18FDG PET/CT in the early assessment of non-small cell lung cancer response to immunotherapy: frequency and clinical significance of atypical evolutive patterns.

PURPOSE: This prospective study aimed (1) to assess the non-small cell lung cancer (NSCLC) evolutive patterns to immunotherapy using FDG-PET and (2) to describe their association with clinical outcome. DESIGN: Fifty patients with metastatic NSCLC were included before pembrolizumab or nivolumab initiation. FDG-PET scan was performed at baseline and after 7 weeks of treatment (PETinterim1) and different criteria/parameters of tumor response were assessed, including PET response criteria in solid tumors (PERCIST). If a first PERCIST progressive disease (PD) without clinical worsening was observed, treatment was continued and a subsequent FDG-PET (PETinterim2) was performed at 3 months of treatment. Pseudo-progression (PsPD) was defined as a PERCIST response/stability on PETinterim2 after an initial PD. If a second PERCIST PD was assessed on PETinterim2, a homogeneous progression of lesions (termed immune homogeneous progressive-disease: iPDhomogeneous) was distinguished from a heterogeneous evolution (termed immune dissociated-response: iDR). A durable clinical benefit (DCB) of immunotherapy was defined as treatment continuation over a 6-month period. The association between PET evolutive profiles and DCB was assessed. RESULTS: Using PERCIST on PETinterim1, 42% (21/50) of patients showed a response or stable disease, most of them (18/21) reached a DCB. In contrast, 58% (29/50) showed a PD, but more than one-third (11/29) were misclassified as they finally reached a DCB. No standard PETinterim1 criteria could accurately distinguished responding from non-responding patients. Treatment was continued in 19/29 of patients with a first PERCIST PD; the subsequent PETinterim2 demonstrated iPDhomogeneous, iDR and PsPD in 42% (8/19), 26% (5/19), and 32% (6/19), respectively. Whereas no patients with iPDhomogeneous experienced a DCB, all patients with iDR and PsPD reached a clinical benefit to immunotherapy. CONCLUSION: In patients with a first PD on PERCIST and treatment continuation, a subsequent PET identifies more than half of them with iDR and PsPD, both patterns being strongly associated with a clinical benefit of immunotherapy.

The reversed clock drawing test phenomenon in Alzheimer's disease: A perfusion SPECT study.

AIM: To unveil a brain single photon emission computed tomography (SPECT) pattern in Alzheimer's disease (AD) patients, showing a reversed clock drawing test (CDT) phenomenon. PATIENTS AND METHODS: Among 1,005 consecutive subjects, 9 AD patients who drew a reversed CDT (AD-R) underwent SPECT, which was analysed (SPM2) versus a group of 10 AD patients performing the CDT correctly (AD+) and versus 15 controls (CTR). Brain SPECT in 11 AD patients who mistook the CDT in a common way (AD-) was compared with AD+ and CTR groups. RESULTS: Relative hypoperfusion was found in AD-R versus CTR in right medial frontal, parahippocampal and subcallosal gyri, and in left insula and superior temporal gyrus. Hypoperfusion was found in AD-R versus AD+ in the right uncus, superior temporal and parahippocampal gyri. In the AD- versus CTR comparison, hypoperfusion was found in left hippocampus, parahippocampal gyrus and superior parietal lobule. In AD-R versus AD+ and CTR merged together, the analysis showed hypoperfusion in the right parahippocampus, medial frontal gyrus, superior temporal gyrus and uncus, in the left insula and superior temporal gyrus. CONCLUSION: Fronto-temporal dysfunction, especially in the right hemisphere, plays a role in the reversed CDT phenomenon in AD patients, whereas matched AD patients mistaking the CDT in a common way show left posterior temporo-parietal hypoperfusion.

Model-based respiratory motion compensation for emission tomography image reconstruction.

In emission tomography imaging, respiratory motion causes artifacts in lungs and cardiac reconstructed images, which lead to misinterpretations, imprecise diagnosis, impairing of fusion with other modalities, etc. Solutions like respiratory gating, correlated dynamic PET techniques, list-mode data based techniques and others have been tested, which lead to improvements over the spatial activity distribution in lungs lesions, but which have the disadvantages of requiring additional instrumentation or the need of discarding part of the projection data used for reconstruction. The objective of this study is to incorporate respiratory motion compensation directly into the image reconstruction process, without any additional acquisition protocol consideration. To this end, we propose an extension to the maximum likelihood expectation maximization (MLEM) algorithm that includes a respiratory motion model, which takes into account the displacements and volume deformations produced by the respiratory motion during the data acquisition process. We present results from synthetic simulations incorporating real respiratory motion as well as from phantom and patient data.

Combined constraints for efficient algebraic regularized methods in fully 3D reconstruction.

SPECT systems incorporate the use of one or more rotating gamma cameras which can be equipped with cone-beam collimators to improve the trade-off between spatial resolution and sensitivity. The geometry of the cone-beam collimators implies that a specific 3D reconstruction algorithm must be applied. Algebraic methods provide the possibility of including the physical characteristics, such as attenuation, Compton scatter and detector response, in the reconstruction process. However, the reconstruction problem is an ill-posed problem which should be regularized. This paper presents a 3D algebraic method that combines three regularizing constraints. These constraints deal respectively with penalizing negative voxels, local noise smoothing and missing data compensation. The results presented were obtained from imaging simulations, phantom data and from a thyroid clinical study of a normal volunteer.

18F-FDOPA PET for the diagnosis of parkinsonian syndromes.

18F-FDOPA PET has been historically used for the evaluation of parkinsonian syndromes in research settings. With the wider availability of PET cameras and 18F-DOPA this method can be used as a clinical diagnostic tool. Current acquisition protocols are simple with a 10 minute static acquisition performed 90 minutes post injection. Criteria for precise visual analysis of the images are defined. The performances of the method are reviewed throughout the literature. The method is very sensitive for detection of IPD versus normal patients. Few studies comparing 18F-FDOPA PET and DAT SPECT did not show any difference in diagnostic accuracy. 18F-FDOPA PET is reliable for evaluation of IPD progression. In general, atypical Parkinson's syndromes cannot be reliably differentiated from IPD since they share a similar nigro-striatal degeneration process. However, some patterns such as the asymmetrical faint homogeneous striatal uptake reduction pattern of CBD can be recognized. The short acquisition protocol, the various indications in oncology of 18F-FDOPA and the high quality of PET images are in favor of this technique in daily clinical practice for the improvement of diagnosis of parkinsonian syndromes.

The need of appropriate brain SPECT templates for SPM comparisons.

AIM: Statistical parametric mapping (SPM) is used worldwide to compare brain perfusion single photon emission computed tomography (SPECT) data. The default template within the SPM package used for SPECT image normalization includes images of a group of healthy subjects studied with [(99m)Tc]HMPAO. Since [(99m)Tc]HMPAO and [(99m)Tc]ECD have shown to distribute differently in SPECT studies, we formulated the hypothesis that comparing set of [(99m)Tc]ECD data normalized by means of a [(99m)Tc]HMPAO template may lead to incorrect results. METHODS: A customized [(99m)Tc]ECD template was built with SPECT and magnetic resonance imaging (MRI) images of 22 neurologically healthy women. Then, two sets of subjects, i.e. a group of patients with very early Alzheimer's disease (eAD) and a matched control group, studied by means of [(99m)Tc]ECD SPECT, were chosen for comparisons. The same statistical approach (t-test between eAD patients and controls and correlation analysis between brain SPECT and a cognitive score) was applied twice, i.e. after normalization with either the default [(99m)Tc]HMPAO template or the customized [(99m)Tc]ECD template. RESULTS: In the comparison between eAD and controls, a cluster of difference in the posterior cingulate gyrus of both hemispheres was only highlighted when using the customized [(99m)Tc]ECD template, but was missed when using the default [(99m)Tc]HMPAO template. In the correlation between brain perfusion and a cognitive score, the significant cluster was more significant and far more extended, also including the right superior temporal gyrus, using the customized [(99m)Tc]ECD template than using the default [(99m)Tc]HMPAO template. CONCLUSION: These data suggest the need of customized, radiopharmaceutical-matched SPECT templates to be used within the SPM package. The present customized [(99m)Tc]ECD template is now freely available on the web.

99mTc-HMPAO and 99mTc-ECD brain uptake correlates of verbal memory in Alzheimer's disease.

AIM: Technetium-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO) and technetium-99m N,N-1,2-ethylene diylbis-Lcysteine diethyl ester dihydrochloride ((99m)Tc-ECD) SPECT are widely used in Dementia Clinics for early and differential diagnosis. They have been shown to perform differently in Alzheimer's disease (AD), but the impact of such differences on both research and clinical work is unknown. We investigated the differences between the 2 compounds in research work by assessing correlation between performance on a verbal memory task and cerebral perfusion in 2 matched groups of AD patients. METHODS: Nineteen pairs of patients with mild to moderate AD undergoing SPECT with either 99mTc-HMPAO or (99m)Tc-ECD were retrospectively selected in a Memory Clinic. Patients were matched for sex, age (+/-3 years) and the Mini-Mental State Examination score (+/-2 points) with a case-control procedure, thus obtaining 2 well-matched groups. The score on the Grober-Buschke selective reminding test (SRT) was correlated with SPECT in each group by means of statistical parametric mapping 99 (height threshold: P<0.01). RESULTS: (99m)Tc-HMPAO SPECT yielded 3 significant correlation clusters involving inferior and middle frontal gyri, para-hippocampal gyrus and putamen in the right hemisphere; the middle and superior temporal gyri, insula and claustrum in the left hemisphere. (99m)Tc-ECD gave a significant cluster of correlation in left postcentral gyrus and inferior parietal lobule. CONCLUSION: (99m)Tc-HMPAO SPECT correlation sites seem more consistent than (99m)Tc-ECD ones with the neurophysiological models of verbal memory, as designed both in normal individuals and in pathological conditions. The demonstration of such relevant differences introduces a source of variability among studies performed with either of the 2 compounds, which must be considered when interpreting results.

Brain perfusion correlates of the apathy inventory dimensions of Alzheimer's disease.

BACKGROUND: Apathy is defined as a lack of motivation in behavior, cognition and affect. This syndrome is frequent in various neuropsychiatric diseases but little is known about its pathophysiology. OBJECTIVES: The aim of this study was to investigate the metabolic correlates of the behavioral, cognitive and emotional, aspects of apathy in Alzheimer's disease (AD). METHOD: Thirty AD patients were included. Lack of initiative, lack of interest and of emotional blunting were assessed with the Apathy Inventory (IA), a tool designed to provide a separate assessment of the behavioral, cognitive and emotional, aspects of apathy. Brain perfusion was measured by (99m)Tc-labeled bicisate (ECD) single photon emission tomography. RESULTS: The Statistical Parametric Mapping software provides negative correlation between IA total score and brain perfusion in left and right superior orbito-frontal gyrus, and to a lesser extent in left middle frontal gyrus (BA10). Lack of initiative score was negatively correlated with perfusion in right anterior cingulate cortex. Lack of interest score was negatively correlated with perfusion in right middle orbitofrontal gyrus). Emotional blunting score correlated negatively with in left superior dorsolateral prefrontal cortex activity. CONCLUSION: These results underline that the cognitive, behavioral and affective components of motivation are mediated by different fronto-sub-cortical circuits and are differently lateralized. In particular, left prefrontal hypoperfusion is involved in emotional blunting, as it was often demonstrated in depressive disorders. These distinct components of apathy may be targeted by different therapeutic means, in which dopaminergic enhancement might play a major role.

Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer's disease and nondemented patients.

Apathy is the most frequent behavioral symptom in Alzheimer's disease and is also frequently reported in other brain organic disorders occurring in the elderly. Based on the literature, we hypothesized that apathy was related to an anterior cingulate hypofunction. Forty-one subjects were studied. According to ICD 10 diagnostic criteria, 28 patients had Alzheimer dementia (demented: diagnostic group 1), and 13 had organic personality disorders or mild cognitive impairment not attributable to dementia (nondemented: diagnostic group 2). Apathy was evaluated by the Neuro-Psychiatric Inventory. As a result each diagnostic group was divided into two symptomatic subgroups: apathetic or nonapathetic. Brain perfusion was measured by (99m)Tc-labeled bicisate (ECD) brain SPECT and the images were compared using Statistical Parametric Mapping (SPM96). We began by comparing apathetic vs nonapathetic patients, whatever their diagnostic group (whole population), then analyzed them within each group. Twenty-one subjects were apathetic (14 in group 1 and 7 in group 2) and 20 were not (14 in group 1 and 6 in group 2). For the whole population, the Z map showed a significant decrease in ECD uptake for the apathetic patients in the anterior cingulate (P < 0.002) bilaterally. This area was also identified as hypoactive by SPM analysis in the demented (P < 0.035) and in the nondemented (P < 0.02) apathetic patient groups. Finally, conjunction analysis indicated that the anterior cingulate was the common hypoactive structure of the two apathetic subgroups (Z = 4.35, P < 0.0009). These results point to a close relationship between apathy and the anterior cingulate region.