Hedok Lee

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimers disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimers disease susceptibility and progression in the live human brain.

Neural correlates of emotion processing in borderline personality disorder

Emotional instability is a hallmark feature of borderline personality disorder (BPD), yet its biological underpinnings are poorly understood. We employed functional magnetic resonance imaging (fMRI) to compare patterns of regional brain activation in BPD patients and healthy volunteers as they process positive and negative social emotional stimuli. fMRI images were acquired while 19 BPD patients and 17 healthy controls (HC) viewed emotion-inducing pictures from the International Affective Pictures System set. Activation data were analyzed with SPM5 ANCOVA models to derive the effects of diagnosis and stimulus type. BPD patients demonstrated greater differences in activation than controls, when viewing negative pictures compared with rest, in the amygdala, fusiform gyrus, primary visual areas, superior temporal gyrus (STG), and premotor areas, while healthy controls showed greater differences than BPD patients in the insula, middle temporal gyrus and dorsolateral prefrontal cortex (BA46). When viewing positive pictures compared with rest, BPD patients showed greater differences in the STG, premotor cortex, and ventrolateral prefrontal cortex. These findings suggest that BPD patients show greater amygdala activity and heightened activity of visual processing regions relative to findings for HC subjects in the processing of negative social emotional pictures compared with rest. The patients activate neural networks in emotion processing that are phylogeneticall older and more reflexive than those activated by HC subjects.

Cerebrovascular effects of hemodialysis in chronic kidney disease

Patients with end-stage renal disease (ESRD) undergoing hemodialysis are known to suffer cognitive deficits and stroke of unknown etiology. It has been suspected that the treatment itself may contribute to the syndrome by unknown mechanisms, which we investigated in this study. End-stage renal disease patients on hemodialysis (n = 19) or peritoneal dialysis (PD, n = 5) were compared with 14 healthy controls. Subjects participated in magnetic resonance imaging (MRI) measurements of cerebral atrophy, cerebral blood flow (CBF) arterial spin labeled-MRI (ASL-MRI), quantitative Doppler blood flow through the internal carotid artery, and cerebral oxymetry. The Doppler and oxymetry procedures were also performed at the beginning and end of a single hemodialysis session. End-stage renal disease patients on hemodialysis showed significant cerebral atrophy, associated with longer hemodialysis duration and cognitive deficits, including focal bilateral lesions in the caudate nucleus and midbrain. Cerebral oxygenation was extremely low before dialysis (rSO2 41 ± 13, compared with 70 ± 2 in controls, P < 0.02) and improved only slightly after dialysis. Carotid blood flow was also very low at the start of dialysis (115 ± 28mL/sec, versus 193 ± 56 in controls, P < 0.005) but normalized at the end of the session (181 mL/sec). The PD patients showed intermediate values, between the hemodialysis and controls. Notably, duration of hemodialysis treatment predicted global gray-matter volume (r = −0.74), change of blood flow during dialysis (r = −0.65), and baseline rSO2 (r = −0.65). The findings suggest that ESRD patients on hemodialysis suffer low CBF during the interdialytic cycle. Coupled with low cerebral oxygenation levels and atherosclerosis, this may contribute significantly to the etiology of the observed cerebral atrophy, cognitive deficits, and high stroke prevalence.

MR Imaging of Familial Creutzfeldt-Jakob Disease : A Blinded and Controlled Study

BACKGROUND AND PURPOSE: The E200K mutation of the PRNP (prion protein) gene is the most common cause of familial Creutzfeldt-Jakob disease (fCJD), which has imaging and clinical features that are similar to the sporadic form. The purpose of this study was to conduct a controlled and blinded evaluation of the sensitivity and specificity of MR imaging in this unique population. MATERIALS AND METHODS: We compared the MR imaging characteristics of 15 early stage familial CJD patients (age, 60 ± 7 years) with a group of 22 healthy subjects from the same families (age, 61 ± 8 years). MR imaging included diffusion-weighted imaging (DWI), T2-weighted fast spin-echo imaging, and a fluid-attenuated inversion recovery (FLAIR) sequence. The scans were rated for abnormalities by an experienced neuroradiologist blind to diagnosis, group assignment, age, and sex. RESULTS: Thirteen of 15 fCJD subjects had abnormal MR imaging. FLAIR signal intensity abnormality in the caudate or putamen nuclei demonstrated a sensitivity of 87% and specificity of 91%. DWI abnormality in the caudate nucleus showed a sensitivity of 73% and a specificity of 100%. Abnormalities in the thalamus (6 patients), cingulate gyrus (6 patients), frontal lobes (4 patients), and occipital lobes (3 patients) were best detected with DWI. No signal intensity abnormalities were demonstrated in the cerebellum. T2-weighted and T1-weighted sequences were uninformative. CONCLUSIONS: FLAIR and DWI abnormalities in the caudate nucleus and putamen offer the best sensitivity and specificity for diagnosing fCJD. Our findings support recent recommendations that MR imaging should be added to the diagnostic evaluation of CJD.

The metabolomic profile during isoflurane anesthesia differs from propofol anesthesia in the live rodent brain

Development of noninvasive techniques to discover new biomarkers in the live brain is important to further understand the underlying metabolic pathways of significance for processes such as anesthesia-induced apoptosis and cognitive dysfunction observed in the undeveloped brain. We used in vivo proton magnetic resonance spectroscopy and two different signal processing approaches to test the hypothesis that volatile (isoflurane) and intravenous (propofol) anesthetics at equipotent doses produce distinct metabolomic profiles in the hippocampus and parietal cortex of the live rodent. For both brain regions, prolonged isoflurane anesthesia was characterized by higher levels of lactate (Lac) and glutamate compared with long-lasting propofol. In contrast, propofol anesthesia was characterized by very low concentrations of Lac ([lac]) as well as glucose. Quantitative analysis revealed that the [lac] was fivefold higher with isoflurane compared with propofol anesthesia and independent of [lac] in blood. The metabolomic profiling further demonstrated that for both brain regions, Lac was the most important metabolite for the observed differences, suggesting activation of distinct metabolic pathways that may impact mechanisms of action, background cellular functions, and possible agent-specific neurotoxicity.

Metabolomic Profiling of Children’s Brains Undergoing General Anesthesia with Sevoflurane and Propofol

Background:We recently applied proton magnetic resonance spectroscopy (1HMRS) to investigate metabolic consequences of general anesthesia in the rodent brain, and discovered that isoflurane anesthesia was characterized by higher concentrations of lactate, glutamate, and glucose in comparison with propofol. We hypothesized that the metabolomic differences between an inhalant and intravenous anesthetic observed in the rodent brain could be reproduced in the human brain. Methods:1HMRS-based metabolomic profiling was applied to characterize the cerebral metabolic status of 59 children undergoing magnetic resonance imaging during anesthesia with either sevoflurane or propofol. 1HMRS scans were acquired in the parietal cortex after approximately 60 min of anesthesia. Upon emergence the children were assessed using the pediatric anesthesia emergence delirium scale. Results:With sevoflurane anesthesia, the metabolic signature consisted of higher concentrations of lactate and glucose compared with children anesthetized with propofol. Further, a correlation and stepwise regression analysis performed on emergence delirium scores in relation to the metabolic status revealed that lactate and glucose correlated positively and total creatine negatively with the emergence delirium score. Conclusions:Our results demonstrating higher glucose and lactate with sevoflurane in the human brain compared with propofol could reflect greater neuronal activity with sevofluane resulting in enhanced glutamate-neurotransmitter cycling, increased glycolysis, and lactate shuttling from astrocytes to neurons or mitochondrial dysfunction. Further, the association between emergence delirium and lactate suggests that anesthesia-induced enhanced cortical activity in the unconscious state may interfere with rapid return to “coherent” brain connectivity patterns required for normal cognition upon emergence of anesthesia.

Enhanced Detection of Diffusion Reductions in Creutzfeldt-Jakob Disease at a Higher B Factor

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) is sensitive to the cerebral manifestations of human prion diseases. The magnitude of diffusion weighting, termed “b factor,” has only been evaluated at the standard b = 1000 s/mm2. This is the first rigorous evaluation of b = 2000 s/mm2 in Creutzfeldt-Jakob Disease (CJD). MATERIALS AND METHODS: We compared DWI characteristics of 13 patients with CJD and 15 healthy controls at b = 1000 s/mm2 and b = 2000 s/mm2. Apparent diffusion coefficients (ADC) were computed and analyzed for the whole brain by voxel-wise analysis (by SPM5) as well as in anatomically defined volumes of interest (by FSL FIRST). RESULTS: Measured ADC was significantly lower (by approximately 5%–15%) at b = 2000 s/mm2 than at b = 1000 s/mm2 and significantly lower in patients than in controls. The differences between patients and controls were greater and more extensive at b = 2000 s/mm2 than at b = 1000 s/mm2 in the expected regions (thalamus, putamen, and caudate nucleus). CONCLUSIONS: Because higher b factors change the absolute value of observed ADC, as well as lesion detection, care should be taken when combining studies using different b factors. While the clinical application of high b factors is currently limited by a low signal intensity–to-noise ratio, it may offer more information in questionable cases, and our results confirm and extend the central role of diffusion imaging in human prion diseases.

Thalamo-striatal diffusion reductions precede disease onset in prion mutation carriers

Human prion diseases present substantial scientific and public health challenges. They are unique in being sporadic, infectious and inherited, and their pathogen is distinct from all other pathogens in lacking nucleic acids. Despite progress in understanding the molecular structure of prions, their initial cerebral pathophysiology and the loci of cerebral injury are poorly understood. As part of a large prospective study, we analysed early diffusion MRI scans of 14 patients with the E200K genetic form of Creutzfeldt-Jakob Disease, 20 healthy carriers of this mutation that causes the disease and 20 controls without the mutation from the same families. Cerebral diffusion was quantified by the Apparent Diffusion Coefficient, and analysed by voxel-wise statistical parametric mapping technique. Compared to the mutation-negative controls, diffusion was significantly reduced in a thalamic-striatal network, comprising the putamen and mediodorsal, ventrolateral and pulvinar thalamic nuclei, in both the patients and the healthy mutation carriers. With disease onset, these diffusion reductions intensified, but did not spread to other areas. The caudate nucleus was reduced only after symptomatic onset. These findings indicate that cerebral diffusion reductions can be detected early in the course of Creutzfeldt-Jakob Disease, and years before symptomatic onset in mutation carriers, in a distinct subcortical network. We suggest that this network is centrally involved in the pathogenesis of Creutzfeldt-Jakob Disease, and its anatomical connections are sufficient to account for the common symptoms of this disease. Further, we suggest that the abnormalities in healthy mutation-carrying subjects may reflect the accumulation of abnormal prion protein and/or associated vacuolation at this time, temporally close to disease onset.

Cerebral White Matter Disruption in Creutzfeldt-Jakob Disease

BACKGROUND AND PURPOSE: Human prion diseases are known to cause gray matter degeneration in specific cerebral structures, but evidence for white matter involvement is scarce. We used DTI to test the hypothesis that white matter integrity is disrupted in human CJD during the early stages of the disease. MATERIALS AND METHODS: Twenty-one patients with the E200K variant of CJD and 19 controls participated in DTI studies conducted on a 1.5T MR imaging scanner. The data were quantitatively analyzed and mapped with a voxelwise TBSS method. RESULTS: We found significant reductions of FA in patients with CJD in distinct and functionally relevant white matter pathways, including the corticospinal tract, internal capsule, external capsule, fornix, and posterior thalamic radiation. Moreover, these FA deficits increased with disease duration, and were mainly determined by increase of radial diffusivity, suggesting elevated permeability of axonal membranes. CONCLUSIONS: The findings suggest that some of the symptoms of CJD may be caused by a functional dysconnection syndrome, and that the leukoencephalopathy is progressive and detectable fairly early in the course of the disease.

MRI Detection of the Cerebellar Syndrome in Creutzfeldt–Jakob Disease

Creutzfeldt–Jakob Disease (CJD) is characterized by bilateral basal ganglia hyperintensities on T2W and diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) scans, consistent with its extrapyramidal neurological manifestations. MRI is diagnostically uninformative about the cerebellar symptoms, equally prominent in CJD. This study was undertaken to explain this apparent paradox. Eleven CJD patients with definite cerebellar or brain stem symptoms were selected from a large prospective study, as well as 11 healthy controls matched for age and gender. All subjects participated in a standardized MRI protocol, including SPGR, fluid-attenuated inversion recovery (FLAIR), DWI and diffusion tensor imaging (DTI). All subjects underwent detailed examination by a neurologist blinded to the radiological findings, who predicted the expected site of cerebral abnormalities. MRI showed good sensitivity for the abnormalities predicted in the cortex (80–90%) and basal ganglia (100%). None of the standard MRI sequences, including DWI, DTI, and FLAIR, revealed any tissue abnormalities in cerebellum or brain stem. Apparent diffusion coefficient (ADC) values, however, were substantially and significantly elevated in several cerebellar structures, where also the volumetric (VBM) analysis revealed elevated cerebrospinal fluid volume, suggesting focal cerebellar atrophy in these CJD patients. In patients with CJD, DWI appears sensitive to the reduced diffusivity in cortex and basal ganglia but insensitive to cerebellar involvement. We propose that the radiological hallmark of cerebellar pathology in CJD is atrophy, revealed quantitatively by both VBM and elevated diffusivity, which is identifiable on ADC maps but poorly visualized in nonquantitative DWI images.