Consistency between Treatment Effects on Clinical and Brain Atrophy Outcomes in Alzheimer's Disease Trials.

BACKGROUND: Longitudinal changes in volumetric MRI outcome measures have been shown to correlate well with longitudinal changes in clinical instruments and have been widely used as biomarker outcomes in clinical trials for Alzheimer's disease (AD). While instances of discordant findings have been noted in some trials, especially the recent amyloid-removing therapies, the overall relationship between treatment effects on brain atrophy and clinical outcomes, and how it might depend on treatment target or mechanism, clinical instrument or imaging variable is not yet clear. OBJECTIVE: To systematically assess the consistency and therapeutic class-dependence of treatment effects on clinical outcomes and on brain atrophy in published reports of clinical trials conducted in mild cognitive impairment (MCI) and/or AD. DESIGN: Quantitative review of the published literature. The consistency of treatment effects on clinical and brain atrophy outcomes was assessed in terms of statistical agreement with hypothesized equal magnitude effects (e.g., 30% slowing of both) and nominal directional concordance, as a function of therapeutic class. SETTING: Interventional randomized clinical trials. PARTICIPANTS: MCI or AD trial participants. INTERVENTION: Treatments included were those that involved ingestion or injection of a putatively active substance into the body, encompassing both pharmacological and controlled dietary interventions. MEASUREMENTS: Each trial included in the analysis reported at least one of the required clinical outcomes (ADAS-Cog, CDR-SB or MMSE) and at least one of the required imaging outcomes (whole brain, ventricular or hippocampal volume). RESULTS: Data from 35 trials, comprising 185 pairwise comparisons, were included. Overall, the 95% confidence bounds overlapped with the line of identity for 150/185 (81%) of the imaging-clinical variable pairs. The greatest proportion of outliers was found in trials of anti-amyloid antibodies that have been shown to dramatically reduce the level of PET-detectable amyloid plaques, for which only 13/33 (39%) of observations overlapped the identity line. A Deming regression calculated using all data points yielded a slope of 0.54, whereas if data points from the amyloid remover class were excluded, the Deming regression line had a slope of 0.92. Directional discordance of treatment effects was also most pronounced for the amyloid-removing class, and for comparisons involving ventricular volume. CONCLUSION: Our results provide a frame of reference for the interpretation of clinical and brain atrophy results from future clinical trials and highlight the importance of mechanism of action in the interpretation of imaging results.

In Vivo Detection of Changes Related to Cortical Columnar Organization and Neuroinflammation Across the AD Continuum.

BACKGROUND: Alzheimer's disease (AD) neuropathology reveals progressive microstructural alterations of cortical architecture. Recent studies reported intriguing biphasic trajectories of cortical structural changes in the early stages of Alzheimer's disease (AD), comprising decreased mean diffusivity (MD) and increased cortical thickness in cognitively normal amyloid-positive individuals, ahead of increases and decreases, respectively, in subsequent disease stages. OBJECTIVE: To better understand the cytoarchitectural correlates of these observations, we assessed novel cortical diffusion tensor imaging (DTI) metrics that are correlated with disruption of cortical minicolumns and protein deposition. DESIGN: Cross-sectional and longitudinal analysis of whole brain and temporal lobe cortical diffusivity measures. Investigation of associations between baseline cortical diffusivity values and 24-month longitudinal structural-MRI changes. Investigations of the relationships between cortical diffusivity measures and biomarkers of neuroinflammation. SETTING: Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS: Twenty-four amyloid-negative controls (CN-), 28 amyloid-positive controls (CN+), 46 amyloid-positive subjects with mild cognitive impairment (MCI+) and 22 amyloid-positive subjects with AD were included. MEASUREMENTS: 3DT1 and DTI scans at baseline and approximately 24-month follow-up were used to calculate cortical MD and three novel cortical diffusivity measures: the angle between the radial minicolumnar axis and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD+), and the principal diffusion component parallel with the minicolumns (ParlPD). Cortical macrostructural measurements (cortical volume fraction and cortical thickness), were used to test the hypothesis that baseline cortical diffusivity values can predict change in structural MRI outcomes over approximately 24 months. CSF soluble TREM2 and progranulin (PGRN) concentrations were used to investigate associations with microglial activity and potentially other aspects of neuroinflammation. RESULTS: Cortical diffusivity metrics revealed a dependence on disease stage, with AngleR and PerpPD+ displaying biphasic relationships and ParlPD a monotonic relationship with clinical severity. The novel metrics were able to differentiate between Amyloid+ and Amyloid- controls (AngleR) and to differentiate among disease stages along the AD continuum (PerpPD+). Linear regression revealed significant associations between baseline cortical diffusivity values and subsequent 24-month longitudinal structural-MRI changes. AngleR values were significantly associated with CSF sTREM2 and PGRN concentrations. CONCLUSIONS: Cortical diffusivity parameters reflecting minicolumnar organization and neuroinflammation may provide a sensitive and biologically interpretable measurement of cortex quality and microstructure across the AD continuum.

The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity.

One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p = 0.0004, r²â€¯= 0.46; p = 0.004, r²â€¯= 0.33; p = 0.002, r²â€¯= 0.37; p = 0.02, r²â€¯= 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.

Brain network reorganization differs in response to stress in rats genetically predisposed to depression and stress-resilient rats.

Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the specificity of the involved brain circuits. The rat strain bred for negative cognitive state (NC) represents a genetic animal model of TRD with high face, construct and predictive validity. Vice versa, the positive cognitive state (PC) strain represents a stress-resilient phenotype. Although NC rats show depressive-like behavior, some symptoms such as anhedonia require an external trigger, i.e. a stressful event, which is similar to humans when stressful event induces a depressive episode in genetically predisposed individuals (gene-environment interaction). We aimed to distinguish neurobiological predisposition from the depressogenic pathology at the level of brain-network reorganization. For this purpose, resting-state functional magnetic resonance imaging time series were acquired at 9.4 Tesla scanner in NC (N=11) and PC (N=7) rats before and after stressful event. We used a graph theory analytical approach to calculate the brain-network global and local properties. There was no difference in the global characteristics between the strains. At the local level, the response in the risk strain was characterized with an increased internodal role and reduced local clustering and efficiency of the anterior cingulate cortex (ACC) and prelimbic cortex compared to the stress-resilient strain. We suggest that the increased internodal role of these prefrontal regions could be due to the enhancement of some of their long-range connections, given their connectivity with the amygdala and other default-mode-like network hubs, which could create a bias to attend to negative information characteristic for depression.

Species-conserved reconfigurations of brain network topology induced by ketamine.

Species-conserved (intermediate) phenotypes that can be quantified and compared across species offer important advantages for translational research and drug discovery. Here, we investigate the utility of network science methods to assess the pharmacological alterations of the large-scale architecture of brain networks in rats and humans. In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species. As these alterations are opposed to those commonly observed in patients suffering from depression, they might indicate systems-level correlates of the antidepressant effect of ketamine.

Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.

Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release. Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification. We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects. The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain.

In vivo imaging of tau pathology using multi-parametric quantitative MRI.

As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.

Quantifying the attenuation of the ketamine pharmacological magnetic resonance imaging response in humans: a validation using antipsychotic and glutamatergic agents.

Ketamine acts as an N-methyl-D-aspartate receptor antagonist and evokes psychotomimetic symptoms resembling schizophrenia in healthy humans. Imaging markers of acute ketamine challenge have the potential to provide a powerful assay of novel therapies for psychiatric illness, although to date this assay has not been fully validated in humans. Pharmacological magnetic resonance imaging (phMRI) was conducted in a randomized, placebo-controlled crossover design in healthy volunteers. The study comprised a control and three ketamine infusion sessions, two of which included pretreatment with lamotrigine or risperidone, compounds hypothesized to reduce ketamine-induced glutamate release. The modulation of the ketamine phMRI response was investigated using univariate analysis of prespecified regions and a novel application of multivariate analysis across the whole-brain response. Lamotrigine and risperidone resulted in widespread attenuation of the ketamine-induced increases in signal, including the frontal and thalamic regions. A contrasting effect across both pretreatments was observed only in the subgenual prefrontal cortex, in which ketamine produced a reduction in signal. Multivariate techniques proved successful in both classifying ketamine from placebo (100%) and identifying the probability of scans belonging to the ketamine class (ketamine pretreated with placebo: 0.89). Following pretreatment, these predictive probabilities were reduced to 0.58 and 0.49 for lamotrigine and risperidone, respectively. We have provided clear demonstration of a ketamine phMRI response and its attenuation with both lamotrigine and risperidone. The analytical methodology used could be readily applied to investigate the mechanistic action of novel compounds relevant for psychiatric disorders such as schizophrenia and depression.

Test-retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers.

The pharmacological MRI (phMRI) technique is being increasingly used in both pre-clinical and clinical models to investigate pharmacological effects on task-free brain function. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, induces a strong phMRI response and represents a promising pharmacological model to investigate the role of glutamatergic abnormalities in psychiatric symptomatology. The aim of this study was to assess whether the brain response to ketamine is reliable in order to validate ketamine phMRI as a mechanistic marker of glutamatergic dysfunction and to determine its utility in repeated measures designs to detect the modulatory effect of other drugs. Thus we assessed the test-retest reliability of the brain response to ketamine in healthy volunteers and identified an optimal modelling approach with reliability as our selection criterion. PhMRI data were collected from 10 healthy male participants, at rest, on two separate occasions. Subanaesthetic doses of I.V. ketamine infusion (target plasma levels 50 ng/mL and 75 ng/mL) were administered in both sessions. Test-retest reliability of the ketamine phMRI response was assessed voxel-wise and on pre-defined ROIs for a range of temporal design matrices including different combinations of nuisance regressors designed to model shape variance, linear drift and head motion. Effect sizes are also reported. All models showed a significant and widespread response to low-dose ketamine in predicted cerebral networks and as expected, increasing the number of model parameters improved model fit. Reliability of the predefined ROIs differed between the different models assessed. Using reliability as the selection criterion, a model capturing subject motion and linear drift performed the best across two sessions. The anatomical distribution of effects for all models was consistent with results of previous imaging studies in humans with BOLD signal increases in regions including midline cingulate and supracingulate cortex, thalamus, insula, anterior temporal lobe and ventrolateral prefrontal structures, and BOLD signal decreases in the subgenual cingulate cortex. This study represents the first investigation of the test-retest reliability of the BOLD phMRI response to acute ketamine challenge. All models tested were effective at describing the ketamine response although the design matrix associated with the highest reliability may represent a robust and well-characterised ketamine phMRI assay more suitable for repeated-measures designs. This ketamine assay is applicable as a model of neurotransmitter dysfunction suitable as a pharmacodynamic imaging tool to test and validate modulatory interventions, as a model of NMDA hypofunction in psychiatric disorders, and may be adapted to understand potential antidepressant and analgesic effects of NMDAR antagonists.

The low-frequency blood oxygenation level-dependent functional connectivity signature of the hippocampal-prefrontal network in the rat brain.

Interactions between the hippocampus and the prefrontal cortex (PFC) are of major interest in the neurobiology of psychiatric and neurodegenerative disorders and are central to many experimental rodent models. Non-invasive imaging techniques offer a translatable approach to probing this system if homologous features can be identified across species. The objective of the present study was to systematically characterize the rat brain connectivity signature derived from low-frequency resting blood oxygenation level-dependent (BOLD) oscillations associated with and within the hippocampal-prefrontal network, using an array of small seed locations within the relatively large anatomical structures comprising this system. A heterogeneous structure of functional connectivity, both between and within the hippocampal-prefrontal brain structures, was observed. In the hippocampal formation, the posterior (subiculum) region correlated more strongly than the anterior dorsal hippocampus with the PFC. A homologous relationship was found in the human hippocampus, with differential functional connectivity between hippocampal locations proximal to the fornix body relative to locations more distal being localized to the medial prefrontal regions in both species. The orbitofrontal cortex correlated more strongly with sensory cortices and a heterogeneous dependence of functional coupling on seed location was observed along the midline cingulate and retrosplenial cortices. These findings are all convergent with known anatomical connectivity, with stronger BOLD correlations corresponding to known monosynaptic connections. These functional connectivity relationships may provide a useful translatable probe of the hippocampal-prefrontal system for the further study of rodent models of disease and potential treatments, and inform electrode placement in electrophysiology to yield more precise descriptors of the circuits at risk in psychiatric disease.

Applications of imaging biomarkers in the early clinical development of central nervous system therapeutic agents.

The early clinical drug development process increasingly utilizes imaging biomarkers to provide key information in response to a sequential series of questions about potential therapeutic agents. We present several examples of how imaging can answer some of these questions pertaining to the central nervous system (CNS) during the early phases of development of drugs to treat diseases involving the CNS. We also present an overview of the challenges and the potential of using and further qualifying imaging biomarkers for clinical trials.

In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial.

The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

Concurrent pharmacological MRI and in situ microdialysis of cocaine reveal a complex relationship between the central hemodynamic response and local dopamine concentration.

The mechanisms underlying the signal changes observed with pharmacological magnetic resonance imaging (phMRI) remain to be fully elucidated. In this study, we obtained microdialysis samples in situ at 5-min intervals during phMRI experiments using a blood pool contrast agent to correlate relative cerebral blood volume (rCBV) changes with changes in dopamine and cocaine concentrations following acute cocaine challenge (0.5 mg/kg iv) in the rat over a duration of 30 min. Three brain areas were investigated: the dorsal striatum (n = 8), the medial prefrontal cortex (mPFC; n = 5), and the primary motor cortex (n = 8). In the striatum and mPFC groups, cocaine and dopamine temporal profiles were tightly correlated, peaking during the first 5-min period postinjection, then rapidly decreasing. However, the local rCBV changes were uncorrelated and exhibited broader temporal profiles than those of cocaine and dopamine, attaining maximal response 5-10 min later. This demonstrates that direct vasoactivity of dopamine is not the dominant component of the hemodynamic response in these regions. In the motor cortex group, microdialysis revealed no local change in dopamine in any of the animals, despite large local cocaine increase and strong rCBV response, indicating that the central hemodynamic response following acute iv cocaine challenge is not driven directly by local dopamine changes in the motor cortex. The combination of phMRI and in situ microdialysis promises to be of great value in elucidating the relationship between the phMRI response to psychoactive drugs and underlying neurochemical changes.

Early in vivo detection of metabolic response: a pilot study of 1H MR spectroscopy in extracranial lymphoma and germ cell tumours.

Monitoring therapeutic efficacy is essential in oncological practice. We have investigated the feasibility of using proton (1)H MR spectroscopy (MRS), localized to malignant lymphoma and germ cell lesions outside the cranial cavity, to monitor tumour metabolism in vivo during chemotherapy treatment. (1)H single voxel MRS, (stimulated echo acquisition mode, repetition time/echo time=2000/20 ms) was performed prior to treatment in patients with lymphoma or germ cell tumours, and during the first cycle of chemotherapy. Patient response was assessed by independent clinical follow-up at a median of 57 days (range 44-93 days) post-treatment. All 12 non-cystic lesions scanned showed a signal assigned to choline-containing metabolites (tCho); 9 were scanned both pre- and post-treatment. Changes in the tCho:water ratio following treatment were found to predict subsequent patient response. In seven of these nine patients, the tCho:water ratio decreased in the first post-treatment scan, and all subsequently achieved a partial response to treatment. In the remaining two patients, both of whom progressed on treatment, the tCho:water ratio did not change significantly. Normalized to pre-treatment values, the non-responder group values (1.07 and 0.97) were clearly distinct from the responder group, whose values ranged from 0.43 to below detection level. To our knowledge, this is the first report of (1)H MR spectra from these tumour types and sites. These preliminary results indicate that metabolite signals can be detected using (1)H MRS in these tumour types and locations, as has already been established in the brain, breast and prostate. Moreover, the differential changes observed in the tCho region of the spectrum suggest that (1)H MRS could provide an early and sensitive indicator of metabolic response to chemotherapy.

SAR and tissue heating with a clinical (31)P MRS protocol using surface coils, adiabatic pulses, and proton-decoupling.

In MRS studies using surface transmit coils, accurate assessment of local SAR and RF heating represents a difficult problem involving the coil geometry and electromagnetic and geometric tissue properties. Methodologies to determine the optimum operating parameters for dual-resonant surface coil measurements are presented, based on a standardized coil and protocol used in a multicenter (31)P MRS clinical trial, using adiabatic pulses and bilevel proton decoupling. Spatial distributions of absorbed radiation in human calf and in a tissue-equivalent gel phantom were modeled using finite-element simulations and realistic conductivity and permittivity values. Local SAR in worst-case 1 cm(3) volumes of interest (VOIs) in calf is predicted to be below international guidelines, and the temperature at the skin surface was found to increase due to the RF by less than 2 degrees C and remain below 37 degrees C. The heating rate and maximum temperature in the gel, at positions guided by the simulations, were within guideline values for both extremities and trunk and in reasonable agreement with that predicted.

Implications of respiratory motion for the quantification of 2D MR spectroscopic imaging data in the abdomen.

Magnetic resonance spectroscopic imaging (MRSI) studies in the abdomen or breast are acquired in the presence of respiratory motion. This modifies the point spread function (PSF) and hence the reconstructed spectra. We evaluated the quantitative effects of both periodic and aperiodic motion on spectra localized by MRSI. Artefactual signal changes, both the modification of native to a voxel and spurious signals arising elsewhere, depend primarily upon the motion amplitude relative to the voxel dimension. A similar dependence on motion amplitude was observed for simple harmonic motion (SHM), quasi-periodic motion and random displacements. No systematic dependence upon the period or initial phase of SHM or on the array size was found. There was also no significant variation with motion direction relative to the internal and external phase-encoding directions. In measured excursion ranges of 20 breast and abdominal tumours, 70% moved < or = 5 mm, while 30% moved 6-23 mm. The diaphragm and fatty tissues in the gut typically moved approximately 15-20 mm. While tumour/organ excursions less than half the voxel dimension do not substantially affect native signals, the bleeding in of strong lipid signals will be problematic in 1H studies. MRSI studies in the abdomen, even of relatively well-anchored tumours, are thus likely to benefit from the addition of respiratory triggering or other motion compensation strategies.

Proton spectroscopic imaging of polyacrylamide gel dosimeters for absolute radiation dosimetry.

Proton spectroscopy has been evaluated as a method for quantifying radiation induced changes in polyacrylamide gel dosimeters. A calibration was first performed using BANG-type gel samples receiving uniform doses of 6 MV photons from 0 to 9 Gy in 1 Gy intervals. The peak integral of the acrylic protons belonging to acrylamide and methylenebisacrylamide normalized to the water signal was plotted against absorbed dose. Response was approximately linear within the range 0-7 Gy. A large gel phantom irradiated with three, coplanar 3 x 3 cm square fields to 5.74 Gy at isocentre was then imaged with an echo filter technique to map the distribution of monomers directly. The image, normalized to the water signal, was converted into an absolute dose map. At the isocentre the measured dose was 5.69 Gy (SD = 0.09) which was in good agreement with the planned dose. The measured dose distribution elsewhere in the sample shows greater errors. A T2 derived dose map demonstrated a better relative distribution but gave an overestimate of the dose at isocentre of 18%. The data indicate that MR measurements of monomer concentration can complement T2-based measurements and can be used to verify absolute dose. Compared with the more usual T2 measurements for assessing gel polymerization, monomer concentration analysis is less sensitive to parameters such as gel pH and temperature, which can cause ambiguous relaxation time measurements and erroneous absolute dose calculations.

Acute effect of brief low- and high-intensity exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-binding protein-3 and its proteolysis in young healthy men.

We measured circulating levels of the GH insulin-like growth factor (IGF) system in response to brief exercise of different intensities. Ten males (mean age 28 +/- 5 yr) were studied on three separate occasions: once under resting conditions (control) and once each performing 10 min of low- or high-intensity exercise. Blood samples were assayed by RIA for GH, IGF-I and -II, IGF-binding protein-3 (IGFBP-3), and IGFBP-3 proteolytic activity. After 10 min of low-intensity exercise, IGF-I and IGFBP-3 had increased over preexercise baseline by 7.7 +/- 2.7% (P < 0.05) and 12.5 +/- 3.3% (P < 0.004), respectively. After 10 min of high-intensity exercise, all measured components of the IGF system were increased: IGF-I by 13.3 +/- 3.2% (P < 0.002), IGF-II by 15.7 +/- 3.1 (P < 0.01), and IGFBP-3 by 23 +/- 6% (P < 0.001). IGFBP-3 proteolytic activity also was increased (44 +/- 14% above baseline, P < 0.05). GH reached its peak 10 min after the cessation of high-intensity exercise, unlike the earlier peaks of IGF-I and II. In summary: 1) brief exercise leads to small but significant increases in circulating IGF-I, IGF-II, IGFBP-3, and IGFBP-3 proteolysis; and 2) these responses may be influenced by exercise intensity. The IGF responses seem to be unrelated to GH. Acute exercise-induced proteolysis of IGFBP-3 may contribute to anabolic effects of physical activity by increasing the bioavailability of IGF-I.