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1.  Age, sex and APOE ε4 effects on memory, brain structure and β-amyloid across the adult lifespan 
JAMA neurology  2015;72(5):511-519.
Importance
Typical cognitive aging may be defined as age associated changes in cognitive performance in individuals who remain free of dementia. Ideally the full adult age spectrum should be included to assess brain imaging findings associated with typical aging.
Objective
To compare age, sex and Apolipoprotein E (APOE ε4) effects on memory, brain structure (adjusted hippocampal volume, HVa) and amyloid PET in cognitively normal individuals aged 30 to 95 years old.
Design, Setting, and Participants
Cross sectional observational study (Marc 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal subjects; 1209 participants aged 50–95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30–49.
Main Outcomes and Measures
Memory, HVa, and amyloid PET
Results
Overall, memory worsened from age 30 years through the 90s. HVa worsened gradually from 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than women overall (p<0.001) and more specifically beyond age 40 years. HVa was lower in men than women overall (p<0.001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 at any age. From age 70 years onward APOE ε4 carriers had significantly greater median amyloid PET load than noncarriers. However the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for non-carriers.
Conclusions and Relevance
Male sex is associated with worse memory and HVa among cognitively normal individuals while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET values (from age 70 years onward) while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer’s disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.
doi:10.1001/jamaneurol.2014.4821
PMCID: PMC4428984  PMID: 25775353
Cognitive Aging; Amyloid Imaging; Alzheimer Disease; Memory Performance; Brain Atrophy
2.  Working memory and language network dysfunction in logopenic aphasia: a task-free fMRI comparison to Alzheimer’s dementia 
Neurobiology of aging  2014;36(3):1245-1252.
We aimed to determine whether network-level functional connectivity differs in two clinical variants of Alzheimer’s disease: logopenic primary progressive aphasia (lvPPA) and dementia of the Alzheimer’s type (DAT). Twenty-four lvPPA subjects with amyloid deposition on PET and task-free fMRI were matched to 24 amyloid-positive DAT subjects and 24 amyloid-negative controls. Independent-component analysis and spatial-temporal dual-regression were used to assess functional connectivity within the language network, left and right working memory networks and ventral default mode network. lvPPA showed reduced connectivity in left temporal language network and inferior parietal and prefrontal regions of the left working memory network compared to controls and DAT. Both groups showed reduced connectivity in parietal regions of the right working memory network compared to controls. Only DAT showed reduced ventral default mode network connectivity compared to controls. Aphasia severity correlated with connectivity in left working memory network within lvPPA. Patterns of network dysfunction differ across these two clinical variants of Alzheimer’s disease, with lvPPA particularly associated with disruptions in the language and left working memory networks.
doi:10.1016/j.neurobiolaging.2014.12.013
PMCID: PMC4346438  PMID: 25592958
Alzheimer’s disease; primary progressive aphasia; language; MRI; functional imaging
3.  Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration 
Neurology  2014;82(18):1605-1612.
Objective:
To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample.
Methods:
A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A−) and baseline hippocampal volume (N+ or N−). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups.
Results:
At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A−N−), 29 (12%) amyloid negative and neurodegeneration positive (A−N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N−), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+.
Conclusions:
We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging–Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.
doi:10.1212/WNL.0000000000000386
PMCID: PMC4013810  PMID: 24706010
4.  Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity 
Neurology  2013;81(20):1732-1740.
Objective:
To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.
Methods:
Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison.
Results:
Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline.
Conclusions:
The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both “amyloid-first” and “neurodegeneration-first” biomarker profile pathways to preclinical AD exist.
doi:10.1212/01.wnl.0000435556.21319.e4
PMCID: PMC3821718  PMID: 24132377
5.  Non-Stationarity in the “Resting Brain’s” Modular Architecture 
PLoS ONE  2012;7(6):e39731.
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain’s modular organization and assign each region to a “meta-modular” group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer’s dementia and 56 cognitively normal elderly subjects matched 1∶2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer’s disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer’s dementia.
doi:10.1371/journal.pone.0039731
PMCID: PMC3386248  PMID: 22761880

Results 1-5 (5)