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1.  Correspondence between in vivo 11C-PiB PET amyloid imaging and post-mortem, region-matched assessment of plaques 
Acta neuropathologica  2012;124(6):823-831.
The definitive Alzheimer’s disease diagnosis requires post-mortem confirmation of neuropathological hallmarks – amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The advent of radiotracers for amyloid imaging presents an opportunity to investigate amyloid deposition in vivo. The 11C-Pittsburgh Compound-B (PiB) PET ligand remains the most widely studied to date; however, regional variations in 11C-PiB binding and the extent of agreement with neuropathological assessment have not been thoroughly investigated. We examined the correspondence among quantitative immunohistological assessments of Aβ and NFTs, regional 11C-PiB load, and brain atrophy (MRI) in six older Baltimore Longitudinal Study of Aging participants who came to autopsy (imaging-autopsy interval range 0.2–2.4 years). The total number of Aβ plaques (6E10) and NFTs (PHF1) in paraffin sections from hippocampus, orbito-frontal cortex, anterior and posterior cingulate gyrus, precuneus and cerebellum were quantified using a technique guided by unbiased stereological principles. We report a general agreement between the regional measures of amyloid obtained via stereological assessment and imaging, with significant relationships evident for the anterior (r=0.87; p=0.02) and posterior (r=0.93; p=0.007) cingulate gyri, and the precuneus (r=0.98; p=0.001). Moreover, higher Aβ count in the hippocampus was associated with lower hippocampal volume (r= −0.86; p=0.03). No associations were observed between 11C-PiB load and NFT count for any of the regions examined (p>0.2 in all regions) or between regional NFT count and corresponding brain volumes. The strong associations of PiB retention with region-matched, quantitative analyses of Aβ in post-mortem tissue offer support for the validity of 11C-PiB-PET imaging as a method for evaluation of plaque burden in vivo.
PMCID: PMC3566238  PMID: 22864813
plaques; tangles; stereology; PiB; Alzheimer; neuroimaging
2.  Lack of association between 11C-PiB and longitudinal brain atrophy in non-demented older individuals 
Neurobiology of aging  2010;32(12):2123-2130.
Amyloid-β plaques (Aβ) are a hallmark of Alzheimer's disease (AD), begin deposition decades before the incipient disease, and are thought to be associated with neuronal loss, brain atrophy and cognitive impairment. We examine associations between 11C-PiB-PET measurement of Aβ burden and brain volume changes in the preceding years in 57 non-demented individuals (age 64-86; M = 78.7). Participants were prospectively followed through the Baltimore Longitudinal Study of Aging, with up to 10 consecutive MRI scans (M = 8.1) and an 11C-PiB scan approximately 10 years after the initial MRI. Linear mixed effects models were used to determine whether mean cortical 11C-PiB distribution volume ratios, estimated by fitting a reference tissue model to the measured time activity curves, were associated with longitudinal regional brain volume changes of the whole brain, ventricular CSF, frontal, temporal, parietal, and occipital white and gray matter, the hippocampus, orbito-frontal cortex, and the precuneus. Despite significant longitudinal declines in the volumes of all investigated regions (p < 0.05), no associations were detected between current Aβ burden and regional brain volume decline trajectories in the preceding years, nor did the regional volume trajectories differ between those with highest and lowest Aβ burden. Consistent with a threshold model of disease, our findings suggest that Aβ load does not seem to affect brain volume changes in individuals without dementia.
PMCID: PMC2908199  PMID: 20176414
Alzheimer's Disease; BLSA; Volumetric MRI; Normal Aging: PET; 11C-PiB
3.  Weight Change and Cognitive Function: Findings from the Women's Health Initiative Study of Cognitive Aging 
Obesity (Silver Spring, Md.)  2011;19(8):1595-1600.
Although studies exploring relationships between obesity and cognitive impairment in the elderly are conflicting, literature suggests that overweight and obesity may be protective against cognitive impairment and dementia in older women. We examine the associations between changes in weight and waist circumference with global and domain-specific cognitive function in a large, well-defined cohort of 2283 older, post-menopausal women (age 65-79) prospectively followed through the Women's Health Initiative (WHI) Study of Cognitive Aging (WHISCA). We assessed the associations between changes in weight and waist circumference collected up to 5 years prior to WHISCA enrollment and mean levels of global and domain-specific cognitive performance across an average of 5.4 years of subsequent follow-up. There was a lack of associations between weight and cognition in women who remained stable or gained weight. The only significant relationships observed were in association with weight loss (p≤0.05), most likely signaling incipient disease. Moreover, cognition was not related to changes in waist circumference. Relationships were largely independent of initial BMI, self-reported caloric intake or dieting. The lack of associations between weight gain and cognition in women is consistent with the existent literature.
PMCID: PMC3175491  PMID: 21394095
4.  Plasma BDNF Is Associated with Age-Related White Matter Atrophy but Not with Cognitive Function in Older, Non-Demented Adults 
PLoS ONE  2012;7(4):e35217.
Brain derived neurotrophic factor (BDNF) seems to be involved in regulation of synaptic plasticity and neurogenesis. BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether BDNF plasma concentration was associated with rates of age-related change in cognitive performance (n = 429) and regional brain volume (n = 59). Plasma BDNF levels, which were significantly higher in females (p<0.05), were not associated with either concurrent cognitive performance or rates of age-related change in performance across cognitive domains (p's>0.05). Sex differences in the relationship between BDNF and the trajectories of regional brain volume changes were observed for the whole brain and frontal white matter volumes (p<0.05), whereby lower plasma BDNF was associated with steeper volume decline in females but not males. Together, our findings contribute to furthering the understanding of the relationships between plasma BDNF, structural brain integrity and cognition. Potential mechanisms mediating these relationships merit further investigation.
PMCID: PMC3327651  PMID: 22523577
5.  In Vivo Fibrillar β-Amyloid Detected Using [11C]PiB Positron Emission Tomography and Neuropathologic Assessment in Older Adults 
Archives of neurology  2011;68(2):232-240.
In demented older adults, in vivo amyloid imaging shows agreement with diagnostic neuropathologic assessment of β-amyloid (Aβ). However, the extent of agreement in nondemented older adults remains unclear.
To compare Aβ quantified using in vivo carbon 11–labeled Pittsburgh Compound B positron emission tomography and postmortem neuropathologic assessment of Aβ in older adults.
Case series.
Community-dwelling older adults who came to autopsy.
Five nondemented and 1 demented participant from the Baltimore Longitudinal Study of Aging.
Main Outcome Measure
Agreement between the mean cortical distribution volume ratio and the Consortium to Establish a Registry for AD (CERAD) neuritic plaque (NP) score used for pathologic diagnosis of Alzheimer disease.
Of the 6 participants, 4 had moderate NPs, 2 had sparse or no detectable NPs, and 3 had microscopic findings of cerebral amyloid angiopathy at autopsy. On in vivo imaging, the mean cortical distribution volume ratio ranged from 0.96 to 1.59. Although there was agreement between in vivo amyloid imaging and CERAD NP scores in participants with either high or negligible Aβ levels in vivo, only limited agreement was observed among those with intermediate levels of Aβ. The best overall agreement was achieved at a distribution volume ratio of 1.2.
In older adults, variable agreement between in vivo imaging and CERAD NP score was observed. The limited agreement may, in part, reflect differences in typical measurements of Aβ using imaging compared with the CERAD neuropathologic protocol. Direct quantification of regional Aβ in relation to in vivo imaging is necessary to further enhance our understanding of the imaging–pathologic assessment correlation.
PMCID: PMC3082956  PMID: 21320990
6.  Neuropathologic Studies of the Baltimore Longitudinal Study of Aging (BLSA) 
The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The BLSA is supported by the National Institute of Aging (NIA) and its mission is to learn what happens to people as they get old and how to sort out changes due to aging and from those due to disease or other causes. In 1986, an autopsy program combined with comprehensive neurologic and cognitive evaluations was established in collaboration with the Johns Hopkins University Alzheimer’s Disease Research Center (ADRC). Since then, 211 subjects have undergone autopsy. Here we review the key clinical neuropathological correlations from this autopsy series. The focus is on the morphological and biochemical changes that occur in normal aging, and the early neuropathological changes of neurodegenerative diseases, especially Alzheimer’s disease (AD). We highlight the combined clinical, pathologic, morphometric, and biochemical evidence of asymptomatic AD, a state characterized by normal clinical evaluations in subjects with abundant AD pathology. We conclude that in some individuals, successful cognitive aging results from compensatory mechanisms that occur at the neuronal level (i.e., neuronal hypertrophy and synaptic plasticity) whereas a failure of compensation may culminate in disease.
PMCID: PMC2978421  PMID: 19661626
α-synuclein; Alzheimer’s disease; asymptomatic Alzheimer’s disease; amyloid-β; dementia; Parkinson’s disease; stereology; successful aging; tau
7.  Circulating Brain-Derived Neurotrophic Factor and Indices of Metabolic and Cardiovascular Health: Data from the Baltimore Longitudinal Study of Aging 
PLoS ONE  2010;5(4):e10099.
Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF) is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile.
Methodology/Principal Findings
To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age ∼70), in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3), and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin.
Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain) remains to be determined.
PMCID: PMC2852401  PMID: 20404913

Results 1-7 (7)