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The human brain is a complex organ underlying many cognitive and physiological processes, affected by a wide range of diseases. Genetic associations with macroscopic brain structure are emerging, providing insights into genetic sources of brain variability and risk for functional impairments and disease. However, specific associations with measures of local brain folding, associated with both brain development and decline, remain under-explored. Here we carried out detailed large-scale genome-wide associations of regional brain cortical sulcal measures derived from magnetic resonance imaging data of 40,169 individuals in the UK Biobank. Combining both genotyping and whole-exome sequencing data (∼12 million variants), we discovered 388 regional brain folding associations across 77 genetic loci at p−8, which replicated at pKCNK2 locus with a cortex-specific KCNK2 eQTL. Genetic correlations with neuropsychiatric conditions highlighted emerging patterns across distinct sulcal parameters and related phenotypes. We provide an interactive 3D visualisation of our summary associations, making complex association patterns easier to interpret, and emphasising the added resolution of regional brain analyses compared to global brain measures. Our results offer new insights into the genetic architecture underpinning brain folding and provide a resource to the wider scientific community for studies of pathways driving brain folding and their role in health and disease.

Financial capacity is an important instrumental activity of daily life that comprises those abilities needed for an individual independently to manage financial affairs in a manner consistent with personal self-interest and values. In this chapter, we examine the topic of financial capacity and decision-making in older adults in our aging society. Specifically, we discuss the crucial phenomenon of cognitive aging and diminished financial capacity, the impact on financial skills of cognitive disorders such as mild cognitive impairment (MCI) and Alzheimer’s disease (AD), and early warning signs of diminished financial capacity. We present a useful clinical conceptual model of financial capacity, describe different approaches to assessing financial capacity, and then discuss empirical studies of financial capacity in older adults with a focus on patients with MCI and AD. This chapter concludes with sections addressing exciting new neuroimaging investigations of financial decision-making and capacity, the importance of psychiatric and other non-cognitive contributions to financial capacity in aging, and directions for future research.

While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer’s disease dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the preclinical and prodromal stages of the disease. Paradoxically, very early in the Alzheimer’s disease process, individuals may experience heightened awareness of memory changes before any objective cognitive deficits can be detected, here referred to as hypernosognosia. In contrast, awareness of memory dysfunction shown by individuals with mild cognitive impairment (MCI) is very variable, ranging from marked concern to severe lack of insight. This study aims at improving our mechanistic understanding of how alterations in memory self-awareness are related to pathological changes in clinically normal (CN) adults and MCI patients. 297 CN and MCI patients underwent PiB-PET (Positron Emission Tomography using Pittsburgh Compound B) in vivo amyloid imaging. Amyloid burden was estimated from Alzheimer’s disease vulnerable regions, including the frontal, lateral parietal and lateral temporal, and retrosplenial cortex. Memory self-awareness was assessed using discrepancy scores between subjective and objective measures of memory function. A set of univariate analysis of variance were performed to assess the relationship between self-awareness of memory and amyloid pathology. Whereas CN individuals harboring amyloid pathology demonstrated hypernosognosia, MCI patients with increased amyloid pathology demonstrated anosognosia. In contrast, MCI patients with low amounts of amyloid were observed to have normal insight into their memory functions. Altered self-awareness of memory tracks with amyloid pathology. The findings of variability of awareness may have important implications for the reliability of self-report of dysfunction across the spectrum of preclinical and prodromal Alzheimer’s disease.

We investigated individual differences in longitudinal trajectories of brain aging in cognitively normal healthy adults from the Seattle Longitudinal Study covering 8 years of longitudinal change (across 5 occasions) in cortical thickness in 249 midlife and older adults (52-95 years old). We aimed to understand true brain change; examine the influence of salient risk factors that modify an individual's rate of cortical thinning; and compare cross-sectional age-related differences in cortical thickness to longitudinal within-person cortical thinning. We used Multivariate Multilevel Modeling to simultaneously model dependencies among 5 lobar composites (Frontal, Parietal, Temporal, Occipital, and Cingulate [CING]) and account for the longitudinal nature of the data. Results indicate (1) all 5 lobar composites significantly atrophied across 8 years, showing nonlinear longitudinal rate of cortical thinning decelerated over time, (2) longitudinal thinning was significantly altered by hypertension and Apolipoprotein-E ε4 (APOEε4), varying by location: Frontal and CING thinned more rapidly in APOEε4 carriers. Notably, thinning of parietal and occipital cortex showed synergistic effect of combined risk factors, where individuals who were both APOEε4 carriers and hypertensive had significantly greater 8-year thinning than those with either risk factor alone or neither risk factor, (3) longitudinal thinning was 3 times greater than cross-sectional estimates of age-related differences in thickness in parietal and occipital cortices.

OBJECTIVE: To evaluate the risk of Alzheimer’s disease-related neuropathology burden at autopsy given older adults’ current cognitive state. METHOD: Participants included 1,303 individuals who enrolled in the Religious Orders Study (ROS) and 1,789 who enrolled in the Rush Memory and Aging Project (MAP). Cognitive status was evaluated via standardized assessments of global cognition and episodic memory. At the time of analyses, about 50% of participants were deceased with the remaining numbers right censored. Using multi-state Cox proportional hazard models, we compared the cognitive status of all subjects alive at a given age and estimated future risk of dying with different AD related neuropathologies. Endpoints considered were Braak Stages (0-2,3-4,5-6), CERAD (0,1,2,3) and TDP-43 (0,1,2,3) level. RESULTS: For all three pathological groupings (Braak, CERAD, TDP-43), we found that a cognitive test score one standard deviation below average put individuals at up to three times the risk for being diagnosed with late stage AD at autopsy according to pathological designations. The effect remained significant after adjusting for sex, APOE-e4 status, smoking status, education level, and vascular health scores. CONCLUSION: Applying multi-state modeling techniques, we were able to identify those at risk of exhibiting specific levels of neuropathology based on current cognitive test performance. This approach presents new and approachable possibilities in clinical settings for diagnosis and treatment development programs.

Objective:To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion.Methods:Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer’s Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation.Results:Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (β > 0.02, p < 0.001), and slower rates of ventricular dilation (β < −4.7, p < 2 × 10−15). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline.Conclusions:Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.

We sought to characterize electrophysiological, eye-tracking and behavioral correlates of face-name recognition memory in healthy younger adults using high-density electroencephalography (EEG), infrared eye-tracking (ET), and neuropsychological measures. Twenty-one participants first studied 40 face-name (FN) pairs; 20 were presented four times (4R) and 20 were shown once (1R). Recognition memory was assessed by asking participants to make old/new judgments for 80 FN pairs, of which half were previously studied items and half were novel FN pairs (N). Simultaneous EEG and ET recording were collected during recognition trials. Comparisons of event-related potentials (ERPs) for correctly identified FN pairs were compared across the three item types revealing classic ERP old/new effects including 1) relative positivity (1R > N) bi-frontally from 300 to 500 ms, reflecting enhanced familiarity, 2) relative positivity (4R > 1R and 4R > N) in parietal areas from 500 to 800 ms, reflecting enhanced recollection, and 3) late frontal effects (1R > N) from 1000 to 1800 ms in right frontal areas, reflecting post-retrieval monitoring. ET analysis also revealed significant differences in eye movements across conditions. Exploration of cross-modality relationships suggested associations between memory and executive function measures and the three ERP effects. Executive function measures were associated with several indicators of saccadic eye movements and fixations, which were also associated with all three ERP effects. This novel characterization of face-name recognition memory performance using simultaneous EEG and ET reproduced classic ERP and ET effects, supports the construct validity of the multimodal FN paradigm, and holds promise as an integrative tool to probe brain networks supporting memory and executive functioning.

In neuroimaging, functional magnetic resonance imaging (fMRI) measures the blood-oxygenation-level dependent (BOLD) signal in the brain. The degree of correlation of the BOLD signal in spatially independent regions of the brain defines the functional connectivity of those regions. During a cognitive fMRI task, a psychophysiological interaction (PPI) analysis can be used to examine changes in the functional connectivity during specific contexts defined by the cognitive task. An example of such a task is one that engages the memory system, asking participants to learn pairs of unrelated words (encoding) and recall the second word in a pair when presented with the first word (retrieval). In the present study, we used this type of associative memory task and a generalized PPI (gPPI) analysis to compare changes in hippocampal connectivity in older adults who are carriers of the Alzheimer's disease (AD) genetic risk factor apolipoprotein-E epsilon-4 (APOEε4). Specifically, we show that the functional connectivity of subregions of the hippocampus changes during encoding and retrieval, the two active phases of the associative memory task. Context-dependent changes in functional connectivity of the hippocampus were significantly different in carriers of APOEε4 compared to non-carriers. PPI analyses make it possible to examine changes in functional connectivity, distinct from univariate main effects, and to compare these changes across groups. Thus, a PPI analysis may reveal complex task effects in specific cohorts that traditional univariate methods do not capture. PPI analyses cannot, however, determine directionality or causality between functionally connected regions. Nevertheless, PPI analyses provide powerful means for generating specific hypotheses regarding functional relationships, which can be tested using causal models. As the brain is increasingly described in terms of connectivity and networks, PPI is an important method for analyzing fMRI task data that is in line with the current conception of the human brain.

International audience; Localizing the center of the spinal cord on MR images is a critical step toward fully automated and robust quantitative analysis, which is essential to achieve clinical utilization. While automatic localization of the spinal cord might appear as a simple task, that has already been addressed extensively, it is much more challenging to achieve this across the large variation in MRI contrasts, field of view, resolutions and pathologies. In this study, we introduce a novel method, called “OptiC”, to automatically and robustly localize the spinal cord on a large variety of MRI data. Starting from a localization map computed by a linear Support Vector Machine trained with Histogram of Oriented Gradient features, the center of the spinal cord is localized by solving an optimization problem, that introduces a trade-off between the localization map and the cord continuity along the superior-inferior axis. The OptiC algorithm features an efficient search (with a linear complexity in the number of voxels) and ensures the global minimum is reached. OptiC was compared to a recently-published method based on the Hough transform using a broad range of MRI data, involving 13 different centers, 3 contrasts (T2-weighted n=278, T1-weighted n=112 and T∗2-weighted n=263), with a total of 441 subjects, including 133 patients with traumatic and neurodegenerative diseases. Overall, OptiC was able to find 98.5% of the gold-standard centerline coverage, with a mean square error of 1.21 mm, suggesting that OptiC could reliably be used for subsequent analyses tasks, such as cord segmentation, opening the door to more robust analysis in patient population.

Functional connectivity magnetic resonance imaging (fcMRI) is a powerful tool for understanding the network level organization of the brain in research settings and is increasingly being used to study large-scale neuronal network degeneration in clinical trial settings. Presently, a variety of techniques, including seed-based correlation analysis and group independent components analysis (with either dual regression or back projection) are commonly employed to compute functional connectivity metrics. In the present report, we introduce template based rotation,(1) a novel analytic approach optimized for use with a priori network parcellations, which may be particularly useful in clinical trial settings. Template based rotation was designed to leverage the stable spatial patterns of intrinsic connectivity derived from out-of-sample datasets by mapping data from novel sessions onto the previously defined a priori templates. We first demonstrate the feasibility of using previously defined a priori templates in connectivity analyses, and then compare the performance of template based rotation to seed based and dual regression methods by applying these analytic approaches to an fMRI dataset of normal young and elderly subjects. We observed that template based rotation and dual regression are approximately equivalent in detecting fcMRI differences between young and old subjects, demonstrating similar effect sizes for group differences and similar reliability metrics across 12 cortical networks. Both template based rotation and dual-regression demonstrated larger effect sizes and comparable reliabilities as compared to seed based correlation analysis, though all three methods yielded similar patterns of network differences. When performing inter-network and sub-network connectivity analyses, we observed that template based rotation offered greater flexibility, larger group differences, and more stable connectivity estimates as compared to dual regression and seed based analyses. This flexibility owes to the reduced spatial and temporal orthogonality constraints of template based rotation as compared to dual regression. These results suggest that template based rotation can provide a useful alternative to existing fcMRI analytic methods, particularly in clinical trial settings where predefined outcome measures and conserved network descriptions across groups are at a premium.

Functional neuroimaging tools, such as fMRI methods, may elucidate the neural correlates of clinical, behavioral, and cognitive performance. Most functional imaging studies focus on regional task-related activity or resting state connectivity rather than how changes in functional connectivity across conditions and tasks are related to cognitive and behavioral performance. To investigate the promise of characterizing context-dependent connectivity-behavior relationships, this study applies the method of generalized psychophysiological interactions (gPPI) to assess the patterns of associative-memory-related fMRI hippocampal functional connectivity in Alzheimer's disease (AD) associated with performance on memory and other cognitively demanding neuropsychological tests and clinical measures. Twenty-four subjects with mild AD dementia (ages 54-82, nine females) participated in a face-name paired-associate encoding memory study. Generalized PPI analysis was used to estimate the connectivity between the hippocampus and the whole brain during encoding. The difference in hippocampal-whole brain connectivity between encoding novel and encoding repeated face-name pairs was used in multiple-regression analyses as an independent predictor for 10 behavioral, neuropsychological and clinical tests. The analysis revealed connectivity-behavior relationships that were distributed, dynamically overlapping, and task-specific within and across intrinsic networks; hippocampal-whole brain connectivity-behavior relationships were not isolated to single networks, but spanned multiple brain networks. Importantly, these spatially distributed performance patterns were unique for each measure. In general, out-of-network behavioral associations with encoding novel greater than repeated face-name pairs hippocampal-connectivity were observed in the default-mode network, while correlations with encoding repeated greater than novel face-name pairs hippocampal-connectivity were observed in the executive control network (p

Objectives: Although age-related brain changes are becoming better understood, midlife patterns of change are still in need of characterization, and longitudinal studies are lacking. The aim of this study was to determine if baseline fractional anisotropy (FA), obtained from diffusion tensor imaging (DTI) predicts volume change over a 4-year interval. Experimental design: Forty-four cognitively healthy middle-age adults underwent baseline DTI and longitudinal T1-weighted magnetic resonance imaging. Tensor-based morphometry methods were used to evaluate volume change over time. FA values were extracted from regions of interest that included the cingulum, entorhinal white matter, and the genu and splenium of the corpus callosum. Baseline FA was used as a predictor variable, whereas gray and white matter atrophy rates as indexed by Tensor-based morphometry were the dependent variables. Principal observations: Over a 4-year period, participants showed significant contraction of white matter, especially in frontal, temporal, and cerebellar regions (P < 0.05, corrected for multiple comparisons). Baseline FA in entorhinal white matter, genu, and splenium was associated with longitudinal rates of atrophy in regions that included the superior longitudinal fasciculus, anterior corona radiata, temporal stem, and white matter of the inferior temporal gyrus (P < 0.001, uncorrected for multiple comparisons). Conclusions: Brain change with aging is characterized by extensive shrinkage of white matter. Baseline white matter microstructure as indexed by DTI was associated with some of the observed regional volume loss. The findings suggest that both white matter volume loss and microstructural alterations should be considered more prominently in models of aging and neurodegenerative diseases. Hum Brain Mapp 35:2044–2054, 2014. © 2013 Wiley Periodicals, Inc.

fMRI studies have linked the posteromedial cortex to episodic learning (encoding) and remembering (retrieval) processes. The posteromedial cortex is considered part of the default network and tends to deactivate during encoding but activate during retrieval, a pattern known as the encoding/retrieval flip. Yet, the exact relationship between the neural correlates of memory performance (hit/miss) and memory stage (encoding/retrieval) and the extent of overlap with intrinsic cortical networks remains to be elucidated. Using task-based fMRI, we isolated the pattern of activity associated with memory performance, memory stage, and the interaction between both. Using resting-state fMRI, we identified which intrinsic large-scale functional networks overlapped with regions showing task-induced effects. Our results demonstrated an effect of successful memory performance in regions associated with the control network and an effect of unsuccessful memory performance in the ventral attention network. We found an effect of memory retrieval in brain regions that span the default and control networks. Finally, we found an interaction between memory performance and memory stage in brain regions associated with the default network, including the posteromedial cortex, posterior parietal cortex, and parahippocampal cortex. We discuss these findings in relation to the encoding/retrieval flip. In general, the findings demonstrate that task-induced effects cut across intrinsic cortical networks. Furthermore, regions within the default network display functional dissociations, and this may have implications for the neural underpinnings of age-related memory disorders.

Neurodegenerative diseases comprise a broad swath of different neurologic diseases characterized by loss of neurons in the central nervous system. The most common neurodegenerative disease is Alzheimer disease, a dementing disease. Dementia is commonly understood as loss of function in at least two cognitive domains that is severe enough to affect daily activities in the social or occupational spheres. Elderly adults represent a significant and rapidly expanding proportion of the population. Some estimates state that by 2030 there will be 72 million individuals over the age of 65 years in the United States, constituting 19% of the population. The World Health Organization estimated in 2010 that there were 36.5 million people worldwide living with dementia, with the global cost for care being $604 billion per year. A new case of dementia is diagnosed approximately every 4 seconds. As the prevalence of many neurologic diseases increases with age, it can be difficult to differentiate between the effects of aging and those of prodromal age-related disease. Advances in neuroimaging have afforded significant insight into progressive neurodegenerative disorders and their mimics. Besides the improvements in structural imaging that have come about through thinner slices, 3-dimensional volumes, and higher spatial resolution, molecular and cellular imaging have made a big impact on how we look at the brain and its function. MR spectroscopy, diffusion tensor imaging, perfusion imaging, functional MRI, and PET scans have further increased our understanding of the pathophysiology of neurodegenerative disorders. Distinguishing between preventable diseases, potentially reversible diseases, and progressive, irreversible diseases is important in planning for a patient’s future medical, social, and economic spheres. Imaging of Neurodegenerative Disorders is a comprehensive, updated reference covering the latest techniques used in neuroimaging as well as the basic structural imaging that facilitates diagnosis of various neurodegenerative disorders. Because there never has been a dedicated textbook on the imaging of neurodegenerative diseases, the aim of this book is to cover each disease as it is currently understood and to show what it might look like using various imaging techniques. Imaging helps enormously in affirming suspicions, differentiating entities that have a clinical overlap, and charting the progression of neurodegenerative diseases. The book is organized into 16 parts with 41 chapters written by 83 contributors who have brought fresh insights and expertise that encompass many disease entities. They attempt to fill the gap of knowledge that exists in the imaging and understanding of neurodegenerative diseases. Chapters are arranged by specific diseases and cover their clinical features, pathologic characteristics, and imaging. Along with a brief discussion of each disease are the images themselves—superb in quality and quite illustrative—in addition to what tests to order, what to look for, what one expects to see for each disorder, and what new clinical and research modalities are available. This book is useful for radiologists, neuroradiologists, neurologists, neurosurgeons, and other internal or family medical physicians, as well as anyone seeking to understand neurodegenerative disorders through the lens of imaging techniques that are becoming increasingly sophisticated.

After traumatic injury, the brain undergoes a prolonged period of degenerative change that is paradoxically accompanied by cognitive recovery. The spatiotemporal pattern of atrophy and the specific relationships of atrophy to cognitive changes are ill understood. The present study used tensor-based morphometry and neuropsychological testing to examine brain volume loss in 17 traumatic brain injury (TBI) patients and 13 controls over a 4-year period. Patients were scanned at 2 months, 1 year, and 4 years post-injury. High-dimensional warping procedures were used to create change maps of each subject's brain for each of the two intervals. TBI patients experienced volume loss in both cortical areas and white matter regions during the first interval. We also observed continuing volume loss in extensive regions of white matter during the second interval. Neuropsychological correlations indicated that cognitive tasks were associated with subsequent volume loss in task-relevant regions. The extensive volume loss in brain white matter observed well beyond the first year post-injury suggests that the injured brain remains malleable for an extended period, and the neuropsychological relationships suggest that this volume loss may be associated with subtle cognitive improvements. (JINS, 2012,18, 1–13)

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a large multi-center study designed to develop optimized methods for acquiring longitudinal neuroimaging, cognitive, and biomarker measures of AD progression in a large cohort of patients with Alzheimer’s disease (AD), patients with mild cognitive impairment, and healthy controls. Detailed neuropsychological testing was conducted on all participants. We examined the factor structure of the ADNI Neuropsychological Battery across older adults with differing levels of clinical AD severity based on the Clinical Dementia Rating Scale (CDR). Confirmatory factor analysis (CFA) of 23 variables from 10 neuropsychological tests resulted in five factors (memory, language, visuospatial functioning, attention, and executive function/processing speed) that were invariant across levels of cognitive impairment. Thus, these five factors can be used as valid indicators of cognitive function in older adults who are participants in ADNI.

The goal of the current study was to examine cognitive change in both healthy controls (n = 229) and individuals with mild cognitive impairment (MCI) (n = 397) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We applied latent growth modeling to examine baseline and longitudinal change over 36 months in five cognitive factors derived from the ADNI neuropsychological test battery (memory, executive function/processing speed, language, attention and visuospatial). At baseline, MCI patients demonstrated lower performance on all of the five cognitive factors when compared to controls. Both controls and MCI patients declined on memory over 36 months; however, the MCI patients declined at a significantly faster rate than controls. The MCI patients also declined over 36 months on the remaining four cognitive factors. In contrast, the controls did not exhibit significant change over 36 months on the non-memory cognitive factors. Within the MCI group, executive function declined faster than memory, while the other factor scores changed slower than memory over time. These findings suggest different patterns of cognitive change in healthy older adults and MCI patients. The findings also suggest that, when compared with memory, executive function declines faster than other cognitive factors in patients with MCI. Thus, decline in non-memory domains may be an important feature for distinguishing healthy older adults and persons with MCI.

There are several magnetic resonance (MR) imaging techniques that benefit from high-field MR imaging. This article describes a range of novel techniques that are currently being used clinically or will be used in the future for clinical purposes as they gain popularity. These techniques include functional MR imaging, diffusion tensor imaging, cortical thickness assessment, arterial spin labeling perfusion, white matter hyperintensity lesion assessment, and advanced MR angiography.

Higher serum homocysteine (Hcy) levels in humans are associated with vascular pathology and greater risk for dementia, as well as lower global and regional volumes in frontal lobe and hippocampus. Calorie restriction (CR) in rhesus monkeys (Macaca mulatta) may confer neural protection against age- or Hcy-related vascular pathology. Hcy was collected proximal to a magnetic resonance imaging (MRI) acquisition in aged rhesus monkeys and regressed against volumetric and diffusion tensor imaging indexes using voxel-wise analyses. Higher Hcy was associated with lower white matter volume in pons and corpus callosum. Hcy was correlated with lower gray matter volume and density in prefrontal cortices and striatum. CR did not influence Hcy levels. However, control monkeys exhibited a strong negative correlation between Hcy and global gray matter, whereas no relationship was evident for the CR monkeys. Similar group differences were also seen across modalities in the splenium of the corpus callosum, prefrontal cortices, hippocampus, and somatosensory areas. The data suggest that CR may ameliorate the influence of Hcy on several important age-related parameters of parenchymal health.

Background: Rate of decline in 6-L-[18F]fluorodopa (FDOPA) uptake within the striatum has been reported as showing regional differences in Parkinson's disease (PD). Methods: We acquired longitudinal brain FDOPA positron emission tomography (PET) studies in 26 PD subjects and 11 controls over 4.5 years. We analyzed both spatially normalized voxel-wise maps of radiotracer influx (Kocc) and average Kocc values for six non-overlapping volumes of interest (VOIs) encompassing the striatum. Results: The voxel-wise analysis showed that in PD, FDOPA Kocc decline spanned the striatum but was greatest in the posterior putamen ipsilateral and anterior putamen contralateral to initial symptoms. The VOI approached showed that absolute rates of Kocc decline were significantly greater in PD than control subjects, but that the slope of decline did not differ between subregions. In PD, ratios of uptake between subregions did not change during the study with the exception of the ipsilateral putamen/caudate ratio. Decline rates were marginally greater during earlier time segments. Both male gender and advancing age were associated with lower baseline FDOPA uptake, but no difference in decline rates. VOI Kocc values were significantly correlated with disease duration, but only moderately correlated with clinical measures. Discussion: We conclude that FDOPA uptake in subregions of the striatum is strongly correlated with disease duration and age, and declines approximately equally from symptom onset in PD. This implies that in idiopathic PD, relative preservation of uptake in the anterior striatum reflects a delay in pathologic involvement of nigrostriatal projections to this region. © 2011 Movement Disorder Society

Systemic levels of proinflammatory cytokines such as interleukin-6 (IL-6) increase in old age and may contribute to neural atrophy in humans. We investigated IL-6 associations with age in T1-weighted segments and microstructural diffusion indices using MRI in aged rhesus monkeys (Macaca mulatta). Further, we determined if long-term 30% calorie restriction (CR) reduced IL-6 and attenuated its association with lower tissue volume and density. Voxel-based morphometry (VBM) and diffusion-weighted voxelwise analyses were conducted. IL-6 was associated with less global gray and white matter (GM and WM), as well as smaller parietal and temporal GM volumes. Lower fractional anisotropy (FA) was associated with higher IL-6 levels along the corpus callosum and various cortical and subcortical tracts. Higher IL-6 concentrations across subjects were also associated with increased mean diffusivity (MD) throughout many brain regions, particularly in corpus callosum, cingulum, and parietal, frontal, and prefrontal areas. CR monkeys had significantly lower IL-6 and less associated atrophy. An IL-6xCR interaction across modalities also indicated that CR mitigated IL-6 related changes in several brain regions compared to controls. Peripheral IL-6 levels were correlated with atrophy in regions sensitive to aging, and this relationship was decreased by CR.

Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measuredin vivousing magnetic resonance imaging, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n= 24, 13 males, 11 females) and standard (n= 17, 8 males, 9 females) diets. Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A Diet × Age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.

Voxel-based morphometry studies have become increasingly common in human neuroimaging over the past several years; however, few studies have utilized this method to study morphometry changes in non-human primates. Here we describe the application of voxel-wise morphometry methods to the rhesus macaque (Macaca mulatta) using the 112RM-SL template and priors (McLaren et al. (2009) [42]) and as an illustrative example we describe age-associated changes in grey matter morphometry. Specifically, we evaluated the unified segmentation routine implemented using Statistical Parametric Mapping (SPM) software and the FMRIB's Automated Segmentation Tool (FAST) in the FMRIB Software Library (FSL); the effect of varying the smoothing kernel; and the effect of the normalization routine. We found that when studying non-human primates, brain images need less smoothing than in human studies, 2-4mm FWHM. Using flow field deformations (DARTEL) improved inter-subject alignment leading to results that were more likely due to morphometry differences as opposed to registration differences.

Although it is established that Alzheimer's disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging.

First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimer's disease.

We used fMRI to identify brain areas activated during tactile attention tasks. Participants detected the interval containing target stimulation of higher vibrotactile frequency or longer duration. Attributes were selectively or neutrally cued. A control backwards-counting task included concurrent, but irrelevant corresponding vibrotactile stimulation. Group analyses of average F-statistic maps, participant conjunction maps, and estimated time courses utilized data mapped to a standard average surface atlas (PALS B12). Repeated-measures, random-effects MANOVA examined blood oxygenation level-dependent (BOLD) signal modulation differences amongst tasks in defined regions, where significant responses occurred in at least 50% of the group. Greater than 0.1% increase in BOLD responses were found during at least one of the tactile attention tasks in contralateral parietal opercular OP1, BA 4 finger region, frontal eye field, dorsal premotor, anterior and posterior BA 7, and bilaterally in superior temporal sulcal cortex (BA 22), ventral premotor, supplementary motor area, and frontal operculum/insula. The same tasks suppressed activity in ipsilateral OP4. The BA 22 ROI showed larger responses during neutral cuing. The control task suppressed BOLD in ipsilateral OP1 and OP4 and bilaterally in BA 40, but significantly enhanced responses in dorsal parietal-frontal regions compared with tactile attention tasks. No regional differences were found between selectively cued frequency and duration tasks. Tactile attention effects were most prominent in OP1. Posterior parietal responses possibly reflected the visual attention required for backwards-counting, whereas the frontal regions potentially related to goal-directed behavior when identifying target stimulation.

Visual cortex activity in the blind has been shown in Braille literate people, which raise the question of whether Braille literacy influences cross-modal reorganization. We used fMRI to examine visual cortex activation during semantic and phonological tasks with auditory presentation of words in two late-onset blind individuals who lacked Braille literacy. Multiple visual cortical regions were activated in the Braille naive individuals. Positive BOLD responses were noted in lower tier visuotopic (e.g., V1, V2, VP, and V3) and several higher tier visual areas (e.g., V4v, V8, and BA 37). Activity was more extensive and cross-correlation magnitudes were greater during the semantic compared to the phonological task. These results with Braille naive individuals plausibly suggest that visual deprivation alone induces visual cortex reorganization. Cross-modal reorganization of lower tier visual areas may be recruited by developing skills in attending to selected non-visual inputs (e.g., Braille literacy, enhanced auditory skills). Such learning might strengthen remote connections with multisensory cortical areas. Of necessity, the Braille naive participants must attend to auditory stimulation for language. We hypothesize that learning to attend to non-visual inputs probably strengthens the remaining active synapses following visual deprivation, and thereby, increases cross-modal activation of lower tier visual areas when performing highly demanding non-visual tasks of which reading Braille is just one example.

carriers, compared to their younger counterparts, demonstrate lower blood flow in right middle frontal gyrus a pattern opposite that of APOE4 noncarriers. This pattern may be part of a cascade of changes in brain structure and function that lead to cognitive decline, but further investigation is required. This research was sponsored by NIH grants R01-AG-031790, ADRC-P50-AG033514, T32-HL-007936, and 1UL1RR025011.

Background: Functional neuroimaging studies have observed preserved neural activation to personally relevant stimuli in patients within the disorders of consciousness (DOC) spectrum. As the majority of studies have focused on adult DOC patients, little is known about preserved activation in the developing brain of children with impaired consciousness.Case study: The aim of this study is to use fMRI to measure preserved neural activation to personally relevant stimuli (subject’s own name and familiar voice) in a paediatric patient who sustained a traumatic brain injury and anoxic-ischaemia following a motor vehicle accident at 18 months of age rendering her probable for minimally conscious state. Contrasts revealed activation in the right middle frontal gyrus when hearing the subject’s own name and the anterior supramarginal gyrus when hearing a familiar voice.Conclusion: This study provides preliminary support for fMRI as a method to measure preserved cognitive functioning in paediatric DOC patients.

Although age-related brain changes are becoming better understood, midlife patterns of change are still in need of characterization, and longitudinal studies are lacking. The aim of this study was to determine if baseline fractional anisotropy (FA), obtained from diffusion tensor imaging (DTI) predicts volume change over a 4-year interval.Forty-four cognitively healthy middle-age adults underwent baseline DTI and longitudinal T1-weighted magnetic resonance imaging. Tensor-based morphometry methods were used to evaluate volume change over time. FA values were extracted from regions of interest that included the cingulum, entorhinal white matter, and the genu and splenium of the corpus callosum. Baseline FA was used as a predictor variable, whereas gray and white matter atrophy rates as indexed by Tensor-based morphometry were the dependent variables.Over a 4-year period, participants showed significant contraction of white matter, especially in frontal, temporal, and cerebellar regions (P0.05, corrected for multiple comparisons). Baseline FA in entorhinal white matter, genu, and splenium was associated with longitudinal rates of atrophy in regions that included the superior longitudinal fasciculus, anterior corona radiata, temporal stem, and white matter of the inferior temporal gyrus (P0.001, uncorrected for multiple comparisons).Brain change with aging is characterized by extensive shrinkage of white matter. Baseline white matter microstructure as indexed by DTI was associated with some of the observed regional volume loss. The findings suggest that both white matter volume loss and microstructural alterations should be considered more prominently in models of aging and neurodegenerative diseases.

Background: Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal "executive" and ventral "affective" processing systems are necessary for adequate responses in various emotive situations. Methods: We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions. Results: Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition. Conclusions: During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs. © 2012 van Holst et al.

Background: Previous studies have revealed that functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signal in specific brain regions correlates with cross-sectional performance on standardized clinical trial measures in Alzheimer’s disease (AD); however, the relationship between longitudinal change in fMRI-BOLD signal and neuropsychological performance remains unknown. Objective: To identify changes in regional fMRI-BOLD activity that tracks change in neuropsychological performance in mild AD dementia over 6 months. Methods: Twenty-four subjects (mean age 71.6) with mild AD dementia (mean Mini Mental State Examination 21.7, Global Clinical Dementia Rating 1.0) on stable donepezil dosing participated in two task-related fMRI sessions consisting of a face-name paired associative encoding memory paradigm 24 weeks apart during a randomized placebo-controlled pharmaco-fMRI drug study. Regression analysis was used to identify regions where the change in fMRI activity for Novel > Repeated stimulus contrast was associated with the change scores on postscan memory tests and the Free and Cued Selective Reminding Test (FCSRT). Results: Correlations between changes in postscan memory accuracy and changes in fMRI activity were observed in regions including the angular gyrus, parahippocampal gyrus, inferior frontal gyrus and cerebellum. Correlations between changes in FCSRT-free recall and changes in fMRI were observed in regions including the inferior parietal lobule, precuneus, hippocampus and parahippocampal gyrus. Conclusion: Changes in encoding-related fMRI activity in regions implicated in mnemonic networks correlated with changes in psychometric measures of episodic memory retrieval performed outside the scanner. These exploratory results support the potential of fMRI activity to track cognitive change and detect signals of short-term pharmacologic effect in early-phase AD studies.

Functional MRI (fMRI) allows one to study task-related regional responses and task-dependent connectivity analysis using psychophysiological interaction (PPI) methods. The latter affords the additional opportunity to understand how brain regions interact in a task-dependent manner. The current implementation of PPI in Statistical Parametric Mapping (SPM8) is configured primarily to assess connectivity differences between two task conditions, when in practice fMRI tasks frequently employ more than two conditions. Here we evaluate how a generalized form of context-dependent PPI (gPPI; http://www.nitrc.org/projects/gppi), which is configured to automatically accommodate more than two task conditions in the same PPI model by spanning the entire experimental space, compares to the standard implementation in SPM8. These comparisons are made using both simulations and an empirical dataset. In the simulated dataset, we compare the interaction beta estimates to their expected values and model fit using the Akaike information criterion (AIC). We found that interaction beta estimates in gPPI were robust to different simulated data models, were not different from the expected beta value, and had better model fits than when using standard PPI (sPPI) methods. In the empirical dataset, we compare the model fit of the gPPI approach to sPPI. We found that the gPPI approach improved model fit compared to sPPI. There were several regions that became non-significant with gPPI. These regions all showed significantly better model fits with gPPI. Also, there were several regions where task-dependent connectivity was only detected using gPPI methods, also with improved model fit. Regions that were detected with all methods had more similar model fits. These results suggest that gPPI may have greater sensitivity and specificity than standard implementation in SPM. This notion is tempered slightly as there is no gold standard; however, data simulations with a known outcome support our conclusions about gPPI. In sum, the generalized form of context-dependent PPI approach has increased flexibility of statistical modeling, and potentially improves model fit, specificity to true negative findings, and sensitivity to true positive findings.

Rate of decline in 6-L-[(18)F]fluorodopa (FDOPA) uptake within the striatum has been reported as showing regional differences in Parkinson's disease (PD).We acquired longitudinal brain FDOPA positron emission tomography (PET) studies in 26 PD subjects and 11 controls over 4.5 years. We analyzed both spatially normalized voxel-wise maps of radiotracer influx (Kocc) and average Kocc values for six non-overlapping volumes of interest (VOIs) encompassing the striatum.The voxel-wise analysis showed that in PD, FDOPA Kocc decline spanned the striatum but was greatest in the posterior putamen ipsilateral and anterior putamen contralateral to initial symptoms. The VOI approached showed that absolute rates of Kocc decline were significantly greater in PD than control subjects, but that the slope of decline did not differ between subregions. In PD, ratios of uptake between subregions did not change during the study with the exception of the ipsilateral putamen/caudate ratio. Decline rates were marginally greater during earlier time segments. Both male gender and advancing age were associated with lower baseline FDOPA uptake, but no difference in decline rates. VOI Kocc values were significantly correlated with disease duration, but only moderately correlated with clinical measures.We conclude that FDOPA uptake in subregions of the striatum is strongly correlated with disease duration and age, and declines approximately equally from symptom onset in PD. This implies that in idiopathic PD, relative preservation of uptake in the anterior striatum reflects a delay in pathologic involvement of nigrostriatal projections to this region.

The goal of this study was to determine whether functional changes in cortical control of swallowing are evident in early Alzheimer's disease (AD), before dysphagia (swallowing impairment) is evident. Cortical function was compared between an early AD group and a group of age-matched controls during swallowing. Swallowing oropharyngeal biomechanics examined from videofluoroscopic recordings were also obtained to more comprehensively characterize changes in swallowing associated with early AD. Our neuroimaging results show that the AD group had significantly lower Blood-Oxygen-Level-Dependent (BOLD) response in many cortical areas that are traditionally involved in normal swallowing (i.e., pre and postcentral gyri, Rolandic and frontal opercula). There were no regions where the AD group showed more brain activity than the healthy controls during swallowing, and only 13% of all active voxels were unique to the AD group, even at this early stage. This suggests that the AD group is not recruiting new regions, nor are they compensating within regions that are active during swallowing. In videofluoroscopic measures, the AD group had significantly reduced hyo-laryngeal elevation than the controls. Although, swallowing impairment is usually noted in the late stages of AD, changes in cortical control of swallowing may begin long before dysphagia becomes apparent.

Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer’s disease (FHAD) alters this effect. Methods: T1-weighted MRI was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 ± 8.0 years) using voxel-based morphometry. A nonparametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. Results: HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center of Epidemiological Studies Depression Scale. Conclusions: These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline.

Rhesus macaques on a calorie restricted diet (CR) develop less age-related disease, have virtually no indication of diabetes, are protected against sarcopenia, and potentially live longer. Beneficial effects of caloric restriction likely include reductions in age-related inflammation and oxidative damage. Oligodendrocytes are particularly susceptible to inflammation and oxidative stress, therefore, we hypothesized that CR would have a beneficial effect on brain white matter and would attenuate age-related decline in this tissue. CR monkeys and controls underwent diffusion tensor imaging (DTI). A beneficial effect of CR indexed by DTI was observed in superior longitudinal fasciculus, fronto-occipital fasciculus, external capsule, and brainstem. Aging effects were observed in several regions, although CR appeared to attenuate age-related alterations in superior longitudinal fasciculus, frontal white matter, external capsule, right parahippocampal white matter, and dorsal occipital bundle. The results, however, were regionally specific and also suggested that CR is not salutary across all white matter. Further evaluation of this unique cohort of elderly primates to mortality will shed light on the ultimate benefits of an adult-onset, moderate CR diet for deferring brain aging.