Alterations in nicotinic α4ß2 receptor binding in vascular dementia using ¹²³I-5IA-85380 SPECT: comparison with regional cerebral blood flow.

OBJECTIVE: To investigate differences in distribution of α4ß2 subtypes of nicotinic acetylcholine receptors (nAChRs) using the ligand ¹²³I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in subjects with vascular dementia and age-matched controls. ¹²³I-5IA-85380 binding was compared to corresponding regional cerebral blood flow (rCBF) changes in the same subjects. METHODS: Thirty subjects (14 vascular dementia and 16 controls) underwent ¹²³I-5IA-85380 and rCBF ((99m)Tc-exametazime) SPECT scanning. Image analysis was performed on voxel basis using statistical parametric mapping (SPM2). RESULTS: Compared to controls, reductions in relative ¹²³I-5IA-85380 uptake were identified in dorsal thalamus and right caudate in vascular dementia. Increase in scaled ¹²³I-5IA-85380 uptake in cuneus was also demonstrated in vascular dementia relative to controls. Perfusion deficits in anterior cingulate were apparent in the patient group and did not appear to be associated with ¹²³I-5IA-85380 changes. CONCLUSIONS: Reduced ¹²³I-5IA-85380 uptake in vascular dementia was confined to sub-cortical regions, unlike the cortical reductions previously described in Alzheimer's disease. Elevation of normalised ¹²³I-5IA-85380 uptake in cuneus in vascular dementia could be a compensatory response to reduced cholinergic activity in dorsal thalamus.

Alpha4beta2 nicotinic receptor status in Alzheimer's disease using 123I-5IA-85380 single-photon-emission computed tomography.

BACKGROUND: Loss of the alpha4beta2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease. OBJECTIVE: To investigate in vivo changes in this receptor using single-photon-emission CT (SPECT) with 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the alpha4beta2 receptor. METHODS: 32 non-smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I-5IA-85380 and perfusion (99mTc-hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation. RESULTS: Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I-5IA-85380 and 99mTc-HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD. CONCLUSION: Using 123I-5IA-85380 SPECT we found changes consistent with significant reductions in the nicotinic alpha4beta2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.

Nicotinic acetylcholine receptor distribution in Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and vascular dementia: in vitro binding study using 5-[(125)i]-a-85380.

Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a novel nAChR marker, binding predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-[(125)I]-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-[(125)I]-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-[(125)I]-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson's disease (PD), loss of striatal 5-[(125)I]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[(125)I]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer's disease (AD) reduced striatal 5-[(125)I]-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-I-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.

Spatial normalization of lesioned HMPAO-SPECT images.

We investigated the effect of nonlinear alignment on SPECT images with lesions. Linear alignment produces reliable results but the introduction of nonlinear methods can improve matching by accounting for global brain shape. We examined the hypothesis that nonlinear alignment can introduce unwanted image distortions when lesions are present. We set out to quantify possible distortions by constructing artificial lesions in order to obtain images with controllable characteristics. We examined the use of basis functions (in SPM96 and SPM99) and other nonlinear models (in AIR3.08) designed to achieve optimum alignment between image and template. We found that the use of models with high degrees of nonlinearity will result in unwanted deformations and that the safest way to align images with lesions is to use 12-point linear affine transformations. Masking was examined as a remedy to distortions caused by nonlinear methodologies and produced significantly improved results.

Effects of level of retrieval success on recall-related frontal and medial temporal lobe activations.

Brain dedicated single photon emission computed tomography (SPECT) was used to compare the neuroactivation produced by the cued recall of response words in a set of studied word pairs with that produced by the cued retrieval of words semantically related to unstudied stimulus words. Six of the 12 subjects scanned were extensively trained so as to have good memory of the studied pairs and the remaining six were minimally trained so as to have poor memory. When comparing episodic with semantic retrieval, the well-trained subjects showed significant left medial temporal lobe activation, which was also significantly greater than that shown by the poorly trained subjects, who failed to show significant medial temporal lobe activation. In contrast, the poorly trained subjects showed significant bilateral frontal lobe activation, which was significantly greater than that shown by the well-trained subjects who failed to show significant frontal lobe activation. The frontal activations occurred mainly in the dorsolateral region, but extended into the ventrolateral and, to a lesser extent, the frontal polar regions. It is argued that whereas the medial temporal lobe activation increased as the proportion of response words successfully recalled increased, the bilateral frontal lobe activation increased in proportion to retrieval effort, which was greater when learning had been less good.

Correlation of Parkinson's disease severity and duration with 123I-FP-CIT SPECT striatal uptake.

The variability in clinical features and the masking effects of drug therapy in Parkinson's disease (PD) can affect clinical assessment of disease severity. The aim of this study was to assess the imaging of dopamine transporters using 123I-FP-CIT SPECT and its correlation with disease staging, severity, and duration. Differences between the clinical severity of the onset and non-onset side and the corresponding striatal uptake ratios were also examined. Forty-one patients with PD (nine unilateral, 32 bilateral clinical features) were studied. Clinical severity was determined by using the Unified Parkinson's Disease Rating Score (UPDRS). Unilateral UPDRS was calculated from unilateral arm and leg resting and action tremor, rigidity, finger taps, hand movements, alternating movements, and leg agility. 123I-FP-CIT striatal uptake was expressed as the ratio of specific:nonspecific (SP:NS) uptake for defined brain areas. Patients with PD who had unilateral symptoms showed a significant difference between the ipsilateral and contralateral SP:NS ratios in both the caudate and putamen, but there was a considerable overlap between between the two sides. This result was repeated in patients with bilateral symptoms and there was overlap of SP:NS ratios between the two groups. For the whole group of patients with PD, striatum, caudate, and putamen SP:NS ratios correlated with disease severity assessed by UPDRS and duration of disease. The SP:NS ratios correlated with the bradykinesia subscore but not with rigidity or tremor subscore. In conclusion, this study provides further evidence that the SP:NS ratio is a robust measure of disease severity correlating with duration of PD. However, variability in uptake values suggest that factors other than nigrostriatal degeneration may contribute to disease severity. Correlation with bradykinesia but not with tremor may indicate an origin for tremor outwith the dopamine transporter system. 123I-FP-CIT SPECT offers significant potential in defining the nigrostriatal changes in PD.

Analysis of HMPAO SPECT scans in head injury using Statistical Parametric Mapping.

The paper examines the ability of Statistical Parametric Mapping (SPM) to contribute towards the quantitative analysis of HMPAO SPECT images containing lesions. A validation study is described in which SPECT images were created that contained synthetic lesions and were analysed with SPM. The study established a set of guidelines concerning the alignment, smoothing, and statistical analysis of images. These were then applied to analysis of SPECT scans from head injured patients. A demonstration is given of the use of SPM to identify localised blood flow abnormalities associated with cognitive deficits after head injury. Correlations between blood flow abnormalities and a test of visual memory are illustrated.

The use of statistical parametric mapping (SPM96) as a decision aid in the differential diagnosis of dementia using 99mTc-HMPAO SPECT.

In this study standard patterns of cerebral perfusion based on classifications described in the literature have been chosen and the ability of experienced imaging specialists to categorise the 99m Tc HMPAO SPECT scans of patients referred to the department for investigation of dementia has been compared before and after the calculation of Statistical Parametric Maps (SPM - Wellcome Dept of Cognitive Neurology). The primary aim was to investigate whether SPM is an effective decision aid and whether it impacts on the confidence of image reporting. The secondary aim was to examine the influence of SPM on the agreement between image reporting and clinical diagnosis. The results showed that there was a slight decrease in agreement between the imaging specialists after the introduction of additional information from SPM (K=0.57 to K=0.5) and that agreement between imaging reporting (including information from SPM) and clinical diagnosis was moderate (K=0.28). This study was able to confirm that SPM is capable of producing meaningful significance maps of individual patients in a routine clinical environment. However, there was no overwhelming evidence that SPM was able to resolve many of the dilemmas associated with the use of SPECT for the differential diagnosis of dementia. In particular, interpretation of SPECT perfusion patterns in dementia is a bigger problem than the initial identification of abnormalities.

Cingulate abnormalities associated with PANSS negative scores in first episode schizophrenia.

There is evidence for the involvement of the cingulate gyrus in schizophrenia. We present details of a Statistical Parametric Mapping (SPM) analysis of SPECT data from the largest study (N = 39) of drug naive schizophrenic patients. The main findings are that there is decreased perfusion in the anterior cingulate during verbal fluency when patients are compared to controls (matched individually by age, gender and father's social class as determined by occupation) and also that PANSS negative scores correlate negatively with regional cerebral blood flow in the cingulate gyrus (Pearson's Correlation coefficient of r = - 0.49 and significance p< 0.005). This suggests that measurement of change of perfusion in this region could be a useful biological marker in assessing the effect of neuroleptics on negative symptoms.

Validation of statistical parametric mapping (SPM) in assessing cerebral lesions: A simulation study.

Simulated abnormalities were introduced in a normal SPECT with known and controllable characteristics (abnormality size and depth) in an attempt to provide validation for the analysis of SPECT lesion studies using SPM. Two simulations were carried out. The first determined the minimum hypoperfusion depth detectable using SPM by altering mean local intensity while keeping the size of the lesion constant. This was done by changing the mean local intensity in percentile increments of 10 down to -100 and up to 50. The second simulation determined the cluster size that SPM can detect by keeping the mean intensity of the lesion constant while altering its size from 4 voxels to 63,000 voxels in a total brain volume of 300, 000 voxels. Both simulations determined which method of normalization is most appropriate, what level of grey matter thresholding should be used, and at what statistical probability peak threshold (u) the results should be determined. Proportional scaling was found to be the most appropriate normalization method. ANCOVA was useful where very large abnormalities were present and normalization external to SPM was not available. In those cases, ANCOVA was used in conjunction with measurement of an unaffected part of the brain (in this case medial occipital lobe). For better results statistical probability peak threshold was set to p(u) = 0. 01 and grey matter threshold was set to a value below 0.5. SPM produced best results when the abnormality represented a decrease of about -50% from the normal or more and detected other decreases in an acceptable manner.

Technology for health in the future.

Developments in biogenetics, medical devices, information and communication technologies, and in environmental technologies will have a profound impact on health in the coming decades. However, there are major barriers to the appropriate and effective utilization of current and future technologies, particularly for developing countries. This paper intends to strike a balance between the exciting potential of technologies and the conditions that need to be fulfilled to ensure that technologies are utilized appropriately and effectively. It will emphasize the significance of knowledge associated with technologies, the importance of technology assessment and the need for a broad and comprehensive technology management policy.

Associative encoding of pictures activates the medial temporal lobes.

It remains unresolved whether the medial temporal lobe activations found in recent neuroimaging studies are mediated by novelty detection alone, by specific kinds of encoding or consolidation operations, or both. This study attempted to see whether associative encoding or consolidation is sufficient to cause such activation by matching for novelty across conditions. Using single-photon emission computer tomography (SPECT) (with TC99mHMPAO), we compared the activation patterns produced by the associative encoding and the perceptual matching of novel complex scenes in 10 normal subjects using both statistical parametric mapping (SPM) and a regions-of-interest (ROI) approach. During the encoding condition, significant activations were detected in the left hippocampal/parahippocampal region, the left cingulate cortex, and the right prefrontal cortex, using both statistical techniques. Additionally, activation was found in the right cingulate cortex, and a trend towards activation was found in the right hippocampal/parahippocampal region using the ROI approach. In contrast, no medial temporal activations were found during the matching condition, which produced bilateral occipito-parietal and right posterior inferior parietal (supramarginal gyrus) activations. These results no only confirm that the associative encoding and/or consolidation of complex scenes is partially mediated by medial temporal lobe structures, but also demonstrate, for the first time, that associative encoding/consolidation is sufficient to produce such an activation. The implications of the high degree of consistency revealed by the results of the SPM and ROI comparison are discussed.

SPECT, CT, and MRI in head injury: acute abnormalities followed up at six months.

Neuroimaging with single photon emission computed tomography (SPECT) using the cerebral blood flow tracer 99Tc(m)-HMPAO has been used to study acute functional alterations after head injury and residual abnormalities at six month follow up in 32 patients. Comparison has been made with anatomical abnormalities defined acutely with CT and on follow up with MRI. SPECT showed slightly more abnormalities than CT in the acute phase (49 regions of abnormally low tracer uptake on SPECT and 45 lesions on CT). Twenty two of the acute SPECT abnormalities were in normal regions on CT. At follow up MRI showed more abnormalities than SPECT (30 on SPECT and 48 on MRI). Ten of the SPECT deficits were in regions with normal MRI. Comparison of the intensity of late and early SPECT deficits showed that only four early deficits deteriorated whereas 28 improved. Only five of 27 lesions seen on both acute SPECT and CT resolved compared with 16 of 22 lesions seen on SPECT but not on CT. Regions of abnormally high tracer uptake were detected in the acute stage in five of the patients. No high focal uptake was evident on follow up. Ten patients with a residual SPECT abnormality and eight with residual MRI lesions were graded clinically in the upper band of good recovery.

First SPET images of glutamate (NMDA) receptor activation in vivo in cerebral ischaemia.

This report describes the initial clinical assessment of (+)-3-[123I]Iodo-MK-801 and its potential to provide single photon emission tomographic (SPET) images in vivo of NMDA receptor activation during cerebral ischaemia. Multiple SPET images were obtained in the 120 min after the administration of 150 MBq of (+)-3-[123I]Iodo-MK-801 to five patients with cerebral ischaemia (due to cerebral haemorrhages) and to five normal volunteers. In normal subjects, (+)-3-[123I]Iodo-MK-801 has a rapid uptake into the brain. The tracer has a high non-specific retention in the central nervous system due to its lipophilicity, which was made evident by the retention of tracer in the cerebellum and white matter (brain areas with few NMDA receptors). In all patients with cerebral haemorrhages, the initial uptake of (+)-3-[123I]Iodo-MK-801 into the ipsilateral hemisphere was markedly reduced, consistent with a reduced level of cerebral blood flow. In two of five patients, relatively increased tracer retention at later time points (60-120 min after tracer administration) could be seen in cortical areas adjacent to the site of the haemorrhage, consistent with activated NMDA receptors. In three of the patients, no relatively enhanced tracer retention could be identified. Using (+)-3-[123I]Iodo-MK-801, it may be possible to image excessive glutamate (NMDA) receptor activation during an ischaemic episode in living human patients. The utility of (+)-3-[123I]Iodo-MK-801 as a SPET ligand for assessing modest alterations in NMDA receptor activity may ultimately be limited by its lipophilicity and consequent high non-specific binding.

Image quality versus statistical power.

We investigated whether SPET studies of neuroactivation might benefit from a similar approach used in PET; that is, increase the number of scans per task and accept poorer individual scan quality. Different study paradigms were simulated by varying the scanning parameters: (1) administered radiation activity per scan, (2) number of scans per task and (3) scan acquisition time. The maximum total dose received by each simulated subject remained the same. Areas of activation of varying signal strength were added to the scans using a customized graphics package. To establish the statistical benefits of a replication paradigm versus a non-replication paradigm, the datasets were analysed using SPM95 statistics software. This simulation was able to show that, when an SPM investigation is used for data analysis, study replication is more important than the individual image quality typically available from a high-performance SPET system.

123Iodo-MK-801: a spect agent for imaging the pattern and extent of glutamate (NMDA) receptor activation in Alzheimer's disease.

Glutamate, and the NMDA glutamate receptor, may be involved in Alzheimer's Disease (AD). Reductions in NMDA receptors are found in AD, possibly contributing to memory deficits. However the NMDA receptor is involved in excitotoxicity, which may play a role in cell death and the production of neurofibrillary tangles in AD; although with lower levels of glutamate than occur in cerebral ischaemia. Therefore reductions in the NMDA receptor may worsen memory deficit in AD, but increased stimulation of the receptor may contribute to the progress of the disease. MK-801 has been used to image excessive glutamate activation following ischaemia in rats. However, it is unclear how effective MK-801 is in conditions with lower levels of glutamate release. This study attempts to gain insight into the utility of the tracer in these conditions, exploring glutamatergic mechanisms in AD. It describes the retention and elimination of 123iodo-MK-801 in five AD and five control subjects, comparing this to regional cerebral blood flow (rCBF). The initial uptake of 123I-MK-801 is dominated by delivery of the ligand. However, despite significant reductions in rCBF in the AD patients, there is no significant difference in the uptake of 123I-MK-801. This suggests increased retention of 123I-MK-801 in the AD patients. In addition the washout of 123I-MK-801 was less in the AD patients, again suggesting increased retention, although this only reached significance in one region. Theses data hint at possible increases in NMDA activation in AD but ultimately 123I-MK-801 does not provide a sufficiently accurate measurement to demonstrate this conclusively. Further NMDA ligands are now at a late stage of development and may provide more conclusive answers to the role of glutamate in AD.

Longitudinal changes in cognitive function and regional cerebral function in Alzheimer's disease: a SPECT blood flow study.

In Alzheimer's disease (AD), SPECT imagining of regional cerebral blood flow (rCBF) has emphasized deficits in the posterior association cortex. Previous studies have shown an association between these deficits and cognitive performance, both on overall cognitive tests and more specific tests such as praxis and language. Frontal deficits have been reported in more severe patients. This has led to the conclusion that the deficit in AD, at least with functional neuroimaging, starts in the posterior association cortex, and later in the disease process "spreads" to involve the frontal cortex. This study set out to measure, in a group of AD patients, the change over time of cognitive performance and the pattern of functional deficit measured by neuroimaging. Change in function was measured using 99TCm-HMPAO and SPECT and change in cognitive function using the CAMCOG. Two time points were used, 0 and 2 years. Twenty-four patients satisfying the DSM-III R criteria for probable AD were studied, nine of whom were subsequently diagnosed as having AD at post-mortem. The most striking finding was the effect that decreases in frontal lobe function had on cognitive function. A similar study by the same group, using the same techniques and many of the same patients but at only one time point, showed a correlation between cognitive function and rCBF in the parietal and posterior temporal lobes. This suggests that as AD patients deteriorate from unaffected to mild or moderately affected, the posterior association cortex exerts the greatest effect on cognitive deficit. In this longitudinal study, we found, using a MANOVA, that there were significant decreases over time for all the cortical regions studied, but that no region decreased significantly more than any other. In addition we found a correlation between change in frontal rCBF and change in cognitive function (both overall cognitive function and the CAMCOG sub tests of language and praxis). These data suggest, in contrast to the previous study, that as the disease progresses from mild or moderate to moderate or severe, the frontal cortex exerts the greatest effect on cognitive decline. These data support the concept of the deficit in functional imaging spreading from posterior to anterior as the disease progresses. However, both the initial pattern of deficit and the change over time were very heterogeneous when examined qualitatively. A posterior to anterior spread is the predominant pattern for the group as a whole, but individual patients, and possibly groups of patients, may well show alternative patterns.