Sterling C Johnson

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (188)1010.48 Total impact

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    ABSTRACT: The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer's disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimer's Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aβ42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aβ and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aβ42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aβ burden, that is, increased PiB-PET binding or reduced CSF Aβ42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aβ-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD. (JINS, 2015, 21, 841-850).
    Journal of the International Neuropsychological Society 11/2015; 21(10):841-850. DOI:10.1017/S1355617715000843 · 2.96 Impact Factor
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    ABSTRACT: The hippocampus is critical for cognition and memory formation and is vulnerable to age-related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging. Here, we show significant regional effects in hippocampal energy metabolism that are responsive to age and CR, implicating metabolic pathways in neuronal protection. In situ mitochondrial cytochrome c oxidase activity was region specific and lower in aged mice, and the impact of age was region specific. Multiphoton laser scanning microscopy revealed region- and age-specific differences in nicotinamide adenine dinucleotide (NAD)-derived metabolic cofactors. Age-related changes in metabolic parameters were temporally separated, with early and late events in the metabolic response to age. There was a significant regional impact of age to lower levels of PGC-1α, a master mitochondrial regulator. Rather than reversing the impact of age, CR induced a distinct metabolic state with decreased cytochrome c oxidase activity and increased levels of NAD(P)H. Levels of hippocampal PGC-1α were lower with CR, as were levels of GSK3β, a key regulator of PGC-1α turnover and activity. Regional distribution and colocalization of PGC-1α and GSK3β in mouse hippocampus was similar in monkeys. Furthermore, the impact of CR to lower levels of both PGC-1α and GSK3β was also conserved. The studies presented here establish the hippocampus as a highly varied metabolic environment, reveal cell-type and regional specificity in the metabolic response to age and delayed aging by CR, and suggest that PGC-1α and GSK3β play a role in implementing the neuroprotective program induced by CR.
    Aging cell 11/2015; DOI:10.1111/acel.12418 · 6.34 Impact Factor
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    ABSTRACT: Although cerebrovascular disease has long been known to co-occur with Alzheimer's disease (AD), recent studies suggest an etiologic contribution to AD pathogenesis. We used four dimensional (4D)-flow magnetic resonance imaging (MRI) to evaluate blood flow and pulsatility indices in the circle of Willis. We hypothesized decreased mean blood flow and increased pulsatility, metrics indicative of poor vascular health, would be associated with cerebral atrophy and an AD cerebrospinal fluid (CSF) profile.
    10/2015; DOI:10.1016/j.dadm.2015.09.005
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    ABSTRACT: Higher local carotid artery strain has previously been shown to be a characteristic of unstable carotid plaques. These plaques may be characterized by microvascular changes that predispose to intraplaque hemorrhage, increasing the likelihood of embolization. Little is known however, about how these strain indices correspond with imaging markers of brain health and metrics of brain structure. White matter hyperintensities (WMHs), which are bright regions seen on T2-weighted brain MRI imaging, are postulated to result from cumulative ischemic vascular injury. Consequently, we hypothesized that plaques that are more prone to microvascular changes and embolization, represented by higher strain indices on ultrasound, would be associated with an increased amount of WMH lesion volume. This relationship would suggest not only emboli as a cause for the brain degenerative changes, but more importantly, a common microvascular etiology for large and small vessel contributions to this process. Subjects scheduled to undergo a carotid endarterectomy were recruited from a neurosurgery clinic. Prior to surgery, participating subjects underwent both ultrasound strain imaging and brain MRI scans as part of a larger clinical study on vascular health and cognition. A linear regression found that maximum absolute strain and peak to peak strain in the surgical side carotid artery were predictive of WMH burden. Furthermore, the occurrence of microembolic signals monitored using transcranial Doppler (TCD) ultrasound examinations also correlated with increasing lesion burden. It is becoming increasingly recognized that cognitive decline is often multifactorial in nature. One contributing extra-brain factor may be changes in the microvasculature that produce unstable carotid artery plaques. In this study, we have shown that higher strain indices in carotid artery plaques are significantly associated with an increased WMH burden, a marker of vascular mediated brain damage.
    Clinical neuroimaging 09/2015; 9:216-222. DOI:10.1016/j.nicl.2015.08.011 · 2.53 Impact Factor
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    ABSTRACT: Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET). To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake. Regional glucose uptake determined using FDG-PET and neuropsychological factors. Higher HOMA-IR was associated with lower global glucose metabolism (β = -0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores. Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.
    07/2015; 72(9). DOI:10.1001/jamaneurol.2015.0613
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    ABSTRACT: Higher occupational attainment has previously been associated with increased Alzheimer's disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:
    Archives of Clinical Neuropsychology 07/2015; DOI:10.1093/arclin/acv041 · 1.99 Impact Factor
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    ABSTRACT: The mild cognitive impairment (MCI) stage of Alzheimer's disease (AD) may be optimal for clinical trials to test potential treatments for preventing or delaying decline to dementia. However, MCI is heterogeneous in that not all cases progress to dementia within the time frame of a trial and some may not have underlying AD pathology. Identifying those MCIs who are most likely to decline during a trial and thus most likely to benefit from treatment will improve trial efficiency and power to detect treatment effects. To this end, using multimodal, imaging-derived, inclusion criteria may be especially beneficial. Here, we present a novel multimodal imaging marker that predicts future cognitive and neural decline from [F-18]fluorodeoxyglucose positron emission tomography (PET), amyloid florbetapir PET, and structural magnetic resonance imaging, based on a new deep-learning algorithm (randomized denoising autoencoder marker, rDAm). Using ADNI2 MCI data, we show that using rDAm as a trial enrichment criterion reduces the required sample estimates by at least five times compared with the no-enrichment regime and leads to smaller trials with high statistical power, compared with existing methods. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 06/2015; DOI:10.1016/j.jalz.2015.01.010 · 12.41 Impact Factor
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    ABSTRACT: In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology. PET imaging with carbon 11-labeled Pittsburgh compound B examined the pattern of amyloid-β deposition in 68 nondemented adults with DS (30-53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellum as the reference region. Multiple linear regression revealed slight but highly significant (corrected P < .05) positive correlations between SUVR and age. The striatum showed the strongest correlation, followed by precuneus, parietal cortex, anterior cingulate, frontal cortex, and temporal cortex. There is an age-related amyloid-β deposition in the DS population, but as a pattern of elevated cortical retention becomes apparent, the correlation of SUVR with age ceases to be significant. Factors unrelated to aging may drive an increase in deposition during early Alzheimer's disease pathogenesis. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 06/2015; 249. DOI:10.1016/j.jalz.2015.05.013 · 12.41 Impact Factor
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    Won Hwa Kim · Barbara B. Bendlin · Moo K. Chung · Sterling C. Johnson · Vikas Singh ·
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    ABSTRACT: Statistical analysis of longitudinal or cross sectional brain imaging data to identify effects of neurodegenerative diseases is a fundamental task in various studies in neuro-science. However, when there are systematic variations in the images due to parameter changes such as changes in the scanner protocol, hardware changes, or when combining data from multi-site studies, the statistical analysis becomes problematic. Motivated by this scenario, the goal of this paper is to develop a unified statistical solution to the problem of systematic variations in statistical image analysis. Based in part on recent literature in harmonic analysis on diffusion maps, we propose an algorithm which compares operators that are resilient to the systematic variations. These operators are derived from the empirical measurements of the image data and provide an efficient surrogate to capturing the actual changes across images. We also establish a connection between our method to the design of wavelets in non-Euclidean space. To evaluate the proposed ideas, we present various experimental results on detecting changes in simulations as well as show how the method offers improved statistical power in the analysis of real longitudinal PIB-PET imaging data acquired from participants at risk for Alzheimer's disease (AD).
    Computer Vision and Pattern Recognition (CVPR); 06/2015
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    ABSTRACT: This study examined the relationship between phonemic and semantic (category) verbal fluency and cognitive status in the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal cohort enriched for family history of Alzheimer's disease. Participants were 283 WRAP subjects (age 53.1[6.5] years at baseline); who had completed three waves of assessment, over ∼6 years and met psychometric criteria either for "cognitively healthy" (CH) or for psychometric amnestic mild cognitive impairment (aMCI) using an approach that did not consider fluency scores. CH and aMCI groups differed significantly on phonemic total scores, category total scores, phonemic switching, and category mean cluster size. These results suggest that measures of both phonemic and semantic fluency yield lower scores in persons with evidence of psychometric aMCI compared with those who are CH. Differences have not previously been reported in a group this young, and provide evidence for the importance of including multiple verbal fluency tests targeting preclinical Alzheimer's disease. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:
    Archives of Clinical Neuropsychology 05/2015; 30(5). DOI:10.1093/arclin/acv030 · 1.99 Impact Factor
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    ABSTRACT: There is significant interest, both from basic and applied research perspectives, in understanding how structural/functional connectivity changes can explain behavioral symptoms and predict decline in neurodegenerative diseases such as Alzheimer's disease (AD). The first step in most such analyses is to encode the connectivity information as a graph; then, one may perform statistical inference on various 'global' graph theoretic summary measures (e.g., modularity, graph diameter) and/or at the level of individual edges (or connections). For AD in particular, clear differences in connectivity at the dementia stage of the disease (relative to healthy controls) have been identified. Despite such findings, AD-related connectivity changes in preclinical disease remain poorly characterized. Such preclinical datasets are typically smaller and group differences are weaker. In this paper, we propose a new multi-resolution method for performing statistical analysis of connectivity networks/graphs derived from neuroimaging data. At the high level, the method occupies the middle ground between the two contrasts - that is, to analyze global graph summary measures (global) or connectivity strengths or correlations for individual edges similar to voxel based analysis (local). Instead, our strategy derives a Wavelet representation at each primitive (connection edge) which captures the graph context at multiple resolutions. We provide extensive empirical evidence of how this framework offers improved statistical power by analyzing two distinct AD datasets. Here, connectivity is derived from diffusion tensor magnetic resonance images by running a tractography routine. We first present results showing significant connectivity differences between AD patients and controls that were not evident using standard approaches. Later, we show results on populations that are not diagnosed with AD but have a positive family history risk of AD where our algorithm helps in identifying potentially subtle differences between patient groups. We also give an easy to deploy open source implementation of the algorithm for use within studies of connectivity in AD and other neurodegenerative disorders. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 05/2015; 118. DOI:10.1016/j.neuroimage.2015.05.050 · 6.36 Impact Factor
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    ABSTRACT: Midlife may be an ideal window for intervention in Alzheimer's disease (AD). To determine whether sleep is associated with early signs of AD neuropathology (amyloid deposition) in late midlife, we imaged brain amyloid deposits using positron emission tomography with [C-11]Pittsburgh Compound B (PiB), and assessed sleep with the Epworth Sleepiness Scale and the Medical Outcomes Study Sleep Scale in 98 cognitively healthy adults (aged 62.4 ± 5.7 years) from the Wisconsin Registry for Alzheimer's Prevention. We used multiple regressions to test the extent to which sleep scores predicted regional amyloid burden. Participants reporting less adequate sleep, more sleep problems, and greater somnolence on the Medical Outcomes Study had greater amyloid burden in AD-sensitive brain regions (angular gyrus, frontal medial orbital cortex, cingulate gyrus, and precuneus). Amyloid was not associated with reported sleep amount, symptoms of sleep-disordered breathing, trouble falling asleep, or Epworth Sleepiness Scale. Poor sleep may be a risk factor for AD and a potential early marker of AD or target for preventative interventions in midlife. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 05/2015; 36(9). DOI:10.1016/j.neurobiolaging.2015.05.004 · 5.01 Impact Factor
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    ABSTRACT: Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology. To investigate whether cognitive reserve (CR) modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD. A cross-sectional cohort of 268 individuals (211 in a cognitively normal group and 57 in a cognitively impaired group) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. In addition, we computed t-tau/Aβ42 and p-tau/Aβ42 ratios. Cognitive reserve was indexed by years of education, with 16 or more years taken to confer high reserve. Covariate-adjusted regression analyses were used to test whether the effect of age on CSF biomarkers was modified by CR. The study dates were March 5, 2010, to February 13, 2013. Cerebrospinal fluid levels of Aβ42, t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42. There were significant age × CR interactions for CSF t-tau (β [SE] = -6.72 [2.84], P = .02), p-tau (β [SE] = -0.71 [0.27], P = .01), t-tau/Aβ42 (β [SE] = -0.02 [0.01], P = .02), and p-tau/Aβ42 (β [SE] = -0.002 [0.001], P = .004). With advancing age, individuals with high CR exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low CR. This attenuation of age effects by CR tended to be more pronounced in the cognitively impaired group compared with the cognitively normal group. There was evidence of a dose-response relationship such that the effect of age on the biomarkers was progressively attenuated given additional years of schooling. In a sample composed of a cognitively normal group and a cognitively impaired group, higher CR was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which CR might favorably alter lifetime risk for symptomatic AD.
    04/2015; 72(6). DOI:10.1001/jamaneurol.2015.0098
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    ABSTRACT: Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer's disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer's Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Aβ42, P-Tau181, and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOE ε4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF Aβ42. No significant main effects of HOMA-IR on P-Tau181, T-Tau, or Aβ42 were observed; however, significant interactions were observed between HOMA-IR and APOE ε4 on CSF markers related to tau. Among APOE ε4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOE ε4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Aβ42 levels in CSF. IR among asymptomatic APOE ε4 carriers was associated with higher P-Tau181 and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life.
    Journal of Alzheimer's disease: JAD 03/2015; 46(2). DOI:10.3233/JAD-150072 · 4.15 Impact Factor
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    ABSTRACT: Subjective memory complaints (SMCs) represent an individual's perception of subtle changes in memory in the absence of objective impairment in memory. However, it is not fully known whether persons with SMCs harbor brain alterations related to Alzheimer's disease (AD) or whether they indeed demonstrate poorer cognitive performance. Participants were 261 middle-aged adults (mean age=54.30 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention, a registry of cognitively normal adults at risk for AD. They answered a question pertaining to subjective memory, completed a comprehensive neuropsychological exam, and subsequently underwent a volumetric MRI scan. Cortical thickness measurements were derived from 10 a priori regions of interest involved in AD. Analyses of covariance were conducted to investigate group differences in cortical thickness and neuropsychological measures. Compared with individuals without SMCs, individuals with SMCs had significant cortical thinning in the entorhinal, fusiform, posterior cingulate, and inferior parietal cortices, as well as significantly reduced amygdala volume. Similarly, those with SMCs had significantly lower test scores on measures of Immediate Memory, Verbal Learning & Memory, and Verbal Ability. Additional adjustment for depressive symptoms (which differed between the groups) attenuated only the findings for the entorhinal cortex (p=.061) and Verbal Ability (p=.076). At-risk, cognitively healthy individuals with SMCs exhibit cortical thinning in brain regions affected by AD as well as poorer performance on objective memory tests. These findings suggest that, in some individuals, SMCs might represent the earliest stages of AD.
    03/2015; 1(1):33-40. DOI:10.1016/j.dadm.2014.11.010
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    ABSTRACT: Cognitive decline is one of the hallmark features of Alzheimer's disease, but many studies struggle to find strong associations between cognitive function and genetic variants. In order to identify which aspects of cognition are more likely to have a strong genetic component, we assessed the heritability of various cognitive functions related to Alzheimer's disease in 303 initially asymptomatic middle-aged adult siblings with a parental history of Alzheimer's disease from the Wisconsin Registry for Alzheimer's Prevention. Participants underwent extensive cognitive testing, and six cognitive factors were identified via factor analysis. Working Memory and Visual Learning & Memory had the highest heritability (52% and 41%, respectively). Inclusion of APOE allele counts did not notably change heritability estimates, indicating that there are likely additional genetic variants contributing to cognition. These findings suggest that future genetic studies should focus on the cognitive domains of Working Memory and Visual Learning & Memory.
    Journal of Alzheimer's disease: JAD 02/2015; 45(4). DOI:10.3233/JAD-142658 · 4.15 Impact Factor
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    ABSTRACT: Canonical correlation analysis (CCA) is a widely used statistical technique to capture correlations between two sets of multi-variate random variables and has found a multitude of applications in computer vision, medical imaging and machine learning. The classical formulation assumes that the data live in a pair of vector spaces which makes its use in certain important scientific domains problematic. For instance, the set of symmetric positive definite matrices (SPD), rotations and probability distributions, all belong to certain curved Riemannian manifolds where vector-space operations are in general not applicable. Analyzing the space of such data via the classical versions of inference models is sub-optimal. Using the space of SPD matrices as a concrete example, we present a principled generalization of the well known CCA to the Riemannian setting. Our CCA algorithm operates on the product Riemannian manifold representing SPD matrix-valued fields to identify meaningful correlations. As a proof of principle, we present experimental results on a neuroimaging dataset to show the applicability of these ideas.
    Riemannian Computing and Statistical Inferences in Computer Vision, 01/2015; Springer., ISBN: 978-3-319-22956-0
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    ABSTRACT: Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ-) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ- in all three ROIs and in Aβi compared to Aβ- in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.
    Clinical neuroimaging 12/2014; 4. DOI:10.1016/j.nicl.2014.02.001 · 2.53 Impact Factor
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    ABSTRACT: Subtle cognitive and behavioral changes are common in early Parkinson's disease. The cause of these symptoms is probably multifactorial but may in part be related to extra-striatal dopamine levels. 6-[(18) F]-Fluoro-L-dopa (FDOPA) positron emission tomography has been widely used to quantify dopamine metabolism in the brain; the most frequently measured kinetic parameter is the tissue uptake rate constant, Ki. However, estimates of dopamine turnover, which also account for the small rate of FDOPA loss from areas of specific trapping, may be more sensitive than Ki for early disease-related changes in dopamine biosynthesis. The purpose of the present study was to compare effective distribution volume ratio (eDVR), a metric for dopamine turnover, to cognitive and behavioral measures in Parkinson's patients. We chose to focus the investigation on anterior cingulate cortex, which shows highest FDOPA uptake within frontal regions and has known roles in executive function. Fifteen non-demented early-stage PD patients were pretreated with carbidopa and tolcapone, a central catechol-O-methyl transferase (COMT) inhibitor, and then underwent extended imaging with FDOPA PET. Anterior cingulate eDVR was compared with composite scores for language, memory, and executive function measured by neuropsychological testing, and behavior change measured using two informant-based questionnaires, the Cambridge Behavioral Inventory and the Behavior Rating Inventory of Executive Function-Adult Version. Lower mean eDVR (thus higher dopamine turnover) in anterior cingulate cortex was related to lower (more impaired) behavior scores. We conclude that subtle changes in anterior cingulate dopamine metabolism may contribute to dysexecutive behaviors in Parkinson's disease.
    Brain Imaging and Behavior 12/2014; DOI:10.1007/s11682-014-9338-4 · 4.60 Impact Factor
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    ABSTRACT: Unlabelled: The serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A-specific antagonist radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-(18)F-fluoromethylcyclohexane)carboxamide ((18)F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of (18)F-mefway in humans. Methods: Dynamic (18)F-mefway PET data were acquired for 6 healthy volunteers (4 women, 2 men; age, 22-38 y). Scans were initiated with the injection of 192-204 MBq of radiotracer, and data were acquired for 2 h. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of (18)F-mefway. To examine the test-retest variability of (18)F-mefway, a second PET scan was acquired at least 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone. Results: (18)F-mefway uptake in the brain occurred quickly, with a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4-0.9 at 120 min. Rapid metabolism of (18)F-mefway was observed, with no detected (18)F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in the insular cortex and 0.7-1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min of dynamic data. Average test-retest variability was 8%. No evidence of radioactivity uptake in bone was observed. Conclusion: (18)F-mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make (18)F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention.
    Journal of Nuclear Medicine 11/2014; 55(12):1973-1979. DOI:10.2967/jnumed.114.145151 · 6.16 Impact Factor

Publication Stats

6k Citations
1,010.48 Total Impact Points


  • 2004-2015
    • University of Wisconsin–Madison
      • Department of Medicine
      Madison, Wisconsin, United States
  • 2010
    • Santa Casa de Porto Alegre
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 2007-2010
    • St. Mary's Hospital (WI, USA)
      Madison, Wisconsin, United States
    • Case Western Reserve University
      • Institute of Pathology
      Cleveland, OH, United States
  • 2008
    • University of Kentucky
      Lexington, Kentucky, United States
  • 2001-2004
    • Barrow Neurological Institute
      • Department of Neurology
      Phoenix, Arizona, United States
  • 2003
    • Mayo Clinic - Scottsdale
      Scottsdale, Arizona, United States
    • St. Joseph Medical Center
      Houston, Texas, United States
  • 2000
    • Dartmouth Medical School
      • Department of Psychiatry
      Hanover, New Hampshire, United States
  • 1994-1996
    • Brigham Young University - Provo Main Campus
      • Department of Psychology
      Provo, Utah, United States