Early-stage differentiation between presenile Alzheimer's disease and frontotemporal dementia using arterial spin labeling MRI.

OBJECTIVE: To investigate arterial spin labeling (ASL)-MRI for the early diagnosis of and differentiation between the two most common types of presenile dementia: Alzheimer's disease (AD) and frontotemporal dementia (FTD), and for distinguishing age-related from pathological perfusion changes. METHODS: Thirteen AD and 19 FTD patients, and 25 age-matched older and 22 younger controls underwent 3D pseudo-continuous ASL-MRI at 3 T. Gray matter (GM) volume and cerebral blood flow (CBF), corrected for partial volume effects, were quantified in the entire supratentorial cortex and in 10 GM regions. Sensitivity, specificity and diagnostic performance were evaluated in regions showing significant CBF differences between patient groups or between patients and older controls. RESULTS: AD compared with FTD patients had hypoperfusion in the posterior cingulate cortex, differentiating these with a diagnostic performance of 74 %. Compared to older controls, FTD patients showed hypoperfusion in the anterior cingulate cortex, whereas AD patients showed a more widespread regional hypoperfusion as well as atrophy. Regional atrophy was not different between AD and FTD. Diagnostic performance of ASL to differentiate AD or FTD from controls was good (78-85 %). Older controls showed global hypoperfusion compared to young controls. CONCLUSION: ASL-MRI contributes to early diagnosis of and differentiation between presenile AD and FTD. KEY POINTS: ASL-MRI facilitates differentiation of early Alzheimer's disease and frontotemporal dementia. Posterior cingulate perfusion is lower in Alzheimer's disease than frontotemporal dementia. Compared to controls, Alzheimer's disease patients show hypoperfusion in multiple regions. Compared to controls, frontotemporal dementia patients show focal anterior cingulate hypoperfusion. Global decreased perfusion in older adults differs from hypoperfusion in dementia.

Diagnostic classification of arterial spin labeling and structural MRI in presenile early stage dementia.

Because hypoperfusion of brain tissue precedes atrophy in dementia, the detection of dementia may be advanced by the use of perfusion information. Such information can be obtained noninvasively with arterial spin labeling (ASL), a relatively new MR technique quantifying cerebral blood flow (CBF). Using ASL and structural MRI, we evaluated diagnostic classification in 32 prospectively included presenile early stage dementia patients and 32 healthy controls. Patients were suspected of Alzheimer's disease (AD) or frontotemporal dementia. Classification was based on CBF as perfusion marker, gray matter (GM) volume as atrophy marker, and their combination. These markers were each examined using six feature extraction methods: a voxel-wise method and a region of interest (ROI)-wise approach using five ROI-sets in the GM. These ROI-sets ranged in number from 72 brain regions to a single ROI for the entire supratentorial brain. Classification was performed with a linear support vector machine classifier. For validation of the classification method on the basis of GM features, a reference dataset from the AD Neuroimaging Initiative database was used consisting of AD patients and healthy controls. In our early stage dementia population, the voxelwise feature-extraction approach achieved more accurate results (area under the curve (AUC) range = 86 - 91%) than all other approaches (AUC = 57 - 84%). Used in isolation, CBF quantified with ASL was a good diagnostic marker for dementia. However, our findings indicated only little added diagnostic value when combining ASL with the structural MRI data (AUC = 91%), which did not significantly improve over accuracy of structural MRI atrophy marker by itself.

Exploration of MR-guided head and neck hyperthermia by phantom testing of a modified prototype applicator for use with proton resonance frequency shift thermometry.

Magnetic resonance thermometry (MRT) offers non-invasive temperature imaging and can greatly contribute to the effectiveness of head and neck hyperthermia. We therefore wish to redesign the HYPERcollar head and neck hyperthermia applicator for simultaneous radio frequency (RF) heating and magnetic resonance thermometry. In this work we tested the feasibility of this goal through an exploratory experiment, in which we used a minimally modified applicator prototype to heat a neck model phantom and used an MR scanner to measure its temperature distribution. We identified several distorting factors of our current applicator design and experimental methods to be addressed during development of a fully MR compatible applicator. To allow MR imaging of the electromagnetically shielded inside of the applicator, only the lower half of the HYPERcollar prototype was used. Two of its antennas radiated a microwave signal (150 W, 434 MHz) for 11 min into the phantom, creating a high gradient temperature profile (ΔTmax = 5.35 °C). Thermal distributions were measured sequentially, using drift corrected proton resonance frequency shift-based MRT. Measurement accuracy was assessed using optical probe thermometry and found to be about 0.4 °C (0.1-0.7 °C). Thermal distribution size and shape were verified by thermal simulations and found to have a good correlation (r(2 )= 0.76).

Validation of MR thermometry: method for temperature probe sensor registration accuracy in head and neck phantoms.

PURPOSE: Magnetic resonance thermometry (MRT) is an attractive means to non-invasively monitor in vivo temperature during head and neck hyperthermia treatments because it can provide multi-dimensional temperature information with high spatial resolution over large regions of interest. However, validation of MRT measurements in a head and neck clinical set-up is crucial to ensure the temperature maps are accurate. Here we demonstrate a unique approach for temperature probe sensor localisation in head and neck hyperthermia test phantoms. METHODS: We characterise the proton resonance frequency shift temperature coefficient and validate MRT measurements in an oil-gel phantom by applying a combination of MR imaging and 3D spline fitting for accurate probe localisation. We also investigate how uncertainties in both the probe localisation and the proton resonance frequency shift (PRFS) thermal coefficient affect the registration of fibre-optic reference temperature probe and MRT readings. RESULTS: The method provides a two-fold advantage of sensor localisation and PRFS thermal coefficient calibration. We provide experimental data for two distinct head and neck phantoms showing the significance of this method as it mitigates temperature probe localisation errors and thereby increases accuracy of MRT validation results. CONCLUSIONS: The techniques presented here may be used to simplify calibration experiments that use an interstitial heating device, or any heating method that provides rapid and spatially localised heat distributions. Overall, the experimental verification of the data registration and PRFS thermal coefficient calibration technique provides a useful benchmarking method to maximise MRT accuracy in any similar context.

Microstructural brain injury in post-concussion syndrome after minor head injury.

INTRODUCTION: After minor head injury (MHI), post-concussive symptoms commonly occur. The purpose of this study was to correlate the severity of post-concussive symptoms in MHI patients with MRI measures of microstructural brain injury, namely mean diffusivity (MD) and fractional anisotropy (FA), as well as the presence of microhaemorrhages. METHODS: Twenty MHI patients and 12 healthy controls were scanned at 3 T using diffusion tensor imaging (DTI) and high-resolution gradient recalled echo (HRGRE) T2*-weighted sequences. One patient was excluded from the analysis because of bilateral subdural haematomas. DTI data were preprocessed using Tract Based Spatial Statistics. The resulting MD and FA images were correlated with the severity of post-concussive symptoms evaluated with the Rivermead Postconcussion Symptoms Questionnaire. The number and location of microhaemorrhages were assessed on the HRGRE T2*-weighted images. RESULTS: Comparing patients with controls, there were no differences in MD. FA was decreased in the right temporal subcortical white matter. MD was increased in association with the severity of post-concussive symptoms in the inferior fronto-occipital fasciculus (IFO), the inferior longitudinal fasciculus and the superior longitudinal fasciculus. FA was reduced in association with the severity of post-concussive symptoms in the uncinate fasciculus, the IFO, the internal capsule and the corpus callosum, as well as in the parietal and frontal subcortical white matter. Microhaemorrhages were observed in one patient only. CONCLUSIONS: The severity of post-concussive symptoms after MHI was significantly correlated with a reduction of white matter integrity, providing evidence of microstructural brain injury as a neuropathological substrate of the post-concussion syndrome.

Postconcussion syndrome after minor head injury: brain activation of working memory and attention.

After minor head injury (MHI) postconcussive symptoms (PCS) such as memory and attention deficits frequently occur. It has been hypothesised that PCS are caused by microstructural damage to the brain due to shearing injury, which is not detectable with conventional imaging, and may be responsible for a functional deficit. The purpose of this study was to correlate functional magnetic resonance imaging brain activation of working memory and selective attention with PCS. 21 MHI patients and 12 healthy controls were scanned at 3T. Stimulation paradigms were the n-back and Counting Stroop tasks to engage working memory and selective attention, respectively. Functional data analysis consisted of random effects group analyses, correlating brain activation patterns with the severity of PCS as evaluated with the Rivermead postconcussion symptoms questionnaire. At minimal working memory load, activation was seen in patients with greater severity of PCS in the working memory network. With an increase of working memory load, increase of activation was more pronounced in patients with greater severity of PCS. At high and increased working memory load, activation associated with the severity of PCS was seen in the posterior parietal area, parahippocampal gyrus, and posterior cingulate gyrus. Activation related to selective attention processing was increased with greater severity of PCS. The increased activity in relation to working memory and attention, and the recruitment of brain areas outside the working memory network at high working memory load, may be considered a reflection of the brain's compensatory response to microstructural injury in patients with PCS.

Ultrashort TE evaluation of the osteochondral junction in vivo: a feasibility study.

OBJECTIVE: To determine whether differences in the osteochondral junction (OCJ) in two different age groups could be detected with ultrashort time-to-echo (UTE) MRI in vivo. METHODS: 10 healthy controls aged 20-30 years (Group 1) and 10 patients aged 40-50 years with knee pain but no evidence of osteoarthritis (OA) (Group 2) underwent 3-T MRI of the knee using a two-dimensional UTE sequence. Evaluation of the presence/absence of a high-signal-intensity (SI) line at the medial tibial/lateral tibial (MT/LT) OCJ was performed. Regions of interest (ROI) were created at the MT OCJ and LT OCJ. The peak OCJ SI ratio was calculated by measuring peak OCJ SI using averaged craniocaudal SI profiling, then dividing by the mean SI of a background ROI to standardize between studies. Groups were compared using χ(2) and Mann-Whitney U tests. RESULTS: A high SI line was present in significantly more Group 1 subjects at both MT (p < 0.001) and LT (p = 0.002). There was a significant difference (p < 0.001) in MT peak OCJ SI ratio between Group 1 (mean ± SD = 0.85 ± 0.10) and Group 2 (0.77 ± 0.12). There was no significant difference (p = 0.19) in LT peak OCJ SI ratio between Group 1 (0.81 ± 0.23) and Group 2 (0.80 ± 0.13). CONCLUSION: Significant differences in the UTE MR characteristics of the OCJ were demonstrated between the two age groups. ADVANCES IN KNOWLEDGE: Alterations in the UTE appearances of the tibial plateau OCJ in the older group with knee pain compared with a younger, healthy control cohort may reflect the very early stages of OA.

Mapping of the cerebral response to acetazolamide using graded asymmetric spin echo EPI.

Cerebral vascular reactivity in different regions of the rat brain was quantitatively characterized by spatial and temporal measurements of blood oxygenation level-dependent (BOLD)-fMRI signals following intravenous administration of the carbonic anhydrase inhibitor acetazolamide: this causes cerebral vasodilatation through a cerebral extracellular acidosis that spares neuronal metabolism and vascular smooth muscle function, thus separating vascular and cerebral metabolic events. An asymmetric spin echo-echo planar imaging (ASE-EPI) pulse sequence sensitised images selectively to oxygenation changes in the microvasculature; use of a surface coil receiver enhanced image signal-to-noise ratios (SNRs). Image SNRs and hardware integrity were verified by incorporating quality assurance procedures; cardiorespiratory stability in the physiological preparations were monitored and maintained through the duration of the experiments. These conditions made it possible to apply BOLD contrast fMRI to map regional changes in cerebral perfusion in response to acetazolamide administration. Thus, fMRI findings demonstrated cerebral responses to acetazolamide that directly paralleled the known physiological actions of acetazolamide and whose time courses were similar through all regions of interest, consistent with acetazolamide's initial distribution in brain plasma, where it affects cerebral haemodynamics by acting at cerebral capillary endothelial cells. However, marked variations in the magnitude of the responses suggested relative perfusion deficits in the hippocampus and white matter regions correlating well with their relatively low vascularity and the known vulnerability of the hippocampus to ischaemic damage.

Cell quantification: evolution of compartmentalization and distribution of iron-oxide particles and labeled cells.

The purpose of the study was to show the feasibility of quantification in the case of cell death, cell migration and cell division by parametric MRI. We identify limitations for quantitative cell tracking owing to mixed parallel processes. Various intravoxel SPIO-labeled cell, super paramagnetic iron oxide particles (SPIO) and micron-sized paramagnetic iron oxide (MPIO) particle distributions were prepared by methods mimicking biologically relevant processes (compartmentalization, migration, division and cell death). R(2)* and R(2) relaxometry measurements were performed at 3.0 T; iron concentration was measured by optical emission spectrometry. The effects of spatial distribution and compartmentalization of paramagnetic iron-oxide particles on relaxivity were analyzed. Assessment of R(2)' (R(2)*-R(2)) allowed differentiation between intracellular and extracellular SPIO only if no high-iron-content extracellular particles were present. Relaxivity was sensitive to variations in cell labeling. Samples of the same cell types embedded in the same suspension media at the same cell density produced different relaxivity values, depending on the preparation of the labeled cells. In the case of cell division, a unique relationship between relaxation rate and iron concentration was found, where the relaxivity proved to be independent of initial cell labeling. In case of cell mixing, the cell density could be derived from relaxation values, even if iron concentration was undetermined. We demonstrated that relaxometry does not allow labeled cell quantification when multiple physiological processes such as cell division and cell migration coexist. The measured transversal relaxation rates were sensitive to the labeling technique. However, under special circumstances, despite the numerous limiting factors, quantification of the number of labeled cells by relaxometry was feasible.

Variations in labeling protocol influence incorporation, distribution and retention of iron oxide nanoparticles into human umbilical vein endothelial cells.

Various studies have shown that various cell types can be labeled with iron oxide particles and visualized by magnetic resonance imaging (MRI). However, reported protocols for cell labeling show a large variation in terms of labeling dose and incubation time. It is therefore not clear how different labeling protocols may influence labeling efficiency. Systematic assessment of the effects of various labeling protocols on labeling efficiency of human umbilical vein endothelial cells (HUVEC) using two different types of iron oxide nanoparticles, i.e. super paramagnetic iron oxide particles (SPIOs) and microparticles of iron oxide (MPIOs), demonstrated that probe concentration, incubation time and particle characteristics all influence the efficiency of label incorporation, label distribution, label retention and cell behavior. For SPIO the optimal labeling protocol consisted of a dose of 12.5 µg iron/2 ml/9.5 cm(2) and an incubation time of 24 h, resulting in an average iron load of 12.0 pg iron/per cell (uptake efficiency of 9.6%). At 4 h many SPIOs are seen sticking to the outside of the cell instead of being taken up by the cell. For MPIO optimal labeling was obtained with a dose of 50 µg iron/2 ml/9.5 cm(2). Incubation time was of less importance since most of the particles were already incorporated within 4 h with a 100% labeling efficiency, resulting in an intracellular iron load of 626 pg/cell. MPIO were taken up more efficiently than SPIO and were also better tolerated. HUVEC could be exposed to and contain higher amounts of iron without causing significant cell death, even though MPIO had a much more pronounced effect on cell appearance. Using optimal labeling conditions as found for HUVEC on other cell lines, we observed that different cell types react differently to identical labeling conditions. Consequently, for each cell type separately an optimal protocol has to be established.

Pigmentation predicts the shift in the line of decussation in humans with albinism.

In albinism a large proportion of nerve fibres originating in temporal retina cross the midline at the chiasm and project to the contralateral hemisphere. Studies in rodents with albinism have suggested that the extent of this misrouting at the chiasm is inversely related to pigmentation levels. Here, we examine whether there is evidence for a similar relationship in humans with albinism. Functional MRI was performed on 18 subjects with albinism, 17 control subjects and six controls with nystagmus as they underwent hemifield visual stimulation of nasal or temporal retina. Functional activation in 16 coronal slices beginning at the posterior occipital lobes were analysed and the extent of hemispheric response lateralization at each slice position was determined. During temporal retina stimulation, the control response was lateralized to the hemisphere ipsilateral to the stimulated eye for all slices. In albinos, the response in posterior slices was predominantly in the contralateral hemisphere, consistent with misrouting of temporal retina fibres. However, as slice location became progressively anterior, response lateralization reverted to the ipsilateral hemisphere. The slice location at which the transition from contra- to ipsilateralization occurred provided an estimate of the extent of fibre misrouting in the individual. The slice transition location correlated negatively with pigmentation level, providing the first evidence for a relationship between pigmentation and the extent of misrouting in humans with albinism.

Retinal abnormalities in human albinism translate into a reduction of grey matter in the occipital cortex.

Albinism is a genetic condition associated with abnormalities of the visual system. Defects in melanin production cause underdevelopment of the fovea, reduced retinal cell numbers and abnormal routing of ganglion cell nerve fibres at the optic chiasm. We examined 19 subjects with albinism and 26 control subjects to determine whether retinal abnormalities affect the structure of the visual cortex. Whole-brain, high-resolution anatomical magnetic resonance imaging volumes from each subject were obtained on a 1.5-T scanner and segmented into grey and white matter. A voxel-wise statistical comparison of grey and white matter volumes in the occipital lobes between the two groups was performed using voxel-based morphometry. Our analysis revealed a regionally specific decrease in grey matter volume at the occipital poles in albinism. The location of the decrease in grey matter corresponds to the cortical representation of the central visual field. This reduction is likely to be a direct result of decreased ganglion cell numbers in central retina in albinism.

Temporal characterisation of amphetamine-induced dopamine release assessed with [11C]raclopride in anaesthetised rodents.

Competition between endogenous neurotransmitters and radiolabelled tracers, as measured by positron emission tomography (PET), may provide a measure of endogenous neurotransmitter flux in vivo. For example, carbon-11 labelled raclopride has been effectively used to monitor dopamine release following pharmacological and behavioural manipulations. The current study describes a rodent model of amphetamine-induced [11C]raclopride reduction, which allowed the characterisation of the dose-response and temporal dynamics of this reduction over a 24-h time course. Over the range studied, a monotonic dose-response relationship between amphetamine dose and [11C]raclopride reduction was observed. When compared with previously published microdialysis data, an approximate 16% reduction in [11C]raclopride binding potential was associated with a approximately 25-fold increase in extracellular dopamine. A reduction of 20-30% in raclopride binding was observed 30 min after amphetamine injection (4 mg/kg i.p.). This reduction in [11C]raclopride binding persisted for 4 h but returned to baseline by 8 h. The data suggest a persistent amphetamine-induced raclopride displacement in rodents and reinforce findings from nonhuman primates that a simple competitive occupancy model may not adequately explain the temporal characteristics of the amphetamine-induced decrease in radiotracer binding.