Diffusion tensor imaging of the hippocampus predicts the risk of dementia; the RUN DMC study.

INTRODUCTION: Cerebral small vessel disease is one of the most important risk factors for dementia, and has been related to hippocampal atrophy, which is among the first observed changes on conventional MRI in patients with dementia. However, these volumetric changes might be preceded by loss of microstructural integrity of the hippocampus for which conventional MRI is not sensitive enough. Therefore, we investigated the relation between the hippocampal diffusion parameters and the risk of incident dementia, using diffusion tensor imaging, independent of hippocampal volume. METHODS: The RUNDMC study is a prospective study among 503 elderly with small vessel disease, without dementia, with 5 years follow-up in 2012 (99.6% response-rate). Cox regression analysis was performed to calculate hazard ratios for dementia, of fractional anisotropy and mean diffusivity within the hippocampus, adjusted for demographics, hippocampal volume, and white matter. This was repeated in participants without evident hippocampal volume loss, because in these participants the visible damage might not yet have already started, whereas damage might have started on a microstructural level. RESULTS: 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95%CI 7.7-14.6). Higher mean diffusivity was associated with an increased 5-year risk of dementia. In the subgroup of participants with the upper half hippocampal volume, higher hippocampal mean diffusivity, more than doubled the 5-year risk of dementia. CONCLUSION: This is the first prospective study showing a relation between a higher baseline hippocampal mean diffusivity and the risk of incident dementia in elderly with small vessel disease at 5-year follow-up, independent of hippocampal volume and white matter volume.

An investigation into the functional and structural connectivity of the Default Mode Network.

Connectivity analyses based on both resting-state (rs-)fMRI and diffusion weighted imaging studies suggest that the human brain contains regions that act as hubs for the entire brain, and that elements of the Default Mode Network (DMN) play a pivotal role in this network. In the present study, the detailed functional and structural connectivity of the DMN was investigated. Resting state fMRI (35 minute duration) and Diffusion Weighted Imaging (DWI) data (256 directions) were acquired from forty-seven healthy subjects at 3 T. Tractography was performed on the DWI data. The resting state data were analysed using a combination of Independent Component Analysis, partial correlation analysis and graph theory. This forms a data driven approach for examining the connectivity of the DMN. ICA defined regions of interest were used as a basis for a partial correlation analysis. The resulting partial correlation coefficients were used to compute graph theoretical measures. This was performed on a single subject basis, and combined to compute group results depicting the spatial distribution of betweenness centrality within the DMN. Hubs with high betweenness centrality were frequently found in association areas of the brain. This approach makes it possible to distinguish the hubs in the DMN as belonging to different anatomical association systems. The start and end points of the fibre tracts coincide with hubs found using the resting state analysis.

Microstructural integrity of the cingulum is related to verbal memory performance in elderly with cerebral small vessel disease: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) is related to verbal memory failures. It is suggested that early white matter damage, is located, among others, in the (posterior) cingulum at an early stage in neurodegeneration. Changes in the microstructural integrity of the cingulum assessed with diffusion tensor imaging (DTI), beyond detection with conventional MRI, may precede macrostructural changes and be related to verbal memory failures. OBJECTIVE: To investigate the relation between cingular microstructural integrity and verbal memory performance in 503 non-demented elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study in elderly (50-85 years) with cerebral SVD. All participants underwent T1 MPRAGE, FLAIR and DTI scanning and the Rey Auditory Verbal Learning Test. Mean diffusivity (MD) and fractional anisotropy (FA) were assessed in six different cingular regions of interests (ROIs). Linear regression analysis was used to assess the relation between verbal memory performance and cingular DTI parameters, with appropriate adjustments. Furthermore a TBSS analysis of the whole brain was performed to investigate the specificity of our findings. RESULTS: Both our ROI-based and TBSS analysis showed that FA was positively related to immediate memory, delayed recall, delayed recognition and overall verbal memory performance of the cingulum, independent of confounders. A similar distribution was seen for the inverse association with MD and verbal memory performance with TBSS analysis. No significant relations were found with psychomotor speed, visuospatial memory and MMSE. When stratified on hippocampal integrity, the MD and FA values of the cingular ROIs differed significantly between participants with a good and poor hippocampal integrity. CONCLUSION: Microstructural integrity of the cingulum, assessed by DTI, is specifically related to verbal memory performance, in elderly with SVD. Furthermore we found that when the integrity of the hippocampus is disrupted, the cingulum integrity is impaired as well.

Observation of ground-state quantum beats in atomic spontaneous emission.

We report ground-state quantum beats in spontaneous emission from a continuously driven atomic ensemble. Beats are visible only in an intensity autocorrelation and evidence spontaneously generated coherence in radiative decay. Our measurement realizes a quantum eraser where a first photon detection prepares a superposition and a second erases the "which path" information in the intermediate state.

White matter changes and gait decline in cerebral small vessel disease.

The relation between progression of cerebral small vessel disease (SVD) and gait decline is uncertain, and diffusion tensor imaging (DTI) studies on gait decline are lacking. We therefore investigated the longitudinal associations between (micro) structural brain changes and gait decline in SVD using DTI. 275 participants were included from the Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort (RUN DMC), a prospective cohort of participants with cerebral small vessel disease aged 50-85 years. Gait (using GAITRite) and magnetic resonance imaging measures were assessed during baseline (2006-2007) and follow-up (2011 - 2012). Linear regression analysis was used to investigate the association between changes in conventional magnetic resonance and diffusion tensor imaging measures and gait decline. Tract-based spatial statistics analysis was used to investigate region-specific associations between changes in white matter integrity and gait decline. 56.2% were male, mean age was 62.9 years (SD8.2), mean follow-up duration was 5.4 years (SD0.2) and mean gait speed decline was 0.2 m/s (SD0.2). Stride length decline was associated with white matter atrophy (ß = 0.16, p = 0.007), and increase in mean white matter radial diffusivity and mean diffusivity, and decrease in mean fractional anisotropy (respectively, ß = - 0.14, p = 0.009; ß = - 0.12, p = 0.018; ß = 0.10, p = 0.049), independent of age, sex, height, follow-up duration and baseline stride length. Tract-based spatial statistics analysis showed significant associations between stride length decline and fractional anisotropy decrease and mean diffusivity increase (primarily explained by radial diffusivity increase) in multiple white matter tracts, with the strongest associations found in the corpus callosum and corona radiata, independent of traditional small vessel disease markers. White matter atrophy and loss of white matter integrity are associated with gait decline in older adults with small vessel disease after 5 years of follow-up. These findings suggest that progression of SVD might play an important role in gait decline.

Reduced functional connectivity within the primary motor cortex of patients with brachial plexus injury.

This study aims at the effects of traumatic brachial plexus lesion with root avulsions (BPA) upon the organization of the primary motor cortex (M1). Nine right-handed patients with a right BPA in whom an intercostal to musculocutaneous (ICN-MC) nerve transfer was performed had post-operative resting state fMRI scanning. The analysis of empirical functional correlations between neighboring voxels revealed faster correlation decay as a function of distance in the M1 region corresponding to the arm in BPA patients as compared to the control group. No differences between the two groups were found in the face area. We also investigated whether such larger decay in patients could be attributed to a gray matter diminution in M1. Structural imaging analysis showed no difference in gray matter density between groups. Our findings suggest that the faster decay in neighboring functional correlations without significant gray matter diminution in BPA patients could be related to a reduced activity in intrinsic horizontal connections in M1 responsible for upper limb motor synergies.

Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances.

Middle cerebral artery occlusion was performed in rats while the animals were inside the nuclear magnetic resonance (NMR) tomograph. Successful occlusion was confirmed by the collapse of amplitude on an electrocorticogram. The ultrafast NMR imaging technique UFLARE was used to measure the apparent diffusion coefficient (ADC) immediately after the induction of cerebral ischemia. ADC values of normal cortex and caudate-putamen were 726 +/- 22 x 10(-6) mm2/s and 659 +/- 17 x 10(-6) mm2/s, respectively. Within minutes of occlusion, a large territory with reduced ADC became visible in the ipsilateral hemisphere. Over the 2 h observation period, this area grew continuously. Quantitative analysis of the ADC reduction in this region showed a gradual ADC decrease from the periphery to the core, the lowest ADC value amounting to about 60% of control. Two hours after the onset of occlusion, the regional distribution of ATP and tissue pH were determined with bioluminescence and fluorescence techniques, respectively. There was a depletion of ATP in the core of the ischemic territory (32 +/- 20% of the hemisphere) and an area of tissue acidosis (57 +/- 19% of the hemisphere) spreading beyond that of ATP depletion. Regional CBF (rCBF) was measured autoradiographically with the iodo[14C]antipyrine method. CBF gradually decreased from the periphery to the ischemic core, where it declined to values as low as 5 ml 100 g-1. When reductions in CBF and in ADC were matched to the corresponding areas of energy breakdown and of tissue acidosis, the region of energy depletion corresponded to a threshold in rCBF of 18 +/- 14 ml 100 g-1 min-1 and to an ADC reduction to 77 +/- 3% of control. Tissue acidosis corresponded to a flow value below 31 +/- 11 ml 100 g-1 min-1 and to an ADC value below 90 +/- 4% of control. Thus, the quantification of ADC in the ischemic territory allows the distinction between a core region with total breakdown of energy metabolism and a corona with normal energy balance but severe tissue acidosis.

Characterization of middle cerebral artery occlusion infarct development in the rat using fast nuclear magnetic resonance proton spectroscopic imaging and diffusion-weighted imaging.

A nuclear magnetic resonance study of the middle cerebral artery occlusion in the rat is presented. Experiments were performed on seven animals before and after occlusion, which occurred in situ. The emphasis in this study was on evaluating rapid proton spectroscopic imaging. Data were acquired with experimental durations of between 4 and 15 minutes for a 32 by 32 spatial matrix, with 64 spectroscopic data points per spatial element. The spectroscopic data were interleaved with diffusion-weighted nuclear magnetic resonance water images of the same slice. The study was terminated at about 6 hours after occlusion. The brains were then frozen in liquid nitrogen for biochemical imaging. The results showed that the signal from N-acetyl aspartate decreased and that of lactate increased within the infarcted region. The temporal course of these intensity changes varied between animals. Nineteen cortical spreading depressions (CSD) were observed by electrophysiologic monitoring during the experiments. Of these, 11 could be unambiguously detected in the lactate images, and a further 3 were on the threshold of detectability. As only a single slice could be examined, it is possible that the centers of depression for the remaining 6 CSD were outside the slice. To the authors' knowledge, this is the first report of the measurement of CSD using proton spectroscopic imaging. Thus, it is shown that this method is valuable not only in following the continuous evolution of proton metabolites with a good spatial and temporal resolution, but also in observing transient phenomena which are believed to play an important role in the expansion of the infarcted territory.

Focal encephalopathy following methotrexate therapy. Administration via a misplaced intraventricular catheter.

Two patients with lymphoreticular malignant neoplasms and leptomeningeal tumor spread were treated with intraventricular administration of methotrexate via an Ommaya reservoir. The intraventricular instillation of methotrexate resulted in focal CNS damage in brain parenchyma inadvertently pierced by the shunt. Disorientation, aphasia, and right hemiparesis developed in both patients. Computed tomography disclosed a contrast-enhancing, low-density mass in the left cerebral cortex where the distal shunt tip was lodged. In one case the lesion was pathologically consistent with chronic inflammation. A lesion occurred in one patient despite repositioning of the shunt prior to methotrexate instillation. Shunt removal and administration of systemic corticosteroids resulted in resolution of symptoms in one patient.

Cortical reafferentation following left subcortical hemorrhage: a serial functional MR study.

A 48-year-old patient who had aphasia due to a left subcortical hemorrhage underwent three follow-up examinations to assess MR signal changes accompanying recovery. A word classification task was applied. During the 6-month follow-up period, we observed a dynamic change from negative toward positive blood oxygenation level-dependent MR signals, i.e., task-related reafferentation of eloquent cortices occurred. Clinical improvement from aphasia paralleled the MR signal changes.

Desquamative interstitial pneumonitis in children.

Interstitial pneumonitis in children is a rare and poorly understood disease. Controversy exists as to whether the varoius histologic changes encountered represent different disease or a spectrum of the same disease. Fourteen biopsy-confirmed cases of desquamative interstitial pneumonitis in children were seen at the Mayo Clinic between 1953 and 1975. A search of the literature revealed 14 additional cases but no series of exclusively desquamative interstitial pneumonitis. The most frequent symptoms were retardation of growth and dyspnea, often accompanied by cough. Tachypnea was the most common finding on examination; rales, cyanosis, and clubbing were variably present. The chest roentgenogram was distinctly abnormal in all cases; it usually revealed a combined interstitial and alveolar pattern extending bilaterally from the hilus to the base. Results of laboratory studies were nonspecific for desquamative interstitial pneumonitis. All 28 patients in this review were treated with corticosteroids; 17 (61 percent) survived. Desquamative interstitial pneumonitis was found in association with a variety of other major illnesses. The cause remains unknown.

Velocity selective radiofrequency pulse trains.

The incorporation of velocity-encoding gradient pulses in RF-pulse trains is proposed and examined. Velocity selective perturbation is shown to be analogous in many respects to the well established use of trains of short RF-pulses for chemical shift selective perturbation. Velocity selective perturbation is viable in a biomedical setting only if additional RF refocusing pulses are inserted between the individual RF-pulse elements. Aspects of velocity selective excitation saturation and inversion are examined, and new inversion pulse trains proposed. The selective perturbation of both flowing and stationary spins is demonstrated in phantoms and possible biomedical applications of these pulse trains are discussed.

Improved relapse-free survival in medulloblastoma utilizing modern techniques.

Between 1969 and 1979, 22 patients with medulloblastoma were treated by the same surgical group and radiation therapy group. The patients were divided into two groups because of the clinical availability in December 1974 of the computed tomographic (CT) scanner and of the operating microscope used in the initial surgical procedure. There were 11 patients in each group. The percentage of patients with a relapse-free survival in the group treated between 1969 and 1974 (Group 1) was 38% at 4 years. The survival in the 11 patients treated between 1974 and 1979 (Group 2) was 84% at 4 years. This improvement is statistically significant (P less than or equal to 0.001). All patients received the same dose of radiation. Efforts to minimize the tumor burden by total surgical resection did not increase postoperative morbidity or mortality. These results are discussed, along with the relative impact of the CT scan, total resection at operation, and increased focus for radiation therapy on the improved outcome.

Relationships between in-hospital and 30-day standardized hospital mortality: implications for profiling hospitals.

OBJECTIVE: To examine the relationship of in-hospital and 30-day mortality rates and the association between in-hospital mortality and hospital discharge practices. DATA SOURCES/STUDY SETTING: A secondary analysis of data for 13,834 patients with congestive heart failure who were admitted to 30 hospitals in northeast Ohio in 1992-1994. DESIGN: A retrospective cohort study was conducted. DATA COLLECTION: Demographic and clinical data were collected from patients' medical records and were used to develop multivariable models that estimated the risk of in-hospital and 30-day (post-admission) mortality. Standardized mortality ratios (SMRs) for in-hospital and 30-day mortality were determined by dividing observed death rates by predicted death rates. PRINCIPAL FINDINGS: In-hospital SMRs ranged from 0.54 to 1.42, and six hospitals were classified as statistical outliers (p <.05); 30-day SMRs ranged from 0.63 to 1.73, and seven hospitals were outliers. Although the correlation between in-hospital SMRs and 30-day SMRs was substantial (R = 0.78, p < .001), outlier status changed for seven of the 30 hospitals. Nonetheless, changes in outlier status reflected relatively small differences between in-hospital and 30-day SMRs. Rates of discharge to nursing homes or other inpatient facilities varied from 5.4 percent to 34.2 percent across hospitals. However, relationships between discharge rates to such facilities and in-hospital SMRs (R = 0.08; p = .65) and early post-discharge mortality rates (R = 0.23; p = .21) were not significant. CONCLUSIONS: SMRs based on in-hospital and 30-day mortality were relatively similar, although classification of hospitals as statistical outliers often differed. However, there was no evidence that in-hospital SMRs were biased by differences in post-discharge mortality or discharge practices.

An assessment of eddy current sensitivity and correction in single-shot diffusion-weighted imaging.

Artefacts caused by eddy currents are a major problem in diffusion weighted imaging. This is particularly acute in experiments in which a number of images with differing degrees of diffusion weighting and/or differently oriented diffusion-weighting gradients need to be combined. The echo-planar imaging sequence is particularly sensitive to the effects of residual eddy currents, especially due to the low bandwidth in the phase-encoding direction. Two published schemes are investigated regarding the effectiveness of eddy current correction. That of Jezzard et al (1998 Magn. Reson. Med. 39 801-12) requires the acquisition of additional experimental data in order to perform a post-acquisition correction, whereas that of Wider et al (1994 J. Magn. Reson. A 108 255-8) attempts to reduce the eddy currents directly. It is found that the latter experiment gives a somewhat superior performance and a combination of the two approaches results in an almost complete elimination of artefact. An alternative single-shot imaging experiment to echo-planar imaging is given by sequences based on fast spin-echo methods, which should be insensitive to the effects of constant eddy currents. It is shown that the intrinsic eddy-current-related artefact level in such experiments is indeed low, residual artefacts being attributed to eddy current decay during the echo train. In situations of poor main magnetic field homogeneity or large eddy currents such sequences may be gainfully used instead of echo-planar imaging.

Concomitant magnetic field gradients and their effects on imaging at low magnetic field strengths.

Low-field NMR imaging systems which use large amplitude field gradient pulses (e.g., in flow velocity encoding) may be subject to the undesirable effects of concomitant gradients. We demonstrate the effects of these extra gradients, which arise from Maxwell's equations, and show that the resultant image phase shifts and amplitude changes are consistent with theory.

Dynamic imaging with T2* contrast using U-FLARE.

Dynamic changes in T2* in the rat brain induced by the injection of Gd-DTPA are monitored using the U-FLARE sequence. Sensitivity to T2* is easily introduced into this sequence and may be freely varied. The images obtained display an adequate spatial resolution and contrast, for a temporal resolution of 1 s. Intensity-time curves and parametric images of regional cerebral blood flow (rCBV) are presented for three different blood pCO2 values. The results presented clearly demonstrate that U-FLARE is a viable method for dynamically measuring changes in T2*, and thus has application in imaging of both perfusion and functional activation.

Incidence of apparent restricted diffusion in three different models of cerebral infarction.

High speed magnetic resonance imaging (MRI) and short diffusion times are used to investigate the appearance of restricted diffusion in three different models of cerebral infarction. The models are: the middle cerebral artery occlusion (MCAO) model in the rat, the carotid occlusion model in the gerbil, and the Rose Bengal microvascular occlusion model in the rat. All three were investigated for 16 b-values equally spaced between 10 and 1510 s/mm2 using two distinct experiments. In the ct (constant time) experiment, the diffusion time was held constant at 11.7 ms while the b-value was varied with the gradient strength. In the cg (constant gradient) experiment, the gradient strength was held constant and the b-value increased by varying the diffusion time from 4.4 to 11.7 ms. A monoexponential decay of the signal intensity with b-value in the ct experiment accompanied by nonmonoexponential (NME) decay in the cg experiment is indicative of restricted diffusion. As this phenomenon is detectable only at short diffusion times, it cannot be due to restriction by impermeable membranes, and we have thus termed this apparent restriction. For the MCAO model and the carotid occlusion model, apparent restriction was found both inside the infarct territory and in some regions outside it. No definite evidence for restriction was found for the Rose Bengal model, which was, however, only studied from 24 h post-insult.

Pretransplant chemotherapy in pediatric hepatocellular carcinoma.

The prognosis for pediatric patients with hepatocellular carcinoma is poor, except for fewer than half the patients, who can be rendered disease-free with conventional liver resection. Multicentric, bilobar liver cancer remains unresectable, even after radiation and chemotherapy. Liver transplantation alone for primary hepatic cancer has had limited success. Chemotherapy has been reserved for use after transplantation, with little demonstrable benefit. A pilot program of pretransplant chemotherapy was undertaken. Four adolescent patients with unresectable, multicentric, bilobar hepatocellular carcinoma were staged noninvasively, underwent chemotherapy followed by a final staging laparotomy, and then had liver transplantation. Three of the four patients survived and have no evidence of recurrence 84, 67, and 47 months after diagnosis and 76, 65, and 44 months after transplantation. Pretransplant chemotherapy has four potential advantages: (1) minimized risk of posttransplant opportunistic infections, (2) less tumor bulk at the time of transplantation, (3) fewer local recurrences, and (4) a lower rate of metastasis.

Systemic lupus erythematosus in children: the complex problems of diagnosis and treatment encountered in 101 such patients at the Mayo Clinic.

Between 1945 and 1970, 101 children (86 girls and 15 boys) with systemic lupus erythematosus were evaluated at the Mayo Clinic. Only 9 children were less than 9 years old at the time of diagnosis. The most frequent presenting complaint was arthralgia; fever, fatigue, and a "butterfly" malar rash also were common. Renal involvement, found in more than 76 per cent of patients, was a prognostically poor sign. The overall survival of children with renal involvement is improved by the use of adequate steroid therapy.