Faculty Bibliography

Background: A great deal of current research is aiming to better understand what happens to brains affected by Alzheimer's disease, both structurally and metabolically. However, little is known about how the brain ages in the cognitively normal adult population. There is also a limited understanding as to how glucose metabolism and brain atrophy interact in the normal human brain. To our knowledge, this study is the first to longitudinally analyze measures of atrophy and metabolism in both MRI and FDG-PET in cognitively normal subjects. Methods: 45 cognitively normal subjects were studied longitudinally over a span of at least 1.5 years (average = 5.99 years). Each had at least two structural MRIs and 2 FDG-PET scans. Free Surfer was used to analyze ventricle and intracranial volume. This was turned into an intracranial volume ratio to get a normalized picture of brain atrophy. A hippocampal masking technique (HipMask) was used to analyze the FDG-PET scans for changes in metabolic rates in regions normally affected by Alzheimer's disease (precuneus/posterior cingulate, hippocampus, inferior parietal lobe), as well as regions affected by normal aging (prefrontal cortex and cerebellum). Results: Mixed model analysis indicates that ventricle enlargement occurs in the cognitively normal adult brain as early as adult middle age (t = 7.050, p < .001), with a particular acceleration after the age of 65 (t = 2.878, p = .004). However, the mixed model results did not show any evidence of a concomitant decrease in rate with age, nor any acceleration, in regional metabolism after controlling for brain atrophy. Conclusions: Our results show that brain atrophy increases over the adult lifespan. These changes appear to accelerate over time. However, metabolically, we did not find any significant results with regard to change over time. This is in contrast to Alzheimer's disease, where literature has shown metabolic decreases in frontal and parietal regions, particularly in precuneus/posterior cingulate. Our !

Numerous studies have shown that Alzheimer's Disease (AD) pathology begins before the onset of clinical symptoms. Because therapies are likely to be more effective if they are implemented early in the disease progression, it is necessary to identify reliable biomarkers to detect AD pathology in the early stages of the disease, ideally in presymptomatic individuals. Recent research has identified three candidate cerebrospinal fluid (CSF) biomarkers that reflect AD pathology: amyloid beta, total tau protein (t-tau), and tau protein phosphorylated at AD-specific epitopes (p-tau). They are useful in supporting the AD diagnosis and have predictive value for AD when patients are in the stage of mild cognitive impairment (MCI). However, their predictive utility in cognitively healthy subjects is still being evaluated. We conducted a review of studies published between 1993 and 2011 and summarized their findings on the role of CSF biomarkers for AD in healthy elderly.

OBJECTIVE: To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) epsilon4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease. DESIGN: Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal epsilon4 homozygotes, epsilon4 heterozygotes, and noncarriers. SETTING: Academic medical center. PARTICIPANTS: A total of 31 epsilon4 homozygotes, 42 epsilon4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. MAIN OUTCOME MEASURES: The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. RESULTS: Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P = .60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P = .001). The APOE epsilon4 gene dose was significantly associated with posterior cingulate glucose metabolism (r = 0.29, P = .0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P < .05, determined by use of pairwise Fisher z tests). CONCLUSIONS: Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.

This study examines the relationship between fibrillar beta-amyloid (Abeta) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r /= 69% for MH vs. NH and >/= 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Abeta increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.

RATIONALE: Previous studies have shown that sleep-disordered breathing (S

There is growing evidence that cerebrovascular reactivity to carbon dioxide (CVRCO2) is impaired in Alzheimer's disease (AD). Preclinical and animal studies suggest chronic hypercontractility in brain vessels in AD. We review (a) preclinical studies of mechanisms for impaired CVRCO2 in AD; (b) clinical studies of cerebrovascular function in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition. Although results of clinical studies are inconclusive, an increasing number of reports reveal an impairment of vascular reactivity to carbon dioxide in subjects with AD, and possibly also in MCI. Thus, CVRCO2 may be an attractive means to detect an early vascular dysfunction in subjects at risk.

Amyloid plaques are a key pathological hallmark of Alzheimer's disease (AD). The detection of amyloid plaques in the brain is important for the diagnosis of AD, as well as for following potential amyloid targeting therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques using magnetic resonance microimaging (microMRI) in AD transgenic mice, where we used mannitol to enhance blood brain barrier (BBB) permeability. In the present study, we used bifunctional ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Abeta1-42 peptide to image amyloid plaque deposition in the mouse brain. We coupled the nanoparticles to polyethylene glycol (PEG) in order to improve BBB permeability. These USPIO-PEG-Abeta1-42 nanoparticles were injected intravenously in AD model transgenic mice followed by initial and subsequent muMRI. A 3D gradient multi-echo sequence was used for imaging with a 100 microm isotropic resolution. The amyloid plaques detected by T2*-weighted muMRI were confirmed with matched histological sections. The region of interest-based quantitative measurement of T2* values obtained from the muMRI showed contrast injected AD Tg mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based analysis (VBA) using statistical parametric mapping (SPM) for comparison of USPIO-PEG-Abeta1-42 injected AD transgenic and USPIO alone injected AD transgenic mice. The regional differences seen by VBA in the USPIO-PEG-Abeta1-42 injected AD transgenic correlated with the amyloid plaque distribution histologically. Our results indicate that USPIO-PEG-Abeta1-42 can be used for amyloid plaque detection by intravenous injection without the need to co-inject an agent which increases permeability of the BBB. This technique could aid the development of novel amyloid targeting drugs by allowing therapeutic effects to be followed longitudinally in model AD mice.

Introduction: Our previous work in cognitively normal elderly shows sleep-disordered breathing (S