David J. Wyper

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 Parkinsons 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 Parkinsons 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.

Nicotinic Acetylcholine Receptor Distribution in Alzheimer's Disease, Dementia with Lewy Bodies, Parkinson's Disease, and Vascular Dementia: In Vitro Binding Study Using 5-[125I]-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 α4β2 subtype. This in vitro autoradiography study describes the distribution of 5-[125I]-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-[125I]-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-[125I]-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 Parkinsons disease (PD), loss of striatal 5-[125I]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[125I]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimers disease (AD) reduced striatal 5-[125I]-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.

Measurements of regional cerebral blood flow and cognitive performance in Alzheimer's disease.

Single photon emission computed tomography (SPECT) with 99mTc-HMPAO was used to image 26 patients with dementia of the Alzheimer type (DAT) and 10 healthy controls. Regional cerebral blood flow (rCBF) data indicated a relative sparing of the occipital regions in DAT. Normalisation to occipital flow illustrated highly significant CBF deficits in a number of cortical regions, particularly in the left and right posterior--temporal cortex in DAT compared to controls. The cognitive performance of DAT patients was measured using a clinical cognitive assessment procedure (CAMCOG) and numerous correlations between these scores and rCBF were obtained. The implications and value of this investigative technique are discussed.

Image non-uniformity in magnetic resonance imaging: its magnitude and methods for its correction

Image non-uniformity in magnetic resonance imaging (MRI) is a recognised problem when using surface coils but is rarely mentioned with respect to standard head coils, yet it can be a source of error in clinical interpretation of images. Figure 1 demonstrates the type of artefacts due to image non-uniformity for a large, homogeneous solution of water and copper sulphate. The image was acquired in the coronal section using a standard head coil, and vertical (i.e. read direction) and horizontal (i.e. phase encode direction) pixel intensity profiles through the centre of the image are illustrated. The standard deviation of pixel intensities, expressed as a percentage of the mean value, is greater than ±27% along the 23 cm length of this phantom. Figure 2 demonstrates how these image nonuniformities can affect the sagittal image of a normal volunteer. The display window width and level have been chosen to produce optimum visual contrast at the level of the cerebellum and brain stem but, as a result to image no...

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.

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 not 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. Hum. Brain Mapping 6:85–104, 1998.

Muscarinic receptors in basal ganglia in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease.

Derivatives of the muscarinic antagonist 3-quinuclidinyl-4-iodobenzilate (QNB), particularly [123I]-(R,R)-I-QNB, are currently being assessed as in vivo ligands to monitor muscarinic receptors in Alzheimers disease (AD) and dementia with Lewy bodies (DLB), relating changes to disease symptoms and to treatment response with cholinergic medication. To assist in the evaluation of in vivo binding, muscarinic receptor density in post-mortem human brain was measured by autoradiography with [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB and compared to M1 ([3H]pirenzepine) and M2 and M4 ([3H]AF-DX 384) receptor binding. Binding was calculated in tissue containing striatum, globus pallidus (GPe), claustrum, and cingulate and insula cortex, in cases of AD, DLB, Parkinsons disease (PD) and normal elderly controls. Pirenzepine, AF-DX 384 and (R,S)-I-QNB binding in the striatum correlated positively with increased Alzheimer-type pathology, and AF-DX 384 and (R,R)-I-QNB cortical binding correlated positively with increased Lewy body (LB) pathology; however, striatal pirenzepine binding correlated negatively with cortical LB pathology. M1 receptors were significantly reduced in striatum in DLB compared to AD, PD, and controls and there was a significant correlation between M1 and dopamine D2 receptor densities. [3H]AF-DX 384 binding was higher in the striatum and GPe in AD. Binding of [125I]-(R,R)-I-QNB, which may reflect increased muscarinic M4 receptors, was higher in cortex and claustrum in DLB and AD. [125I]-(R,S)-I-QNB binding was higher in the GPe in AD. Low M1 and D2 receptors in DLB imply altered regulation of the striatal projection neurons which express these receptors. Low density of striatal M1 receptors may relate to the extent of movement disorder in DLB, and to a reduced risk of parkinsonism with acetylcholinesterase inhibition.

Comparative distribution of binding of the muscarinic receptor ligands pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to human brain

Quinuclidinyl benzilate (QNB) and its derivatives are being developed to investigate muscarinic receptor changes in vivo in Alzheimers disease and dementia with Lewy bodies. This is the first study of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB binding in vitro in human brain. We have compared the in vitro binding of the muscarinic ligands [3H]pirenzepine and [3H]AF-DX 384, which have selectivity for the M1 and M2/M4 receptor subtypes, respectively, to the binding of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB. This will provide a guide to the interpretation of in vivo SPET images generated with [123I]-(R,R)-I-QNB and [123I]-(R,S)-I-QNB. Binding was investigated in striatum, globus pallidus, thalamus and cerebellum, and cingulate, insula, temporal and occipital cortical areas, which show different proportions of muscarinic receptor subtypes, in post-mortem brain from normal individuals. M1 receptors are of high density in cortex and striatum and are relatively low in the thalamus and cerebellum, while M4 receptors are mainly expressed in the striatum, and M2 receptors are most evident in the cerebellum and thalamus. [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB density distribution patterns were consistent with binding to both M1 and M4 receptors, with [125I]-(R,R)-I-QNB additionally binding to a non-cholinergic site not displaceable by atropine. This distribution can be exploited by in vivo imaging, developing ligands for both SPET and PET, to reveal muscarinic receptor changes in Alzheimers disease and dementia with Lewy bodies during the disease process and following cholinergic therapy.

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.

Deficits in iodine-labelled 3-quinuclidinyl benzilate binding in relation to cerebral blood flow in patients with Alzheimer's disease.

A loss of acetylcholine is one of the most consistent neurochemical findings in Alzheimers disease (AD) post-mortem, but the debate concerning receptor abnormalities is unresolved. The aim of this investigation was to measure the density of acetylcholine muscarinic receptors in AD patients at various stages in the disease (N = 8) by synthesising a radio-iodinated version of quinuclidinyl benzilate QNB, a potent muscarinic antagonist. Deficits were identified by comparison with a control data set obtained from four elderly volunteers and then compared to the deficit in total functional activity in the same brain regions measured using the cerebral perfusion tracer technetium-99m hexamethylpropylene amine oxime. Iodine-123 (R, R)quinuclidinyl benzilate (QNB) was synthesised using a CuI assisted nucleophilic aromatic exchange reaction. 160 MBq of the radioligand (specific activity 400 Ci/mmol: dose 90 ng/kg) was administered to each subject. Diagnosis of AD was made using the CAMDEX and DSMIIIR criteria with a physical examination, full blood screen, CT and chest X-ray. All subjects were scanned at 21 h post injection on an SME810 emission tomograph. 123I(R, R)QNB activity in the controls was found to be consistent with the known distribution of muscarinic receptors with no activity in the cerebellum and low activity in the thalamus. In the AD patients deficits in 123I-QNB binding which exceeded the corresponding total functional regional perfusion deficit were not found in six of the patiens and were observed only in the two most severely affected patients, both of whom were untestable on the cognitive battery. This adds weight to the evidence that a major reduction in postsynaptic receptor density takes place only at a very late stage of AD.