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Background: Epileptic seizures are an established comorbidity of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG. However, SEA might lead to faster cognitive decline in AD., Aims: 1. To estimate the prevalence of SEA and interictal epileptic discharges (IEDs) in a well-defined cohort of participants belonging to the AD continuum, including preclinical AD subjects, as compared with cognitively healthy controls. 2. To evaluate whether long-term-EEG (LTM-EEG), high-density-EEG (hd-EEG) or MEG is superior to detect SEA in AD. 3. To characterise AD patients with SEA based on clinical, neuropsychological and neuroimaging parameters., Methods: Subjects (n = 49) belonging to the AD continuum were diagnosed according to the 2011 NIA-AA research criteria, with a high likelihood of underlying AD pathophysiology. Healthy volunteers (n = 24) scored normal on neuropsychological testing and were amyloid negative. None of the participants experienced a seizure before. Subjects underwent LTM-EEG and/or 50-min MEG and/or 50-min hd-EEG to detect IEDs., Results: We found an increased prevalence of SEA in AD subjects (31%) as compared to controls (8%) (p = 0.041; Fisher's exact test), with increasing prevalence over the disease course (50% in dementia, 27% in MCI and 25% in preclinical AD). Although MEG (25%) did not withhold a higher prevalence of SEA in AD as compared to LTM-EEG (19%) and hd-EEG (19%), MEG was significantly superior to detect spikes per 50 min (p = 0.002; Kruskall-Wallis test). AD patients with SEA scored worse on the RBANS visuospatial and attention subset (p = 0.009 and p = 0.05, respectively; Mann-Whitney U test) and had higher left frontal, (left) temporal and (left and right) entorhinal cortex volumes than those without., Conclusion: We confirmed that SEA is increased in the AD continuum as compared to controls, with increasing prevalence with AD disease stage. In AD patients, SEA is associated with more severe visuospatial and attention deficits and with increased left frontal, (left) temporal and entorhinal cortex volumes., Trial Registration: Clinicaltrials.gov, NCT04131491. 12/02/2020., (© 2024. The Author(s).)

Amyloid deposition can lead to Alzheimer disease and cerebral amyloid angiopathy. Rarely, it presents as a solitary focal deposition, primary cerebral amyloidoma, which can be misinterpreted as a neoplasm because of the "tumor-like" appearances. We present the case of a 54-year-old woman where MRI revealed a T2-hyperintense mass periventricular in the white matter with moderate contrast enhancement. Pathological investigation revealed AL (lambda) amyloidoma. F-florbetapir PET/CT was used to support the diagnosis and in follow-up. This case highlights that F-florbetapir PET/CT might play a role in the diagnostic workup of patients suggestive of cerebral amyloidoma, especially in cases where biopsy is not feasible.

Introduction: Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-β deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase 18 F-florbetapir (eAV45), the 18 F-AV45 delivery rate (R1), and 18 F-FDG against 15 O-H 2 O PET and assess how they change with disease severity., Methods: This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed., Results: FDG standardized uptake value ratio, eAV45 (0-2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H 2 O PET (regional Pearson r = 0.54-0.82, 0.70-0.94, and 0.65-0.92, respectively; P < .001). All modalities confirmed reduced cerebral blood flow in the posterior cingulate of patients with amnestic mild cognitive impairment and AD dementia, which was associated with lower cognition (r = 0.36-0.65, P < .025) and could discriminate between patient and control groups (area under the curve > 0.80). However, eAV45 was less sensitive to reflect the disease severity than AV45-R1 or FDG., Discussion: R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare bloodpool SPECT with planar imaging in bone SPECT/CT of painful total knee arthroplasty (TKA) with respect to inter-rater agreement, confidence, prosthesis outcome, and biomechanical functioning., Methods: Retrospective study of bloodpool SPECT and planar control images. Four raters used the validated Bruderholz scheme and a 5-point scale to grade uptake. Inter-rater agreement and overall confidence scores were calculated. Variable cluster analysis was performed to identify patterns of uptake, and associations between patterns and prosthesis outcome and biomechanical functioning were examined., Results: In all, 55 knees in 43 patients were analyzed (median follow-up 17 months; revision rate 21.8%). SPECT significantly improved inter-rater agreement in 24% of regions (all P < 0.05) and overall confidence by 20% (P < 0.001). Regional uptake cluster analysis showed improved antero-posterior separation with SPECT, and distinct patterns associated with prosthesis survival in lateral femoral (P = 0.041) and medial tibial (P < 0.001) regions. The prognostic value of SPECT outperformed planar imaging for tibial (P < 0.001), patellar (P = 0.009), and synovial (P = 0.040) assessment. Internal femoral malrotation resulted in increased uptake in posteromedial (P = 0.042) and anterolateral (P = 0.016) femoral, and lateral patellar (P = 0.011) regions. Internal tibial malrotation increased uptake in posterolateral (P = 0.026) and posteromedial tibial (P = 0.005), and medial patellar regions (P = 0.004). Bloodpool SPECT improved the prognostic value of late-phase SPECT/CT for the assessment of the medial tibial region., Conclusions: Bloodpool SPECT outperforms planar assessment of painful TKAs and the identification of distinct uptake patterns make it a potentially clinically relevant biomarker of prosthesis survival and biomechanical functioning.

Objective: To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers., Method: Second-generation radioligand [ 18 F]-PBR111 TSPO PET-CT was used for longitudinal dynamic imaging in 14 male psychosis patients and 17 male age-matched healthy control subjects. Patients were first scanned during an acute psychotic episode followed by a second scan after treatment. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- and mixed-affinity binders. The main outcome was regional volume of distribution (V T ), representing TSPO binding. Plasma concentrations of CRP, cytokines and kynurenines were measured at each timepoint., Results: We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in V T existed between cohorts during the psychotic state, but not at follow-up. Patients' relative change in V T over time correlated with age (cortical grey matter Pearson's r.574). PANSS positive subscale scores correlated with regional V T during psychosis (cortical grey matter r.767). Plasma CRP and quinolinic acid were independently associated with lower V T ., Conclusions: We identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18 F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18 F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18 F-FDG SUVR. CSF measures included Aβ 1-42 , Aβ 1-40 , T-tau, P-tau 181 , and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p < 0.001] and + 0.37 [p = 0.005], resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aβ burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: β = -0.28 [p = 0.020]). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or 18 F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood problems. Recently, occipital nerve field stimulation (ONS) has been proposed as an effective potential treatment for fibromyalgia-related pain. The aim of this study is to unravel the neural mechanism behind occipital nerve stimulation's ability to suppress pain in fibromyalgia patients., Materials and Methods: Seven patients implanted with subcutaneous electrodes in the C2 dermatoma were enrolled for a Positron Emission Tomography (PET) H 2 15 O activation study. These seven patients were selected from a cohort of 40 patients who were part of a double blind, placebo-controlled study followed by an open label follow up at six months. The H 2 15 O PET scans were taken during both the "ON" (active stimulation) and "OFF" (stimulating device turned off) conditions. Electroencephalogram (EEG) data were also recorded for the implanted fibromyalgia patients during both the "ON" and "OFF" conditions., Results: Relative to the "OFF" condition, ONS stimulation resulted in activation in the dorsal lateral prefrontal cortex, comprising the medial pain pathway, the ventral medial prefrontal cortex, and the bilateral anterior cingulate cortex as well as parahippocampal area, the latter two of which comprise the descending pain pathway. Relative deactivation was observed in the left somatosensory cortex, constituting the lateral pain pathway as well as other sensory areas such as the visual and auditory cortex. The EEG results also showed increased activity in the descending pain pathway. The pregenual anterior cingulate cortex extending into the ventral medial prefrontal cortex displayed this increase in the theta, alpha1, alpha2, beta1, and beta2 frequency bands., Conclusion: PET shows that ONS exerts its effect via activation of the descending pain inhibitory pathway and the lateral pain pathway in fibromyalgia, while EEG shows activation of those cortical areas that could be responsible for descending inhibition system recruitment., Trial Registration: This study is registered with ClinicalTrials.gov , number NCT00917176 (June 10, 2009).

Activated microglia express the translocator protein (TSPO) on the outer mitochondrial membrane. 18 F-PBR111 is a second-generation PET ligand that specifically binds the TSPO, allowing in vivo visualization and quantification of neuroinflammation. The aim of this study was to evaluate whether the test-retest variability of 18 F-PBR111 in healthy controls is acceptable to detect a psychosis-associated neuroinflammatory signal in schizophrenia. Methods: Dynamic 90-min 18 F-PBR111 scans were obtained in 17 healthy male controls (HCs) and 11 male schizophrenia patients (SPs) during a psychotic episode. Prior genotyping for the rs6917 polymorphism distinguished high-affinity binders (HABs) and mixed-affinity binders (MABs). Total volume of distribution (V T ) was determined from 2-tissue-compartment modeling with vascular trapping and a metabolite-corrected plasma input function. A subgroup of HCs ( n = 12; 4 HABs and 8 MABs) was scanned twice to assess absolute test-retest variability and intraclass correlation coefficients of the regional V T values. Differences in TSPO binding between HC and SP were assessed using mixed model analysis adjusting for age, genotype, and age*cohort. The effect of using different scan durations (V T-60 min versus V T-90 min ) was determined based on Pearson r. Data were mean ± SD. Results: Mean absolute variability in V T ranged from 16% ± 14% (19% ± 20% HAB; 15% ± 11% MAB) in the cortical gray matter to 22% ± 15% (23% ± 15% HAB; 22% ± 16% MAB) in the hippocampus. Intraclass correlation coefficients were consistently between 0.64 and 0.82 for all tested regions. TSPO binding in SP compared with HC depended on age (cohort*age: P < 0.05) and was increased by +14% ± 4% over the regions. There was a significant effect of genotype on TSPO binding, and V T of HABs was 31% ± 8% (HC: 17% ± 5%, SP: 61% ± 14%) higher than MABs. Across all clinical groups, V T-60 min and V T-90 min were strongly correlated ( r > 0.7, P < 0.0001). Conclusion: 18 F-PBR111 can be used for monitoring of TSPO binding, as shown by medium test-retest variability and reliability of V T in HCs. Microglial activation is present in SPs depending on age and needs to be adjusted for genotype., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Increased brain uptake of 18 F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (V T ) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min 18 F-AV45 (291 ± 67 MBq) and 1-min 15 O-H 2 O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). 18 F-AV45 V T was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min after injection, using either cerebellar gray matter (SUVR CB ) or whole subcortical white matter (SUVR WM ) as the reference. Additionally, whole cerebellum, pons, centrum semiovale, and a composite region were examined as alternative references. Blood flow was quantified by 15 O-H 2 O SUV. Data are presented as mean ± SEM. Results: There was rapid metabolization of 18 F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with V T , differences in cortical Aβ load between aMCI and AD were overestimated by SUVR WM (+4% ± 2%) and underestimated by SUVR CB (-10% ± 2%). V T correlated better with SUVR WM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVR CB (Pearson r: from 0.51 for temporal lobe [ P = 0.002] to 0.82 for precuneus [ P < 0.0001]) in all tested regions. Correlation results for the alternative references were in between those for CB and WM. 15 O-H 2 O data showed that blood flow was decreased in AD compared with aMCI in cortical regions (-5% ± 1%) and in the reference regions (CB, -9% ± 8%; WM, -8% ± 8%). Conclusion: Increased brain uptake of 18 F-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVR WM is better correlated with V T and more closely reflects V T differences between aMCI and AD than SUVR CB ., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone., Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting., Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181)., Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

We identified in a cohort of patients with frontotemporal dementia (n = 481) or amyotrophic lateral sclerosis (n = 147), 10 index patients carrying a TBK1 loss of function mutation reducing TBK1 expression by 50%. Here, we describe the clinical and pathological characteristics of the 10 index patients and six of their affected relatives carrying a TBK1 mutation. Six TBK1 carriers were diagnosed with frontotemporal dementia, seven with amyotrophic lateral sclerosis, one with both clinical phenotypes and two with dementia unspecified. The mean age at onset of all 16 TBK1 carriers was 62.1 ± 8.9 years (range 41-73) with a mean disease duration of 4.7 ± 4.5 years (range 1-13). TBK1 carriers with amyotrophic lateral sclerosis had shorter disease duration than carriers with frontotemporal dementia. Six of seven TBK1 carriers were diagnosed with the behavioural variant of frontotemporal dementia, presenting predominantly as disinhibition. Memory loss was an important associated symptom in the initial phase of the disease in all but one of the carriers with frontotemporal dementia. Three of the patients with amyotrophic lateral sclerosis exhibited pronounced upper motor neuron symptoms. Overall, neuroimaging displayed widespread atrophy, both symmetric and asymmetric. Brain perfusion single-photon emission computed tomography or fluorodeoxyglucose-positron emission tomography showed asymmetric and predominantly frontotemporal involvement. Neuropathology in two patients demonstrated TDP-43 type B pathology. Further, we compared genotype-phenotype data of TBK1 carriers with frontotemporal dementia (n = 7), with those of frontotemporal dementia patients with a C9orf72 repeat expansion (n = 65) or a GRN mutation (n = 52) and with frontotemporal dementia patients (n = 259) negative for mutations in currently known causal genes. TBK1 carriers with frontotemporal dementia had a later age at onset (63.3 years) than C9orf72 carriers (54.3 years) (P = 0.019). In clear contrast with TBK1 carriers, GRN carriers were more often diagnosed with the language variant than the behavioural variant, and presented in case of the diagnosis of behavioural variant, more often than TBK1 carriers with apathy as the predominant characteristic (P = 0.004). Also, TBK1 carriers exhibited more often extrapyramidal symptoms than C9orf72 carriers (P = 0.038). In conclusion, our study identified clinical differences between the TBK1, C9orf72 and GRN carriers, which allows us to formulate guidelines for genetic diagnosis. After a negative result for C9orf72, patients with both frontotemporal dementia and amyotrophic lateral sclerosis should be tested first for mutations in TBK1. Specifically in frontotemporal dementia patients with early memory difficulties, a relatively late age at onset or extrapyramidal symptoms, screening for TBK1 mutations should be considered., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC)., Methods: Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions., Results: Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8-10.5) and 4.2 months (95% CI: 3.4-4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS., Conclusion: The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC., Trial Registration: ClinicalTrials.gov NCT01290926.

Objective: Conversion deafness is characterized by sudden hearing loss without any identifiable cause. In the current study, we investigated presumed conversion deafness in a cochlear implant user using H₂¹⁵O-positron emission tomography (PET) scan with speech and noise stimuli in conjunction with audiologic tests such as impedance test and auditory response telemetry. Also, by performing a follow-up PET scan after recovery and comparing prerecovery and postrecovery scans, we attempted to find possible neural substrates of conversion deafness., Patient: A 51-year-old man with conversion deafness after 4 years of successful cochlear implant use., Intervention: Supportive psychotherapy., Main Outcome Measures: Prerecovery and postrecovery H₂¹⁵O-PET scans, Results: The prerecovery H₂¹⁵O-PET scan revealed auditory cortex activation by sound stimuli, which verified normal stimulation of the central auditory pathway. Notably, compared with the prerecovery state, the postrecovery state showed relative activation in the right auditory cortex both under the speech and noise stimulus conditions. Moreover, the bilateral prefrontal and parietal areas were activated more in the postrecovery state than in the prerecovery state. In other words, relative deactivation of the prefronto-parieto-temporal network, a network responsible for conscious sensory perception, or relative dysfunction of top-down and bottom-up attention shifting mediated by the ventral and the dorsal parietal cortices, may have resulted in conversion deafness in the patient., Conclusion: Relative deactivation of the prefronto-parieto-temporal network or dysfunction in the ventral and the dorsal parietal cortices may be related to the development of conversion deafness.