Aging is associated with decreased resting-state functional connectivity (RSFC) within the default mode network (DMN), but most functional imaging studies have restricted the analysis to specific brain regions or networks, a strategy not appropriate to describe system-wide changes. Moreover, few investigations have employed operational psychiatric interviewing procedures to select participants; this is an important limitation since mental disorders are prevalent and underdiagnosed and can be associated with RSFC abnormalities. In this study, resting-state fMRI was acquired from 59 adults free of cognitive and psychiatric disorders according to standardized criteria and based on extensive neuropsychological and clinical assessments. We tested for associations between age and whole-brain RSFC using Partial Least Squares, a multivariate technique. We found that normal aging is not only characterized by decreased RSFC within the DMN but also by ubiquitous increases in internetwork positive correlations and focal internetwork losses of anticorrelations (involving mainly connections between the DMN and the attentional networks). Our results reinforce the notion that the aging brain undergoes a dedifferentiation processes with loss of functional diversity. These findings advance the characterization of healthy aging effects on RSFC and highlight the importance of adopting a broad, system-wide perspective to analyze brain connectivity.

Melatonin, a pineal hormone synthesized at night, is critical for the synchronization of circadian and seasonal rhythms, being a key regulator of energy metabolism in many animal species. Although studies in humans are lacking, several reports, mainly on hibernating animals, demonstrated that melatonin supplementation and a short photoperiod increase brown adipose tissue (BAT) mass. The present proof-of-concept study is the first, to our knowledge, to evaluate BAT in patients with melatonin deficiency (radiotherapy or surgical removal of pineal gland) before and after daily melatonin (3 mg) replacement for 3 months. All four studied patients presented increased BAT volume and activity measured by positron emission tomography-MRI. We also found an improvement in total cholesterol and triglyceride blood levels without significant effects on body weight, liver fat, and HDL and LDL levels. Albeit not statistically significant, fasting insulin levels and HOMA of insulin resistance decreased in all four patients. The present results show that oral melatonin replacement increases BAT volume and activity and improves blood lipid levels in patients with melatonin deficiency, suggesting that melatonin is a possible BAT activator. Future studies are warranted because hypomelatoninemia is usually present in aging and appears as a result of light-at-night exposure and/or the use of b-blocker drugs.Melatonin, a pineal hormone synthesized and released at night that plays a critical role in the synchronization of circadian and seasonal rhythms, has been studied as a key regulator of energy metabolism in many animal species for a long time (1,2). Pinealectomized rats show increased body weight gain and metabolic disturbances that are prevented by daily melatonin supplementation at night, without decreasing energy intake (1-5). This suggests that melatonin also regulates energy metabolism by its action on energy expenditure, possibly as related to the activation of brown adipose tissue (

A BS TRACT: Background: Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome related to multiple underlying pathologies. Objective: To investigate if individual brain [ 18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) patterns could distinguish CBS due to Alzheimer's disease (AD) from other pathologies based on [ 11 C]Pittsburgh Compound-B (PIB)-PET. Methods: Forty-five patients with probable CBS were prospectively evaluated regarding cognitive and movement disorders profile. They underwent FDG-PET and were distributed into groups: likely related to AD (CBS FDG-AD) or likely non-AD (CBS FDG-nonAD) pathology. Thirty patients underwent PIB-PET on a hybrid PETmagnetic resonance imaging equipment to assess their amyloid status. FDG and PIB-PET images were classified individually based on visual and semi-quantitative analysis, blinded to each other. Quantitative group analyses were also performed. Results: CBS FDG-AD group demonstrated worse cognitive performances, mostly concerning attention, memory, visuospatial domains, and displayed more myoclonus and hallucinations. The non-AD metabolic group presented more often limb dystonia, ocular motor dysfunction, motor perseveration, and dysarthria. All patients classified as CBS FDG-AD tested positive at PIB-PET compared to 3 of 20 in the non-AD group. The individual FDG-PET classification demonstrated 76.92% of sensitivity, 100% of specificity and positive predictive value and 88.5% of balanced accuracy to detect positive PIB-PET scans. Individuals with positive and negative PIB-PET showed hypometabolism in posterior temporoparietal areas and in thalamus and brainstem, respectively, mainly contralateral to most affected side, disclosing possible metabolic signatures of CBS variants. Conclusion: FDG-PET was useful to predict AD and non-AD CBS variants depicting their specific degeneration patterns, different clinical features, and brain amyloid deposition.

Pretargeted imaging, based on the highly reactive process between [1,2,4,5]tetrazines with trans-cyclooctene (TCO), appears as an attractive strategy to overcome disadvantages associated with traditional radioimmunoconjugates. To be successful, the radiolabeled component should react in vivo with the conjugated antibody and the non reactive excess clear fast from the organism. Herein, we explore the in vivo effects of hydrophilic linker incorporation into [1,2,4,5]tetrazine systems bearing a 6-hydrazinonicotinyl (HYNIC) moiety for technetium-99m coordination. Incorporation of a polypeptide chain containing hydrophilic aminoacids, resulted in a derivative with renal clearance. Pretargeted bevacizumab imaging was used as proof of concept.