoms, but their detailed pathophysiology remains unknown. To investigate why patients with Alzheimer's disease have greater difficulty performing visuoconstructive (magnocellular-dominated) tasks than face- or color-perception (parvocellular-dominated) tasks, the authors measured brain activation in response to a temporally graded visual stimulus (neural stress test) during positron emission tomography. Method: The stress test measured regional cerebral blood flow (CBF) in response to a patterned flash stimulus in the resting state (0 Hz in the dark) and at frequencies of 1, 2, 4, 7, and 14 Hz. Ten patients with Alzheimer's disease and 12 age- and sex-matched comparison subjects were studied. Results: The striate response at 7 Hz and 14 Hz (the degree of regional CBF increase from that at 0 Hz) was significantly less in the patients than in the comparison subjects, whereas the change in regional CBF at the lower frequencies did not differ between groups. In bilateral middle temporal association areas activated by motion and dominated by magnocellular input, regional CBF at 1 Hz (the frequency with maximal apparent motion) was significantly greater than at 0 Hz in the comparison subjects but not in the patients. Conclusions: The magnocellular visual system normally responds to high-frequency input and motion; the failure of response in the striate cortex at high but not low frequencies in the Alzheimer's patients suggests greater magnocellular than parvocellular dysfunction at these levels. Activation failure in the middle temporal areas in the patients supports magnocellular dysfunction. The finding that the Alzheimer's disease group had abnormal visual cortical function emphasizes the importance of clinical visuospatial evaluation of patients with Alzheimer's disease to fully understand symptom production and to plan interventions.

PMID: 16480900;PMCID: PMC1941663;Abstract:

Measures of brain change can be computed from sequential MRI scans, providing valuable information on disease progression, e.g., for patient monitoring and drug trials. Tensor-based morphometry (TBM) creates maps of these brain changes, visualizing the 3D profile and rates of tissue growth or atrophy, but its sensitivity depends on the contrast and geometric stability of the images. As part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), 17 normal elderly subjects were scanned twice (at a 2-week interval) with several 3D 1.5 T MRI pulse sequences: high and low flip angle SPGR/FLASH (from which Synthetic T1 images were generated), MP-RAGE, IR-SPGR (N = 10) and MEDIC (N = 7) scans. For each subject and scan type, a 3D deformation map aligned baseline and follow-up scans, computed with a nonlinear, inverse-consistent elastic registration algorithm. Voxelwise statistics, in ICBM stereotaxic space, visualized the profile of mean absolute change and its cross-subject variance; these maps were then compared using permutation testing. Image stability depended on: (1) the pulse sequence; (2) the transmit/receive coil type (birdcage versus phased array); (3) spatial distortion corrections (using MEDIC sequence information); (4) B1-field intensity inhomogeneity correction (using N3). SPGR/FLASH images acquired using a birdcage coil had least overall deviation. N3 correction reduced coil type and pulse sequence differences and improved scan reproducibility, except for Synthetic T1 images (which were intrinsically corrected for B1-inhomogeneity). No strong evidence favored B0 correction. Although SPGR/FLASH images showed least deviation here, pulse sequence selection for the ADNI project was based on multiple additional image analyses, to be reported elsewhere. © 2006 Elsevier Inc. All rights reserved.