BACKGROUND AND PURPOSE Prior MR imaging studies, primarily at 1.5T, established hippocampal atrophy as a biomarker for Alzheimer disease. 3T MR imaging offers a higher contrast and signal-to-noise ratio, yet distortions and intensity uniformity are harder to control. We applied our automated hippocampal segmentation technique to 1.5T and 3T MR imaging data, to determine whether hippocampal atrophy detection was enhanced at 3T. MATERIALS AND METHODS We analyzed baseline MR imaging data from 166 subjects from the Alzheimer’s Disease Neuroimaging Initiative-1 (37 with Alzheimer disease, 76 with mild cognitive impairment, and 53 healthy controls) scanned at 1.5T and 3T. Using multiple linear regression, we analyzed the effect of clinical diagnosis on hippocampal radial distance, while adjusting for sex. 3D statistical maps were adjusted for multiple comparisons by using permutation-based statistics at a threshold of P < .01. RESULTS Bilaterally significant radial distance differences in the areas corresponding to the cornu ammonis 1, cornu ammonis 2, and subiculum were detected for Alzheimer disease versus healthy controls and mild cognitive impairment versus healthy controls at 1.5T and more profoundly at 3T. Comparison of Alzheimer disease with mild cognitive impairment did not reveal significant differences at either field strength. Subjects who converted from mild cognitive impairment to Alzheimer disease within 3 years of the baseline scan versus nonconverters showed significant differences in the area corresponding to cornu ammonis 1 of the right hippocampus at 3T but not at 1.5T. CONCLUSIONS While hippocampal atrophy patterns in diagnostic comparisons were similar at 1.5T and 3T, 3T showed a superior signal-to-noise ratio and detected atrophy with greater effect size compared with 1.5T.
This study modeled predementia Alzheimer’s disease (AD) clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the AD Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures including: the Clinical Dementia Rating scale sum of boxes (CDR-sb), Mini Mental Status Examination (MMSE), AD assessment scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning task (RAVLT). We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using RAVLT total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n=499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the CDR-sb consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in AD is enhanced by the use of biomarker inclusion criteria.
Background/Aims: Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are the two most common neurodegenerative dementias. During the early stages, clinical distinction between them is often challenging. Our objective is to compare hippocampal atrophy patterns in mild AD and mild DLB. We hypothesized that DLB subjects have milder hippocampal atrophy relative to AD subjects. Methods: We analyzed the T1-weighted magnetic resonance imaging data from 113 subjects: 55 AD, 16 DLB and 42 cognitively normal elderly (normal controls, NC). Using the hippocampal radial distance technique and multiple linear regression, we analyzed the effect of clinical diagnosis on hippocampal radial distance, while adjusting for gender and age. Three-dimensional statistical maps were adjusted for multiple comparisons using permutation-based statistics with a threshold of p < 0.01. Results: Compared to NC, AD exhibited significantly greater atrophy in the cornu ammonis (CA)1, CA2–3 and subicular regions bilaterally while DLB showed left-predominant atrophy in the CA1 region and subiculum. Compared directly, AD and DLB did not reveal statistically significant differences. Conclusion: Hippocampal atrophy, while present in mildly impaired DLB subjects, is less severe than atrophy seen in mildly impaired AD subjects, when compared to NC. Both groups show predominant atrophy of the CA1 subfield and subiculum.
Apolipoprotein E (APOE) genotype is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD), but the utility of plasma ApoE levels for assessing the severity of underlying neurodegenerative changes remains uncertain. Here, we examined cross-sectional associations between plasma ApoE levels and volumetric magnetic resonance imaging indices of the hippocampus from 541 participants [57 with normal cognition (NC), 375 with mild cognitive impairment (MCI), and 109 with mild AD] who were enrolled in the Alzheimer's Disease Neuroimaging Initiative. Across the NC and MCI groups, lower plasma ApoE levels were significantly correlated with smaller hippocampal size, as measured by either hippocampal volume or hippocampal radial distance. These associations were driven primarily by findings from carriers of an APOE ε4 allele and are consistent with prior reports that lower plasma ApoE levels correlate with greater global cortical Pittsburgh Compound B retention. In this high-risk group, plasma ApoE levels may represent a peripheral marker of underlying AD neuropathology in nondemented elderly individuals.
Repeat sequence protein polymer (RSPP) technology provides a platform to design and make protein-based performance polymers and represents the best nature has to offer. We report here that the RSPP platform is a novel approach to produce functional protein polymers that have both biomechanical and biofunctional blocks built into one molecule by design, using peptide motifs. We have shown that protein-based designer biopolymers can be made using recombinant DNA technology and fermentation and offer the ability to screen for desired properties utilizing the tremendous potential diversity of amino acid combinations. The technology also allows for large-scale manufacturing with a favorable fermentative cost-structure to deliver commercially viable performance polymers. Using three diverse examples with antimicrobial, textile targeting, and UV-protective agent, we have introduced functional attributes into structural protein polymers and shown, for example, that the functionalized RSPPs have possible applications in biodefense, industrial biotechnology, and personal care areas. This new class of biobased materials will simulate natural biomaterials that can be modified for desired function and have many advantages over conventional petroleum-based polymers.
The hallmark of Alzheimer's disease (AD) is declarative memory loss, but deficits in semantic fluency are also observed. We assessed how semantic fluency relates to cortical atrophy to identify specific regions that play a role in the loss of access to semantic information. Whole-brain structural magnetic resonance imaging (MRI) data were analyzed from 9 Normal Control (NC)(M=76.7, SD=5.6), 40 Mild Cognitive Impairment (MCI) (M=74.4, SD=8.6), and 10 probable AD (M=72.4, SD=8.0) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). They all were administered the Category Fluency (CF) animals and vegetables tests. Poorer semantic fluency was associated with bilateral cortical atrophy of the inferior parietal lobule (Brodman areas (BA) 39 and 40) and BA 6, 8, and 9 in the frontal lobe, as well as BA 22 in the temporal lobe. More diffuse frontal associations were seen in the left hemisphere involving BA 9, 10, 32, 44, 45, and 46. Additional cortical atrophy was seen in the temporoparietal (BA 37) and the right parastriate (BA 19, 18) cortices. Associations were more diffuse for performance on vegetable fluency than animal fluency. The permutation-corrected map-wise significance for CF animals was pcorrected=0.01 for the left hemisphere, and pcorrected=0.06 for the right hemisphere. The permutation-corrected map-wise significance for CF vegetables was pcorrected=0.009 for the left hemisphere, and pcorrected=0.03 for the right hemisphere. These results demonstrate the profound effect of cortical atrophy on semantic fluency. Specifically, tapping into semantic knowledge involves the frontal lobe in addition to the language cortices of the temporoparietal region.
BackgroundImaging techniques used to measure hippocampal atrophy are key to understanding the clinical progression of Alzheimer's disease (AD). Various semi-automated hippocampal segmentation techniques are available and require human expert input to learn how to accurately segment new data. Our goal was to compare 1) the performance of our automated hippocampal segmentation technique relative to manual segmentations, and 2) the performance of our automated technique when provided with a training set from two different raters. We also explored the ability of hippocampal volumes obtained using manual and automated hippocampal segmentations to predict conversion from MCI to AD.MethodsWe analyzed 161 1.5 T T1-weighted brain magnetic resonance images (MRI) from the ADCS Donepezil/Vitamin E clinical study. All subjects carried a diagnosis of mild cognitive impairment (MCI). Three different segmentation outputs (one produced by manual tracing and two produced by a semi-automated algorithm trained with training sets developed by two raters) were compared using single measure intraclass correlation statistics (smICC). The radial distance method was used to assess each segmentation technique's ability to detect hippocampal atrophy in 3D. We then compared how well each segmentation method detected baseline hippocampal differences between MCI subjects who remained stable (MCInc) and those who converted to AD (MCIc) during the trial. Our statistical maps were corrected for multiple comparisons using permutation-based statistics with a threshold of p < .01.ResultsOur smICC analyses showed significant agreement between the manual and automated hippocampal segmentations from rater 1 [right smICC = 0.78 (95%CI 0.72–0.84); left smICC = 0.79 (95%CI 0.72–0.85)], the manual segmentations from rater 1 versus the automated segmentations from rater 2 [right smICC = 0.78 (95%CI 0.7–0.84); left smICC = 0.78 (95%CI 0.71–0.84)], and the automated segmentations of rater 1 versus rater 2 [right smICC = 0.97 (95%CI 0.96–0.98); left smICC = 0.97 (95%CI 0.96–0.98)]. All three segmentation methods detected significant CA1 and subicular atrophy in MCIc compared to MCInc at baseline (manual: right pcorrected = 0.0112, left pcorrected = 0.0006; automated rater 1: right pcorrected = 0.0318, left pcorrected = 0.0302; automated rater 2: right pcorrected = 0.0029, left pcorrected = 0.0166).ConclusionsThe hippocampal volumes obtained with a fast semi-automated segmentation method were highly comparable to the ones obtained with the labor-intensive manual segmentation method. The AdaBoost automated hippocampal segmentation technique is highly reliable allowing the efficient analysis of large data sets.
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