Biomedical subjects
Jean-Claude Baron
Publications and source records attributed to Jean-Claude Baron.
The diffusion-weighted lesion in acute stroke: heterogeneous patterns of flow/metabolism uncoupling as assessed by quantitative positron emission tomography.
BACKGROUND: To investigate what the hyperintense lesion in diffusion-weighted imaging (DWI) of acute ischaemic stroke represents metabolically, we prospectively imaged acute carotid-territory stroke patients with DWI along with fully quantitative positron emission tomography (PET), which gives physiological maps of cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2) and the oxygen extraction fraction (OEF). METHOD: Of 10 patients who consented, 5 (3 males, 2 females, 53-84 years, NIHSS 6-16) completed the imaging protocol of back-to-back DWI and PET within 21 (mean 15.7, range 7-21) h of stroke onset. All images were co-registered with the DWI lesion forming a region of interest (ROI) that was transferred to the PET parametric maps (OEF, CBF, CMRO2). Patterns of blood flow and metabolism were assessed within the DWI ROI. RESULTS: Within the DWI lesions, the following patterns were observed: very low CBF and CMRO2/variable OEF; low CBF/high OEF, and high CBF/low OEF. There was a heterogeneity of patterns between and within DWI lesions. In addition, areas of hyperperfusion (with low OEF) and areas of hypoperfusion (with high OEF) were seen outside the DWI lesions. CONCLUSION: The DWI lesion does not have a single flow/metabolism counterpart, suggesting that it reflects various stages of the ischaemic process.
The pathophysiology of watershed infarction in internal carotid artery disease: review of cerebral perfusion studies.
BACKGROUND AND PURPOSE: In carotid disease, infarcts can occur in the cortical as well as internal watershed (WS), or both. Better understanding the pathophysiology of WS infarcts would guide treatment. Two distinct hypotheses, namely low-flow and micro-embolism, are equally supported by neuropathological and physiological studies. Here we review the evidence regarding the mechanisms for WS stroke in carotid disease and whether they differ between cortical and internal WS infarcts. SUMMARY OF REVIEW: After a brief account of the anatomy of the WS and the cerebrovascular physiology in circumstances of low perfusion pressure, the literature concerning the mechanisms of WS infarction in carotid disease is reviewed and discussed with emphasis on imaging and ultrasound studies of the cerebral hemodynamics. CONCLUSIONS: The evidence strongly favors a hemodynamic mechanism for internal WS infarction, especially regarding the so-called rosary-like pattern in the centrum semiovale. However, the relationships between cortical WS infarction and hemodynamic compromise appear more complicated. Thus, although severe hemodynamic compromise appears to underlie combined cortical and internal WS infarction, artery-to-artery embolism may play an important role in isolated cortical WS infarcts. Based on the high prevalence of microembolic signals documented by ultrasound in symptomatic carotid disease, a recent hypothesis postulates that embolism and hypoperfusion play a synergetic role, according to which small embolic material prone to lodge in distal field arterioles would be more likely to result in cortical micro-infarcts when chronic hypoperfusion prevails. Future studies combining imaging of brain perfusion, diffusion-weighted imaging, and ultrasound detection of microembolic signals should help resolve these issues.
Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.
The effects of sodium nitroprusside (SNP), a potent hypotensive agent, on cerebral blood flow (CBF) have been extensively studied in clinical and experimental situations but the results remain controversial. Whereas its properties would predict a dilatation of cerebral blood vessels, most studies report either no change or a decrease in CBF. The aim of this study was to investigate the effects of SNP on CBF, cerebral blood volume (CBV), and cerebral oxygen metabolism (CMRO2), by means of positron emission tomography in the anaesthetized baboon. Measurements were performed during normotension (mean arterial pressure (MABP): 97+/-16 mm Hg) and repeated following SNP-induced hypotension (MABP: 44+/-9 mm Hg). Sodium nitroprusside led to an increase in CBF and CBV (+30% and +37%, respectively, P<0.05), whereas no change in CMRO2 was noted. Linear regression analysis of CBF values as a function of MABP confirmed that CBF increases when MABP is reduced by SNP. The comparison between these cerebrovascular changes and those found during trimetaphan-induced hypotension in our previously published studies further argues for a direct dilatatory effect of SNP on cerebral blood vessels.
FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment.
The accurate prediction, at a pre-dementia stage of Alzheimer's disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.
The potential for utilizing the "mirror neurone system" to enhance recovery of the severely affected upper limb early after stroke: a review and hypothesis.
Recovery of upper limb movement control after stroke might be enhanced by repetitive goal-directed functional activities. Providing such activity is challenging in the presence of severe paresis. A possible new approach is based on the discovery of mirror neurons in the monkey cortical area F5, which are active both in observing and executing a movement. Indirect evidence for a comparable human "mirror neurone system" is provided by functional imaging. The primary motor cortex, the premotor cortex, other brain areas, and muscles appropriate for the action being observed are probably activated in healthy volunteers observing another's movement. These findings raise the hypothesis that observation of another's movement might train the movement execution system of stroke patients who have severe paresis to bring them to the point at which they could actively participate in rehabilitation consisting of goal-directed activities. The point of providing an observation therapy would be to facilitate the voluntary production of movement; therefore, the condition of interest would be observation with intent to imitate. However, there is as yet insufficient evidence to enable the testing of this hypothesis in stroke patients. Studies in normal subjects are needed to determine which brain sites are activated in response to observation with intent to imitate. Studies in stroke subjects are needed to determine how activation is affected after damage to different brain areas. The information from such studies should aid identification of those stroke patients who might be most likely to benefit from observation to imitate and therefore guide phase I clinical studies.
'In the course of time': a PET study of the cerebral substrates of autobiographical amnesia in Alzheimer's disease.
Neuroimaging studies in healthy subjects have yielded controversial results about the neural substrates of autobiographical memory. Moreover, the neural networks responsible for autobiographical amnesia remain poorly understood. Since autobiographical memory is frequently altered in Alzheimer's disease (AD), we used this degenerative disorder as a model and applied a correlative approach between resting cerebral glucose utilization (CMRGlc) and temporally graded memory scores to identify the cerebral structures whose synaptic dysfunction subserves the impairment in autobiographical memory. To this end, we studied a group of 17 AD patients with mild to moderate dementia in whom autobiographical memory was assessed using a specially designed task from three broad time periods [the previous 5 years (period A); middle age (period B); and teenage and childhood (period C)], and measures of resting CMRGlc were obtained with PET. The patients performed less well than a control group for all three time periods and showed the expected temporal gradient, with the most remote period being best preserved (Ribot's gradient). Qualitative analysis showed that remote memories concerned generic (i.e. semantic) rather than specific (i.e. episodic) events. We found a significant positive correlation between autobiographical scores and the metabolism of the right hippocampus (extending to the lingual gyrus), restricted to period A. In addition, period A scores were significantly correlated with the right middle and inferior frontal gyri and the right middle temporal gyrus. Period B scores correlated chiefly with the prefrontal cortex bilaterally (bilateral superior, bilateral middle and right inferior gyri). Metabolic correlations with period C scores were restricted to the left middle frontal gyrus. These findings show striking differences in metabolic correlations with the autobiographical time period, in agreement with prevalent theories of normal functioning of human memory. Thus, in accordance with theories of long-term memory consolidation, we find the expected implication of the hippocampal region in the recall of recent memories, and a disengagement of this structure when the retention interval is beyond 5 years. Moreover, according to the hemispheric encoding/retrieval asymmetry model based on activation studies in healthy subjects, the fact that recent memories preferentially involved the right prefrontal cortex whereas remote memories involved the left prefrontal cortex supports the notion of semanticization of memories with time interval, such that preserved remote memories in AD have a predominantly semantic character.
Executive processes in Parkinson's disease: FDG-PET and network analysis.
It is assumed widely that the clinical expression of Parkinson's Disease (PD), both motor and cognitive, is subtended by topographically distributed brain networks. However, little is known about the functional neuroanatomy of executive dysfunction in PD. Our objective was to validate further in a PD group the use of network analysis to assess the relationship between executive processes and pathological disorganization of frontostriatal networks. We studied 15 patients with idiopathic PD, and 7 age-matched normal controls, using resting [(18)F]fluorodeoxyglucose (FDG) and high-resolution positron emission tomography (PET). We carried out network analysis on regional metabolic data to identify specific covariation patterns associated with motor and executive dysfunction. We detected two independent patterns relating respectively to the two clinical abnormalities. The first pattern (principal component 1) was topographically similar to that described previously in other PD populations. Subject scores for this pattern discriminated patients from controls and correlated significantly with bradykinesia ratings (P = 0.013, r = 0.655) in PD patients. The second pattern (principal component 2) was characterized by relative ventromedial frontal, hippocampal, and striatal hypometabolism, associated with mediodorsal thalamic hypermetabolism. In the PD group, scores from this pattern correlated with scores on the conditional associative learning (CAL; P = 0.01, r = 0.690) and the Brown Peterson paradigm (BPP; P = 0.017, r = -0.651) tests, respectively assessing strategy and planning, and working memory. According to these findings, the networks subserving bradykinesia and executive dysfunction in PD seems to be topographically distinct and to involve different aspects of subcortico-cortical processing.
Re-experiencing old memories via hippocampus: a PET study of autobiographical memory.
The time-scale of medial temporal lobe (MTL) involvement in storage and retrieval of episodic memory is keenly debated. To test competitive theories of long-term memory consolidation, the present work aimed at characterizing which cerebral regions are involved during retrieval of recent and remote strictly episodic autobiographical memory. Using positron emission tomography (PET), we examined mental retrieval of recent (0-1 year) and remote (5-10 years) autobiographical memories, controlling for the nature of the autobiographical memories (i.e., specificity, state of consciousness, vividness of mental visual imagery, emotion) retrieved during scanning by behavioral measures assessed at debriefing for each event recalled. Cognitive results showed that specificity and emotion did not change with time interval although both autonoetic consciousness and mental image quality were significantly higher for recent memories, suggesting an underlying shift in the phenomenal experience of remembering with the passage of time. The SPM analysis revealed common activations during the recollection of recent and remote memories that involved a widespread but mainly left-sided cerebral network, consistent with previous studies. Subtraction analysis demonstrated that the retrieval of recent (relative to remote) autobiographical memories principally activated the left dorsolateral prefrontal cortex whereas the retrieval of remote (relative to recent) autobiographical memories activated the inferior parietal cortex bilaterally. ROIs analysis revealed more hippocampal activity for remote memories than for recent ones and a preferentially right-sided involvement of the hippocampal responses whatever the remoteness of autobiographical memories. New insights based on higher hippocampal response to the remoteness of episodic autobiographical memories challenge the standard model and are less discrepant with the multiple trace theory.
Outcome of acutely ischemic brain tissue in prolonged middle cerebral artery occlusion: a serial positron emission tomography investigation in the baboon.
Thrombolysis within 3 to 6 hours of symptom onset is recommended therapy for acute middle cerebral artery (MCA) stroke, but recent imaging studies in humans suggest that the penumbra may last much longer in some patients. It is therefore important to study the events that take place with occlusions that last longer than 6 hours. Based upon positron emission tomography (PET), the tissue with high oxygen extraction fraction (OEF) is at risk of infarction. In a previous sequential PET study in anesthetized baboons, we documented that when reperfusion was initiated at 6 hours after MCA occlusion, the region with the acutely highest OEF was not incorporated within the final magnetic resonance imaging (MRI)-defined infarct, suggesting reperfusion prevented such demise. In agreement with this hypothesis, we report here using the same sequential PET paradigm with final chronic-stage volume MRI that a 20-hour MCA occlusion resulted in, on average, 36% of the highest OEF area being recruited into the final infarct. We also found that the portion of the highest OEF area that went on to infarct had at the earliest time-point significantly lower cerebral blood flow and cerebral oxygen metabolism (mean reductions relative to unoccluded side, 56% and 32%, respectively) than the portion that did not (41% and 11%, respectively) and that some reperfusion occurred in the latter at second time-point, that is, before recanalization. Thus, apart from duration of occlusion, the fate of the at-risk tissue is predicated by the initial severity of the ischemia as well as by early secondary events such as partial spontaneous reperfusion.
Imaging the ischaemic penumbra.
PURPOSE OF REVIEW: Imaging the penumbra is essential, not only to identify patients who might benefit from thrombolysis, but also to further understanding of the ischaemic process, thereby potentially revealing new opportunities for therapeutic intervention. Here we review recent imaging studies of the acute stroke process. RECENT FINDINGS: Perfusion-computed tomography and computed tomography angiography enable assessment of the haemodynamic status and site of occlusion, leading to their promising use in guiding thrombolysis. The magnetic resonance concept of the diffusion-perfusion 'mismatch' being representative of penumbra appears to be an oversimplification. The mapping of simple variables such as time-to-peak might not directly reveal true penumbral perfusion levels. Also, lesions seen with diffusion-weighted imaging may be reversible as a result of early reperfusion. This reversal with subsequent normalization may represent selective neuronal damage. Late secondary injury, as indicated by the reappearance of the diffusion-weighted imaging lesion, has recently been documented; the mechanisms are unknown but form potential targets for future therapies. Despite these caveats, diffusion-weighted imaging-perfusion-weighted imaging remains the most useful approach to map the pathophysiology of stroke in the clinical setting. Acute/subacute flumazenil positron emission tomography studies are being used as markers of neuronal integrity to help shed further light on infarction thresholds, and potentially document selective neuronal loss. F-labelled fluoromisonidazole positron emission tomography imaging of brain hypoxia documents the temporal and spatial progression of the penumbra. SUMMARY: The goal of understanding the complex process that is acute ischaemia in stroke, and subsequently the development of therapeutic strategies, continues to be advanced by imaging the penumbra in novel ways.
Does the acute diffusion-weighted imaging lesion represent penumbra as well as core? A combined quantitative PET/MRI voxel-based study.
In acute ischemic stroke, the diffusion-weighted imaging (DWI) lesion is widely held to represent the core of irreversible damage and is therefore crucial in selecting patients for thrombolysis. However, recent research suggests it may also represent penumbra. An illustrative patient was imaged 7 hours after stroke onset with back-to-back 3T diffusion tensor imaging and quantitative positron emission tomography, which showed a DWI lesion and misery perfusion, respectively. Using previously validated voxel-based probabilistic CBF, CMRO2, and Oxygen Extraction Fraction (OEF) thresholds, the authors show that the DWI lesion contained not only core but also substantial proportions of penumbra. Also, severe apparent diffusion coefficient reductions were present within the potentially salvageable penumbra as well as in the core. These findings have potential implications regarding treatment decisions.
Neuroimaging in stroke recovery: a position paper from the First International Workshop on Neuroimaging and Stroke Recovery.
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Voxel-based mapping of cortical ischemic damage using Tc 99m L,L-ethyl cysteinate dimer SPECT in acute stroke.
BACKGROUND AND PURPOSE: When performed soon after stroke onset, single-photon emission computed tomography (SPFCT) with hexamethylpropylenamine oxime or Tc 99m L,L-ethyl cysteinate dimer (ECD) has significant added predictive value compared to neurological scores. With ECD SPECT, the degree of tracer uptake reduction predicts neurological recovery, and using a 40% threshold to characterize irreversibly damaged tissue (IDT), significant correlations have been observed. However, correlations between this uptake threshold and tissue outcomes have not been assessed. The purpose of this study was to validate the 40% ECD uptake threshold for the probabilistic mapping of IDT using an automatic, voxel-based approach. METHODS: In 10 acute stroke patients, the authors first compared early ECD SPECT and late coregistered magnetic resonance imaging (MRI) data and assessed for IDT and "tissue at risk" (i.e., tissue with ECD uptake below and above 40%) the percentage of voxels ultimately infarcted and noninfarcted on late brain MRI. They then assessed the correlations between the volumes of brain tissue compartments and subsequent neurological recovery. Finally, to assess whether visual SPECT analysis is reliable compared to the more complex voxel-based approach, the authors compared the predictive value of the 2 methods for neurological recovery. RESULTS: The majority of IDT voxels (average = 84%), defined by ECD uptake < 40%, evolved toward infarction, and 51.8% to 100% of at-risk voxels (average = 89%) escaped infarction. The extent of IDT correlated significantly with neurological recovery (P = .0009). There was good agreement between visual and voxel-based analyses (P = .0004). CONCLUSION: The results support the validity of the ECD uptake thresholds chosen, suggesting that ECD uptake can reflect neuronal viability and that ECD SPECT can be useful for the early detection of potentially salvageable tissue and irreversible damage. These preliminary results encourage the use of this method in a clinical setting for fast decision making in choosing acute therapy.
Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction.
UNLABELLED: We present software for integrated analysis of brain PET studies and coregistered segmented MRI that couples a module for automated placement of regions of interest (ROI) with 4 alternative methods for partial-volume-effect correction (PVEc). The accuracy and precision of these methods have been measured using 4 simulated (18)F-FDG PET studies with increasing degrees of atrophy. METHODS: The software allows the application of a set of labels, defined a priori in the Talairach space, to segmented and coregistered MRI. Resulting ROIs are then transferred onto the PET study, and corresponding values are corrected according to the 4 PVEc techniques under investigation, providing corresponding corrected values. To evaluate the PVEc techniques, the software was applied to 4 simulated (18)F-FDG PET studies, introducing increasingly larger experimental errors, including errors in coregistration (0- to 6-pixel misregistration), segmentation (-13.7% to 14.1% gray matter [GM] volume change) and resolution estimate errors (-16.9% to 26.8% full-width-at-half-maximum mismatch). RESULTS: Even in the absence of segmentation and coregistration errors, uncorrected PET values showed -37.6% GM underestimation and 91.7% WM overestimation. Voxel-based correction only for the loss of GM activity as a result of spill-out onto extraparenchymal tissues left a residual underestimation of GM values (-21.2%). Application of the method that took into account both spill-in and spill-out effects between any possible pair of ROIs (R-PVEc) and of the voxel-based method that corrects also for the WM activity derived from R-PVEC (mMG-PVEc) provided an accuracy above 96%. The coefficient of variation of the GM ROIs, a measure of the imprecision of the GM concentration estimates, was 8.5% for uncorrected PET data and decreased with PVEc, reaching 6.0% for mMG-PVEc. Coregistration errors appeared to be the major determinant of the imprecision. CONCLUSION: Coupling of automated ROI placement and PVEc provides a tool for integrated analysis of brain PET/MRI data, which allows a recovery of true GM ROI values, with a high degree of accuracy when R-PVEc or mMG-PVEc is used. Among the 4 tested PVEc methods, R-PVEc showed the greatest accuracy and is suitable when corrected images are not specifically needed. Otherwise, if corrected images are desired, the mMG-PVEc method appears the most adequate, showing a similar accuracy.
Behavioral and neurofunctional changes over time in healthy and aphasic subjects: a PET Language Activation Study.
BACKGROUND AND PURPOSE: Follow-up neuroimaging studies of aphasia never addressed a comparison between aphasic and healthy subjects. Investigation of changes over time in healthy subjects during language tasks seems a prerequisite before interpretation of longitudinal changes in aphasic patients. METHODS: Six healthy subjects and 8 aphasic patients were PET scanned twice (PET1 and PET2) at a 1-year interval during a word generation task. Using SPM99, language-rest main effect was compared at PET1 and PET2 in each group, whereas group effect was assessed at each session. Correlations were analyzed in each group between performance indexes and changes in regional cerebral flood flow (rCBF) between the 2 sessions. RESULTS: Language performances were improved in both groups. rCBF decreased from PET1 to PET2 in the healthy group and increased in the aphasic group in perisylvian regions bilaterally. Correlations between performance and rCBF changes across sessions were similar in the 2 groups; positive correlations involved superior temporal cortexes bilaterally, and negative correlations concerned superior frontal and medial temporal regions. CONCLUSIONS: Increased perisylvian activation over time probably reflects improved performance at the expenses of cognitive effort in aphasic patients. Decreased activation in different neural systems suggests a familiarization effect with reduced emotional load.