Nutrient patterns and brain biomarkers of Alzheimer's disease in cognitively normal individuals.

OBJECTIVES: Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease (AD) is rapidly increasing. However, there is little or no evidence for a direct association between dietary nutrients and brain biomarkers of AD. This study identifies nutrient patterns associated with major brain AD biomarkers in a cohort of clinically and cognitively normal (NL) individuals at risk for AD. DESIGN: Cross-sectional study. SETTING: Manhattan (broader area). PARTICIPANTS: Fifty-two NL individuals (age 54+12 y, 70% women, Clinical Dementia Rating=0, MMSE>27, neuropsychological test performance within norms by age and education) with complete dietary information and cross-sectional, 3D T1-weighted Magnetic Resonance Imaging (MRI; gray matter volumes, GMV, a marker of brain atrophy), 11C-Pittsburgh compound-B (PiB; a marker of fibrillar amyloid-ß, Aß) and 18F-fluorodeoxyglucose (FDG; a marker of glucose metabolism, METglc) Positron Emission Tomography (PET) scans were examined. MEASUREMENTS: Dietary intake of 35 nutrients associated with cognitive function and AD was assessed using the Harvard/Willet Food Frequency Questionnaire. Principal component analysis was used to generate nutrient patterns (NP) from the full nutrient panel. Statistical parametric mapping and voxel based morphometry were used to assess the associations of the identified NPs with AD biomarkers. RESULTS: None of the participants were diabetics, smokers, or met criteria for obesity. Five NPs were identified: NP1 was characterized by most B-vitamins and several minerals [VitB and Minerals]; NP2 by monounsaturated and polyunsaturated fats, including ω-3 and ω-6 PUFA, and vitamin E [VitE and PUFA]; NP3 by vitamin A, vitamin C, carotenoids and dietary fibers [Anti-oxidants and Fibers]; NP4 by vitamin B12, vitamin D and zinc [VitB12 and D]; NP5 by saturated, trans-saturated fats, cholesterol and sodium [Fats]. Voxel-based analysis showed that NP4 scores [VitB12 and D] were positively associated with METglc and GMV, and negatively associated with PiB retention in AD-vulnerable regions (p<0.001). In addition, both METglc and GMV were positively associated with NP2 scores [VitE and PUFA], and negatively associated with NP5 scores [Fats] (p<0.001), and METglc was positively associated with higher NP3 scores [Anti-oxidants and Fibers] (p<0.001). Adjusting for age, gender, ethnicity, education, caloric intake, BMI, alcohol consumption, family history and Apolipoprotein E (APOE) status did not attenuate these relationships. The identified 'AD-protective' nutrient combination was associated with higher intake of fresh fruit and vegetables, whole grains, fish and low-fat dairies, and lower intake of sweets, fried potatoes, high-fat dairies, processed meat and butter. CONCLUSION: Specific dietary NPs are associated with brain biomarkers of AD in NL individuals, suggesting that dietary interventions may play a role in the prevention of AD by modulating AD-risk through its effects on Aß and associated neuronal impairment.

Looking at my body. Similarities and differences between anorexia nervosa patients and controls in body image visual processing.

BACKGROUND: Body image distortion is a core symptom of eating disorders. Functional magnetic resonance imaging (fMRI) studies on body image processing, described different patterns of neural response, mainly involving the inferior and superior parietal lobules, and the dorsolateral prefrontal cortex (DLPFC), with conflicting results. METHODS: The neural response to the view of their own body pictures (normal size and distorted) was evaluated in 18 female anorexia nervosa (AN) restricting type patients, and in 19 healthy female subjects (HC) using fMRI. Clinical assessment was performed by means of the structured clinical interview for DSM-IV and self-reported questionnaires. RESULTS: In response to the body image distortion, patients and controls showed an inverse pattern of activation, with the widest extent of activation in the oversize condition in AN, while in the undersize condition in HC. AN and HC showed a similar pattern of neural response to the view of their own body, with an increased activation in the extrastriate body area, superior and inferior parietal lobule and prefrontal areas, although the extent of activation in HC was more limited as compared with AN patients. Increased activity in AN patients, compared with HC, was observed in the DLPFC in response to the oversized body picture and a significant correlation was found in AN patients between DLPFC activation and eating disorder psychopathology. CONCLUSIONS: Our findings suggest the existence of a continuum from normalcy to pathology in neural response to body image, and confirm the clinical relevance of body image distortion in AN, reinforcing the key role of attentive, executive and self-evaluation networks in AN visual processing of own distorted body image.

Alternative normalization methods demonstrate widespread cortical hypometabolism in untreated de novo Parkinson's disease.

AIM: Previous positron emission tomography (PET) [18F]fluorodeoxyglucose ([18F]FDG) studies in Parkinson's disease (PD) demonstrated that moderate to late stage patients display widespread cortical hypometabolism, whereas early stage PD patients exhibit little or no cortical changes. However, recent studies suggested that conventional data normalization procedures may not always be valid, and demonstrated that alternative normalization strategies better allow detection of low magnitude changes. We hypothesized that these alternative normalization procedures would disclose more widespread metabolic alterations in de novo PD. METHODS: [18F]FDG PET scans of 26 untreated de novo PD patients (Hoehn & Yahr stage I-II) and 21 age-matched controls were compared using voxel-based analysis. Normalization was performed using gray matter (GM), white matter (WM) reference regions and Yakushev normalization. RESULTS: Compared to GM normalization, WM and Yakushev normalization procedures disclosed much larger cortical regions of relative hypometabolism in the PD group with extensive involvement of frontal and parieto-temporal-occipital cortices, and several subcortical structures. Furthermore, in the WM and Yakushev normalized analyses, stage II patients displayed more prominent cortical hypometabolism than did stage I patients. CONCLUSION: The use of alternative normalization procedures, other than GM, suggests that much more extensive cortical hypometabolism is present in untreated de novo PD patients than hitherto reported. The finding may have implications for our understanding of the basic pathophysiology of early-stage PD.

Functional neuroimaging in anorexia nervosa: a clinical approach.

AIMS: To provide a review of the available literature about the functional neuroimaging of anorexia nervosa, and to summarize the possible role of neurobiological factors in its pathogenesis. METHODS: A systematic review of the literature was performed using PubMed and Medline electronic database (1950-September 2009). Eligible studies were restricted to those involving the main parameters of cerebral activity and functional neuroimaging techniques. Findings of the reviewed studies have been grouped on a diagnostic subtype basis, and their comparison has been interpreted in terms of concordance. RESULTS: We found a high level of concordance among available studies with regard to the presence of frontal, parietal and cingulate functional disturbances in both anorexia nervosa restricting and binge/purging subtypes. Concordance among studies conducted regardless of the anorexia nervosa subtypes suggests an alteration in temporal and parietal functions and striatal metabolism. CONCLUSIONS: The most consistent alterations in anorexia nervosa cerebral activity seem to involve the dorsolateral prefrontal cortex, the inferior parietal lobule, the anterior cingulate cortex and the caudate nucleus. They may affect different neural systems such as the frontal visual system, the attention network, the arousal and emotional processing systems, the reward processing network, and the network for the body schema.

Cyclic DGR-peptidomimetic containing a bicyclic reverse turn inducer as a selective alpha(v)beta (5) integrin ligand.

3-Aza-6,8-dioxabicyclo[3.2.1]octane-based amino acids as reverse turn inducers have been introduced into cyclic peptidomimetics containing the RGD or DGR retro-sequence, in order to achieve a stereochemical scanning of the binding capability of the resulting molecules towards alpha(v)beta(3) and alpha(v)beta(5) integrins, resulting in retro-inverso DGR peptides as micromolar ligands. A comparative analysis between the conformational preferences of 4 and of its isomer 3, having the opposite RGD sequence, was reported with respect to the binding activity, giving insight into the factors affecting the preferential binding of 4 to the alpha(v)beta(5) integrin.

Decreased [99mTc]Sestamibi uptake with dobutamine versus dipyridamole stress.

AIM: Animal studies suggest an interference of dobutamine on [99mTc]sestamibi uptake. In this study dobutamine was compared to dipyridamole rest-stress [99mTc]sestamibi uptake ratio (UR). METHODS: Twenty-five patients with suspect coronary artery disease (CAD) underwent rest, dobutamine, and dipyridamole [99mTc]sestamibi SPECT at 24-h intervals and coronary angiography. UR was calculated separately for each coronary territory considering injected dose and acquisition delay. RESULTS: There were 38 CAD territories in 20 patients. On a patient basis, dipyridamole SPECT sensitivity was 85%, versus 70% for dobutamine. On a territory basis, sensitivity was 66% versus 42% (P<0.05), and specificity 92% versus 86%, respectively for dipyridamole versus dobutamine. In the 38 CAD territories, dipyridamole UR was -4.1+/-29.4%, and dobutamine UR was -13.1+/-19.9% (P<0.05). In the 37 no-CAD territories, UR was 34+/-23.6% for dipyridamole and -0.4+/-17.8% for dobutamine (P<0.0001). UR difference between CAD versus no-CAD territories was larger using dipyridamole (P<0.0001) than dobutamine (P<0.005). CONCLUSIONS: The UR comparison confirms that [99mTc]sestamibi uptake underestimates the blood flow heterogeneity induced by dobutamine more than that produced by dipyridamole.

Role of whole-body 18F-choline PET/CT in disease detection in patients with biochemical relapse after radical treatment for prostate cancer.

PURPOSE: The aim of this study was to evaluate the role of whole body 18F-choline (FCH) positron emission tomography-computed tomography (PET-CT) in detecting and localising disease recurrence in patients presenting biochemical relapse after radical treatment for prostate cancer. MATERIALS AND METHODS: Fifty-six consecutive patients with increased serum prostate-specific antigen (PSA) levels after radical prostatectomy were included in the study. None of them was receiving hormone treatment at the time of the examination or had been treated during the previous 6 months. All patients underwent whole-body 18F-choline PET imaging, and the pathological findings were compared with those of further imaging exams, biopsy and follow-up. On the basis of the PSA levels, we divided our patient population into three subgroups: PSA < or = 1, 1 < PSA < or = 5, and PSA > 5 ng/ml. RESULTS: Overall, the PET scan detected disease relapse in 42.9% of cases (24/56). PET sensitivity was closely related to serum PSA levels, showing values of 20%, 44% and 81.8% in the PSA < or = 1, 1 < PSA < or = 5 and PSA > 5 ng/ml subgroups, respectively. CONCLUSIONS: In patients with biochemical relapse after radical treatment for prostate cancer, 18F-choline PET-CT represents a single step, whole-body, noninvasive study that allows disease detection and localisation. The disease detection rate is related to serum PSA levels.

Determinants of final infarct size and incidence of aborted infarction in patients treated with primary coronary intervention and adjunctive abciximab therapy.

AIMS: Assess the determinants of final infarct size in patients successfully treated with primary percutaneous coronary intervention (PCI) and abciximab therapy and check whether infarct abortion may occur. PATIENTS, METHODS: In 208 patients we examined the parameters that predict final infarct size and the incidence of aborted infarction, defined by completely normal perfusion and regional wall motion plus >50% left ventricular ejection fraction (LVEF) in gated single-photon emission computed tomography (SPECT) acquired at one month. RESULTS: In linear regression analysis, sex (p<0.0001), high cholesterol (p<0.05), Killip class (p<0.0001), symptom-to-reperfusion time (p<0.001), admission ST segment elevation (p<0.0001), infarct related artery (p<0.05), and pre-procedural TIMI flow (p<0.002) were significant univariate predictors of final infarct size. In multiple linear regression analysis, symptom-to-reperfusion time (p<0.001), Killip class (p<0.0001), ST segment elevation (p<0.003), and sex (p<0.03) remained significant predictors, model R(2)=0.53. Aborted infarction was registered in 32 patients, more frequently female (59% versus 21%, p<0.00001), older (p<0.02), with larger prevalence of TIMI grade 3 (p<0.05) and lower ST segment elevation at admission (p<0.05). CONCLUSIONS: Sex, reperfusion delay, and initial infarct severity as indicated by Killip class and/or ST segment elevation appear the determinants of final infarct size in patients treated with primary PCI. The presence of aborted infarction seems related to the same factors and to preserved TIMI 3 flow.

The need of appropriate brain SPECT templates for SPM comparisons.

AIM: Statistical parametric mapping (SPM) is used worldwide to compare brain perfusion single photon emission computed tomography (SPECT) data. The default template within the SPM package used for SPECT image normalization includes images of a group of healthy subjects studied with [(99m)Tc]HMPAO. Since [(99m)Tc]HMPAO and [(99m)Tc]ECD have shown to distribute differently in SPECT studies, we formulated the hypothesis that comparing set of [(99m)Tc]ECD data normalized by means of a [(99m)Tc]HMPAO template may lead to incorrect results. METHODS: A customized [(99m)Tc]ECD template was built with SPECT and magnetic resonance imaging (MRI) images of 22 neurologically healthy women. Then, two sets of subjects, i.e. a group of patients with very early Alzheimer's disease (eAD) and a matched control group, studied by means of [(99m)Tc]ECD SPECT, were chosen for comparisons. The same statistical approach (t-test between eAD patients and controls and correlation analysis between brain SPECT and a cognitive score) was applied twice, i.e. after normalization with either the default [(99m)Tc]HMPAO template or the customized [(99m)Tc]ECD template. RESULTS: In the comparison between eAD and controls, a cluster of difference in the posterior cingulate gyrus of both hemispheres was only highlighted when using the customized [(99m)Tc]ECD template, but was missed when using the default [(99m)Tc]HMPAO template. In the correlation between brain perfusion and a cognitive score, the significant cluster was more significant and far more extended, also including the right superior temporal gyrus, using the customized [(99m)Tc]ECD template than using the default [(99m)Tc]HMPAO template. CONCLUSION: These data suggest the need of customized, radiopharmaceutical-matched SPECT templates to be used within the SPM package. The present customized [(99m)Tc]ECD template is now freely available on the web.

Metabolic correlates of executive dysfunction. Different patterns in mild and very mild Alzheimer's disease.

This study was designed to examine the correlations between resting-state brain glucose metabolism (CMRglc), as measured with Positron Emission Tomography and performance on executive function tasks in Alzheimer's disease (AD), while taking into account the severity of cognitive deterioration. We addressed this issue in 50 AD patients, classified as very mild (n = 22) and mild (n = 28) AD on the basis of an extensive neuropsychological battery. Thirteen healthy subjects were selected as controls for the neuropsychological measures. Statistical Parametric Mapping (SPM) was used to examine voxel-wise correlations between CMRglc and scores on selected cognitive tests of executive functions: the Stroop Test, the Trail Making Test, the Dual Task and the Phonemic Fluency, while correcting for age and global CMRglc. All analyses were done separately for the two AD subgroups. The very mild AD patients showed significant associations between Stroop and Trail Making Test scores and prefrontal regions metabolism, whereas the mild AD patients exhibited more widely distributed cognitive-metabolic correlations extending to the posterior brain regions. These data suggest that a large cortical network is implicated in executive dysfunction in AD, and that the pattern of cognitive-metabolic correlations varies according to disease severity.

Tomographic evaluation of [131I] 6beta-iodomethyl-norcholesterol standardised uptake trend in clinically silent monolateral and bilateral adrenocortical incidentalomas.

AIM: The aim of this study was three-fold: 1) to quantify [131I]-6beta-iodomethyl-norcholesterol ([131I]-NP-59) adrenal uptake trend in patients with incidentalomas, 2) to identify a specific uptake trend (TREND) capable of characterising pre-clinical Cushing syndrome (PC-CS) patients, 3) to assess the clinical availability of TREND as a prognostic factor of late clinical outcome in a cohort of patients with bilateral adrenal adenomas. METHODS: Fifty-seven consecutive patients were examined using three-head SPECT at 24, 48, 72 hours following intravenous injection of [131I ]-NP-59. On the basis of the absence or presence of hormonal abnormalities, the selected population was classified as GR1 or GR2, respectively. Adrenal glands were classified into 4 groups taking into account both the patient group (GR1, GR2) and the presence (+) or absence (-) of the adenoma (AD) on CT scan. Using ROI technique, adrenal-liver uptake ratio (A/L) was estimated bilaterally at 24, 48 and 72 hours. For each adrenal group, mean [131I]-NP-59 uptake trends were derived. RESULTS: TREND was significantly different between GR1/AD+ and GR2/AD+. Among GR2/AD+ patients, TREND correctly identified PC-CS with a global accuracy of 74%. Two patients with bilateral incidentaloma developed an overt CS. In both patients, TREND correctly identified the hyperfunctioning adrenal, thus permitting an effective sparing adrenalectomy. CONCLUSIONS: TREND seems to be a parameter which closely reflects adrenal physiological behaviour, especially in the case of bilateral adrenal involving. The possibility to quantify even contralateral adrenal uptake as standardised index provides additional useful information about normal adrenal parenchyma and, indirectly, about adenoma functional autonomy.

FDG-PET in the management of germ cell tumor.

Germ cell tumor is the most common malignancy in young men. The cure rate of these patients has tremendously increased in the cisplatin era, and recent results have indicated that the management of patients with GCT is still improving. The use of FDG-PET in the management of patients with GCT has been recently investigated. This report attempts to comprehensively review new advances and delineate the potential applications of FDG-PET in GCT.

Metabolic interaction between ApoE genotype and onset age in Alzheimer's disease: implications for brain reserve.

BACKGROUND: Clinically apparent Alzheimer's disease (AD) is thought to result when brain tissue damage exceeds a critical threshold of "brain reserve", a process possibly accelerated by the apolipoprotein E (ApoE) E4 allele. The interaction between onset age and ApoE genotype was investigated to assess whether early disease onset (<65 years) in patients carrying the E4 allele is associated with greater cerebral metabolic (regional cerebral metabolic rate of glucose utilisation, rCMRgl) reduction. METHODS: AD patients, divided into early (EOAD; 27 patients) and late onset (LOAD; 65 patients) groups, both groups balanced as to the number of E4 carriers (E4+) and non-carriers (E4-), and matched controls (NC; 35 cases) underwent (18)F-FDG PET ([(18)F]fluorodeoxyglucose positron emission tomography) scanning. SPM'99 software was used to compare AD patients to NC and to perform a two way ANOVA with onset age and ApoE genotype as grouping factors. Results were considered significant at p<0.001, uncorrected. RESULTS: AD patients demonstrated rCMRgl reductions compared to NC, with rCMRgl lower in association cortex and relatively higher in limbic areas in EOAD compared to LOAD subjects. rCMRgl was lower in the anterior cingulate and frontal cortex for E4+ compared to E4- subjects. A significant onset age by ApoE interaction was detected in the hippocampi and basal frontal cortex, with EOAD E4+ subjects having the greatest rCMRgl reduction. CONCLUSIONS: The interactive effects of early onset age, possibly reflecting lower brain reserve, and ApoE E4 allele, possibly leading to greater tissue damage, lead to reduced tolerance to the pathophysiological effects of AD in key brain regions.

MCI conversion to dementia and the APOE genotype: a prediction study with FDG-PET.

OBJECTIVES: To investigate whether the combination of fluoro-2-deoxy-d-glucose (FDG) PET measures with the APOE genotype would improve prediction of the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). METHOD: After 1 year, 8 of 37 patients with MCI converted to AD (22%). Differences in baseline regional glucose metabolic rate (rCMRglc) across groups were assessed on a voxel-based basis using a two-factor analysis of variance with outcome (converters [n = 8] vs nonconverters [n = 29]) and APOE genotype (E4 carriers [E4+] [n = 16] vs noncarriers [E4-] [n = 21]) as grouping factors. Results were considered significant at p < 0.05, corrected for multiple comparisons. RESULTS: All converters showed reduced rCMRglc in the inferior parietal cortex (IPC) as compared with the nonconverters. Hypometabolism in AD-typical regions, that is, temporoparietal and posterior cingulate cortex, was found for the E4+ as compared with the E4- patients, with the E4+/converters (n = 5) having additional rCMRglc reductions within frontal areas, such as the anterior cingulate (ACC) and inferior frontal (IFC) cortex. For the whole MCI sample, IPC rCMRglc predicted conversion to AD with 84% overall diagnostic accuracy (p = 0.003). Moreover, ACC and IFC rCMRglc improved prediction for the E4+ group, yielding 100% sensitivity, 90% specificity, and 94% accuracy (p < 0.0005), thus leading to an excellent discrimination. CONCLUSION: Fluoro-2-deoxy-d-glucose-PET measures may improve prediction of the conversion to Alzheimer disease, especially in combination with the APOE genotype.

Classification of ischemic dysfunctional myocardium combining perfusion quantification and contractile reserve evaluation using nitrate-enhanced gated single photon emission computed tomography with dobutamine test.

AIM: In patients with ischemic cardiomyopathy, the differentiation of dysfunctional myocardium in scarred versus hibernating is oversimplified. We evaluated a more complex classification using an imaging technique currently employed for viability detection, having as reference the postrevascularization outcome of dysfunctional segments. METHODS: In 35 patients, we performed gated single-photon emission computed tomography (SPECT) (resting and nitrate-enhanced study, the latter with baseline and dobutamine acquisition) before revascularization. The outcome after revascularization was assessed by repeating resting gated SPECT. Dysfunctional segments without functional recovery in postrevascularization gated SPECT were defined scar (either nontransmural or transmural according to tracer activity); those with recovery were divided in stunned (unchanged uptake) or hibernating (improved postrevascularization activity). This reference classification was compared with the categorization based on prerevascularization gated SPECT. RESULTS: Contractile reserve in dobutamine gated SPECT differentiated scarred from viable segments with 78% accuracy. Tracer activity in nitrate imaging distinguished the degree of transmurality. Nitrate-induced activity increase was significantly higher (p<0.0001) in the hibernating segments (14.9+/-20.4%) than in transmural (4.8+/-13.4%) nontransmural scars (3.3+/-13%), or stunned segments (2.2+/-8%). The presence or absence of nitrate-induced activity increase predicted the postrevascularization perfusion changes in viable myocardium and differentiated hibernating from stunned segments. The prerevascularization classification showed a good agreement with the reference categorization (kappa=0.50). Conclusion. Combining contractile reserve evaluation and perfusion quantification within a single study with baseline-nitrate gated SPECT and dobutamine test it is possible to achieve a comprehensive classification of dysfunctional segments.

Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease.

OBJECTIVES: Declines in brain glucose metabolism have been described early in Alzheimer's disease (AD), and there is evidence that a genetic predisposition to AD contributes to accelerate this process. The epsilon 4 (e4) allele of the apolipoprotein E (ApoE) gene has been implicated as a major risk factor in this process. The aim of this FDG-PET study was to assess the ApoE e4 dose related effect on regional cerebral glucose metabolism (METglc) in clinical AD patients, with statistical voxel based methods. METHODS: Eighty six consecutive mild to moderate AD patients included in the Network for Efficiency and Standardisation of Dementia Diagnosis database underwent FDG-PET scans at rest. PCR was used to determine the ApoE genotype. Patients were grouped as e4 non-carriers (n = 46), e3/e4 (n = 27) and e4/e4 (n = 13) carriers. A voxel-based mapping program was used to compare each AD subgroup with a database of 35 sex and age matched controls (p<0.001, corrected for cluster extent) and also to compare between the subgroups (p<0.001, uncorrected). RESULTS: No difference was found as to age at examination, age at onset, sex, disease duration, educational level, or severity of dementia between AD subgroups. Compared with controls, all AD subgroups had equivalent METglc reductions in the precuneus, posterior cingulate, parietotemporal, and frontal regions. Direct comparisons between AD subgroups indicated that patients with at least one e4 allele had METglc reductions within additional associative and limbic areas compared with e4 non-carriers. CONCLUSIONS: The present FDG-PET study showed different metabolic phenotypes related to the ApoE genotype in clinical AD patients, as revealed with voxel based statistical methods. The results suggest a generalised disorder in e4 carriers impairing metabolism globally, in addition to the more localised changes typical of AD patients.

Brain metabolic differences between sporadic and familial Alzheimer's disease.

This FDG-PET study with SPM99 compared 46 patients with sporadic Alzheimer disease (SAD) to 40 patients with familial AD (FAD) and to 35 matched controls. AD groups had equivalent metabolic (METglu) reductions in several cortical and limbic areas with respect to the controls. Patients with FAD showed decreased METglu in the posterior cingulate, parahippocampal, and occipital cortex as compared to the patients with SAD (p < 0.001). Genetic factors lead to phenotypic differences in AD.