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Objective Functional seizures often are managed incorrectly as a diagnosis of exclusion. However, a significant minority of patients with functional seizures may have abnormalities on neuroimaging that typically are associated with epilepsy, leading to diagnostic confusion. We evaluated the rate of epilepsy-associated findings on MRI, FDG-PET, and CT in patients with functional seizures. Methods We studied radiologists' reports from neuroimages at our comprehensive epilepsy center from a consecutive series of patients diagnosed with functional seizures without comorbid epilepsy from 2006 to 2019. We summarized the MRI, FDG-PET, and CT results as follows: within normal limits, incidental findings, unrelated findings, non-specific abnormalities, post-operative study, epilepsy risk factors (ERF), borderline epilepsy-associated findings (EAF), and definitive EAF. Results Of the 256 MRIs, 23% demonstrated ERF (5%), borderline EAF (8%), or definitive EAF (10%). The most common EAF was hippocampal sclerosis, with the majority of borderline EAF comprising hippocampal atrophy without T2 hyperintensity or vice versa. Of the 87 FDG-PETs, 26% demonstrated borderline EAF (17%) or definitive EAF (8%). Epilepsy-associated findings primarily included focal hypometabolism, especially of the temporal lobes, with borderline findings including subtle or questionable hypometabolism. Of the 51 CTs, only 2% had definitive EAF. Significance This large case series provides further evidence that, while uncommon, EAF are seen in patients with functional seizures. A significant portion of these abnormal findings are borderline. The moderately high rate of these abnormalities may represent framing bias from the indication of the study being “seizures,” the relative subtlety of EAF, or effects of antiseizure medications.

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by preclinical, pre-dementia, and dementia phases. Progression of the disease leads to cognitive decline and is associated with loss of functional independence, personality changes, and behavioral disturbances. Current guidelines for AD diagnosis include the use of neuroimaging tools as biomarkers for identifying and monitoring pathological changes. Various imaging modalities, namely magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and PET with amyloid-beta tracers are available to facilitate early accurate diagnoses. Enhancing diagnosis in the early stages of the disease can allow for timely interventions that can delay progression of the disease. This paper will discuss the characteristic findings associated with each of the imaging tools for patients with AD, with a focus on FDG-PET due to its established accuracy in assisting with the differential diagnosis of dementia and discussion of other methods including MRI. Diagnostically-relevant features to aid clinicians in making a differential diagnosis will also be pointed out and multimodal imaging will be reviewed. We also discuss the role of quantification software in interpretation of brain imaging. Lastly, to guide evaluation of patients presenting with cognitive deficits, an algorithm for optimal integration of these imaging tools will be shared. Molecular imaging modalities used in dementia evaluations hold promise toward identifying AD-related pathology before symptoms are fully in evidence. The work describes state of the art functional and molecular imaging methods for AD. It will also overview a clinically applicable quantitative method for reproducible assessments of such scans in the early identification of AD.

Objective To explore the neuropsychological sequelae of blast-induced mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD), several neuropsychological tests and self-reported measures of cognitive and emotional functioning were administered to 138 Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) veterans. We hypothesized that veterans affected by mTBI and PTSD would manifest differences in neuropsychological testing and self-report measures compared to a group of healthy veteran controls and to veterans with only PTSD. Method Participants included 3 groups of veterans: (a) healthy controls (n = 43); (b) PTSD only (n = 48); and (c) comorbid blast-induced mTBI and PTSD (n = 47). An exploratory factor analysis (EFA) was used to extract a smaller number of latent dimensions for group comparison. Results The EFA supported an 8-factor model. A multivariate analysis of variance on the 8 factor scores demonstrated 3 significant factor mean differences: (a) perceived cognitive complications (PCC), (b) perceived emotional distress (PED), and (c) processing speed (PS). Post hoc analyses showed significant group mean difference in PS between the comorbid and the control groups. In addition, the comorbid group presented with the highest levels of PCC and PED. Conclusions Results suggest that among OIF/OEF veterans with blast-induced mTBI, PTSD with its accompanying emotional distress may be a significant determinant of subjective sense of well-being both cognitively and emotionally. The objective discrepancy in PS between the comorbid group and the healthy controls also appears largely due to PTSD more so than the remote blast-induced mTBI, as the group mean difference in PS became negligible after controlling for PTSD levels. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Neuronuclear imaging has been used for several decades in the study of primary neurodegenerative conditions, such as dementia and parkinsonian syndromes, both for research and for clinical purposes. There has been a relative paucity of applications of neuronuclear imaging to evaluate nonneurodegenerative conditions that can also have long-term effects on cognition and function. This article summarizes clinical and imaging aspects of 3 such conditions that have garnered considerable attention in recent years: cancer- and chemotherapy-related cognitive impairment, posttraumatic stress disorder, and traumatic brain injury. Further, we describe current research using neuroimaging tools aimed to better understand the relationships between the clinical presentations and brain structure and function in these conditions.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer’s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, ‘shape connections’ between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus.

Cancer- and treatment-related cognitive changes have been a focus of increasing research since the early 1980s, with meta-analyses demonstrating poorer performance in cancer patients in cognitive domains including executive functions, processing speed, and memory. To facilitate collaborative efforts, in 2011 the International Cognition and Cancer Task Force (ICCTF) published consensus recommendations for core neuropsychological tests for studies of cancer populations. Over the past decade, studies have used neuroimaging techniques, including structural and functional magnetic resonance imaging (fMRI) and positron emission tomography, to examine the underlying brain basis for cancer- and treatment-related cognitive declines. As yet, however, there have been no consensus recommendations to guide researchers new to this field or to promote the ability to combine data sets. We first discuss important methodological issues with regard to neuroimaging study design, scanner considerations, and sequence selection, focusing on concerns relevant to cancer populations. We propose a minimum recommended set of sequences, including a high-resolution T1-weighted volume and a resting state fMRI scan. Additional advanced imaging sequences are discussed for consideration when feasible, including task-based fMRI and diffusion tensor imaging. Important image data processing and analytic considerations are also reviewed. These recommendations are offered to facilitate increased use of neuroimaging in studies of cancer- and treatment-related cognitive dysfunction. They are not intended to discourage investigator-initiated efforts to develop cutting-edge techniques, which will be helpful in advancing the state of the knowledge. Use of common imaging protocols will facilitate multicenter and data-pooling initiatives, which are needed to address critical mechanistic research questions. ispartof: Journal of the National Cancer Institute vol:110 issue:3 pages:223-231 ispartof: location:United States status: published

Background Caprylidene is a ketogen that, when metabolized, produces the ketones beta-hydroxybutyrate and acetoacetate, which can cross the blood brain barrier. It has been hypothesized that ketone bodies can be used as an alternate energy source by neurons with impaired glucose utilization. Caprylidene has been shown to improve cognition in patients with mild-to-moderate Alzheimer's disease (AD) who lacked an AD-predisposing allele (ɛ4) of the gene for apolipoprotein E. In this pilot study, we examined the effects of caprylidene on regional cerebral blood flow (rCBF) in patients with mild to moderate AD. Methods Sixteen subjects with mild-to-moderate AD, based on NINCDS-ADRDA criteria, were enrolled in a double-blinded, placebo-controlled, randomized clinical trial. Fourteen subjects received treatment with caprylidene, and 2 subjects were given placebo. Subjects received 4 15O-water PET scans over the course of the study to assess rCBF: once before receiving a standard caprylidene or placebo dose and 90 min after the dose, on the first day and after 45 days of daily caprylidene or placebo consumption. The scans were examined by standardized volumes of interest (sVOI) and voxel-based statistical parametric mapping (spm) methods of analysis. Results Subjects lacking an ɛ4 allele had significantly elevated rCBF in the left superior lateral temporal cortex by sVOI analysis after adopting a caprylidene diet for 45 days (p = 0.04), which was further corroborated by spm. The anterior cerebellum, left inferior temporal cortex, and hypothalamus were also found by spm to be regions of long-term increase in rCBF in these subjects. In contrast, patients who possessed the ɛ4 allele did not display these changes in rCBF. Conclusion Daily ingestion of caprylidene over 45 days was associated with increased blood flow in specific brain regions in patients lacking an apolipoprotein ɛ4 allele.

Preventive neuroradiology is a new concept supported by a growing literature. The main rationale of preventive neuroradiology is the application of multi-modal brain imaging towards early and subclinical detection of brain disease and subsequent preventive actions through identification of modifiable risk factors. An insightful example of this is in the area of age-related cognitive decline, mild cognitive impairment and dementia with potentially modifiable risk factors such as obesity, diet, sleep, hypertension, diabetes, depression, supplementation, smoking and physical activity. In studying this link between lifestyle and cognitive decline, brain imaging markers may be instrumental as quantitative measures or even indicators of early disease. The purpose of this article is to provide an overview of the major studies reflecting how lifestyle factors affect the brain and cognition ageing. In this hot topics review we will specifically focus on obesity and physical activity.

Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer’s disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.

Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.

Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

FDG-PET is a valuable tool that will continue to aid in identifying AD in its prodromal and early dementia stages, distinguishing it from other causes of dementia, and tracking progression of the disease. As brain FDG-PET scans and well-trained readers of these scans are becoming more widely available to clinicians who are becoming more informed about the role FDG-PET can play in early AD diagnosis, its use is expected to increase.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

The majority of cancer patients treated with chemotherapy complain of fatigue and/or cognitive dysfunction. Although many patients experience improvement shortly after completion of treatment, a substantial number of patients may continue to be symptomatic for years or even decades after their last dose of chemotherapy. This review focuses on the scope of postchemotherapy cognitive dysfunction, spotlights recent studies that investigate this problem in the short- and long-term, examines neuroimaging studies that document regional cerebral alterations observed after chemotherapy, discusses candidate mechanisms and treatments and finally comments on challenges in the field.

As therapeutic treatments for Alzheimer’s disease (AD) are developed, the ability to identify persons prior to the clinical diagnosis of AD becomes increasingly important. Mild cognitive impairment (MCI) (Petersen et al., 1995, 2004) is a cognitive deficit syndrome associated with increased dementia risk. MCI is subtyped as amnestic or nonamnestic involving single or multiple cognitive domains (Winblad et al., 2003). Amnestic MCI, particularly the multiple domain subtype, is associated with highest AD risk (Arnaiez et al., 2004; Bozoki et al., 2001; Petersen et al., 2009; Tabert et al., 2006) and progresses largely to AD at a rate of 10% to 15% annually (Farias et al., 2009). Autopsy studies show AD-like medial temporal neurofibrillary pathology as a predominate feature (Marksbury 2010; Petersen et al., 2006; Price and Morris et al., 1999). Although amnestic subtypes have high AD risk, predicting AD from MCI subtypes is imprecise. Some patients remain stable, while others revert to normal cognition or develop non-AD dementias (e.g. vascular, frontotemporal) (Norbold et al., 2010; Petersen et al., 2004, Rozzini et al., 2007). Some amnestic MCI patients who progress to clinical AD do not demonstrate primary AD neuropathology (Jicah et al., 2008; Marksbury 2010). The neuroimaging biomarker, 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthylethylidene) malononitrile (FDDNP) labels senile plaques (SPs) and neurofibrillary tangles (NFTs) in vitro (Agdeppa et al., 2001). FDDNP-PET neuroimaging distinguishes among cognitively normal, MCI (predominately amnestic subtypes) and AD subjects (Small et al., 2006).DD Recently (Ercoli et al., 2009)D we hypothesized that if older adults vary according to cerebral patterns of SPs and NFTs, then FDDNP-PET imaging might identify homogeneous subgroups, which in turn may have implications for identifying individuals at highest AD risk. We then performed a cluster analysis according to regional FDDNP-PET binding values on a group combining subjects with either normal cognition or amnestic MCI (single or multiple domain subtypes). One FDDNP-subgroup (LG) had low FDDNP binding globally in all brain regions of interest (ROI), and two subgroups had relatively high FDDNP binding. One high binding subgroup demonstrated high frontal, parietal and medial temporal binding (HF/PA subgroup), and the other demonstrated high FDDNP binding in medial and lateral temporal and posterior cingulate regions (HT/PC subgroup). Notably, both the HF/PA and HT/PC subgroups showed similarly elevated medial temporal binding, but differed in binding levels in other ROI. All three clusters included both MCI and cognitively normal subjects, but in different proportions. Most HT/PC and HF/PA subjects had amnestic MCI subtypes (71% for HF/PA; 88% for HT/PC) compared to 21% in LG. The HT/PC and HF/PA subgroups did not differ from each other on cognitive tests; however, both subgroups had worse performances relative to the LG subgroup in several domains. We would expect relatively lower AD risk in subjects with both low FDDNP binding and better cognition (i.e. LG subjects); and higher AD risk in subjects with both high FDDNP bin5ding and poor cognition (HT/PC and HF/PA subjects); however, additional supportive evidence of AD risk is needed. The purpose of the current study was to further assess dementia risk associated with the FDDNP-subgroups by comparing them according to cerebral glucose metabolism with 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET neuroimaging. FDG-PET has high sensitivity and specificity for autopsy confirmed AD and other neurodegenerative dementias (Silverman et al., 2001) D, and thus would provide external validation for dementia risk in the FDDNP-subgroups.

Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively-intact individuals. Herein, 50 women ages 50–65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-ε4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

Differential cerebral metabolic effects of various hormone therapy formulations, and their associations with cognitive status, remain to be established. The principal aim of the current study was to assess relationships between regional cerebral metabolism and estrogen-based hormone therapies. Postmenopausal women (n=53) at elevated risk for Alzheimer's disease (AD) were on estrogen-containing hormone therapy for at least one year prior to enrollment in a prospective, randomized clinical trial. Subjects underwent an FDG-PET scan, along with neuropsychological, medical, and demographic assessments at time of enrollment, to be repeated one year following randomization to hormone therapy continuation versus discontinuation, and results from analyses of the baseline assessments are reported here. Across all subjects, years of endogenous estrogen exposure correlated most closely with metabolism in right superior frontal gyrus (p

Background Premenstrual dysphoric disorder (PMDD) is a debilitating cyclic disorder that is characterized by affective symptoms, including irritability, depression, and anxiety, which arise in the luteal phase of the menstrual cycle and resolve soon after the onset of menses. Despite a prevalence of up to 8% in women of reproductive age, few studies have investigated the brain mechanisms that underlie this disorder. Methods We used positron emission tomography with [ 18 F] fluorodeoxyglucose and self-report questionnaires to assess cerebral glucose metabolism and mood in 12 women with PMDD and 12 healthy comparison subjects in the follicular and late luteal phases of the menstrual cycle. The primary biological end point was incorporated regional cerebral radioactivity (scaled to the global mean) as an index of glucose metabolism. Relationships between regional brain activity and mood ratings were assessed. Blood samples were taken before each session for assay of plasma estradiol and progesterone concentrations. Results There were no group differences in hormone levels in either the follicular or late luteal phase, but the groups differed in the effect of menstrual phase on cerebellar activity. Women with PMDD but not comparison subjects showed an increase in cerebellar activity (particularly in the right cerebellar vermis) from the follicular phase to the late luteal phase ( p = .003). In the PMDD group, this increase in cerebellar activity was correlated with worsening of mood ( p = .018). Conclusions These findings suggest that the midline cerebellar nuclei, which have been implicated in other mood disorders, also contribute to negative mood in PMDD.

6-(18)F-fluoro-l-dopa ((18)F-FDOPA) measured with PET as a biomarker of amino acid uptake has been investigated in brain tumor imaging. The aims of the current study were to determine whether the degree of (18)F-FDOPA uptake in brain tumors predicted tumor grade and was associated with tumor proliferative activity in newly diagnosed and recurrent gliomas.Fifty-nine patients (40 men, 19 women; mean age ± SD, 44.4 ± 12.3 y) with newly diagnosed (n = 22) or recurrent (n = 37) gliomas underwent (18)F-FDOPA PET perioperatively. Tumor tissue was obtained by resection or biopsy in all patients. The tumor grade and Ki-67 proliferation index were obtained by standard pathology assays. Tumor (18)F-FDOPA uptake was quantified by determining various standardized uptake value (SUV) parameters (mean SUV, maximum SUV [SUVmax], mean values of voxels with top 20% SUVs, and tumor-to-normal-brain tissue ratios) that were then correlated with histopathologic grade and Ki-67 proliferation index.Fifty-nine lesions in 59 patients were analyzed. (18)F-FDOPA uptake was significantly higher in high-grade than in low-grade tumors for newly diagnosed tumors (SUVmax, 4.22 ± 1.30 vs. 2.34 ± 1.35, P = 0.005) but not for recurrent tumors that had gone through treatment previously (SUVmax, 3.36 ± 1.26 vs. 2.67 ± 1.18, P = 0.22). An SUVmax threshold of 2.72 differentiated low-grade from high-grade tumors, with a sensitivity and specificity of 85% and 89%, respectively, using receiver-operating-characteristic curve analysis (area under the curve, 0.86). (18)F-FDOPA PET uptake correlated significantly with Ki-67 tumor proliferation index in newly diagnosed tumors (r = 0.66, P = 0.001) but not in recurrent tumors (r = 0.14, P = 0.41).(18)F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between (18)F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, (18)F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas.

Respiratory motion in PET degrades image quality and limits detectability of small or low-contrast lesions. Although image quality can be improved using respiratory-gating, this adds to the complexity and expense of acquiring PET data. We aimed to develop a data-driven method, based on individual voxel signal fluctuations, for accomplishing electronic respiratory gating of clinical PET data, requiring no additional hardware or end-user input. We tested our methods using both simulated PET scans and actual human PET acquisitions. For the simulations, our methods correctly identified the start frame of each respiratory cycle defined for the phantom. Resultant gated images demonstrated improved effective resolution and increased measured uptake for lesions located in the thorax. For human PET data, we were able to recover respiratory phase information with a high signal-to-noise ratio. We report here a method to achieve fully automated voxel-based respiratory gating of PET images, without the need for gating hardware or additional user input, capable of improving effective resolution and increasing lesion detectability.

Objective Because anti-inflammatory drugs may delay cognitive decline and influence brain metabolism in normal aging, the authors determined the effects of the cyclooxygenase-2 inhibitor, celecoxib, on cognitive performance and regional cerebral glucose metabolism in nondemented volunteers with mild age-related memory decline. Design Randomized, double-blind, placebo-controlled, parallel group trial with 18-months of exposure to study medication. Setting University research institute. Participants Eighty-eight subjects, aged 40–81 years (mean: 58.7, SD: 8.9 years) with mild self-reported memory complaints but normal memory performance scores were recruited from community physician referrals, media coverage, and advertising. Forty subjects completed the study. Interventions Daily celecoxib dose of 200 or 400 mg, or placebo. Main Outcome Measures Standardized neuropsychological test battery and statistical parametric mapping (SPM) of FDG-PET scans performed during mental rest. Results Measures of cognition showed significant between-group differences in executive functioning (F [1, 30] = 5.06, p=0.03) and language/semantic memory ( F [1, 31] = 6.19, p=0.02), favoring the celecoxib group compared with the placebo group. Concomitantly, FDG-PET scans demonstrated bilateral metabolic increases in prefrontal cortex in the celecoxib group in the vicinity of Brodmann's areas 9 and 10, but not in the placebo group. SPM analyses of the PET data pooled by treatment arm corresponded to a 6% increase in activity over pretreatment levels (p Conclusions These results suggest that daily celecoxib use may improve cognitive performance and increase regional brain metabolism in people with age-associated memory decline.

The evaluation of primary brain tumor is challenging. Neuroimaging plays a significant role. At diagnosis, imaging is needed to establish a differential diagnosis, provide prognostic information, as well as direct biopsy. After the initial treatment, imaging is needed to distinguish recurrent disease from treatment-related changes such as radiation necrosis. In low-grade gliomas, this also includes monitoring anaplastic transformation into high-grade tumors. Recently, targeted treatments have been an extremely active area of research. Evaluation in clinical trials of such targeted treatments demands advanced roles of imaging such as treatment planning, monitoring response, and predicting treatment outcomes. Current clinical gold standard magnetic resonance imaging provides superior structural detail but poor specificity in identifying viable tumors in treated brain with surgery/radiation/chemotherapy. (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is capable of identifying anaplastic transformation and has prognostic value. The sensitivity and specificity of FDG in evaluating recurrent tumor and treatment-induced changes can be significantly improved by coregistration with magnetic resonance imaging and potentially by delayed imaging 3 to 8 hours after injection. Amino acid PET tracers can be more sensitive than FDG in imaging some recurrent tumors, in particular recurrent low-grade tumors. They are also promising for differentiating between recurrent tumors and treatment-induced changes. Newer PET tracers to image important aspects of tumor biology have been actively studied. Tracers for imaging membrane transport such as (18)F-choline have shown promise in differential diagnosis. (18)F-labeled nucleotide analogs such as 3'-deoxy-3'-[(18)F]-fluorothymidine (FLT) and (18)F-FMAU have been developed to image proliferation. The use of FLT has demonstrated prognostic power in predicting treatment response in patients treated with an antiangiogenic agent. Tracers for imaging hypoxia such as (18)F-FMISO have been studied and appear promising in providing prognostic information as well as planning treatment.

The degree of intactness of human cognitive functioning for a given individual spans a wide spectrum, ranging from normal to severely demented. The differential diagnosis for the causes of impairment along that spectrum is also wide, and often difficult to distinguish clinically, which has led to an increasing role for neuroimaging tools in that evaluation. The most frequent causes of dementia are neurodegenerative disorders, Alzheimer's disease being the most prevalent among them, and they produce significant alterations in brain metabolism, with devastating neuropathologic, clinical, social, and economic consequences. These alterations are detectable through positron emission tomography (PET), even in their earliest stages. The most commonly performed PET studies of the brain are performed with (18)F-fluorodeoxyglucose as the imaged radiopharmaceutical. Such scans have demonstrated diagnostic and prognostic utility for clinicians evaluating patients with cognitive impairment and in distinguishing among primary neurodegenerative disorders and other etiologies contributing to cognitive decline. In addition to focusing on the effects on cerebral metabolism examined with (18)F-fluorodeoxyglucose PET, some other changes occurring in the brains of cognitively impaired patients assessable with other radiotracers will be considered. As preventive and disease-modifying treatments are developed, early detection of accurately diagnosed disease processes facilitated by the use of PET has the potential to substantially impact on the enormous human toll exacted by these diseases.

The use of 3,4-dihydroxy-6-[(18)F]-fluoro-L-phenylalanine ((18)F-FDOPA) with positron emission tomography initially centered on studying central motor disorders and evaluating patients with Parkinsonian symptoms, based on its uptake into presynaptic dopaminergic terminals in the putamen and caudate nuclei of the brain. The roles of this tracer have since expanded to include monitoring disease progression, potentially contributing to drug development, and even questioning the current gold standard for making the diagnosis of Parkinson's disease. As with some other amino acids, (18)F-FDOPA has also been effective for visualizing brain tumors, either at time of diagnosis or when monitoring for recurrence, with high sensitivity and overall accuracy. (18)F-FDOPA may be especially useful for imaging patients with low-grade gliomas, as well in the evaluation of patients with neuroendocrine tumors such as carcinoid and pheochromocytoma, in which its role as a precursor for amine neurotransmitter/neurohormones serves as a basis for its differential uptake.

Purpose Evaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan. Patients and Methods Patients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival. Results Twenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P = .003), and tended to have a prolonged progression-free survival (P = .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P = .006; 6 weeks, P = .002), compared with the MRI responses (P = .060 for both 6-week and best responses). Conclusion FLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.

Ibritumomab tiuxetan radioimmunotherapy produces durable remissions in patients with relapsed/refractory indolent non-Hodgkin lymphoma. The dosing of Yttrium 90 (90Y)-ibritumomab tiuxetan is based on patient weight and platelet count: 0.4 mCi/kg in patients with a countor= 150 x 10(9)/L, to a maximum dose of 32 mCi. Patients weighing80 kg with platelet counts ofor= 150 x 10(9)/L receive a lower dose per unit of body weight. We evaluated whether this influences the safety or efficacy of treatment.Data on efficacy and safety in patients in 3 registration trials who were treated with 90Y ibritumomab tiuxetan at 0.4 mCi/kg (patients weighingor= 80 kg) or 32 mCi (patients weighing80 kg) were collected.Clinical responses were evaluated in 103 patients weighingor= 80 kg (median, 70 kg) and 67 patients weighing80 kg (median, 95 kg). Sex (41% female vs. 73% male) was the only significantly different characteristic between the patients weighingor= 80 kg and80 kg, respectively. The overall response rates were 79% (or= 80 kg) and 70% (80 kg), and the complete response rates were 28% and 34%, respectively. Median times to progression were 8.9 months (or= 80 kg) and 9.5 months (80 kg). There were no significant differences in efficacy measures or in the incidences of grade 3/4 nonhematologic adverse events, neutropenia, thrombocytopenia, or anemia.The dose of 90Y ibritumomab tiuxetan was0.4 mCi/kg in 39% of patients, owing to the 32-mCi dose cap, but the efficacy or safety of 90Y ibritumomab tiuxetan in patients80 kg was not affected.

Cognitive dysfunction occurs in at least one-fifth (and by some reports, more than four-fifths) of breast-cancer patients who previously underwent adjuvant therapy with cytotoxic pharmacologic regimens. The main purpose of this report is to define the scope of the cognitive problems suffered by cancer patients who were previously exposed to cytotoxic chemotherapy, which have come to be grouped under the conceptual umbrella of 'chemobrain'. Second, we aim to spotlight the present inadequacy of clinical care in dealing with chemobrain-related issues – with respect both to the sins of omission of oncologists in obtaining informed consent for the cytotoxic therapies they are planning to prescribe, as well as to the subsequent failure of healthcare providers to address chemobrain-related problems experienced by a substantial proportion of their patients. Finally, we will examine how current investigations employing the tools of neuropsychologic and neuroimaging instruments are figuratively and literally shedding new light (and other wavelengths of the electromagnetic spectrum) on the brains of living chemotherapy-treated subjects, leading to an increased understanding of the chemobrain problem, as well as pointing the way to strategies for diminishing its future impact.

Natural compounds in grapes such as resveratrol are known for their antioxidant and anti-inflammatory properties. Some studies have shown a potential role for grapes or wine in slowing cognitive decline and other effects of aging. However, well-controlled experimental data obtained in human subjects are still in need of further development. Here we aimed to systematically assess effects of grapes on regional cerebral metabolism.Ten subjects with mild decline in cognition (mean, 72.2±4.7years; 50% female) were included in this analysis. Participants were randomized into an active grape formulation arm or a placebo arm which consumed a formulation free of polyphenols for six months. Cognitive performance was measured through neuropsychological assessments performed at baseline and 6months after initiation of therapy. Changes in brain metabolism occurring with each therapy regimen were assessed by brain PET scans with the radiotracer [F-18] fluorodeoxyglucose (FDG), obtained during initial evaluation and 6months later. Standardized volumes of interest (sVOI) and statistical parametric mapping (SPM) methods were applied to FDG-PET scans to identify significant regional cerebral metabolic changes.In contrast to participants taking the active grape formulation, who displayed no significant decline in metabolism, the placebo arm underwent significant metabolic decline in sVOI's of the right posterior cingulate cortex (p=0.01), and left superior posterolateral temporal cortex (p=0.04). SPM analyses also found significant declines in the placebo group, particularly in left prefrontal, cingulate, and left superior posterolateral temporal cortex (p0.01) with stable brain metabolism in the active formulation arm. No significant differences were seen in scores on the neuropsychological battery of tests between the two groups. However, metabolism in right superior parietal cortex and left inferior anterior temporal cortex was correlated with improvements in attention/working memory, as measured with WAIS-III Digital Span within the active formulation group (r=-0.69, p=0.04).The placebo arm had declines in regions of the brain known to be significantly affected in the early stages of Alzheimer's disease, while the active formulation group was spared such decline. This suggests a protective effect of grapes against early pathologic metabolic decline.

Background:Alzheimer’s disease (AD) affects an increasing number of individuals in our societies. It is characterized by accumulation of fibrillary amyloid plaques in the brain. Recently, several studies have emphasized the role of positron emission tomography (PET) using amyloid biomarkers which allow in vivo visualization of plaques to distinguish AD pathology from other forms of protein accumulations leading to dementia. However, very few studies have investigated the role of amyloid imaging in the differential diagnosis of atypical/unclear cases, that is complex dementia syndromes where even a comprehensive investigation yields no clear diagnosis. Moreover, no studies have investigated the impact of a correct diagnosis on caregivers and their perception of the process. Methods:Using a novel amyloid tracer (NAV4694), we scanned 20 patients with an atypical/unclear dementia syndrome as determined by an experienced behavioral neurologist from a tertiary care center. All patients had a full work-up (i.e., clinical, blood tests, neuropsychological evaluation, structural and functional imaging) yet no certain diagnosis. Amyloid-PETs were either positive or negative based on qualitative and quantitative reads by two independent readers. A questionnaire was given to the treating neurologist to determine whether amyloid imaging allowed a more accurate diagnosis and changed treatment plans. Caregivers were met one month after the revelation of the diagnosis and completed a questionnaire followed by a standardized interview designed to assess its impact. Results: A statistically significant increase in confidence levels amongst physicians who ordered amyloid imaging in such cases was found. Revelation of diagnosis to caregivers was associated with better acceptance of the disease as well as a clearer view of future challenges. Conclusions: This study suggests that amyloid imaging is useful in the differential diagnosis of atypical/unclear dementias, and has a positive impact on caregivers. AmyloidPET is indicated in the investigation of complex, atypical/unclear dementing disorders.

Background: A couple of population studies demonstrated that elderly with depression have lower plasma amyloid-b 42 (Ab42) than those without depression, and so called “amyloid depression hypothesis” (i.e., the hypothesis that cerebral amyloid deposition is related to late-life depression) was proposed. This study aimed to investigate the relationship between global cerebral Ab burden and depressive symptoms in elderly individuals with normal cognition (NC), amnestic mild cognitive impairment (MCI) and Alzheimer’s disease dementia (AD). Methods: Twenty-six NC, 23 MCI and 27 AD individuals were recruited. Subjects with history of major depressive episode or stroke were excluded. All subjects received three-dimensional volumetric 3T MRI, Pittsburgh Compound B (PiB)-positron emission tomography (PET) and comprehensive clinical evaluation including vascular burden assessment. Depressive symptoms were measured using Geriatric Depression Scale (GDS) and Hamilton Depression Rating Scale (HAM-D). Results: There were significant group differences of GDS and HAM-D scores among diagnostic groups, and post-hoc tests showed that AD had significantly higher GDS and HAM-D scores than NC (see Table). However, multiple linear regression analysis controlling for age, gender, diagnostic group, and vascular burden did not reveal that global cerebral Ab burden measured by PiBPET was associated with GDS or HAM-D scores. In subgroup analyses for each diagnostic group, we did not find any significant associations between global cerebral Ab burden and GDS or HAM-D scores after controlling age, gender and vascular burden. Conclusions:Our results did not support “amyloid depression hypothesis”, while the relationship between diagnostic group and depression scores implied that late-life depression might be associated with overall brain degeneration.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Purpose To explore the relationship of regional cerebral blood flow and metabolism with cognitive function and past exposure to chemotherapy for breast cancer. Patients and methods Subjects treated for breast cancer with adjuvant chemotherapy remotely (5–10 years previously) were studied with neuropsychologic testing and positron emission tomography (PET), and were compared with control subjects who had never received chemotherapy. [O-15] water PET scans was acquired during performance of control and memory-related tasks to evaluate cognition-related cerebral blood flow, and [F-18] fluorodeoxyglucose (FDG) PET scans were acquired to evaluate resting cerebral metabolism. PET scans were analyzed by statistical parametric mapping and region of interest methods of analysis. Results During performance of a short-term recall task, modulation of cerebral blood flow in specific regions of frontal cortex and cerebellum was significantly altered in chemotherapy-treated subjects. Cerebral activation in chemotherapy-treated subjects differed most significantly from untreated subjects in inferior frontal gyrus, and resting metabolism in this area correlated with performance on a short-term memory task previously found to be particularly impaired in chemotherapy-treated subjects. In examining drug-class specific effects, metabolism of the basal ganglia was significantly decreased in tamoxifen + chemotherapy-treated patients compared with chemotherapy-only breast cancer subjects or with subjects who had not received chemotherapy, while chemotherapy alone was not associated with decreased basal ganglia activity relative to untreated subjects. Conclusion Specific alterations in activity of frontal cortex, cerebellum, and basal ganglia in breast cancer survivors were documented by functional neuroimaging 5–10 years after completion of chemotherapy.

Objective: The objective of this study was to determine the effects of a 14-day healthy longevity lifestyle program on cognition and cerebral metabolism in people with mild age-related memory complaints. Methods: Seventeen nondemented subjects, aged 35–69 years (mean: 53 years, standard deviation: 10) with mild self-reported memory complaints but normal baseline memory performance scores were randomly assigned to 1) the intervention group (N8): a program combining a brain healthy diet plan, relaxation exercises, cardiovascular conditioning, and mental exercise (brain teasers and verbal memory training techniques); or 2) the control group (N 9): usual lifestyle routine. Pre- and postintervention measures included self-assessments of memory ability, objective tests of cognitive performance, and determinations of regional cerebral metabolism during mental rest with [fluorine-18]fluorodeoxyglucose (FDG) positron emission tomography (PET). Results: Subjects in the intervention group objectively demonstrated greater word fluency. Concomitantly, their FDG-PET scans identified a 5% decrease in activity in the left dorsolateral prefrontal cortex. The control group showed no significant change in any of the measures. Conclusions: A short-term healthy lifestyle program combining mental and physical exercise, stress reduction, and healthy diet was associated with significant effects on cognitive function and brain metabolism. Reduced resting activity in left dorsolateral prefrontal cortex may reflect greater cognitive efficiency of a brain region involved in working memory. (Am J Geriatr Psychiatry 2006; 14:538–545)

ω-Conotoxin GVIA is a potent, irreversible antagonist of N-type voltage gated Ca2+ channels. A radiofluorinated analogue of GVIA could be useful in assessing regional synaptic density of the brain, in vivo, using positron emission tomography. N-hydroxy succinimidyl 4-[18F]fluorobenzoate was employed to site-specifically label GVIA, preserving native binding affinity. The tracer was characterized with MALDI-TOF mass spectrometry and colorimetric protein assay. Radiochemical decay-corrected yield of the lysine-24 labeled analogue of [18F]GVIA was 5%. Specific activity of this species was determined to be 1.2 × 105 Ci/mmol. Encapsulation of the tracer in sulfatide containing liposomes, a potential method for enhancing blood–brain penetrance, was accomplished with 40% efficiency. Copyright © 2006 John Wiley & Sons, Ltd.

The usefulness of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) in monitoring breast cancer response to chemotherapy has previously been reported. Elevated uptake of FDG by treated tumors can persist however, particularly in the early period after treatment is initiated. 3'-[F-18]Fluoro-3'-deoxythymidine (FLT) has been developed as a marker for cellular proliferation and, in principle, could be a more accurate predictor of the long-term effect of chemotherapy on tumor viability. We examined side-by-side FDG and FLT imaging for monitoring and predicting tumor response to chemotherapy.Fourteen patients with newly diagnosed primary or metastatic breast cancer, who were about to commence a new pharmacologic treatment regimen, were prospectively studied. Dynamic 3-D PET imaging of uptake into a field of view centered over tumor began immediately after administration of FDG or FLT (150 MBq). After 45 minutes of dynamic acquisition, a clinically standard whole-body PET scan was acquired. Patients were scanned with both tracers on two separate days within one week of each other (1) before beginning treatment, (2) two weeks following the end of the first cycle of the new regimen, and (3) following the final cycle of that regimen, or one year after the initial PET scans, whichever came first. (Median and mean times of early scans were 5.0 and 6.6 weeks after treatment initiation; median and mean times for late scans were 26.0 and 30.6 weeks after treatment initiation.) Scan data were analyzed on both tumor-by-tumor and patient-by-patient bases, and compared to each patient's clinical course.Mean change in FLT uptake in primary and metastatic tumors after the first course of chemotherapy showed a significant correlation with late (av. interval 5.8 months) changes in CA27.29 tumor marker levels (r = 0.79, P = 0.001). When comparing changes in tracer uptake after one chemotherapy course versus late changes in tumor size as measured by CT scans, FLT was again a good predictor of eventual tumor response (r = 0.74, P = 0.01). Tumor uptake of FLT was near-maximal by 10 minutes after injection. The time frame five to 10 minutes postinjection of FLT produced standardized uptake value (SUV) values highly correlated with SUV values obtained after 45-minute uptake (r = 0.83, P0.0001), and changes in these early SUVs after the first course of chemotherapy correlated with late changes in CA27.29 (r = 0.93, P = 0.003).A 10-minute FLT-PET scan acquired two weeks after the end of the first course of chemotherapy is useful for predicting longer-term efficacy of chemotherapy regimens for women with breast cancer.

Steven A. Castellon, Daniel H.S. Silverman, and Patricia A. Ganz Greater Los Angeles VA Healthcare System; Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA; Dept. of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA; Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center; Schools of Medicine and Public Health, University of California Los Angeles; Neuropsychiatric Institute & Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA