Tim D. Fryer

Imaging Atherosclerotic Plaque Inflammation With [18F]-Fluorodeoxyglucose Positron Emission Tomography

Background—Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose (18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques. Methods and Results—Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque. Conclusions—This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions.

Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement

Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment

The neural basis of the amnesia characterizing early Alzheimers disease (AD) remains uncertain. Postmortem pathological studies have suggested early involvement of the mesial temporal lobe, whereas in vivo metabolic studies have shown hypometabolism of the posterior cingulate cortex. Using a technique that combined the anatomic precision of magnetic resonance imaging with positron emission tomography, we found severe reductions of metabolism throughout a network of limbic structures (the hippocampal complex, medial thalamus, mamillary bodies, and posterior cingulate) in patients with mild AD. We then studied a cohort with mild cognitive impairment in whom amnesia was the only cognitive abnormality and found comparable hypometabolism through the same network. The AD and mild cognitive impairment groups were differentiated, however, by changes outside this network, the former showing significant hypometabolism in amygdala and temporoparietal and frontal association cortex, whereas the latter did not. The amnesia of very early AD reflects severe but localized limbic dysfunction.

Declarative memory impairments in Alzheimer's disease and semantic dementia.

Semantic dementia (SD) and Alzheimers disease (AD) are both disorders in which early pathology affects the temporal lobe yet they produce distinct syndromes of declarative memory impairment-loss of established semantic knowledge with relatively preserved episodic memory in the former and the converse in the latter. Groups with mild SD and mild AD who showed a double dissociation in these two aspects of declarative memory were studied-the SD groups episodic memory and the AD groups semantic knowledge each being comparable to controls. Positron emission tomography and volumetric magnetic resonance imaging were used to map deficits in regional cerebral metabolic rate and mesial temporal lobe (MTL) atrophy, respectively. Episodic memory impairment in AD was associated with dysfunction of an integrated network (mesial temporal lobe, mamillary bodies, dorso-mesial thalamus and posterior cingulate). Semantic memory impairment in SD was associated with bilateral rostral temporal lobe hypometabolism. The SD group had comparable MTL atrophy and hypometabolism to that found in AD but the remainder of their limbic-diencephalic network was preserved suggesting that the latter explains their ability to acquire new episodic memories. The results challenge the view that amnesia in early AD can be explained by the degree of MTL damage alone while showing that semantic impairment can occur with damage restricted to the rostral temporal lobes.

Identification of Culprit Lesions After Transient Ischemic Attack by Combined 18F Fluorodeoxyglucose Positron-Emission Tomography and High-Resolution Magnetic Resonance Imaging

Background and Purpose— Carotid endarterectomy is currently guided by angiographic appearance on the assumption that the most stenotic lesion visible at angiography is likely to be the lesion from which future embolic events will arise. However, risk of plaque rupture, the most common cause of atherosclerosis-related thromboembolism, is dictated by the composition of the plaque, in particular the degree of inflammation. Angiography may, therefore, be an unreliable method of identifying vulnerable plaques. In this study, plaque inflammation was quantified before endarterectomy using the combination of 18F fluorodeoxyglucose positron (FDG)-emission tomography (PET) and high-resolution MRI (HRMRI). Methods— Twelve patients, all of whom had suffered a recent transient ischemic attack, had a severe stenosis in the ipsilateral carotid artery, and were awaiting carotid endarterectomy underwent FDG-PET and HRMRI scanning. A semiquantitative estimate of plaque inflammation was calculated for all of the lesions identified on HRMRI. Results— In 7 of 12 patients (58%), high FDG uptake was seen in the lesion targeted for endarterectomy. In the remaining 5 patients, FDG uptake in the targeted lesion was low. In these 5 patients, 3 had nonstenotic lesions identified on HRMRI that exhibited a high level of FDG uptake. All 3 of the highly inflamed nonstenotic lesions were located in a vascular territory compatible with the patients’ presenting symptoms. Conclusions— Our data suggest that angiography may not always identify the culprit lesion. Combined FDG-PET and HRMRI can assess the degree of inflammation in stenotic and nonstenotic plaques and could potentially be used to identify lesions responsible for embolic events.

Effect of hyperventilation on cerebral blood flow in traumatic head injury: Clinical relevance and monitoring correlates

Objective To investigate the effect of hyperventilation on cerebral blood flow in traumatic brain injury. Design A prospective interventional study. Setting A specialist neurocritical care unit. Patients Fourteen healthy volunteers and 33 patients within 7 days of closed head injury. Interventions All subjects underwent positron emission tomography imaging of cerebral blood flow. In patients, Paco2 was reduced from 36 ± 1 to 29 ± 1 torr (4.8 ± 0.1 to 3.9 ± 0.1 kPa) and measurements repeated. Jugular venous saturation (Sjvo2) and arteriovenous oxygen content differences (AVDO2) were monitored in 25 patients and values related to positron emission tomography variables. Measurements and Main Results The volumes of critically hypoperfused and hyperperfused brain (HypoBV and HyperBV, in milliliters) were calculated based on thresholds of 10 and 55 mL·100g−1·min−1, respectively. Whereas baseline HypoBV was significantly higher in patients (p < .05), baseline HyperBV was similar to values in healthy volunteers. Hyperventilation resulted in increases in cerebral perfusion pressure (p < .0001) and reductions in intracranial pressure (p < .001), whereas Sjvo2 (>50%) and AVDO2 (<9 mL/mL) did not exceed global ischemic thresholds. However, despite these beneficial effects, hyperventilation shifted the cerebral blood flow distribution curve toward the hypoperfused range, with a decrease in global cerebral blood flow (31 ± 1 to 23 ± 1 mL·100g−1·min−1;p < .0001) and an increase in HypoBV (22 [1–141] to 51 [2–428] mL;p < .0001). Hyperventilation-induced increases in HypoBV were apparently nonlinear, with a threshold value between 34 and 38 torr (4.5–5 kPa). Conclusions Hyperventilation increases the volume of severely hypoperfused tissue within the injured brain, despite improvements in cerebral perfusion pressure and intracranial pressure. Significant hyperperfusion is uncommon, even at a time when conventional clinical management includes a role for modest hyperventilation. These reductions in regional cerebral perfusion are not associated with ischemia, as defined by global monitors of oxygenation, but may represent regions of potentially ischemic brain tissue.

Incidence and mechanisms of cerebral ischemia in early clinical head injury.

Antemortem demonstration of ischemia has proved elusive in head injury because regional CBF reductions may represent hypoperfusion appropriately coupled to hypometabolism. Fifteen patients underwent positron emission tomography within 24 hours of head injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF). We estimated the volume of ischemic brain (IBV) and used the standard deviation of the OEF distribution to estimate the efficiency of coupling between CBF and CMRO2. The IBV in patients was significantly higher than controls (67 ± 69 vs. 2 ± 3 mL; P < 0.01). The coexistence of relative ischemia and hyperemia in some patients implies mismatching of perfusion to oxygen use. Whereas the saturation of jugular bulb blood (SjO2) correlated with the IBV (r = 0.8, P < 0.01), SjO2 values of 50% were only achieved at an IBV of 170 ± 63 mL (mean ± 95% CI), which equates to 13 ± 5% of the brain. Increases in IBV correlated with a poor Glasgow Outcome Score 6 months after injury (ρ = −0.6, P < 0.05). These results suggest significant ischemia within the first day after head injury. The ischemic burden represented by this “traumatic penumbra” is poorly detected by bedside clinical monitors and has significant associations with outcome.

Retrosplenial cortex (BA 29/30) hypometabolism in mild cognitive impairment (prodromal Alzheimer's disease)

Previous group studies using positron emission tomography to assess resting cerebral glucose metabolism in very early Alzheimers disease and mild cognitive impairment have identified the posterior cingulate and adjacent cingulo‐parietal cortex as the first isocortical area to develop hypometabolism. We studied the profile of resting cerebral glucose metabolism in individuals with mild cognitive impairment to assess whether more specific and stereotyped regional hypometabolism would be evident across subjects. The study found that the most consistently hypometabolic region between individual subjects was a subregion of the posterior cingulate, the retrosplenial cortex (BA 29/30). This result is discussed in the context of regional connectivity, focal lesion evidence and functional activation studies of episodic memory paradigms in both normal and Alzheimers disease groups. We propose that the retrosplenial cortex may represent a key junction between prefrontal areas involved in implementing retrieval strategies for episodic memory and hippocampal‐based mnemonic processing; we therefore interpret the retrosplenial hypometabolism as a probable contributor to the memory impairment seen in mild cognitive impairment by disconnecting these two anatomical networks.

How Reliable Is Perfusion MR in Acute Stroke?: Validation and Determination of the Penumbra Threshold Against Quantitative PET

Background and Purpose— Perfusion magnetic resonance imaging (pMR) is increasingly used in acute stroke, but its physiologic significance is still debated. A reasonably good correlation between pMR and positron emission tomography (PET) has been reported in normal subjects and chronic cerebrovascular disease, but corresponding validation in acute stroke is still lacking. Methods— We compared the cerebral blood flow (CBF), cerebral blood volume, and mean transit time (MTT) maps generated by pMR (deconvolution method) and PET (15O steady-state method) in 5 patients studied back-to-back with the 2 modalities at a mean of 16 hours (range, 7 to 21 hours) after stroke onset. We also determined the penumbra thresholds for pMR-derived MTT, time to peak (TTP), and Tmax against the previously validated probabilistic PET penumbra thresholds. Results— In all patients, the PET and pMR relative distribution images were remarkably similar, especially for CBF and MTT. Within-patient correlations between pMR and PET were strong for absolute CBF (average r2=0.45) and good for MTT (r2=0.35) but less robust for cerebral blood volume (r2=0.24). However, pMR overestimated absolute CBF and underestimated MTT, with substantial variability in individual slopes. Removing individual differences by normalization to the mean resulted in much stronger between-patient correlations. Penumbra thresholds of ≈6, 4.8, and 5.5 seconds were obtained for MTT delay, TTP delay, and Tmax, respectively. Conclusions— Although derived from a small sample studied relatively late after stroke onset, our data show that pMR tends to overestimate absolute CBF and underestimate MTT, but the relative distribution of the perfusion variables was remarkably similar between pMR and PET. pMR appears sufficiently reliable for clinical purposes and affords reliable detection of the penumbra from normalized time-based thresholds.

Hyperventilation following head injury : Effect on ischemic burden and cerebral oxidative metabolism

Objective:To determine whether hyperventilation exacerbates cerebral ischemia and compromises oxygen metabolism (CMRO2) following closed head injury. Design:A prospective interventional study. Setting:A specialist neurocritical care unit. Patients:Ten healthy volunteers and 30 patients within 10 days of closed head injury. Interventions:Subjects underwent oxygen-15 positron emission tomography imaging of cerebral blood flow, cerebral blood volume, CMRO2, and oxygen extraction fraction. In patients, positron emission tomography studies, somatosensory evoked potentials, and jugular venous saturation (SjO2) measurements were obtained at Paco2 levels of 36 ± 3 and 29 ± 2 torr. Measurements and Main Results:We estimated the volume of ischemic brain and examined the efficiency of coupling between oxygen delivery and utilization using the sd of the oxygen extraction fraction distribution. We correlated CMRO2 to cerebral electrophysiology and examined the effects of hyperventilation on the amplitude of the cortical somatosensory evoked potential response. Patients showed higher ischemic brain volume than controls (17 ± 22 vs. 2 ± 3 mL; p ≤ .05), with worse matching of oxygen delivery to demand (p < .001). Hyperventilation consistently reduced cerebral blood flow (p < .001) and resulted in increases in oxygen extraction fraction and ischemic brain volume (17 ± 22 vs. 88 ± 66 mL; p < .0001), which were undetected by SjO2 monitoring. Mean CMRO2 was slightly increased following hyperventilation, but responses were extremely variable, with 28% of patients demonstrating a decrease in CMRO2 that exceeded 95% prediction intervals for zero change in one or more regions. CMRO2 correlated with cerebral electrophysiology, and cortical somatosensory evoked potential amplitudes were significantly increased by hyperventilation. Conclusions:The acute cerebral blood flow reduction and increase in CMRO2 secondary to hyperventilation represent physiologic challenges to the traumatized brain. These challenges exhaust physiologic reserves in a proportion of brain regions in many subjects and compromise oxidative metabolism. Such ischemia is underestimated by common bedside monitoring tools and may represent a significant mechanism of avoidable neuronal injury following head trauma.