John D. Fenwick

Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD

Objective: To compare regional cerebral blood flow (rCBF) changes using 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT in subjects with dementia with Lewy bodies (DLB) and AD and in normal age-matched control subjects; to examine the utility of SPECT changes in the differential diagnosis of AD and DLB. Method: Whole-brain SPECT scans were acquired using a single-headed rotating gamma camera (IGE CamStar XR/T) in elderly subjects with consensus criteria DLB (n = 23; mean age = 79.4 years), National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association AD (n = 50; 81.9 years), and normal control subjects (n = 20; 78.1 years) after injection with 500 MBq of 99mTc-HMPAO. Region-of-interest analysis was performed using a SPECT template registered in Talairach space, with rCBF normalized to cerebellum. Results: Both DLB and AD subjects had significantly reduced rCBF in parietal and temporal regions compared with the control subjects. The AD group also showed a significant reduction in rCBF in the frontal and medial temporal regions and the DLB in the occipital areas compared with control subjects. AD and DLB groups differed only in occipital perfusion (p < 0.01). SPECT measures (occipital and medial temporal) correctly classified 69% of all subjects, with a 65% sensitivity and 87% specificity for DLB against AD and control subjects. Conclusion: Temporoparietal hypoperfusion on SPECT is common to both AD and DLB. Occipital hypoperfusion is more frequently seen in DLB. Although not diagnostically specific in individual cases, occipital hypoperfusion on SPECT should raise suspicion that DLB may be the cause of dementia, prompting careful search for other features of the disorder.

A comparison of 99mTc-HMPAO SPET changes in dementia with Lewy bodies and Alzheimer's disease using statistical parametric mapping

Abstract. Differences in regional cerebral blood flow (rCBF) between subjects with Alzheimers disease (AD), dementia with Lewy bodies (DLB) and healthy volunteers were investigated using statistical parametric mapping (SPM99). Forty-eight AD, 23 DLB and 20 age-matched control subjects participated. Technetium-99m hexamethylpropylene amine oxime (HMPAO) brain single-photon emission tomography (SPET) scans were acquired for each subject using a single-headed rotating gamma camera (IGE CamStar XR/T). The SPET images were spatially normalised and group comparison was performed by SPM99. In addition, covariate analysis was undertaken on the standardised images taking the Mini Mental State Examination (MMSE) scores as a variable. Applying a height threshold of P≤0.001 uncorrected, significant perfusion deficits in the parietal and frontal regions of the brain were observed in both AD and DLB groups compared with the control subjects. In addition, significant temporoparietal perfusion deficits were identified in the AD subjects, whereas the DLB patients had deficits in the occipital region. Comparison of dementia groups (height threshold of P≤0.01 uncorrected) yielded hypoperfusion in both the parietal [Brodmann area (BA) 7] and occipital (BA 17, 18) regions of the brain in DLB compared with AD. Abnormalities in these areas, which included visual cortex and several areas involved in higher visual processing and visuospatial function, may be important in understanding the visual hallucinations and visuospatial deficits which are characteristic of DLB. Covariate analysis indicated group differences between AD and DLB in terms of a positive correlation between cognitive test score and temporoparietal blood flow. In conclusion, we found evidence of frontal and parietal hypoperfusion in both AD and DLB, while temporal perfusion deficits were observed exclusively in AD and parieto-occipital deficits in DLB.

Using a Monte Carlo model to predict dosimetric properties of small radiotherapy photon fields

Accurate characterization of small-field dosimetry requires measurements to be made with precisely aligned specialized detectors and is thus time consuming and error prone. This work explores measurement differences between detectors by using a Monte Carlo model matched to large-field data to predict properties of smaller fields. Measurements made with a variety of detectors have been compared with calculated results to assess their validity and explore reasons for differences. Unshielded diodes are expected to produce some of the most useful data, as their small sensitive cross sections give good resolution whilst their energy dependence is shown to vary little with depth in a 15MV linac beam. Their response is shown to be constant with field size over the range 1-10cm, with a correction of 3% needed for a field size of 0.5cm. BEAMnrc has been used to create a 15MV beam model, matched to dosimetric data for square fields larger than 3cm, and producing small-field profiles and percentage depth doses (PDDs) that agree well with unshielded diode data for field sizes down to 0.5cm. For fields sizes of 1.5cm and above, little detector-to-detector variation exists in measured output factors, however for a 0.5cm field a relative spread of 18% is seen between output factors measured with different detectors-values measured with the diamond and pinpoint detectors lying below that of the unshielded diode, with the shielded diode value being higher. Relative to the corrected unshielded diode measurement, the Monte Carlo modeled output factor is 4.5% low, a discrepancy that is probably due to the focal spot fluence profile and source occlusion modeling. The large-field Monte Carlo model can, therefore, currently be used to predict small-field profiles and PDDs measured with an unshielded diode. However, determination of output factors for the smallest fields requires a more detailed model of focal spot fluence and source occlusion.

Correlations between dose-surface histograms and the incidence of long-term rectal bleeding following conformal or conventional radiotherapy treatment of prostate cancer.

BACKGROUND AND PURPOSE In a randomized trial, the incidence of rectal bleeding among patients treated for prostate cancer using conformal radiotherapy was significantly lower (p = 0.002) than that among those treated conventionally. Here the relationship between rectal dose distributions and incidences of bleeding is assessed. METHODS AND MATERIALS Rectal dose-surface histograms (DSHs) have been calculated for 79 trial patients. The relationship between the DSHs and incidences of Grade 1-3 bleeding has been explored using both semiempiric and biologic (parallel) model-based approaches. RESULTS Semiempiric analysis of the trial data suggests that it is more useful to work with DSH fractional surface areas multiplied by outlined rectal lengths than with either raw DSH fractional areas or fractional areas multiplied by absolute total outlined rectal surface area. Fitting the parallel model to length-multiplied rectal DSHs and complication data reveals the existence of a significant volume effect, the rate of Grade 1-3 bleeding falling by 1.1% (95% confidence interval [0.04, 2.2]%) for each 1% decrease in the fraction of rectal wall (outlined over an 11-cm length) receiving a dose of more than 57 Gy. CONCLUSION The existence of this volume effect suggests that dose escalation can be achieved using conformal techniques, although the extent to which doses may be safely escalated cannot be reliably estimated from the trial data.

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.

The application of statistical parametric mapping to 123I-FP-CIT SPECT in dementia with Lewy bodies, Alzheimer's disease and Parkinson's disease

Dopaminergic loss can be visualised using (123)I-FP-CIT single photon emission computed tomography (SPECT) in several disorders including Parkinsons disease (PD) and dementia with Lewy bodies (DLB). Most previous SPECT studies have adopted region of interest (ROI) methods for analysis, which are subjective and operator-dependent. The purpose of this study was to investigate differences in striatal binding of (123)I-FP-CIT SPECT using the automated technique of statistical parametric mapping (SPM99) in subjects with DLB, Alzheimers disease (AD), PD and healthy age-matched controls. This involved spatial normalisation of each subjects image to a customised template, followed by smoothing and intensity normalisation of each image to its corresponding mean occipital count per voxel. Group differences were assessed using a two-sample t test. Applying a height threshold of P <or= 0.05 corrected, the SPM[t] maps showed a significant bilateral reduced uptake in caudate, anterior and posterior putamen in DLB and PD subjects compared to AD subjects and controls. Significant reduction in binding was also observed bilaterally in the caudate nucleus in AD compared to controls. Striatal binding was indistinguishable between patients with DLB and PD. To investigate the usefulness of SPM as a decision aid in the evaluation of visually rated normal and abnormal patterns of uptake, receiver operator characteristic (ROC) curve analysis was performed using data from single-subject SPMs. The areas under the ROC curves were greater than 0.92, demonstrating comparable discriminatory power with visual rating. The automated voxel-based approach is a viable alternative to the subjective and often time-consuming method of ROI and, in addition, may have the potential to differentiate between normal and abnormal patterns of uptake in a manner similar to visual inspection.

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.

Detector density and small field dosimetry: Integral versus point dose measurement schemes

PURPOSE The Alfonso et al. [Med. Phys. 35, 5179-5186 (2008)] formalism for small field dosimetry proposes a set of correction factors (kQclin,Qmsrfclin,fmsr) which account for differences between the detector response in nonstandard (clinical) and machine-specific-reference fields. In this study, the Monte Carlo method was used to investigate the viability of such small field correction factors for four different detectors irradiated under a variety of conditions. Because kQclin,Qmsrfclin,fmsr values for single detector position measurements are influenced by several factors, a new theoretical formalism for integrated-detector-position [dose area product (DAP)] measurements is also presented and was tested using Monte Carlo simulations. METHODS A BEAMnrc linac model was built and validated for a Varian Clinac iX accelerator. Using the egs++ geometry package, detailed virtual models were built for four different detectors: a PTW 60012 unshielded diode, a PTW 60003 Diamond detector, a PTW 31006 PinPoint (ionization chamber), and a PTW 31018 MicroLion (liquid-filled ionization chamber). The egs_chamber code was used to investigate the variation of kQclin,Qmsrfclin,fmsr with detector type, detector construction, field size, off-axis position, and the azimuthal angle between the detector and beam axis. Simulations were also used to consider the DAP obtained by each detector: virtual detectors and water voxels were scanned through high resolution grids of positions extending far beyond the boundaries of the fields under consideration. RESULTS For each detector, the correction factor (kQclin,Qmsrfclin,fmsr) was shown to depend strongly on detector off-axis position and detector azimuthal angle in addition to field size. In line with previous studies, substantial interdetector variation was also observed. However, it was demonstrated that by considering DAPs rather than single-detector-position dose measurements the high level of interdetector variation could be eliminated. Under small field conditions, mass density was found to be the principal determinant of water equivalence. Additionally, the mass densities of components outside the sensitive volumes were found to influence the detector response. CONCLUSIONS kQclin,Qmsrfclin,fmsr values for existing detector designs depend on a host of variables and their calculation typically relies on the use of time-intensive Monte Carlo methods. Future moves toward density-compensated detector designs or DAP based protocols may simplify the methodology of small field dosimetry.

Helical tomotherapy as a means of delivering accelerated partial breast irradiation.

A novel treatment approach utilizing helical tomotherapy for partial breast irradiation for patients with early-stage breast cancer is described. This technique may serve as an alternative to high dose-rate (HDR) interstitial brachytherapy and standard linac-based approaches. Through helical tomotherapy, highly conformal irradiation of target volumes and avoidance of normal sensitive structures can be achieved. Unlike HDR brachytherapy, it is noninvasive. Unlike other linac-based techniques, it provides image-guided adaptive radiotherapy along with intensity modulation. A treatment planning CT scan was obtained as usual on a post-lumpectomy patient undergoing HDR interstitial breast brachytherapy. The patient underwent catheter placement for HDR treatment and was positioned prone on a specially designed position-supporting mattress during C T. The planning target volume (PTV) was defined as the lumpectomy bed plus a 20 mm margin. The prescription dose was 34 Gy (10 fx of 3.4 Gy) in both the CT based HDR and on the tomotherapy plan. Cumulative dose-volume histograms (DVHs) were generated and analyzed for the target, lung, heart, skin, pectoralis muscle, and chest wall for both HDR brachytherapy and helical tomotherapy. Dosimetric coverage of the target with helical tomotherapy was conformal and homogeneous. “Hot spots” (≥150% isodose line) were present around implanted dwell positions in brachytherapy plan whereas no isodose lines higher than 109% were present in the helical tomotherapy plan. Similar dose coverage was achieved for lung, pectoralis muscle, heart, chest wall and breast skin with the two methods. We also compared our results to that obtained using conventional linac-based three dimensional (3D) conformal accelerated partial breast irradiation. Dose homogeneity is excellent with 3D conformal irradiation, and lung, heart and chest wall dose is less than for either HDR brachytherapy or helical tomotherapy but skin and pectoral muscle doses were higher than with the other techniques. Our results suggest that helical tomotherapy can serve as an effective means of delivering accelerated partial breast irradiation and may offer superior dose homogeneity compared to HDR brachytherapy.

Using cavity theory to describe the dependence on detector density of dosimeter response in non-equilibrium small fields

The dose imparted by a small non-equilibrium photon radiation field to the sensitive volume of a detector located within a water phantom depends on the density of the sensitive volume. Here this effect is explained using cavity theory, and analysed using Monte Carlo data calculated for schematically modelled diamond and Pinpoint-type detectors. The combined impact of the density and atomic composition of the sensitive volume on its response is represented as a ratio, Fw,det, of doses absorbed by equal volumes of unit density water and detector material co-located within a unit density water phantom. The impact of density alone is characterized through a similar ratio, Pρ -, of doses absorbed by equal volumes of unit and modified density water. The cavity theory is developed by splitting the dose absorbed by the sensitive volume into two components, imparted by electrons liberated in photon interactions occurring inside and outside the volume. Using this theory a simple model is obtained that links Pρ - to the degree of electronic equilibrium, see, at the centre of a field via a parameter Icav determined by the density and geometry of the sensitive volume. Following the scheme of Bouchard et al (2009 Med. Phys. 36 4654-63) Fw,det can be written as the product of Pρ -, the water-to-detector stopping power ratio [L[overline](Δ)/ρ](w)(det), and an additional factor Pfl -. In small fields [L[overline](Δ)/ρ](w)(det) changes little with field-size; and for the schematic diamond and Pinpoint detectors Pfl - takes values close to one. Consequently most of the field-size variation in Fw,det originates from the Pρ - factor. Relative changes in see and in the phantom scatter factor sp are similar in small fields. For the diamond detector, the variation of Pρ - with see (and thus field-size) is described well by the simple cavity model using an Icav parameter in line with independent Monte Carlo estimates. The model also captures the overall field-size dependence of Pρ - for the schematic Pinpoint detector, again using an Icav value consistent with independent estimates.