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Este trabajo analiza el deterioro del Estado de Derecho en Polonia desde las elecciones de 2015, en las que el partido ultraconservador Ley y Justicia consiguió la mayoría legislativa y accedió al Gobierno. Desde entonces, esta situación le ha permitido llevar a cabo modificaciones legislativas que han acabado afectando a la independencia judicial en el país. Entre otros factores, la modificación de la composición del Tribunal Constitucional y el Tribunal Supremo o la politización del Consejo Nacional del Poder Judicial, órgano constitucional encargado de los nombramientos judiciales, han contribuido al deterioro del Estado de Derecho en Polonia. Ante esta situación, comienza a producirse una reacción en forma de diálogo entre el TJUE y el TEDH, de forma que ambos Tribunales se aluden mutuamente a través de sus sentencias y desarrollan el concepto de «tribunal establecido por ley». Como resultado de dicha interacción, se amplía el contenido del derecho a un tribunal establecido por la ley y se establece que las irregularidades producidas en el procedimiento de nombramiento de los jueces pueden provocar el menoscabo de aquel derecho. Se acaba incluyendo así la legalidad del procedimiento de nombramiento de los jueces al contenido del derecho a un tribunal establecido por la ley. Recibido: 25 octubre 2022Aceptado: 22 febrero 2023

El presente trabajo presenta uno de los nuevos fondos aprobados por la Unión Europea para hacer frente a las consecuencias socioeconómicas negativas derivadas de la pandemia del COVID-19 en los Estados miembros, el Instrumento de Recuperación de la Unión Europea Next Generation EU, así como uno de los programas que lo componen, el Mecanismo de Recuperación y Resiliencia. Asimismo, se estudia con detalle la legislación aprobada en España para la recepción de estos fondos y su repercusión sobre el régimen jurídico de las subvenciones públicas financiables con fondos europeos.

The study of sex differences in Alzheimer’s disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer’s disease (>90% in the 7th decade). Yet, sex differences in Alzheimer’s disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer’s disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer’s disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.

Background: The introduction of tau positron emission tomography (PET) ligands has allowed for the in vivo assessment of tau pathology in Alzheimer’s disease (AD). The recent development and FDA approval of [18F]flortaucipir (FTP) reader guidelines has enabled standardized visual assessment of FTP PET scans as showing negative, moderate or advanced AD tau patterns, thereby facilitating implementation of FTP scans in clinical practice. Although various studies have reported associations between regional FTP signal and neurodegeneration, the relationship between the standardized visual FTP AD patterns and markers of neurodegeneration has not yet been studied. This study aims to understand how FTP AD visual patterns relate to markers of neurodegeneration from structural MRI and FDG-PET scans. Specifically, it focusses on characterizing regional neurodegeneration associated with the moderate AD pattern, both in cognitively normal (CN) and cognitively impaired participants (CI). Method: Participants from five cohorts were included: the Alzheimer’s Disease Neuroimaging Initiative, Harvard Aging Brain Study, A4 study, the Geneva Memory Clinic cohort and AVID’s A05 study. These cohorts include CN participants, mild cognitively impaired and AD dementia patients who have available FTP, MRI and/or FDG scans, a subset also received follow-up MRI scans. Furthermore, Centiloid values are available for all participants to quantitatively determine amyloid-β (Aβ) positivity. All FTP scans are currently independently evaluated by three trained readers, blinded to clinical and imaging information. Majority read is used to assign scans to the negative, moderate or advanced AD tau pattern groups. Result: A total of 1948 participants underwent baseline FTP PET and MRI scans, a subset of 462 participants also underwent FDG-PET scans. Between-group differences in MRI- and FDG-derived patterns of neurodegeneration are evaluated cross-sectionally. In addition, the value of FTP AD patterns for predicting longitudinal neurodegeneration using MRI-derived atrophy measures is assessed using Linear Mixed Models. All analyses are conducted separately for CN and CI participants, as well as stratified by Aβ (positive vs. negative) status. NB. Results of these analyses will be presented during the conference. Conclusion: This study will contribute to our understanding of the clinical relevance and prognostic value of the moderate and advanced FTP AD patterns in CN and CI individuals.

Background: The advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in-vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD-associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD. Method: We included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow-up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories. Result: A total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β-amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups. Conclusion: Our large-scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.

Introduction: We assessed the influence of education as a proxy of cognitive reserve and age on the dementia with Lewy bodies (DLB) metabolic pattern. Methods: Brain 18F-fluorodeoxyglucose positron emission tomography and clinical/demographic information were available in 169 probable DLB patients included in the European DLB-consortium database. Principal component analysis identified brain regions relevant to local data variance. A linear regression model was applied to generate age- and education-sensitive maps corrected for Mini-Mental State Examination score, sex (and either education or age). Results: Age negatively covaried with metabolism in bilateral middle and superior frontal cortex, anterior and posterior cingulate, reducing the expression of the DLB-typical cingulate island sign (CIS). Education negatively covaried with metabolism in the left inferior parietal cortex and precuneus (making the CIS more prominent). Discussion: These findings point out the importance of tailoring interpretation of DLB biomarkers considering the concomitant effect of individual, non-disease-related variables such as age and cognitive reserve.

to assess if the use of an audiovisual intervention in the uptake room and/or in the scanning room, could help to reduce anxiety during [18F]FDG PET/CT imaging.We prospectively studied 120 patients referred for [18F]FDG PET/CT imaging. Patients were allocated in 4 groups of 30 patients depending on the use of the audiovisual intervention: (1) no audiovisual intervention; (2) audiovisual intervention only in the uptake room; (3) audiovisual intervention only in the scanning room; (4) audiovisual intervention in the uptake and the scanning rooms. In order to measure the anxiety levels of the patients before and after the scan, all patients answered the State-Trait Anxiety Inventory (STAI).The anxiety status across typical situations on a daily basis (STAI-T) of the 4 groups of patients was comparable with no significant differences. The mean State Anxiety (STAI-S) sum-score at prescan and postscan among groups was: (1) 17.5±8.7 vs. 17.3±8.6, p=0.834; (2) 17.4±10.5 vs. 15.8±9.6, p=0.110; (3) 17.5±11.7 vs. 15.1±9.8, p= 0.013; (4) 17.4±9.7 vs. 14.9±8.1, p= 0.009. The percentage of patients with reduction of the STAI-S score among groups 1-4 was 17%, 47%, 50%, and 66%, respectively. The variation of the percentage of patients with lower scores after intervention among groups was statistically significant (p0.001).Audiovisual intervention decreases anxiety levels of patients referred for PET/CT imaging. The results of our study support a beneficial effect of the audiovisual intervention and its potential to alleviate the anxiety of oncological patients who undergo a PET/CT scan.ZIEL: Bewertung, ob der Einsatz der audiovisuellen Intervention im Sprechzimmer und/oder im Untersuchungsraum dazu beitragen könnte, die Angst während der [18F]FDG-PET/CT-Bildgebung zu reduzieren.Wir untersuchten prospektiv 120 Patienten, die zur [18F]FDG-PET/CT-Bildgebung überwiesen wurden. Die Patienten wurden je nach Einsatz der audiovisuellen Intervention in 4 Gruppen von 30 Patienten eingeteilt: (1) keine audiovisuelle Intervention, (2) audiovisuelle Intervention nur im Sprechzimmer, (3) audiovisuelle Intervention nur im Untersuchungsraum, (4) audiovisuelle Intervention im Sprechzimmer und im Untersuchungsraum. Um das Angstniveau der Patienten vor und nach der Untersuchung zu messen, beantworteten alle Patienten das State-Trait Anxiety Inventory (STAI).Der Angststatus in typischen Alltagssituationen (STAI-T) der 4 Patientengruppen war vergleichbar und wies keine signifikanten Unterschiede auf. Der mittlere State-Anxiety (STAI-S) -Summenwert vor der Untersuchung im Vergleich zu danach betrug in den Gruppen: (1) 17,5 ± 8,7 vs. 17,3 ± 8,6, p=0,834; (2) 17,4 ± 10,5 vs. 15,8 ± 9,6, p=0,110; (3) 17,5 ± 11,7 vs. 15,1 ± 9,8, p=0,013; (4) 17,4 ± 9,7 vs. 14,9 ± 8,1, p=0,009. Der Prozentsatz der Patienten mit Reduktion des STAI-S-Scores betrug in den Gruppen 1–4 17% (1), 47% (2), 50% (3) bzw. 66% (4). Der prozentuale Anteil der Patienten mit niedrigeren Werten nach der Intervention war zwischen den Gruppen statistisch signifikant (p0,001).Die audiovisuelle Intervention verringert das Angstniveau von Patienten, die zur PET/CT-Bildgebung überwiesen werden. Die Ergebnisse unserer Studie belegen eine positive Wirkung der audiovisuellen Intervention und ihr Potenzial, die Ängste von onkologischen Patienten, die sich einer PET/CT-Untersuchung unterziehen, zu lindern.

Striatal dopamine transporter (DAT) uptake assessment through I-123-Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the Parkinson's Progression Markers Initiative, we studied 623 participants (431 PD and 192 healthy controls) with available SPECT data. Even though striatal denervation was undoubtedly the imaging hallmark of PD, extrastriatal DAT uptake was also reduced in patients with PD. Topographically, widespread frontal but also temporal and posterior cortical regions showed lower DAT uptake in PD patients with respect to healthy controls. Importantly, a longitudinal voxelwise analysis confirmed an active one-year loss of extrastriatal DAT uptake within the PD group. Extrastriatal DAT uptake also correlated with the severity of motor symptoms, cognitive performance, and cerebrospinal fluid alpha-synuclein levels. In addition, we found an association between the Catechol-O-methyltransferase val158met genotype and extrastriatal DAT uptake. These results highlight the clinical and biological relevance of extrastriatal SPECT-DAT uptake in PD. (C) 2020 Elsevier Inc. All rights reserved.

Resumen La inclusion de la PET 18F-FDG como biomarcador en los criterios de diagnostico clinico de enfermedades neurodegenerativas y su indicacion en el estudio precirugia en la epilepsia resistente a los farmacos permiten mejorar la especificidad del diagnostico. La interpretacion clasica de los estudios PET neurologicos se ha abordado de forma cualitativa, aunque en la ultima decada hemos sido testigos del auge en los sistemas de evaluacion cuantitativa. Este desarrollo tecnico es de vital importancia en la practica clinica, ya que mejora la especificidad y la reproducibilidad y reduce el efecto dependiente del observador derivado del analisis visual. Consideramos que es conveniente exponer la complejidad de las tecnicas de procesamiento de imagen empleadas, lo que permitira al especialista en Medicina Nuclear conocer sus ventajas e inconvenientes a la hora de incluirlas en la practica clinica diaria.

The inclusion of 18F-FDG PET as a biomarker in the diagnostic criteria of neurodegenerative diseases and its indication in the presurgical assessment for drug-resistant epilepsies allow to improve specificity of these diagnosis. The traditional interpretation of neurological PET studies has been performed qualitatively, although in the last decade, several quantitative evaluation methods have emerged. This technical development has become relevant in clinical practice, improving specificity, reproducibility and reducing the interrater reliability derived from visual analysis. In this article we update/review the main imaging processing techniques currently used. This may allow the Nuclear Medicine physician to know their advantages and disadvantages when including these procedures in daily clinical practice.

Background Striatal dopamine deficiency and metabolic changes are well-known phenomena in dementia with Lewy bodies and can be quantified in vivo by I-123-Ioflupane brain single-photon emission computed tomography of dopamine transporter and F-18-fluorodesoxyglucose PET. However, the linkage between both biomarkers is ill-understood. Objective We used the hitherto largest study cohort of combined imaging from the European consortium to elucidate the role of both biomarkers in the pathophysiological course of dementia with Lewy bodies. Methods We compared striatal dopamine deficiency and glucose metabolism of 84 dementia with Lewy body patients and comparable healthy controls. After normalization of data, we tested their correlation by region-of-interest-based and voxel-based methods, controlled for study center, age, sex, education, and current cognitive impairment. Metabolic connectivity was analyzed by inter-region coefficients stratified by dopamine deficiency and compared to healthy controls. Results There was an inverse relationship between striatal dopamine availability and relative glucose hypermetabolism, pronounced in the basal ganglia and in limbic regions. With increasing dopamine deficiency, metabolic connectivity showed strong deteriorations in distinct brain regions implicated in disease symptoms, with greatest disruptions in the basal ganglia and limbic system, coincident with the pattern of relative hypermetabolism. Conclusions Relative glucose hypermetabolism and disturbed metabolic connectivity of limbic and basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies. Identification of specific metabolic network alterations in patients with early dopamine deficiency may serve as an additional supporting biomarker for timely diagnosis of dementia with Lewy bodies. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. Funding Agencies|Velox Foundation [project 1123]; Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung [SNF 320030_169876]

Impulse control disorders (ICD) are a common and disrupting complication of Parkinson’s disease (PD) treatment. Although their relationship with dopaminergic activity is well studied, their brain metabolic correlates are mostly unknown. In this work we studied brain metabolism using brain 18F-FDG-PET. We performed a case-control study nested within a cohort of PD patients free of ICD at baseline to compare ICD patients right after ICD diagnosis and prior to any treatment modification with matched ICD-free patients. We also compared both PD groups with healthy controls. When compared with ICD-free PD patients, PD patients with recently diagnosed ICD showed higher glucose metabolism in widespread areas comprising prefrontal cortices, both amygdalae and default mode network hubs (p

Purpose The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer’s disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model’s performance to that of multiple expert nuclear medicine physicians’ readers. Materials and methods Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer’s disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model’s performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention. Results The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6–100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7–100) in AD, 71.4% (51.6–91.2) in MCI-AD, and 94.7% (90–99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders. Conclusion Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.

Although there is evidence that chemotherapy can have side effects on metabolism and brain function, there are few studies on the occurrence of these side effects with immunotherapy. The present study was conducted to assess whether brain metabolic changes occur in patients with malignant melanoma under immunotherapy. Thirty-nine patients after surgical intervention and with a diagnosis of malignant melanoma were retrospectively included and were divided into two groups: one group under the first-line therapy with anti-programmed cell death-1 +/- anti-cytotoxic T lymphocyte antigen-4 monoclonal antibodies and the other group without any treatment after surgery, which served as a control. Basal and follow-up whole body and brain 2-[F-18]fluoro-2-deoxy-D-glucose (F-18]FDG) PET/computed tomography (CT) studies were performed. Changes in brain glucose metabolism after treatment initiation of the immunotherapy group were compared with the findings in the control group. In addition, longitudinal regression analysis to investigate whether the time under immunotherapy influenced the changes of brain metabolism was performed. None of the patients presented cognitive impairment or other neurological alterations between basal and follow-up brain [F-18]FDG PET/CT examinations. The statistical analysis revealed a significant relative SUV (SUVr)-loss in the left frontal region in patients of the immunotherapy group compared with the control group, with r(adjusted) = -0.62 and P = 0.008. Severity of SUVr-loss was correlated with duration of treatment. Patients with disseminated malignant melanoma receiving immunotherapy may present a decrease of brain metabolism in the left frontal region, which is related with time-under-treatment, without any clinical evidence of neurological disorder.

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73–0.87] and 0.92 [95% CI 0.89–0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS., Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.

Introduction Bilingualism exerts neuroprotective effects against neurodegeneration. In Huntington's disease (HD), the systems involved in bilingual control show early compromise, but the effect of bilingualism on the course of HD is unknown. Methods We addressed the impact of livelong use of bilingualism on the clinical features, brain structure and function in 30 early-mild stage HD patients. Using voxel-wise regression analysis, we explored the effect of levels of use of bilingualism on grey-matter volume (GMV) and 18F-FDG metabolism. Results Higher use of bilingualism was associated with better performance in inhibitory control and set-shifting independently of age and education and with higher GMV in the inferior frontal gyrus. 18F-FDG data revealed a significant effect on multiple fronto-temporal regions, specifically, in the dorsal anterior cingulate cortex, the anterior insula, the ventromedial orbital prefrontal cortex and the inferior frontal gyrus. These changes contributed to better inhibitory control and set-shifting and to more preserved motor and functional capacity. Conclusion In HD, lifelong use of bilingualism is associated with structural and metabolic brain changes that have an impact on cognition, movement and functionality. These findings highlight the importance of stimulating cognitive and brain reserve in HD and in other neurodegenerative conditions.

Objective Normalization to an appropriate reference region in F-18-FDG PET imaging may enhance diagnostic performance in Huntington disease (HD). We aimed to identify stable brain areas that could be used to model neurometabolic degeneration in HD correlating imaging (SUVr(values) at the basal ganglia [BBGG]) and clinical parameters (disease burden score [DBS]). Materials and Methods We performed brain F-18-FDG PET/CT in 38 manifest HD patients (mean(age) +/- SD, 54 +/- 14.3 years; CAG(repeats) +/- SD, 44.2 +/- 3.1), 20 premanifest HD patients (mean(age) +/- SD, 42.7 +/- 11.7 years; CAG(repeats) +/- SD, 40 +/- 3.8), and 18 healthy controls (NC; mean(age) +/- SD, 45 +/- 13.2 years). For quantitative analysis, we selected (a) defined reference regions from the Montreal Neurological Institute space atlas (pons, whole cerebellum, cerebral white matter, thalamus, and a pons-cerebellar vermis region of interest), and (b) reference clusters obtained by voxelwise statistical comparison across groups (P < 0.05 FWE; extent voxel threshold k = 200). Each candidate reference region and reference cluster was quantitatively assessed using imaging and clinical parameters. Results Comparing HD and NC groups, we obtained a reference cluster in the cerebellum, and in temporal and frontal lobes. Comparing manifest HD and premanifest HD patients, we observed reference clusters in the cerebellum, pons, thalamus, parietal lobe, and cuneus. The set of reference regions showed a significant correlation between SUVr(values) at the BBGG and DBS in all HD patients. In premanifest HD patients, the correlation between SUVr(values) at the BBGG and DBS was significant using the pons-cerebellar vermis region of interest, the thalamus as defined reference regions, and the pons and thalamus as reference clusters. In manifest HD patients, the correlation was significant using the temporal and white matter frontal lobe clusters. Variance between SUVr(values) in the set of reference regions and reference clusters was minimal within NC. Conclusions The pons may be a stable and reliable region to calculate SUVr(values) to model the neurometabolic degeneration in quantitative F-18-FDG PET imaging in HD.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive decline and memory loss, and is the most common form of dementia. Amyloid plaques with neurofibrillary tangles are a neuropathological hallmark of AD that produces synaptic dysfunction and culminates later in neuronal loss. Amyloid PET is a useful, available and non-invasive technique that provides in vivo information about the cortical amyloid burden. In the latest revised criteria for the diagnosis of AD biomarkers were defined and integrated: pathological and diagnostic biomarkers (increased retention on fibrillar amyloid PET or decreased Aβ1-42 and increased T-Tau or P-Tau in CSF) and neurodegeneration or topographical biomarkers (temporoparietal hypometabolism on 18F-FDG PET and temporal atrophy on MRI). Recently specific recommendations have been created as a consensus statement on the appropriate use of the imaging biomarkers, including amyloid PET: early-onset cognitive impairment/dementia, atypical forms of AD, mild cognitive impairment with early age of onset, and to differentiate between AD and other neurodegenerative diseases that occur with dementia. Amyloid PET is also contributing to the development of new therapies for AD, as well as in research studies for the study of other neurodegenerative diseases that occur with dementia where the deposition of Aβ amyloid is involved in its pathogenesis. In this paper, we review some general concepts and study the use of amyloid PET in depth and its relationship with neurodegenerative diseases and other diagnostic techniques.

Background The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist. Methods Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design. Results The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported. Conclusion The salvinorin-A–mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.

Introduction Positron emission tomography (PET) amyloid quantification methods require magnetic resonance imaging (MRI) for spatial registration and a priori reference region to scale the images. Furthermore, different tracers have distinct thresholds for positivity. We propose the AMYQ index, a new measure of amyloid burden, to overcome these limitations. Methods We selected 18F-amyloid scans from ADNI and Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) with the corresponding T1-MRI. A subset also had neuropathological data. PET images were normalized, and the AMYQ was calculated based on an adaptive template. We compared AMYQ with the Centiloid scale on clinical and neuropathological diagnostic performance. Results AMYQ was related with amyloid neuropathological burden and had excellent diagnostic performance to discriminate controls from patients with Alzheimer's disease (AD) (area under the curve [AUC] = 0.86). AMYQ had a high agreement with the Centiloid scale (intraclass correlation coefficient [ICC] = 0.88) and AUC between 0.94 and 0.99 to discriminate PET positivity when using different Centiloid cutoffs. Discussion AMYQ is a new MRI-independent index for standardizing and quantifying amyloid load across tracers.

This cohort study examines Alzheimer disease symptoms and age at onset; changes in amyloid, tau, and neurodegeneration biomarkers; and topography of brain changes in adults with Down syndrome., Key Points Question What is the association of the apolipoprotein E (APOE) ɛ4 allele with Alzheimer disease–related clinical and biomarker changes in Down syndrome? Findings In this cohort study of 464 adults with Down syndrome, carriers of the APOE ɛ4 allele showed both earlier clinical symptoms of Alzheimer disease and earlier changes in amyloid (cerebrospinal fluid Aβ1-42/1-40 and amyloid positron emission tomography), tau (plasma phosphorylated tau 181), and neurodegeneration (cerebral glucose hypometabolism and hippocampal atrophy) biomarkers. The APOE ɛ4 allele also altered the topography of neurodegeneration. Meaning Results of this study suggest that the APOE ɛ4 allele can modulate both the clinical expression and the biomarkers of Alzheimer disease in a genetic form of the disease, such as in Down syndrome., Importance Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce. Objective To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS. Design, Setting, and Participants This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers. Main Outcomes and Measures Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18–labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume. Results Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers. Conclusions and Relevance In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.

Approximately 20% of type 1 diabetes (T1D) patients have an impaired awareness of hypoglyceamia (IAH). IAH represents a risk factor for severe and recurrent hypoglycaemic events, which can lead to brain damage. Because no effective treatments are currently available to prevent IAH in this population, characterising the set of brain alterations associated with IAH may reveal novel preclinical diagnostic or therapeutic strategies. Using state-of-the art neuroimaging techniques, we compared 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake at rest between 10 T1D patients with IAH and nine patients with normal awareness of hypoglycaemia (NAH). T1D-IAH patients showed a pattern of increased FDG-PET uptake with respect to NAH patients (P < .05 corrected). Topographically, glucose metabolism was increased in the frontal and precuneus regions. Importantly, within the IAH group, this abnormal hypermetabolism correlated with IAH severity. This hypermetabolic state appeared to be unrelated to compensatory mechanisms as a result of reduced grey matter density or a neuroinflammatory state. We observed an abnormal increase in FDG-uptake in T1D patients with IAH in brain regions strongly related to cognition. Because this hypermetabolic state correlated with IAH severity, its biological characterisation could reveal new preventive or therapeutic strategies. A possible mechanism could be that glucose transport is increased in hypoglycaemia unawareness to compensate for recurrent hypoglycaemia, although this need to be confirmed in further research.

Progressive supranuclear palsy (PSP) is rare neurodegenerative disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells. This disorder is underdiagnosed due to the overlap of the clinical syndrome with other related conditions. The clinical manifestations include cognitive impairment associated with behavioral changes, akinetic rigid syndrome, and prominent oculomotor dysfunction. We present the F-FDG and F-THK5351 PET images of a 71-year-old man diagnosed of probable PSP. This image highlights the hopeful results of the new tau-PET ligands radiotracers, because it allows to assess the distribution of tau-protein over time, closely associated with neurodegeneration in PSP.

Deep brain stimulation (DBS) has been found to be effective in treatment resistant neurological and psychiatric disorders. So far there has been only one completed trial in schizophrenia, in which seven treatment resistant patients received DBS in the subgenual anterior cingulate cortex (sgACC, N = 4) or the nucleus accumbens (NAc, N = 3); four met symptomatic response criteria over the trial period. Six patients underwent 18 F-FDG PET at baseline and after at least 6 months of stimulation. Individual patient analysis indicated that DBS to both the sgACC and NAc was associated with local and distant changes in glucose metabolism. Increments and decrements of brain activity were observed in regions that included the medial prefrontal cortex, the dorsolateral prefrontal cortex, the anterior cingulate cortex, the caudate nucleus, the NAc, the hippocampus and the thalamus. Increased activity appeared to be associated with clinical improvement. These preliminary findings suggest that DBS acts by modulating cerebral activity in the cortico-basal-thalamic-cortical circuit in patients with schizophrenia who show improvement in psychotic symptoms.

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1–42 and 1–40 and their ratio (Aß1–42/1–40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1–42/1–40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer's disease dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90–100% in the seventh decade of life. Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

BACKGROUND Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. OBJECTIVE To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. METHODS 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation. RESULTS Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008). CONCLUSIONS Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.

Background Apathy is the most prevalent and characteristic neuropsychiatric feature of Huntington's disease. Congruent with the main early pathological changes, apathy is primarily associated with subcortical damage in frontal-striatal circuits. However, little is known about its precise subserving mechanisms and the contribution of regions other than the basal ganglia. Objectives We aimed to define the neural correlates of apathy in Huntington's disease based on gray matter volume and PET/CT of 18 F-fluorodeoxyglucose metabolism. Methods We rated the severity of apathy in 40 mild Huntington's disease participants using the Problem Behaviors Assessment for Huntington's disease. Voxelwise regression analysis was performed, controlling for effects of potential confounders, and PET/CT results were corrected for the effects of gray matter atrophy. Results Apathy was strongly associated with decreased gray matter within a spatially distributed cortico-subcortical network, with major compromise of the bilateral amygdala and temporal cortex. PET metabolism was significantly decreased in frontotemporal and parietal regions. Metabolic uptake and gray matter values in the identified clusters showed significant correlations with multiple clinical measures. Conclusions Our findings indicate that apathy in Huntington's disease is not exclusively a consequence of basal ganglia and related frontal-executive alterations. It is subserved by a complex cortico-subcortical network where critical reward and emotional-related prefrontal, temporal, and limbic nodes contribute strongly to its severity. This highlights the contribution of damage in regions other than the basal ganglia to the clinical expression of Huntington's disease. © 2018 International Parkinson and Movement Disorder Society.