Malignant Pleural Effusion: A Multidisciplinary Approach.

Malignant pleural effusion (MPE) has become an increasingly prevalent complication in oncological patients, negatively impacting their quality of life and casting a shadow over their prognosis. Owing to the pathophysiological mechanisms involved and the heterogeneous nature of the underlying disease, this entity is both a diagnostic and therapeutic challenge. Advances in the understanding of MPE have led to a shift in the treatment paradigm towards a more personalized approach. This article provides a comprehensive review and update on the pathophysiology of MPE and describes the diagnostic tools and the latest advances in the treatment of this complex clinical entity.

El derrame pleural maligno (DPM) se ha convertido en una complicación cada vez más prevalente en los pacientes oncológicos, empeorando la calidad de vida y ensombreciendo el pronóstico de los mismos. Debido a los mecanismos fisiopatológicos involucrados y a la naturaleza heterogénea de la enfermedad subyacente, esta entidad representa un desafío diagnóstico y terapéutico. Los avances en la comprensión del DPM han originado un cambio en el paradigma del tratamiento hacia un enfoque más personalizado. Este artículo proporciona una revisión exhaustiva y una actualización sobre la fisiopatología del DPM, y describe las herramientas diagnósticas y los últimos avances en el tratamiento de esta compleja entidad clínica.

Characterization of white matter hyperintensities in Down syndrome.

INTRODUCTION: In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer's disease (AD) biomarkers remain largely unexplored. METHODS: In 261 DS adults and 131 euploid controls, fluid-attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume. RESULTS: In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo-parietal GM volumes. DISCUSSION: WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks. HIGHLIGHTS: White matter hyperintensities (WMHs) increased 10 years before Alzheimer's disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto-temporal areas.

Hypothalamic Inflammation Improves Through Bariatric Surgery, and Hypothalamic Volume Predicts Short-Term Weight Loss Response in Adults With or Without Type 2 Diabetes.

OBJECTIVE: Preclinical research implicates hypothalamic inflammation (HI) in obesity and type 2 diabetes pathophysiology. However, their pathophysiological relevance and potential reversibility need to be better defined. We sought to evaluate the effect of bariatric surgery (BS) on radiological biomarkers of HI and the association between the severity of such radiological alterations and post-BS weight loss (WL) trajectories. The utility of cerebrospinal fluid large extracellular vesicles (CSF-lEVs) enriched for microglial and astrocyte markers in studying HI was also explored. RESEARCH DESIGN AND METHODS: We included 72 individuals with obesity (20 with and 52 without type 2 diabetes) and 24 control individuals. Participants underwent lumbar puncture and 3-T MRI at baseline and 1-year post-BS. We assessed hypothalamic mean diffusivity (MD) (higher values indicate lesser microstructural integrity) and the volume of the whole and main hypothalamic subregions. CSF-lEVs enriched for glial and astrocyte markers were determined by flow cytometry. RESULTS: Compared with control group, the obesity and type 2 diabetes groups showed a larger volume and higher MD in the hypothalamic tubular inferior region, the area encompassing the arcuate nucleus. These radiological alterations were positively associated with baseline anthropometric and metabolic measures and improved post-BS. A larger baseline tubular inferior hypothalamic volume was independently related to lesser WL 1 and 2 years after BS. CSF-lEVs did not differ among groups and were unrelated to WL trajectories. CONCLUSIONS: These findings suggest HI improvement after BS and may support a role for HI in modulating the WL response to these interventions.

Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

PURPOSE: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). METHODS: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. RESULTS: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). CONCLUSION: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Association between maximum standarised uptake value (SUV) and local control in patients with oropharyngeal carcinoma treated with radiotherapy.

OBJECTIVE: To analyse the prognostic ability of the maximum standardised uptake value (SUVmax) on local disease control in patients with oropharyngeal carcinoma treated with radiotherapy. MATERIAL AND METHODS: Retrospective study of 105 patients with oropharyngeal carcinomas treated with radiotherapy, including chemo- and bio-radiotherapy, and who had a PET-CT scan prior to the start of treatment. RESULT: Patients with a SUVmax value higher than 17.2 at the primary tumour site had a significantly higher risk of local recurrence. The 5-year local recurrence-free survival for patients with SUVmax less than or equal to 17.2 (n = 71) was 86.5% (95% CI 78.2-94.7 %), and for patients with SUVmax greater than 17.2 (n = 34) it was 55.8% (95% CI 36.0-75.6 %) (P = 0.0001). This difference in local control was maintained regardless of patients' HPV status. Specific survival was similarly lower for patients with a SUV greater than 17.2. The 5-year specific survival for patients with SUVmax greater than 17.2 was 39.5% (95% CI: 20.6-58.3 %), significantly shorter than that of patients with SUVmax equal to or less than 17.2, which was 77.3% (95% CI: 66.9-87.6 %) (P = 0.0001). CONCLUSIONS: Patients with oropharyngeal carcinomas treated with radiotherapy with a SUVmax greater than 17.2 at the level of the primary tumour site had a significantly higher risk of local recurrence.

Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome.

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-ß 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-ß 42/amyloid-ß 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.

Structural and metabolic brain correlates of arithmetic word-problem solving in Huntington's disease.

Individuals with pre-manifest and early symptomatic Huntington's disease (HD) have shown deficits in solving arithmetic word-problems. However, the neural correlates of these deficits in HD are poorly understood. We explored the structural (gray-matter volume; GMV) and metabolic (18F-FDG PET; SUVr) brain correlates of arithmetic performance using the recently developed HD-word problem arithmetic task (HD-WPA) in seventeen preHD and sixteen HD individuals. Symptomatic participants showed significantly lower scores in the HD-WPA than preHD participants. Lower performance in the HD-WPA was associated with reduced GMV in subcortical, medial frontal, and several posterior-cortical clusters in HD participants. No significant GMV loss was found in preHD participants. 18F-FDG data revealed a widespread pattern of hypometabolism in association with lower arithmetic performance in all participants. In preHD participants, this pattern was restricted to the ventrolateral and orbital prefrontal cortex, the insula, and the precentral gyrus. In HD participants, the pattern extended to several parietal-temporal regions. Word-problem solving arithmetic deficits in HD is subserved by a pattern of asynchronous metabolic and structural compromise across the cerebral cortex as a function of disease stage. In preHD individuals, arithmetic deficits were associated with prefrontal alterations, whereas in symptomatic HD patients, more severe arithmetic deficits are associated with the compromise of several frontal-subcortical and temporo-parietal regions. Our results support the hypothesis that cognitive deficits in HD are not exclusively dominated by frontal-striatal dysfunctions but also involve fronto-temporal and parieto-occipital damage.

Adopting transfer learning for neuroimaging: a comparative analysis with a custom 3D convolution neural network model.

BACKGROUND: In recent years, neuroimaging with deep learning (DL) algorithms have made remarkable advances in the diagnosis of neurodegenerative disorders. However, applying DL in different medical domains is usually challenged by lack of labeled data. To address this challenge, transfer learning (TL) has been applied to use state-of-the-art convolution neural networks pre-trained on natural images. Yet, there are differences in characteristics between medical and natural images, also image classification and targeted medical diagnosis tasks. The purpose of this study is to investigate the performance of specialized and TL in the classification of neurodegenerative disorders using 3D volumes of 18F-FDG-PET brain scans. RESULTS: Results show that TL models are suboptimal for classification of neurodegenerative disorders, especially when the objective is to separate more than two disorders. Additionally, specialized CNN model provides better interpretations of predicted diagnosis. CONCLUSIONS: TL can indeed lead to superior performance on binary classification in timely and data efficient manner, yet for detecting more than a single disorder, TL models do not perform well. Additionally, custom 3D model performs comparably to TL models for binary classification, and interestingly perform better for diagnosis of multiple disorders. The results confirm the superiority of the custom 3D-CNN in providing better explainable model compared to TL adopted ones.

Audiovisual intervention alleviates anxiety of patients during PET/CT imaging.

AIM: 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. METHODS: 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). RESULTS: 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 (p<0.001). CONCLUSION: 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.

Brain metabolic changes in patients with disseminated malignant melanoma under immunotherapy.

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-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 F]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 [ 18 F]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 radjusted = -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.

The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A.

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.

A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimer's disease, and mild cognitive impairment using brain 18F-FDG PET.

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.

Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With 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: Aß1-42, Aß1-40, 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 Aß1-42 to Aß1-40 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.

Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer's disease in adults with Down syndrome.

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.

AMYQ: An index to standardize quantitative amyloid load across PET tracers.

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.

Associations among education, age, and the dementia with Lewy bodies (DLB) metabolic pattern: A European-DLB consortium project.

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.

Increased cerebral FDG-PET uptake in type 1 diabetes patients with impaired awareness of hypoglycaemia.

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.

Extrastriatal SPECT-DAT uptake correlates with clinical and biological features of de novo Parkinson's disease.

Striatal dopamine transporter (DAT) uptake assessment through I123-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 α-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.

Digital versus analog PET/CT in patients with known or suspected liver metastases.

AIM: To assess if digital PET/CT improves liver lesion detectability compared to analog PET/CT in patients with known or suspected liver metastases. MATERIALS AND METHODS: We prospectively included 83 cancer patients, with one or more of these conditions: history of liver metastases, clinical risk of having liver metastases or presence of suspected liver metastases on the first of the two PET/CTs. All patients were consecutively scanned on each PET/CT on the same day after a single [18F]fluorodeoxyglucose dose injection. The order of acquisition was randomly assigned. Three nuclear medicine physicians assessed both PET/CTs by counting the foci of high uptake suspicious of liver metastases. Findings were correlated with appropriate reference standards; 19 patients were excluded from the analysis due to insufficient lesion nature confirmation. The final sample consisted of 64 patients (34 women, mean age 68 ± 12 years). RESULTS: As per-patient analysis, the mean number of liver lesions detected by the digital PET/CT (3.84 ± 4.25) was significantly higher than that detected by the analog PET/CT (2.91 ± 3.31); P < 0.001. Fifty-five patients had a positive PET/CT study for liver lesions. In 26/55 patients (47%), the digital PET/CT detected more lesions; 7/26 patients (27%) had detectable lesions only by the digital system and had <10 mm of diameter. Twenty-nine patients had the same number of liver lesions detected by both systems. In nine patients both PET/CT systems were negative for liver lesions. CONCLUSION: Digital PET/CT offers improved detectability of liver lesions over the analog PET/CT in patients with known or suspected liver metastases.

Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.

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.