Neuroinflammation as potential precursor of leukoencephalopathy in early-stage breast cancer patients:A cross-sectional PET-MRI study

BACKGROUND: Although chemotherapy-induced leukoencephalopathy has been described in case and cohort studies, literature remains inconclusive about its prevalence and mechanisms. Therefore, we investigated the presence of leukoencephalopathy after multiagent chemotherapy in women treated for breast cancer and potential underlying neuroinflammatory processes. METHODS: In this exploratory study, 15 chemotherapy-treated and 15 age-matched chemotherapy-naïve patients with early-stage breast cancer, as well as 15 healthy controls underwent simultaneous PET-MR neuroimaging, including T1-weighted MPRAGE, T2-weighted FLAIR and dynamic PET with the 18-kDA translocator protein (TSPO) radioligand [(18)F]DPA-714. Total and regional (juxtacortical, periventricular, deep white matter and infratentorial) lesion burden were compared between the groups with one-way ANOVA. With paired t-tests, [(18)F]DPA-714 volume of distribution [V(T), including partial volume correction (PVC)] in lesioned and normal appearing white matter (NAWM) were compared within subjects, to investigate inflammation. Finally, two general linear models were used to examine the predictive values of neurofilament light-chain (NfL) serum levels on (1) total lesion burden or (2) PVC [(18)F]DPA-714 V(T) of lesions showing elevated inflammation. RESULTS: No significant differences were found in total or localized lesion burden. However, significantly higher (20–45%) TSPO uptake was observed in juxtacortical lesions (p ≤ 0.008, t ≥ 3.90) compared to NAWM in both cancer groups, but only persisted for chemotherapy-treated patients after PVC (p = 0.005, t = 4.30). NfL serum levels were not associated with total lesion volume or tracer uptake in juxtacortical lesions. CONCLUSION: This multimodal neuroimaging study suggests that neuroinflammatory processes could be involved in the development of juxtacortical, but not periventricular or deep white matter, leukoencephalopathy shortly after chemotherapy for early-stage breast cancer

Regional accuracy of ZTE-based attenuation correction in static and dynamic brain PET/MR

Accurate MR-based attenuation correction (MRAC) is essential for quantitative PET/MR imaging of the brain. In this study, we analyze the regional bias caused by MRAC based on Zero-Echo-Time MR images (ZTEAC) compared to CT-based AC (CTAC) in static and dynamic PET imaging. In addition the results are compared to the performance of the current default Atlas-based AC (AtlasAC) implemented in the GE SIGNA PET/MR. Methods: Thirty static [18F]FDG and 11 dynamic [18}F]PE2I acquisitions from a GE SIGNA PET/MR were reconstructed using ZTEAC (using a research tool, GE Healthcare), single-subject AtlasAC (the current default AC in GE's SIGNA PET/MR) and CTAC (from a PET/CT acquisition of the same day). In the 30 static [18F]FDG reconstructions, the bias caused by ZTEAC and AtlasAC in the mean uptake of 85 anatomical volumes of interest (VOIs) of the Hammers' atlas was analyzed in PMOD. For the 11 dynamic [18}F]PE2I reconstructions, the bias caused by ZTEAC and AtlasAC in the non displaceable binding potential BPnd in the striatum was calculated with cerebellum as the reference region and a simplified reference tissue model. Results: The regional bias caused by ZTEAC in the static [18F]FDG reconstructions ranged from -8.0% to +7.7% (mean 0.1%, SD 2.0%). For AtlasAC this bias ranged from -31.6% to +16.6% (mean -0.4%, SD 4.3%). The bias caused by AtlasAC showed a clear gradient in the cranio-caudal direction (-4.2% in the cerebellum, +6.6% in the left superior frontal gyrus). The bias in the striatal BPnd for the [18F]PE2I reconstructions ranged from -0.8% to +4.8% (mean 1.5%, SD 1.4%) using ZTEAC and from -0.6% to +9.4% using AtlasAC (mean 4.2%, SD 2.6%). Conclusion: ZTEAC provides excellent quantitative accuracy for static and dynamic brain PET/MR, comparable to CTAC, and is clearly superior to the default AtlasAC currently implemented in the GE SIGNA PET/MR.Comment: 23 pages in total, 7 figures, 1 table, 3 supplementary figures, 5 supplementary table

PET imaging of glucose metabolism, neuroinflammation and synaptic density in amyotrophic lateral sclerosis

ALS is a neurodegenerative disease with progressive muscle loss and an average survival of 2 to 5 years after symptom onset. Until now, no curative treatment is available. The general aim of this PhD was to investigate a triad of interrelated in-vivo imaging biomarkers that may be used for diagnosis and prognosis and the study of their physiopathological significance in ALS: glucose metabolism, neuroinflammation and synaptic density. GLUCOSE METABOLISM In early diagnostic stages it can be difficult to discriminate between ALS and diseases mimicking ALS symptoms, also named ALS mimics. We demonstrated that glucose metabolism may increase clinical accuracy in this differential diagnosis by assessing a disease specific [18F]FDG signature in ALS. The combination of brain and spinal cord metabolism could discriminate between ALS and ALS mimics with an accuracy of 81.5% in early disease stages. The observed glucose metabolic pattern in ALS can be reproduced across different centers with similar clinical diagnostic criteria. Using glucose metabolism, patients can be subdivided in 4 different metabolic stadia, which may be useful to create more homogeneous subgroups for therapeutic trials. Altogether, our results show that glucose metabolism is a promising and clinically useful diagnostic biomarker and stratification aid for multicenter studies. (chapter 1) NEUROINFLAMMATION The mitochondrial TSPO receptor is upregulated in neuroinflammation and over the last twenty years several TSPO radioligands have been developed. Currently, all second generation TSPO radioligands still have a relatively low signal-to-noise ratio and require genotyping. Therefore, we investigated a theoretically more specific target for neuroinflammation, the P2X7 receptor. Although, P2X7R radioligands seemed promising to quantify neuroinflammation, we demonstrated no significant differences in ALS vs. HV, so thus far TSPO tracers remain the best option to measure neuroinflammation in symptomatic ALS patients. We proposed a clinically practical imaging protocol and confirmed that (multicentric) pooling of data obtained with different second-generation TSPO tracers is achievable. The latter will facilitate the use and practical feasibility for clinical implementation and in future therapeutic studies. (chapter 2) SYNAPTIC DENSITY Since the FDG signal is, amongst others, determined by (glutamatergic) synaptic activity as well as neuroinflammation, we investigated [11C]UCB-J PET as a biomarker for synaptic density changes in ALS. In our pilot study (n = 11), no significant difference in cerebral synaptic density was observed between ALS patients and HV. (chapter 3) Therefore, this suggests that cerebral synaptic density imaging is probably not valuable as biomarker for use in ALS, in contrast to manifest changes found in other neurodegenerative diseases such as AD (predominantly hippocampal) and PD (predominantly in the substantia nigra). INTERACTION BETWEEN GLUCOSE METABOLISM, NEUROINFLAMMATION AND SYNAPTIC DENSITY In a pilot study, we examined the triad of glucose metabolism, synaptic density and neuroinflammation simultaneously in a subset of ALS patients. Whereas synaptic density was not significantly correlated with TSPO signal or glucose metabolism, a relation between hypermetabolism and neuroinflammation was found, indicating that hypermetabolism in ALS can be - at least partly - attributed to neuroinflammation. (chapter 3) Overall, this PhD thesis demonstrates the utility of [18F]FDG and TSPO PET imaging in the context of early diagnosis, prognosis and patient stratification for (multicentric) therapeutic trials.status: publishe

Loss of Presynaptic Terminal Integrity in the Substantia Nigra in Early Parkinson's Disease

BACKGROUND: It has been hypothesized that the pathology of Parkinson's disease (PD) primarily affects presynaptic terminals and spreads trans-synaptically. OBJECTIVES: The main objective of this study was to assess the magnitude and anatomical extent of presynaptic terminal loss across the brain in early PD. A second objective was to compare loss of presynaptic terminals and cell bodies within the nigrostriatal tract. METHODS: A total of 30 patients with early PD and 20 age- and gender-matched healthy controls underwent positron emission tomography with 11 C-UCB-J, a ligand for the universal presynaptic terminal marker synaptic vesicle protein 2A (SV2A), and with the dopamine transporter ligand 18 F-FE-PE2I, as well as a detailed clinical assessment. Volumes of interest were delineated based on individual 3-dimensional T1 magnetic resonance imaging. BPND images were calculated. RESULTS: Patients with PD showed significant loss of SV2A binding in the substantia nigra only. Loss of dopamine transporter binding in the PD group was much greater in the putamen than in the substantia nigra. We found no correlations between SV2A or dopamine transporter binding and any of the clinical motor or nonmotor scores. Homologous voxel-based analysis in the PD group showed significant correlations between SV2A and dopamine transporter binding in the caudate and substantia nigra. CONCLUSIONS: Presynaptic terminals appear to be the most heavily affected subcellular compartment of nigrostriatal neurons in early PD. Moreover, early PD causes loss of presynaptic terminals that innervate the nigrostriatal neurons. This loss of presynaptic boutons in the substantia nigra may reflect an axonal response to target deprivation or could possibly point to a trans-synaptic mode of propagation of the disease process. © 2020 International Parkinson and Movement Disorder Society.status: publishe

Learning metabolic connectivity in amyotrophic lateral sclerosis with [18F]FDG PET

status: accepte

Mixed response on regorafenib treatment for GIST (gastro-intestinal stromal tumor) according toF-FDG-PET/CT

Gastro-intestinal stromal tumors (GISTs) are very rare tumors of the gastro-intestinal tract, originating from the interstitial cells of Cajal or a common cell precursor which both express type III tyrosine kinase receptors. Regorafenib is an oral multi-kinase inhibitor used to treat gastro-intestinal stromal tumors. To our knowledge this is the first case in literature to show the response of regorafenib on PET.status: publishe

Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. (18)F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-of-interest (VOI) and voxel-based (using a support vector machine [SVM] approach) (18)F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a priori-derived classifiers. Furthermore, the prognostic value of (18)F-FDG PET was evaluated.status: publishe

Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new?

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving upper and lower motor neurons, extra-motor neurons, microglia and astrocytes. The neurodegenerative process results in progressive muscle paralysis and even in cognitive impairment. Within the complex diagnostic work-up, positron emission tomography (PET) represents a valuable imaging tool in the assessment of patients with ALS. PET, by means of different radiotracers (i.e. 18F-fluorodeoxyglucose, 6-[18F]fluoro-L-dopa, [11C]flumazenil) can assess the status of the wide range of brain regions and neural circuits, which can be affected by ALS. Furthermore, experimental radiocompounds have been developed for the evaluation of white matter, which plays a role in the progression of the disease. Here we present a comprehensive review including in different sections the most relevant PET studies: studies investigating ALS and ALS-mimicking conditions (especially primary lateral sclerosis and other neurodegenerative diseases), articles selecting specific subsets of patients (with bulbar or spinal onset), studies investigating patients with familial type of ALS, studies evaluating the role of the white matter in ALS and papers evaluating the diagnostic sensitivity of PET in ALS patients.status: publishe

Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. (18)F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-of-interest (VOI) and voxel-based (using a support vector machine [SVM] approach) (18)F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a priori-derived classifiers. Furthermore, the prognostic value of (18)F-FDG PET was evaluated.status: publishe