Improved predictive model for pre-symptomatic mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: Delineation of gray matter (GM) structures on brain MRI scans is termed segmentation. Accuracy of segmentation is a key factor in the valid comparison of GM density and volume between individuals and groups. Previously, it was demonstrated that a group of normal subjects who later developed mild cognitive impairment (MCI) had decreased GM volume in the medial temporal lobe compared to other normal subjects who remained normal an average 5.4 years after the scan. The objective of this study was to show whether accuracy of this predictive model was increased using an advanced segmentation technique. METHODS: Structural MRI was performed on 74 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 18 later developed MCI, and six of these 18 went on from MCI to an AD diagnosis. We independently delineated GM using both a standard segmentation technique and a local Gaussian active contour (LGAC) technique. We compared the contribution of extracted volumes from each technique to a model predicting subjects who will eventually develop MCI. RESULTS: Accuracy of the standard technique to distinguish pre-MCI from normal using imaging alone was 79% (sensitivity 78% and specificity 73%). Using LGAC, accuracy rose to 84% (sensitivity 78% and specificity 84%). DISCUSSION: Structural brain changes precede MCI in longitudinally followed normal subjects. The LGAC technique improves the accuracy of a predictive model incorporating these structural changes by improving GM segmentation and the specificity of the model.

Brain structural alterations before mild cognitive impairment.

OBJECTIVE: To determine whether alterations of brain structure in normal aged individuals precede the development of mild cognitive impairment (MCI) or Alzheimer disease (AD). BACKGROUND: Persons with MCI and AD demonstrate cortical volume losses vs asymptomatic aged individuals, particularly in the hippocampus, amygdala, and entorhinal cortex. It is unknown whether these losses or other volumetric changes are present, and to what degree, in cognitively normal individuals before the clinical diagnosis of MCI. METHODS: Structural MRI was performed on a cross-section of 136 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 23 later developed MCI, and 9 of these 23 went on to an AD diagnosis. Extracted volumes from voxel-based morphometric analysis were combined with clinical data to compare the 23 subjects who eventually developed MCI to 113 subjects who remained cognitively normal over an average follow-up of 5.4 years. RESULTS: Initially normal subjects who eventually developed MCI demonstrated decreased gray matter volumes in the anteromedial temporal lobes bilaterally and left angular gyrus while still cognitively normal. CONCLUSION: Structural brain changes in anatomic areas involved in higher cognitive processes precede clinical signs and symptoms in longitudinally followed normal subjects destined to develop mild cognitive impairment.

MRI volumetric and intensity analysis of the cerebellum in Parkinson's disease patients infused with glial-derived neurotrophic factor (GDNF).

BACKGROUND: A recent human therapeutic trial using intraputaminal infusion of glial cell-derived neurotrophic factor (GDNF) in Parkinson's disease (PD) was abruptly terminated, partly due to safety concerns raised by the finding of cerebellar lesions in monkeys given high-dose GDNF. METHODS: Magnetic resonance images from nine PD patients participating in this trial were analyzed to determine whether subtle volumetric or intensity changes could be detected in the cerebellum or elsewhere following GDNF treatment for over 1 year. Subtraction images were compared to a reference standard deviation map constructed by using identically-processed paired scans from 25 normal adults. In a separate voxel-based group morphometric (VBM) analysis of the same patient images, grey matter intensity was compared between pre and post-GDNF infusion scans using a repeated measures ANOVA with family-wise error threshold of P = 0.10. Two expert readers independently reviewed serial FLAIR images from all patients. RESULTS: (1) There were no significant cerebellar differences in any of the nine individual PD patients (difference image analysis), (2) there were no significant morphometric differences between pre- and post-GDNF scans (VBM), and (3) there were no signal abnormalities in the cerebellum detected on the FLAIR images in PD patients (clinical scan review). CONCLUSIONS: In concert with lack of evidence of cerebellar dysfunction on clinical examination, we find no imaging evidence of cerebellar injury in human subjects undergoing chronic intracerebral GDNF infusion.