Publications by authors named "Andrés Perissinotti"

21 Publications

  • Page 1 of 1

Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile.

Alzheimers Res Ther 2021 07 27;13(1):134. Epub 2021 Jul 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.

Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F]-FDG, and [F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.

Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.

Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.

Trial Registration: NCT02485730.
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http://dx.doi.org/10.1186/s13195-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314554PMC
July 2021

Development of High-Level Daptomycin Resistance in and Species Isolates from Patients with Infective Endocarditis.

Antimicrob Agents Chemother 2021 09 12;65(10):e0252220. Epub 2021 Jul 12.

Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

and species are fastidious organisms, representing the causative agents of ∼1% to 3% of cases of infective endocarditis (IE). Little is known about the optimal antibiotic treatment for these species, and daptomycin has been suggested as a therapeutic option. We describe the antimicrobial profiles of and IE isolates, investigate high-level daptomycin resistance (HLDR) development, and evaluate daptomycin activity in combination therapy. studies with 16 IE strains (6 Abiotrophia defectiva strains, 9 Granulicatella adiacens strains, and 1 G. elegans strain) were performed using microdilution to determine MICs and time-kill methodology to evaluate combination therapy. Daptomycin nonsusceptibility (DNS) (MIC ≥ 2 mg/liter) and HLDR (MIC ≥ 256 mg/liter) were based on existing Clinical and Laboratory Standards Institute (CLSI) breakpoints for viridans group streptococci. All isolates were susceptible to vancomycin: G. adiacens was more susceptible to penicillin and ampicillin than A. defectiva (22% versus 0% and 67% versus 33%) but less susceptible to ceftriaxone and daptomycin (56% versus 83% and 11% versus 50%). HLDR developed in both A. defectiva (33%) and (78%) after 24 h of exposure to daptomycin. Combination therapy did not prevent the development of daptomycin resistance with ampicillin (2/3 strains), gentamicin (2/3 strains), ceftriaxone (2/3 strains), or ceftaroline (2/3 strains). Once developed, HLDR was stable for a prolonged time (>3 weeks) in , whereas in A. defectiva, HLDR reversed to the baseline MIC at day 10. This study is the first to demonstrate rapid HLDR development in and species . Resistance was stable, and most combination therapies did not prevent it.
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http://dx.doi.org/10.1128/AAC.02522-20DOI Listing
September 2021

How to inject ictal SPECT? From manual to automated injection.

Epilepsy Res 2021 Sep 24;175:106691. Epub 2021 Jun 24.

Clinical Institute of Neurosciences, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background: Successful surgery depends on the accurate localization of epileptogenic zone before surgery. Ictal SPECT is the only imaging modality that allows identification of the ictal onset zone by measuring the regional cerebral blood flow at the time of injection. The main limitation of ictal SPECT in epilepsy is the complex methodology of the tracer injection during a seizure. To overcome this limitation, we present the main features of the first automated injector for ictal SPECT (epijet, LemerPax; La Chapelle -sur-Erdre; France). In this study we compared traditional manual injection with automated injection for ictal SPECT in 122 patients with drug-resistant epilepsy.

Methods: The study included 55 consecutive prospective patients with drug-resistant epilepsy undergoing injection with the automated injector. The control group was our retrospective database of a historic pool of 67 patients, injected manually from 2014 to 2016. Calculated annual exposure/radioactive dose for operators was measured. Injection time, seizure focus localization with ictal SPECT, as well as repeated hospitalizations related to inconclusive findings of the SPECT were compared in these two groups of patients.

Results: There were no differences in the average injection time with epijet (13 s) compared with the traditional manual injection (14 s). The seizure focus was successfully localized with ictal SPECT with epijet in 44/55 (80 %) patients and with manual injection in 46/67 (68 %) patients (p = 0.097). Repeated studies were required in 9/67 (23 %) patients in the manual injection group compared to 3 patients (7%) in the epijet group (p = 0.141). Calculated annual exposure/dose for operators of 0.39 mSv/year and administered dose error inferior to 5% are other advantages of epijet.

Conclusion: The first results using epijet are promising in adjustment of the injection dose, reducing the rate of radiation exposure for patients and nurses, maintaining the same injection time and allowing high SPECT accuracy. These preliminary results support the use of an automated injection system to inject radioactive ictal SPECT doses in epilepsy units.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106691DOI Listing
September 2021

Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum.

Alzheimers Dement 2021 05 4;17(5):788-800. Epub 2021 Mar 4.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Introduction: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages.

Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated.

Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent.

Discussion: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau.
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http://dx.doi.org/10.1002/alz.12245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252618PMC
May 2021

Visual assessment of [F]flutemetamol PET images can detect early amyloid pathology and grade its extent.

Eur J Nucl Med Mol Imaging 2021 07 22;48(7):2169-2182. Epub 2021 Feb 22.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Purpose: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR.

Methods: [F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density.

Results: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERAD-based classification (i.e., any region mCERAD > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aβ plaque was observed in all FP cases. Regional VR was also associated with regional plaque density.

Conclusion: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.
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http://dx.doi.org/10.1007/s00259-020-05174-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175297PMC
July 2021

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease.

Alzheimers Res Ther 2021 02 17;13(1):46. Epub 2021 Feb 17.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.

Methods: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.

Results: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.

Conclusions: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.

Trial Registration: NCT01835717 , NCT02485730 , NCT02685969 .
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http://dx.doi.org/10.1186/s13195-021-00781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890889PMC
February 2021

Quantitative informant- and self-reports of subjective cognitive decline predict amyloid beta PET outcomes in cognitively unimpaired individuals independently of age and .

Alzheimers Dement (Amst) 2020 11;12(1):e12127. Epub 2020 Nov 11.

Barcelonaβeta Brain Research Center (BBRC) Pasqual Maragall Foundation Barcelona Spain.

Introduction: Amyloid beta (Aβ) pathology is an Alzheimer's disease early hallmark. Here we assess the value of longitudinal self- and informant reports of cognitive decline to predict Aβ positron emission tomography (PET) outcome in cognitively unimpaired middle-aged individuals.

Methods: A total of 261 participants from the ALFA+ study underwent [F]flutemetamol PET and Subjective Cognitive Decline Questionnaire (SCD-Q) concurrently, and 3 years before scan. We used logistic regressions to evaluate the ability of SCD-Q scores (self and informant) to predict Aβ PET visual read, and repeated analysis of variance to assess whether changes in SCD-Q scores relate to Aβ status.

Results: Self-perception of decline in memory (odds ratio [OR] = 1.2), and informant perception of executive decline (OR = 1.6), increased the probability of a positive scan. Informant reports 3 years before scanning predicted Aβ PET outcome. Longitudinal increase of self-reported executive decline was predictive of Aβ in women ( = .003).

Discussion: Subjective reports of cognitive decline are useful to predict Aβ and may improve recruitment strategies.
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http://dx.doi.org/10.1002/dad2.12127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656171PMC
November 2020

Comparison of 99mTc-Tilmanocept and Hybrid Indocyanine Green-99mTc-Albumin Nanocolloid Drainage in a Patient With Melanoma in the Scalp.

Clin Nucl Med 2020 Dec;45(12):977-979

Clínic i Provincial Hospital, Barcelona, Spain.

We present the planar lymphoscintigraphies and SPECT/CT images of a 60-year-old man diagnosed as having melanoma (Breslow 1.8 mm) in left parietal scalp, close to head midline. Sentinel lymph node biopsy using Tc-tilmanocept was performed, but the surgery was canceled. Two weeks later, sentinel lymph node biopsy was repeated, but using the hybrid radiotracer indocyanine green-Tc-albumin nanocolloid. The lymphatic drainage in left laterocervical region was similar with these 2 radiotracers, but on the right side, more sentinel lymph nodes were detected with nanocolloid compared with tilmanocept.
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http://dx.doi.org/10.1097/RLU.0000000000003309DOI Listing
December 2020

Prodromal Parkinson disease in patients with idiopathic hyposmia.

J Neurol 2020 Dec 16;267(12):3673-3682. Epub 2020 Jul 16.

Rhinology Unit and Smell and Taste Clinic, Otorhinolaryngology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Catalonia, Spain.

Background: Idiopathic hyposmia (IH) is a prodromal marker of Parkinson disease (PD). However, IH is common in the general population and only a minority will develop PD. Identification of individuals with IH at prodromal stage of PD would serve to select them to implement neuroprotective agents, when available.

Objective: To identify prodromal PD in IH patients using the Movement Disorders Society (MDS) research criteria for prodromal PD.

Methods: We applied the MDS research criteria for prodromal PD to 25 consecutive patients older than 50 years who were self-referred for smell loss and had IH, and to 18 controls. A number of risk and prodromal PD markers were assessed in all participants including REM sleep behavior disorder (RBD) by video-polysomnography and nigrostriatal dopaminergic dysfunction by DAT-SPECT. After follow-up of 4.7 ± 2.2 years, participants were re-assessed to look for incident PD.

Results: Prodromal PD probability was higher in patients than in controls (19.45 ± 34.9% versus 1.74 ± 4.48%; p = 0.019). Four (16%) patients met the criteria of prodromal PD surpassing 80% probability (99.8%, 99.5%, 88.3%, 86.4%). Three (12%) patients had RBD and four (16%) abnormal DAT-SPECT. At the end of follow-up, one (4%) IH patient who had RBD and baseline prodromal PD probability of 86.4% developed PD, while all controls remained disease free.

Conclusions: Prodromal PD is infrequent among IH patients. MDS research criteria for prodromal PD are useful to identify a subgroup of IH patients at high risk of PD when RBD is assessed by video-polysomnography and nigrostriatal dopamine deficiency with DAT-SPECT.
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http://dx.doi.org/10.1007/s00415-020-10048-6DOI Listing
December 2020

Predictive factors of preoperative sentinel lymph node detection in intermediate and high-risk endometrial cancer.

Q J Nucl Med Mol Imaging 2020 Feb 18. Epub 2020 Feb 18.

Department of Nuclear Medicine, Hospital Clínic of Barcelona, Barcelona, Spain.

Background: In endometrial cancer (EC), sentinel lymph node (SLN) mapping has emerged as an alternative to systematic lymphadenectomy. Little is known about factors that might influence SLN preoperative detection. The aim of our study is to evaluate the clinical and technical variables that may influence on the success of SLN detection in preoperative lymphatic mapping in patients with intermediate and high-risk EC when performing Transvaginal Ultrasound-guided Myometrial Injection of Radiotracer (TUMIR).

Methods: Between March 2006 and March 2017, we prospectively enrolled patients with histologically confirmed EC with intermediate or high-risk of lymphatic involvement. All women underwent SLN detection by using TUMIR approach. After radiotracer injection, pelvic and abdominal planar and SPECT/CT images were acquired to obtain a preoperative lymphoscintigraphic mapping. Pattern of drainage was registered and analyzed to identify the factors directly involved in drainage. Sonographer learning curves to perform TUMIR approach were created following Cumulative Sum and Wright methods. Univariate and multivariate analyses were performed using logistic regression.

Results: During study period, 123 patients were included. SLN preoperative detection rate was 70.7%. Age under 75 years at diagnosis (p<0.01), radiotracer injection above 4ml -high- volume- (p<0.01), and tumoral size below 2 cm (p=0.04) were associated with higher SLN preoperative detection rate. Twenty-five procedures were necessary to attain an adequate performance in TUMIR approach.

Conclusions: The higher SLN preoperative detection rate in women with intermediate and high-risk endometrial cancer after TUMIR approach was related with younger age, smaller tumors and high-volume injection of radiotracer. Sonographers are required to perform 25 procedures before acquiring an expertise in radiotracer injection.
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http://dx.doi.org/10.23736/S1824-4785.20.03246-XDOI Listing
February 2020

Is serotonin pathology a good biomarker for early Parkinson's disease?

Ann Transl Med 2019 Dec;7(Suppl 8):S351

Parkinson's Disease & Movement Disorders Unit, Hospital Clínic Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.21037/atm.2019.09.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976432PMC
December 2019

Regional patterns of 18F-florbetaben uptake in presenilin 1 mutation carriers.

Neurobiol Aging 2019 09 17;81:1-8. Epub 2019 May 17.

Alzheimer's disease and other cognitive disorders, Neurology Department, Hospital Clínic, Institut d'investigacions biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain. Electronic address:

Individuals with autosomal dominant Alzheimer's disease (ADAD) present amyloid deposits before symptoms onset. We aimed to investigate efficacy and safety of 18F-florbetaben (FBB) for assessing amyloid deposition in ADAD. We acquired FBB positron emission tomography and magnetic resonance imaging of 25 individuals from PSEN1 families (NCT02362880). We studied individual uptake patterns, group differences, and correlation with estimated years to symptoms onset, as well as adverse events. We found that asymptomatic carriers (N = 14) showed increased FBB uptake across the cerebral cortex and in the caudate. FBB accumulation appeared more than 15 years before onset in the precuneus and bankssts, among other regions, overlapping regions showing increased cortical thickness in the same subjects. FBB uptake correlated with estimated years to symptoms onset in several areas, especially the rostral anterior cingulate. Symptomatic carriers (N = 7) had an elevated FBB uptake plateau. No adverse events were reported. Overall, we found progressive FBB uptake in ADAD starting 2 decades before symptoms. The rostral anterior cingulate is a candidate area to track Aβ deposition in addition to the precuneus.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.04.010DOI Listing
September 2019

Epileptogenic Zone Localization With FDG PET Using a New Dynamic Parametric Analysis.

Front Neurol 2019 17;10:380. Epub 2019 Apr 17.

Nuclear Medicine Department, Hospital Clínic, Barcelona, Spain.

[F]fluorodeoxyglucose (F-FDG) positron emission tomography (PET) is part of the regular preoperative work-up in medically refractory epilepsy. As a complement to visual evaluation of PET, statistical parametric maps can help in the detection of the epileptogenic zone (EZ). However, software packages currently available are time-consuming and little intuitive for physicians. We develop a user-friendly software (referred as PET-analysis) for EZ localization in PET studies that allows dynamic real-time statistical parametric analysis. To evaluate its performance, the outcome of PET-analysis was compared with the results obtained by visual assessment and Statistical Parametric Mapping (SPM). Thirty patients with medically refractory epilepsy who underwent presurgical F-FDG PET with good post-operative outcomes were included. The F-FDG PET studies were evaluated by visual assessment, with SPM8 and PET-analysis. In SPM, parametric T-maps were thresholded at corrected < 0.05 and cluster size k = 50 and at uncorrected < 0.001 and k = 100 (the most used parameters in the literature). Since PET-analysis rapidly processes different threshold combinations, T-maps were thresholded with multiple -value and different clusters sizes. The presurgical EZ identified by visual assessment, SPM and PET-analysis was compared to the confirmed EZ according to post-surgical follow-up. PET-analysis obtained 66.7% (20/30) of correctly localizing studies, comparable to the 70.0% (21/30) achieved by visual assessment and significantly higher ( < 0.05) than that obtained with the SPM threshold < 0.001/k = 100, of 36.7% (11/30). Only one study was positive, albeit non-localizing, with the SPM threshold corrected < 0.05/k = 50. Concordance was substantial for PET-analysis (κ = 0.643) and visual interpretation (κ = 0.622), being fair for SPM (κ = 0.242). Compared to SPM with the fixed standard parameters, PET-analysis may be superior in EZ localization with its easy and rapid processing of different threshold combinations. The results of this initial proof-of-concept study validate the clinical use of PET-analysis as a robust objective complementary tool to visual assessment for EZ localization.
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http://dx.doi.org/10.3389/fneur.2019.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478660PMC
April 2019

Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers.

Alzheimers Res Ther 2019 03 21;11(1):27. Epub 2019 Mar 21.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.

Methods: A total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging ([F]flutemetamol and [F]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aβ, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.

Results: All Centiloid cut-offs fell within the range of 25-35, except for CSF Aβ that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ ratios was higher than that of CSF Aβ. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.

Conclusions: A cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.

Trial Registration: ALFA+ Study, NCT02485730 ALFA PET Sub-study, NCT02685969.
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http://dx.doi.org/10.1186/s13195-019-0478-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429814PMC
March 2019

Melanoma & nuclear medicine: new insights & advances.

Melanoma Manag 2018 Jun 28;5(1):MMT06. Epub 2018 Jun 28.

Nuclear Medicine Section & Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Centre, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.

The contribution of nuclear medicine to management of melanoma patients is increasing. In intermediate-thickness N0 melanomas, lymphoscintigraphy provides a roadmap for sentinel node biopsy. With the introduction of single-photon emission computed tomography images with integrated computed tomography (SPECT/CT), 3D anatomic environments for accurate surgical planning are now possible. Sentinel node identification in intricate anatomical areas (pelvic cavity, head/neck) has been improved using hybrid radioactive/fluorescent tracers, preoperative lymphoscintigraphy and SPECT/CT together with modern intraoperative portable imaging technologies for surgical navigation (free-hand SPECT, portable gamma cameras). Furthermore, PET/CT today provides 3D roadmaps to resect F-fluorodeoxyglucose-avid melanoma lesions. Simultaneously, in advanced-stage melanoma and recurrences, F-fluorodeoxyglucose-PET/CT is useful in clinical staging and treatment decision as well as in the evaluation of therapy response. In this article, we review new insights and recent nuclear medicine advances in the management of melanoma patients.
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http://dx.doi.org/10.2217/mmt-2017-0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122522PMC
June 2018

PISCOM: a new procedure for epilepsy combining ictal SPECT and interictal PET.

Eur J Nucl Med Mol Imaging 2018 12 1;45(13):2358-2367. Epub 2018 Aug 1.

Department of Nuclear Medicine, Hospital Clínic, C/Villarroel 170, 08036, Barcelona, Spain.

Purpose: We present a modified version of the SISCOM procedure that uses interictal PET instead of interictal SPECT for seizure onset zone localization. We called this new nuclear imaging processing technique PISCOM (PET interictal subtracted ictal SPECT coregistered with MRI).

Methods: We retrospectively studied 23 patients (age range 4-61 years) with medically refractory epilepsy who had undergone MRI, ictal SPECT, interictal SPECT and interictal FDG PET and who had been seizure-free for at least 2 years after surgical treatment. FDG PET images were reprocessed (rFDG PET) to assimilate SPECT features for image subtraction. Interictal SPECT and rFDG PET were compared using statistical parametric mapping (SPM). PISCOM and SISCOM images were evaluated visually and using an automated volume of interest-based analysis. The results of the two studies were compared with each other and with the known surgical resection site.

Results: SPM showed no significant differences in cortical activity between SPECT and rFDG PET images. PISCOM and SISCOM showed equivalent results in 17 of 23 patients (74%). The seizure onset zone was successfully identified in 19 patients (83%) by PISCOM and in 17 (74%) by SISCOM: in 15 patients (65%) the two techniques showed concordant successful results. The volume of interest-based analysis showed no significant differences between PISCOM and SISCOM in identifying the extension of the seizure onset zone. However, PISCOM showed a lower amount of indeterminate activity due to propagation, background or artefacts.

Conclusion: Preliminary findings of this initial proof-of-concept study suggest that perfusion and glucose metabolism in the cerebral cortex can be correlated and that PISCOM may be a valid technique for identification of the seizure onset zone. However, further studies are needed to validate these results.
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http://dx.doi.org/10.1007/s00259-018-4080-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208811PMC
December 2018

Clinical use of an opto-nuclear probe for hybrid sentinel node biopsy guidance: first results.

Int J Comput Assist Radiol Surg 2019 Feb 2;14(2):409-416. Epub 2018 Jul 2.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Hospital, Leiden, The Netherlands.

Introduction: Guidelines advocate the use of combined detection techniques to achieve optimal results for sentinel node (SN) biopsy. The fluorescent and radioactive (dual-) tracer ICG-Tc-nanocolloid has been shown to facilitate SN biopsy in several indications. It was reported that an opto-nuclear probe permitted the detection of near-infrared fluorescence and gamma-rays. The aim of the current study was to evaluate this device in a large patient group and to test it in both open and laparoscopic surgery implications.

Methods: Thirty-three patients scheduled for SN biopsy with the dual-tracer were retrospectively analyzed. Pre-operative lymphoscintigraphy was performed in all patients; in 18 patients (55%), a SPECT/CT scan was also performed. Radioactive and fluorescent signatures in the SNs were assessed in vivo and ex vivo using the opto-nuclear probe.

Results: One or more SNs were identified in all patients (identification rate 100%). Planar lymphoscintigraphic images revealed 95 hot spots that were considered as SNs. This number increased to 103 SNs when SPECT/CT was used. During surgery, 106 SNs were excised. In vivo, the fluorescence mode of the opto-nuclear probe was able to locate 79 SNs (74.5%). When the gamma-ray detection option of the same probe was used, this number increased to 99 SNs (93.3%). Ex vivo analysis revealed fluorescence in 93.3% of the excised nodes and radioactivity in 95.2%.

Conclusions: This study underlines the feasibility of using the dual-tracer/opto-nuclear probe combination for SN resections. The use of the opto-nuclear technology has been extended to laparoscopic surgery. This study also underlines the fluorescence tracing can complement traditional radio-tracing approaches.
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http://dx.doi.org/10.1007/s11548-018-1816-5DOI Listing
February 2019

Seizure-onset zone localization by statistical parametric mapping in visually normal (18) F-FDG PET studies.

Epilepsia 2016 08 11;57(8):1236-44. Epub 2016 Jun 11.

Nuclear Medicine Department, Hospital Clinic, Barcelona, Spain.

Objective: Neuroimaging is crucial in the presurgical evaluation of patients with medically refractory epilepsy. To improve the moderate sensitivity of [(18) F]fluorodeoxyglucose-positron emission tomography ((18) F-FDG-PET), our aim was to evaluate the usefulness of statistical parametric mapping (SPM) to localize the seizure-onset zone (SOZ) in PET studies deemed normal by visual assessment.

Methods: Fifty-five patients with medically refractory epilepsy whose (18) F-FDG-PET was visually evaluated as normal were retrospectively included. Twenty of these patients had undergone surgical intervention. PET images were analyzed by SPM8 using a corrected p-value of p < 0.05 and three uncorrected p-values of p < 0.0001, p < 0.001, and p < 0.005, matched with minimum cluster sizes of k > 0, k > 20, k > 100, and k > 200, respectively. The SPM-identified potential seizure zone (SZ) was compared to the SOZ, which was determined by consensus during patient management meetings in the epilepsy unit, taking into account presurgical tests. Studies in which the SPM-identified potential SZ was concordant with the SOZ were considered "correctly localizing."

Results: The SPM threshold combination with the least restrictive p-value and greatest minimum cluster size achieved the highest rate of correctly localizing studies. When p < 0.005/k > 200 was used, 40% (22/55) of studies were correctly localizing, and the concordance obtained in the surgically intervened subgroup was substantial (к = 0.607, 95% confidence interval [CI] 0.258-0.957), which was comparable to the concordance obtained by magnetic resonance imaging (MRI) (к = 0.783, 95% CI 0.509-1.000).

Significance: SPM offers improved SOZ localization in (18) F-FDG-PET studies that are negative on visual assessment. For this purpose, statistical parametric maps could be thresholded with liberal p-values and restrictive cluster sizes.
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http://dx.doi.org/10.1111/epi.13427DOI Listing
August 2016

Melanoma and nuclear medicine.

Melanoma Manag 2014 Aug 5;1(1):57-74. Epub 2014 Sep 5.

Nuclear Medicine Department, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Supported by a large body of published work, the contribution of nuclear medicine technologies to the assessment of melanoma has been increasing in recent years. Lymphoscintigraphy-assisted sentinel lymph node biopsy and PET are in continuous evolution with the aid of technological imaging advances, making it possible to fuse functional and anatomic images (e.g., with SPECT/CT, PET/CT and 3D rendering systems). The development of hybrid fluorescent-radioactive tracers that enable high-quality preoperative lymphoscintigraphy and SPECT/CT, and the optimization of modern intraoperative portable imaging technologies, such as free-hand SPECT and portable γ-cameras, are important innovations that have improved sentinel lymph node identification in complex anatomical areas, such as the pelvis and head and neck. Concurrently, F-fluorodeoxyglucose-PET has proved its usefulness in the clinical staging and treatment decision-making process, and there is also emerging evidence regarding its utility in the evaluation of therapeutic response. The potential uses of other novel PET radiotracers could open up a new field of use for this technique. In this article, we review the current and future role of nuclear medicine in the management of melanoma.
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http://dx.doi.org/10.2217/mmt.14.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094667PMC
August 2014

Clinical Role of Subtraction Ictal SPECT Coregistered to MR Imaging and (18)F-FDG PET in Pediatric Epilepsy.

J Nucl Med 2014 Jul 5;55(7):1099-105. Epub 2014 May 5.

Nuclear Medicine Department, Hospital Clínic, Barcelona, Spain Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBBAPS), Barcelona, Spain University of Barcelona, Barcelona, Spain.

Unlabelled: A precise assessment of the drug-resistant epileptic pediatric population for surgical candidacy is often challenging, and to date there are no evidence-based guidelines for presurgical identification of the epileptogenic zone. To evaluate the usefulness of radionuclide imaging techniques for presurgical evaluation of epileptic pediatric patients, we compared the results of video-electroencephalography (EEG), brain MR imaging, interictal SPECT, ictal SPECT, subtraction ictal SPECT coregistered to MR imaging (SISCOM), and interictal PET with (18)F-FDG.

Methods: Fifty-four children with drug-resistant epilepsy who had undergone video-EEG monitoring, brain MR imaging, interictal and ictal brain perfusion SPECT, SISCOM, and (18)F-FDG PET were included in this study. All abnormal findings revealed by these neuroimaging techniques were compared with the presumed location of the epileptogenic zone (PEZ) as determined by video-EEG and clinical data. The proportion of localizing studies for each technique was statistically compared. In the 18 patients who underwent resective brain surgery, neuroimaging results were compared with histopathology results and surgical outcome.

Results: SISCOM and (18)F-FDG PET concordance with the PEZ was significantly higher than MR imaging (P < 0.05). MR imaging showed localizing results in 21 of 54 cases (39%), SISCOM in 36 of 54 cases (67%), and (18)F-FDG PET in 31 of 54 cases (57%). If we consider SISCOM and (18)F-FDG PET results together, nuclear medicine imaging techniques showed coinciding video-EEG results in 76% of patients (41/54). In those cases in which MR imaging failed to identify any epileptogenic lesion (61% [33/54]), SISCOM or (18)F-FDG PET findings matched PEZ in 67% (22/33) of cases.

Conclusion: SISCOM and (18)F-FDG PET provide complementary presurgical information that matched video-EEG results and clinical data in three fourths of our sample. SISCOM was particularly useful in those cases in which MR imaging findings were abnormal but no epileptogenic lesion was identified. Radionuclide imaging techniques are both useful and reliable, extending the possibility of surgical treatment to patients who may have been discouraged without a nuclear medicine approach.
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http://dx.doi.org/10.2967/jnumed.113.136432DOI Listing
July 2014

Accuracy and reproducibility of lymphoscintigraphy for sentinel node detection in patients with cutaneous melanoma.

J Nucl Med 2012 Aug 27;53(8):1193-9. Epub 2012 Jun 27.

Nuclear Medicine Department (CDI), Hospital Clínic, Barcelona, Spain.

Unlabelled: Lymphoscintigraphy is an important part of the mapping and identification of sentinel lymph nodes (SLNs). However, few studies report its reproducibility, and some concerns prevail. The aim of the study was to determine the reproducibility of lymphoscintigraphy performed by different team members following a strict protocol to assess lymphatic drainage and the location and number of SLNs.

Methods: Sixty-eight melanoma patients were included. All underwent 2 separate lymphoscintigraphy studies, which followed the same acquisition protocol. Discordance was defined as a change in localization or a failure to identify the SLN in one of the studies.

Results: All patients showed lymphatic drainage, and in all cases at least 1 sentinel node was identified. In 65 of 68 patients (96%), the findings of the first lymphoscintigraphy study were similar to those of the second. This similarity was also found in the number of sentinel nodes (171 in the first study and 173 in the second). Eighty percent of patients showed 1-3 SLNs in both lymphoscintigraphy studies. The 2 studies differed in 3 patients (4%): 2 melanomas were located on the trunk and 1 on the head and neck. Drainage was visualized to more than 1 lymphatic basin in 19 patients (28%) in the first study versus 18 patients in the second study.

Conclusion: Lymphoscintigraphy is highly reproducible in the detection of sentinel nodes in melanoma patients. The classic protocol of radiotracer injection is reproducible and reliable enough to guarantee SLN identification, although a slight variation in isolated cases (especially when primary lesions are located on the trunk or the head and neck regions) is inevitable.
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http://dx.doi.org/10.2967/jnumed.112.104463DOI Listing
August 2012
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