Brain, Vol. 124, No. 10, 2014-2027,
October 2001
© 2001 Oxford University Press
In vivo visualization of activated glia by[11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion
1 MRC Cyclotron Unit, Imperial College, Faculty of Medicine, Hammersmith Hospital, 2 Department of Neuropathology and Psychiatry, Imperial College, Faculty of Medicine, Charing Cross Hospital, 3 St Thomas' Hospital, London, 4 MRC Cognition and Brain Sciences Unit, Cambridge, UK and 5 Department of Neuromorphology, Max Planck Institute for Neurobiology, Martinsried, Germany
Correspondence to:
Richard B. Banati, MD, MRC Cyclotron Unit, Imperial College, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK E-mail: richard.banati{at}csc.mrc.ac.uk
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Abstract |
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A major challenge in the assessment of brain injury and its relationship to the ensuing functional deficits is the accurate delineation of the areas of damage. Here, we test the hypothesis that the anatomical distribution pattern of activated microglia, a normally dormant population of resident brain macrophages, can be used as a surrogate marker of neuronal injury not only at the primary lesion site but also in the antero- and retrograde projection areas of the lesioned neurones. Two patients with asymmetrical herpes simplex encephalitis were serially scanned 6 and 12 months after the acute illness using PET with [11C] (R)-PK11195, a marker of activated microglia/brain macrophages. The evolving structural changes in the brain were measured by volumetric MRI and compared with the pattern of [11C](R)-PK11195 binding. Corresponding to the clinically observed cognitive deficits, quantitative [11C](R)-PK11195-PET revealed highly significant signal increases within the affected limbic system and additionally in areas connected to the limbic system by neural pathways, including the lingual gyrus in the occipital lobe and the inferior parietal lobe, which had normal morphology on structural MRI. The increased [11C](R)-PK11195 binding, signifying the presence of activated microglia, persisted many months (>12) after antiviral treatment. Cortical areas that showed early high [11C](R)-PK11195 binding subsequently underwent atrophy. These observations demonstrate that in vivo imaging of activated microglia/brain macrophages provides a dynamic measure of active tissue changes following an acute focal lesion. Importantly, the glial tissue response in the wake of neuronal damage is protracted and widespread within the confines of the affected distributed neural system and can be related to the long-term functional deficits.
microglia; neuropsychology; inflammation; cognition
BP = binding potential; HSV = herpes simplex virus; PBBS = peripheral benzodiazepine binding site; TAC = time-activity curves
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Introduction |
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Post-mortem studies of patients after acute sporadic encephalitis caused by herpes simplex virus (HSV type 1) have shown that histological changes frequently occur far beyond the structurally defined primary lesion site (Esiri et al.1995
; Esiri and Kennedy, 1997). Notably widespread is the presence of activated microglia (Weinstein et al.1990; Esiri et al.1995; Lellouch-Tubiana et al.2000), a cell type of mononuclear phagocyte lineage that represents an important part of the intrinsic immune defence of the CNS (Banati et al.1993; Kreutzberg, 1996). Two mechanisms have been suggested to explain the distribution pattern of brain damage after herpes simplex encephalitis: (i) the inflammatory process progresses locally by spreading into areas of closest anatomical proximity; and (ii) the progressive tissue damage follows a `connectionist' disease model; i.e. pathology outside the primary inflammatory focus is induced in distant areas via the degeneration of neural pathways to those areas (Hierons et al.1978; Kapur et al.1994).
PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] is a specific ligand for the peripheral benzodiazepine binding site (PBBS), which is particularly abundant on cells of mononuclear phagocyte lineage (Benavides et al.1988; Dubois et al.1988; Myers et al.1991; Gavish et al.1999). In normal brain tissue, binding of PK11195 is minimal, whereas in areas containing activated microglia, in vivo binding is significantly increased (Banati et al.1997; Conway et al.1998). [11C]PK11195 or its single enantiomer, [11C](R)-PK11195, and PET have been used to image focal accumulation of macrophages or activated microglia in patients with stroke or epilepsy (Ramsay et al.1992; Banati et al.1999; Pappata et al.2000). Astrocytes that express the binding sites for PK11195 in vitro (Itzhak et al.1993) do not contribute significantly to the binding of (R)-PK11195 in vivo, as shown by double immunocytochemical and high-resolution autoradiographic labelling at the single-cell level (Banati et al.2000). Likewise, astrocytic scars do not have an appreciable [11C](R)-PK11195 signal in patients with hippocampal sclerosis and well-controlled seizures (Banati et al.1999).
In this study, we employed [11C](R)-PK11195-PET and volumetric serial MRI to test whether the visualization of activated microglia/brain macrophages in the presence or absence of obvious structural changes provides a measure not only of the severity of a primary brain lesion but also of its secondary effects in antero- and retrograde neuronal projection pathways.
We specifically selected patients in whom the acute disease was largely confined to one temporal lobe to study (i) the distribution of the damage after herpes encephalitis including areas remote from the primary lesion site; (ii) the relationship between the presence of brain macrophage/activated microglia and regional brain atrophy over a longer period of time; and (iii) the relationship of these in vivo imaging data with the patients' specific cognitive deficits.
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Material and methods |
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Subjects
Patients
Patient 1, a 44-year-old right-handed woman, was scanned with MRI and [11C](R)-PK11195-PET 5 months after the acute onset of predominantly left-sided herpes simplex encephalitis. MRI and PET scans were repeated 12 months later, i.e. 17 months after onset of the disease. Neuropsychological assessment at the time of the first scans demonstrated severe deficits in verbal but not visual memory. The verbal memory index on the Wechsler Memory Scale—Revised was reduced to 71, compared with a visual memory index of 114. In the Recognition Memory Test, the patient's scores reached the 5th percentile for word recognition, compared with the 95th percentile for the face recognition memory test. Performance was within normal range on Raven's Progressive Matrices, the Graded Naming Test, and tests assessing frontal and executive functioning (Wisconsin Card-Sorting Test and FAS verbal fluency test). Whereas attention and concentration were normal, the Wechsler Memory Scale—Revised test showed a significant impairment in delayed recall. The patient's cognitive functions remained stable over the 12-month period of observation except for a slight deterioration in verbal memory.
Patient 2, a 36-year-old right-handed man, was scanned with MRI and [11C](R)-PK11195-PET 8 months after the acute onset of herpes simplex encephalitis that affected predominantly the right temporal lobe. MRI and PET scans were repeated 6 months later, i.e. 14 months after disease onset.
At the time of the first scans, the patient showed a number of cognitive deficits, most prominently affecting visual memory and face processing. Deficits were seen on tests of spatial and visual recognition memory, and visual discrimination and reversal learning from the CANTAB (Cambridge Neuropsychological Test Automated Battery) (Cenes, Cambridge, UK). The deficit in visual memory appeared to be genuinely mnemonic in nature, as deficits increased with increasing delay on a test of delayed matching to sample from the CANTAB. Deficits in unfamiliar face matching (Benton Face Recognition Test), as well as deficits in facial emotion recognition (particularly for negative emotions, including fear, anger and disgust) were seen (Benton et al.1983; Broks et al.1998). There appeared to be relative sparing of performance on tests of aspects of social knowledge (Ellis et al.1994). No obvious change in the degree and pattern of cognitive deficits was seen over the period of observation.
The clinical diagnosis of herpes simplex encephalitis was confirmed in both patients by high titres of antibodies against HSV-1 and the detection of HSV-1 DNA in the cerebrospinal fluid using the polymerase chain reaction. Both patients were committed to an intensive care unit within 1 day after the onset of the acute illness. Patient 1 received 650 mg/day intravenous acyclovir for the 16 days, followed by a 4-week course of 1 g/day oral valacyclovir. Patient 2 was treated with 750 mg/day intravenous acyclovir for 14 days.
Control subjects
To determine binding potential values of [11C](R)-PK11195 in the normal cortex and subcortical cerebral grey matter, a group of 13 healthy subjects (six women, seven men, age range 33–80 years, mean age 53.2 years) were scanned for comparison.
The protocol for patients with inflammatory brain disease and controls was approved by the Royal Postgraduate Medical School, Hammersmith, Queen Charlotte's and Chelsea and Acton Hospitals Research Ethics Committee and the ARSAC (Administration of Radioactive Substances Advisory Committee of the UK). Written consent was obtained from all studied subjects and their carers.
PET study
Data acquisition
A CTI/Siemens (Knoxville, Tenn., USA) ECAT 953B PET scanner was used in 3D acquisition mode with collimating septa withdrawn. This produces a fivefold increase in counts at the centre of the field-of-view compared with that achieved using conventional scanning (Bailey et al.1991). In this study, the single enantiomer [11C](R)-PK11195, which has a higher affinity for the PBBS than the racemic form, was used (Shah et al.1994). The ligand was injected as a bolus 30 s after the beginning of the acquisition scan. The tracer dose (mean ± standard deviation) was 360 ± 30 MBq with a specific activity of 37 ± 1 GBq/mmol. Dynamic data were collected over 60 min as 18 temporal frames. Attenuation correction factors were determined using a 15-min transmission scan. Scatter correction was achieved using a dual-energy window method (Groontoonk et al., 1996). Data were reconstructed with a ramp filter at Nyquist cut-off producing a reconstructed image resolution of 5.8 mm (full-width at half-maximum) at the centre of the field of view.
Kinetic modelling and analysis
Parametric images of regional [11C](R)-PK11195 binding were generated using a simplified reference tissue model (Lammertsma and Hume, 1996; Gunn et al.1997; Banati et al.1999, 2000; Cagnin et al., 2001). In severe brain disease with widespread distribution of pathology throughout the entire brain, the a priori assumption that a given anatomically defined reference region is free of specific binding may not hold. Therefore, we used cluster analysis to classify tissues for the discrimination of concentration time–activity curves (TACs) according to their shape, in order to extract a normal ligand kinetic to serve as an appropriate reference input function (Ashburner et al.1996; Acton et al.1997; Gunn et al.1998; Myers et al.1999; Banati et al.2000). A normalized mean TAC (normal population input kinetic) derived from the healthy cortical brain tissue of a group of 13 control subjects was created, representing the shape of a TAC derived from regional tissue data with no or minimal binding. To ensure that a TAC extracted by cluster analysis (after segmentation into 10 clusters) from the raw dynamic data of a patient was appropriate to serve as the patient's reference ligand kinetic, i.e. a kinetic with the shape of a TAC from normal brain tissue, its shape was assessed by testing for dissimilarity with the previously established normal population input kinetic (
2-test, P < 0.05) (Fig. 1A and B). For validation, the parametric images obtained using cluster analysis were compared with those using a cerebellar reference region, as described previously (Banati et al.1999).
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To allow anatomical localization of the regional [11C](R)-PK11195 binding, the binding potential (BP) images were co-registered to and overlaid on the individuals' own MRIs (Studholme et al.1997
). For the calculation of regional mean BP values, volumes of interest within the limbic system and anatomically connected areas were defined on the individuals' volumetric MRIs and applied to their parametric BP images using Analyze AVW version 3 (Robb and Hanson, 1991).
Additionally, the regional [11C](R)-PK11195 lesion load, i.e. the relative volume (%) with increased signal within in a given region of increased mean BP, was calculated as described previously (Banati et al.1999).
MRI
Each subject underwent a 3D T1-weighted MRI scan (voxel size 1 x 1 x 1.3 mm; 128 contiguous slices; repetition time 35 ms, echo time 6 ms; flip angle 35°) obtained with a 1.0 T Picker (Cleveland, OH, USA) HPQ MRI scanner for the purpose of co-registration with the PET image and, in control subjects, for the exclusion of incidental pathology (Studholme et al.1997). In both herpes encephalitis patients, the structural changes between the first and second MRI scans were assessed with a volumetric MRI technique that used a matching procedure based on summing the least-squares differences of pixel intensity values (Hajnal et al., 1995). The changes between the first and second scans were displayed in a difference image produced by subtracting the first MRI image from the second.
Statistical analysis
Means, standard deviations and Z values were calculated to determine the significance of the regional increase in [11C](R)-PK11195 binding in each patient compared with the group of control subjects. Z values >1.6 (in the one-tailed Z-test, testing for increase in specific binding) were considered statistically significant (P < 0.05). Correlation analysis was performed using Pearson's correlation coefficient and regression analysis.
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Control subjects
Using cluster analysis for the extraction of the normal input kinetic, the BP for the cortex of healthy control subjects was 0.13 ± 0.04 (mean ± standard deviation) and that for the thalamus was 0.40 ± 0.08. These data indicate that, in the absence of any active pathology, [11C](R)-PK11195 binding is minimal in the normal brain, except for some constitutive binding in the thalamus, which has been shown to increase with age (Cagnin et al., 2001
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Patients
In both patients, cluster analysis was used successfully (2-test, P < 0.001) to extract a TAC that had the same shape as the normal population input kinetic described for normal brain tissue and could, therefore, be used as the reference input function for the calculation of BP. High specific binding of [11C](R)-PK11195 was seen in well-delineated limbic structures and some anatomically connected areas, reaching maximal values (BPmax = 1.9–2.00) in focal areas, such as the primarily affected hippocampus. The regional mean BPs are summarized in Tables 1 and 2.
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Patient 1
The T1-weighted volumetric MRI at the time of the first PET scan showed a well-defined lesion with partial loss of tissue in the left hippocampal formation (Fig. 2A–C
). In contrast, the first [11C](R)-PK11195-PET scan revealed a distributed pathology mostly within the limbic system, including the anterior parts of the left parahippocampal, fusiform, inferior and middle temporal gyri, the amygdaloid nuclei, the anterior cingulate gyrus, the orbitofrontal cortex and insulae bilaterally, the area of the anterior commissure and the fornices (Figs 2 and 3). Additionally, increased [11C](R)-PK11195 binding was found in the thalamus ipsilateral to the primarily affected left temporal lobe. With the exception of the thalamus, structures with increased [11C](R)-PK11195 binding in the first scan subsequently developed atrophic changes, as measured by MRI subtraction imaging 12 months later (Figs 2 and 3). The second [11C](R)-PK11195-PET scan, 1 year later, revealed a wider distribution pattern of microglial activation. While there was still partial overlap with areas of previous binding in the hippocampal and parahippocampal formations, binding of [11C](R)-PK11195 increased throughout the left temporal lobe, the right mesial temporal lobe with right insula, and both mammillary bodies (Fig. 2E). In areas that had developed severe atrophy (the hippocampal and parahippocampal formations and the anterior cingulate gyrus), the regional mean BP values remained significantly increased though slightly reduced, probably as a consequence of the loss of volume in these structures (Fig. 5).
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Patient 2
MRI at the time of the first PET scan showed loss of tissue in the right hippocampal and parahippocampal formations, amygdala and insula and a decrease in signal intensity in the entire right temporal lobe. As in Patient 1, the neuroinflammatory pathology was distributed throughout the entire limbic system (Fig. 4
). Binding of [11C](R)-PK11195 detected by the first PET scan was seen diffusely in the right temporal lobe extending into the remaining area of the insular cortex, bilaterally in the orbitofrontal cortex and anterior cingulate gyri, in the contralateral left insula and the left amygdaloid nucleus. Coronal sections revealed increased signal in the white matter above the right circular sulcus of the insula, an area that contains the superior longitudinal fascicle. Importantly, increased [11C](R)-PK11195 binding was present in circumscribed areas in the right inferior parietal lobe and the right lingual gyrus, destruction of which has been hypothesized to underlie deficits in the recognition of emotions in facial expressions (Adolphs et al.1996), such as those seen in this patient. The left hippocampal formation and temporal lobe were relatively spared, which is consistent with the preservation of verbal skills. Again, areas where the first PET scan indicated the presence of activated microglia/brain macrophages were found subsequently to undergo marked atrophy, as detected by subtraction MRI. In the second [11C](R)-PK11195-PET scan, the anatomical pattern of active pathology, i.e. significantly increased binding, was largely maintained. BP values, however, were slightly reduced in all areas of pathology except the right anterior fusiform gyrus (Fig. 5
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Comparison of cluster analysis versus cerebellar reference region
The respective BP values for normal cortex and thalamus using a cerebellar input function were slightly lower [cortex, 0.0 ± 0.08 (mean ± standard deviation); thalamus, 0.15 ± 0.06] than those using the input function derived from cluster analysis. However, a good linear correlation was found between the BP values using a cluster analysis-derived input function and the BP values using a cerebellar input function [control group (BP values from thalamus, temporal lobe and pons): Pearson coefficient r = 0.94, P > 0.01; herpes patients: r = 0.96, P > 0.01) (Fig. 1C
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Discussion |
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Connecting anatomical pathways are the biological basis of models that describe the consequences of brain damage in terms of connectionist networks and ascribe the variations in the functional outcome to the varying extent to which different neural networks have been affected. This approach crucially requires the accurate delineation of the sustained focal damage and a measure of its effects on the wider anatomical connections applicable to the study of individual patients. In the two paradigmatic cases of (asymmetrical) herpes simplex encephalitis investigated here and followed over >1 year, [11C](R)-PK11195-PET provided the important additional information that (i) after a focal brain lesion, activated microglia/brain macrophages can be found widely distributed and remote from sites of obvious structural damage, and that the [11C](R)-PK11195-PET signal follows the location of the affected neural circuitry (in our cases, particularly the limbic structures and their connections); (ii) persistent microglial activation can be detected many months after successful antiviral treatment and cortical areas of high [11C](R)-PK11195 binding may subsequently undergo atrophic structural changes; and (iii) the pattern of cognitive deficits in our patients reflected the lesion pattern, as delineated by the first [11C](R)-PK11195-PET scan after recovery from acute illness.
Neuroinflammation, a non-neuronal surrogate marker of neuronal damage
The use of [11C](R)-PK11195-PET to study the subacute and chronic evolution of brain injury introduces the concept of `neuroinflammation'. It is based on the experimental observation that neuronal injury per se, in the absence of any other contributing pathology, such as damage to blood vessels, evokes a rapid, highly localized activation of microglia, the brain's intrinsic macrophages, around the somata of the injured neurones and in anatomical projection areas (Kreutzberg, 1996), which show no further obvious signs of pathology. This phenomenon is likely to have important functional consequences. For example, after nerve cell injury, even without cell death, discrete ultrastructural changes are observed, such as `synaptic stripping', i.e. the protrusion of activated microglia into the synaptic clefts of the afferent synapses on the injured neurone (Blinzinger and Kreutzberg, 1968). It is conceivable that such subtle structural changes are one cellular correlate of functional disconnection in the absence of readily detectable anatomical abnormalities.
Peripheral nerve transection experiments demonstrate that neuroinflammatory responses are regularly projected bidirectionally along neural fibre tracts. For example, facial nerve transection leads to a retrograde neuronal reaction and rapid induction of microglial PK11195 binding sites around the somata of lesioned motor neurones in the facial nucleus, whereas after sciatic nerve transection an anterograde response with similar time-course occurs in the gracile nucleus in the brainstem, a projection area that contains synaptic terminals from long, ipsilaterally ascending nerve fibres (Kreutzberg, 1996; Banati et al.1997). In the case of herpes simplex encephalitis, the projecting axonal pathways along which microglial activation can occur consist of the large association bundles interconnecting the mesocortical areas, subicular allocortices and subcortical amygdaloid nuclei, which represent the anatomical circuit of Papez and together form the phylogenetically distinct unit of the limbic system (Damasio and Van Hoesen, 1985). In our patients, the distribution pattern of increased [11C](R)-PK11195 binding delineated these limbic and associated structures and predicted the subsequent anatomical pattern of atrophy, as shown by MR difference imaging (Fig. 3).
The distribution of damage detected by the first [11C](R)-PK11195-PET scan after recovery from acute illness was consistent with the pattern of the patients' cognitive deficits. For example, in Patient 2, who had predominantly right-sided herpes simplex encephalitis, [11C](R)-PK11195-PET revealed a circumscribed, discrete pathology in the structurally normal right inferior parietal lobe [Brodmann area 39] and right lingual gyrus (mesial part, Brodmann area 18–19). Structural lesion analysis has indicated that these two regions are of critical importance in the recognition and processing of facial emotions, a cognitive function in which Patient 2 (in contrast to Patient 1) was markedly impaired (Adolphs et al.1996; Hamann et al.1996). Both regions are connected to the frontal lobes by the superior longitudinal fasciculus, a fibre tract that passes through the circular sulcus of the insula. In Patient 2, the superior longitudinal fasciculus co-localized on consecutive coronal planes with a contiguous signal of increased [11C](R)-PK11195 binding (red circle in Fig. 4A). The increase in [11C](R)-PK11195 binding in the morphologically normal right inferior parietal lobe and lingual gyrus of Patient 2 is likely to reflect a `projected neuroinflammatory' response, i.e. the remote activation of microglia as a consequence of the severe damage to the frontotemporal gyri and the connecting superior longitudinal fasciculus, which also appears to be functionally relevant.
The findings of this study demonstrate that the pattern of microglial activation, as a surrogate marker of neuronal damage, helps to delineate the extent to which a focal lesion affects the distributed neural connectivities, which is not obvious when standard structural imaging techniques are used. Principally applicable to other forms of apparently focal brain damage, the study of glial responses should, therefore, help our understanding of the differences, so far unexplained, in the cognitive deficits in patients with apparently similar brain lesions (Eslinger et al.1993). The distribution pattern of activated microglia should also be of use for the precise histopathological description of the effects of neurotoxic lesions compared with focal structural lesions with respect to the observed variations in the functional outcome. Recent comparative studies of the functional deficits caused by the different types of experimental lesions to the hippocampus or adjacent regions have revealed damage that has been unaccounted for so far, and this has led to a reappraisal of the role of the hippocampus in various aspects of memory (Goulet et al.1998; Murray et al.1998).
What is the significance of the persistent neuroinflammatory response?
The long persistence of elevated [11C](R)-PK11195 signals and their further spread along the initially affected neural pathways many months after the onset of disease and clinical recovery is unlikely to have been due to continued viral activity. The assumption that the long-lasting inflammatory tissue response indicates continued activity of the virus itself is difficult to reconcile with the absence of any viral product after the first 3 weeks and the inconsistent detection of viral genome (Sobel et al., 1989; Esiri et al.1995). While the detection of viral DNA may establish the latency of the virus in the central nervous system, the virus appears to be inactive and, therefore, the prolonged presence of post-infectious inflammatory changes must have a different cause. Recently, long-term persistent immune activation was found 3–10 years after acute childhood herpes simplex encephalitis, giving rise to the speculation that severe destructive brain infections may cause self-induced immune activation similar to the secondary neuroinflammatory response seen in our study (Lellouch-Tubiana et al., 2000). Similarly, even years after a single toxic event, such as in parkinsonism induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (Langston et al.1999), activated microglia are present in selective areas, indicating a continuing or secondary neurodegenerative processes. A further important observation is that neuronal death alone, without blood–brain barrier damage, can lead to the recruitment of peripheral T lymphocytes and lead to the appearance of a classical inflammatory reaction despite the absence any infectious agent (Raivich et al.1998). Therefore, the presence of a persistent local immune reaction in the brain should not necessarily be equated with the presence of active infectious disease.
In the patients reported here, the presence of [11C](R)-PK11195 signal after >1 year and in areas previously not delineated by the first [11C](R)-PK11195-PET scan (Fig. 5), such as corresponding regions in the contralateral hemisphere (particularly in Patient 1) and other anatomically connected structures, such as the mammillary bodies, indicates not only the large scale but also the protracted time course of brain reorganization following focal damage. The delayed activation of microglia in additional areas appeared to be restricted to structures directly connected to the primary lesion site and was not accompanied by any obvious further deterioration in cognitive performance. This might suggest that the later additional [11C](R)-PK11195 signals delineated primarily the Wallerian-type degeneration of axons and synaptic terminals of the neurones that were damaged initially. In this type of axonal degeneration, the majority of brain macrophages are derived from locally activated microglia, which initiate the phagocytosis of cellular debris (Lawson et al.1994).
Taken together, our data on a long-lasting, still evolving and neuronally induced glial response may indicate that, after brain damage, the connectionist model used to establish structure–function relationships should take into account a network architecture that is less static than is often assumed implicitly. It remains to be studied in greater detail whether this might have implications for the rehabilitation of patients with brain damage and whether it may be advantageous to reduce the secondary effect on initially undamaged neural systems that could potentially participate in the long-term rehabilitation of lost cognitive functions.
Methodological considerations
Our data show that, despite some small systematic differences in the calculated BP values depending on whether a cerebellar or a cluster analysis-derived input function was used, there was no difference in the overall anatomical pattern of significant binding. This suggests that the cerebellum, if it is indeed spared of significant disease, can serve as a reference tissue. Provided that either method is applied consistently in both patients and controls, the anatomical patterns of pathology that are obtained will not differ. More importantly, our results demonstrate that cluster analysis is a feasible approach to defining a reference input function in brain diseases that do not spare the cerebellum. As discussed previously (Banati et al.2000), the BP obtained using the simplified reference tissue (Gunn et al.1997) is an estimate of the true binding and may contain small errors due to minimal amounts of specific binding in normal white and grey matter.
In summary, the particular value of [11C](R)-PK11195-PET lies in the ability of [11C](R)-PK11195 to bind to brain macrophages/microglia as sensors of neuronal injury. In addition to structural neuroimaging, this technique thus provides a cell-biological measure of active disease, the resulting neuronal disconnection, and the protracted large-scale reorganization of the brain following damage to specific regions or pathways.
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The volumetric MRI analysis was carried out at the MRI Steiner Unit (Professor G. M. Bydder), Imperial College School of Medicine, Hammersmith Hospital, London, UK. We appreciate the support of Professor M. Kopelman, St Thomas's Hospital, London, in the recruitment and assessment of Patient 1. We thank the radiographers A. Blyth, D. Griffith and J. Holmes and Dr P. Bloomfield and L. Schnorr for assistance in image reconstruction, Professor R. Y. Moore, Pittsburgh, and Dr S. Rajeswaran for critical reading of the manuscript and Professor D. J. Brooks for his support of the overall research programme. R.B.B. is funded by the Medical Research Council and received support from L. D. Wedmore, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Max Planck Institute of Neurobiology (Martinsried, Germany) and the Deutsche Forschungsgemeinschaft grant `The mitochondrial benzodiazepine receptor as indicator of early CNS pathology, clinical application in PET'. A.C. is supported by a Fellowship from the European Community (BMH4/CT98/5100) in the Training and Mobility of Researchers Programme in Biomedicine.
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Received March 19, 2001. Revised May 28, 2001. Accepted June 11, 2001.
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