Different associations between amyloid-ßeta 42, amyloid-ßeta 40, and amyloid-ßeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer's disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study.

BACKGROUND: Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aß)42 to detect amyloid pathology, the Aß42/Aß40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aß42 and amyR have different meanings and whether Aß40 represents more than an Aß42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aß42 and amyR to detect AD pathology in terms of p-tau/Aß42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET). METHODS: CSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aß42 and normal p-tau (A + T - = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A - T -). A + T - patients were further stratified into those with normal (CSFAß42 + /amyR - = 46) and pathological amyR (CSFAß42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aß42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls. RESULTS: CSF Aß40 levels were the lowest in A - T - and in CSFAß42 + /amyR - , higher in CSFAß42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aß40 and p-tau in A - T - (ß = 0.58; p < 0.001), CSFAß42 + /amyR - (ß = 0.47; p < 0.001), and CSFAß42 + /amyR + patients (ß = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aß40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aß40: + 4.5 z-score). CSFAß42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aß42 than CSFAß42 + /amyR - (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aß42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAß42 + /amyR - compared to controls, and further reduction in frontal areas in CSFAß42 + /amyR + , like in A + T + . CONCLUSIONS: Pathological p-tau/Aß42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aß42 levels alone. AmyR positivity, associated with higher Aß40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Complementary Role of Combined Indirect and Direct Cardiac Sympathetic (Hyper)Activity Assessment in Patients with Heart Failure by Spectral Analysis of Heart Rate Variability and Nuclear Imaging: Possible Application in the Evaluation of Exercise Training Effects.

In chronic heart failure (CHF), abnormalities in cardiac autonomic control, characterized by sympathetic overactivity, contribute to the progression of the disease and are associated with an unfavorable prognosis. Assessing cardiac autonomic status is clinically important in the management of patients with CHF. To this aim, heart rate variability (HRV) analysis has been extensively used as a non-invasive tool for assessing cardiac autonomic regulation, and has been shown to predict the clinical outcome in patients with CHF. Adrenergic nerve activity has also been estimated using iodine-123 (I-123) metaiodobenzylguanidine (MIBG), a noradrenaline analogue. MIBG is an analogue of norepinephrine sharing the same cellular mechanism of uptake, storage, and release in presynaptic sympathetic neurons. As an innervation tracer, 123I-MIBG allows for the evaluation of cardiac sympathetic neuronal function. Cardiac MIBG imaging has also been reported to predict a poor clinical outcome in CHF. MIBG provides direct information on the function of the presynaptic sympathetic nerve endings, whereas HRV, which depends on postsynaptic signal transduction, reflects the end-organ response of the sinus node. The aim of this brief review is to provide the reader with some basic concepts regarding the spectral analysis of HRV and MIBG, highlighting what is known about their respective roles in detecting cardiac sympathetic hyperactivity in CHF and, in perspective, their possible combined use in assessing non-pharmacological treatments in patients with CHF and reduced ejection fraction, with a particular focus on the effects of exercise training.

Tau Biomarkers in Dementia: Positron Emission Tomography Radiopharmaceuticals in Tauopathy Assessment and Future Perspective.

Abnormal accumulation of Tau protein is closely associated with neurodegeneration and cognitive impairment and it is a biomarker of neurodegeneration in the dementia field, especially in Alzheimer's disease (AD); therefore, it is crucial to be able to assess the Tau deposits in vivo. Beyond the fluid biomarkers of tauopathy described in this review in relationship with the brain glucose metabolic patterns, this review aims to focus on tauopathy assessment by using Tau PET imaging. In recent years, several first-generation Tau PET tracers have been developed and applied in the dementia field. Common limitations of first-generation tracers include off-target binding and subcortical white-matter uptake; therefore, several institutions are working on developing second-generation Tau tracers. The increasing knowledge about the distribution of first- and second-generation Tau PET tracers in the brain may support physicians with Tau PET data interpretation, both in the research and in the clinical field, but an updated description of differences in distribution patterns among different Tau tracers, and in different clinical conditions, has not been reported yet. We provide an overview of first- and second-generation tracers used in ongoing clinical trials, also describing the differences and the properties of novel tracers, with a special focus on the distribution patterns of different Tau tracers. We also describe the distribution patterns of Tau tracers in AD, in atypical AD, and further neurodegenerative diseases in the dementia field.

10-Year Clinical Experience With 18F-Choline PET/CT: An Italian Multicenter Retrospective Assessment of 3343 Patients.

PURPOSE: The primary aim of this multicenter retrospective analysis is to examine the role of F-choline PET/CT as a diagnostic tool for staging and restaging prostate cancer (PCa) in a large population in the light of 10 years of clinical experience. A secondary aim of the study is to produce data on the predictors of a positive F-choline PET/CT result in the setting of PCa primaries and biochemical recurrences. MATERIALS AND METHODS: This multicenter retrospective cohort study is based on data collected by 9 Italian nuclear medicine departments. Between October 2008 and September 2019, 3343 men underwent F-choline PET/CT scans before receiving definitive treatments for a primary PCa or biochemical recurrence. Inclusion criteria were (1) histologically proven PCa (on surgical specimens or prostate biopsies from patients not treated surgically) and (2) availability of clinical and pathological data, including serum prostate specific antigen (PSA) level at the time of PET/CT scanning. RESULTS: F-choline PET/CT was performed in 545 cases (16.4%) for cancer staging and in 2798 (83.6%) for restaging purposes, and the result was positive in 540 (99.1%) for the former and 1993 (71.2%) for the latter. A positive PET/CT result was always associated with a high Gleason score (>7) and high PSA levels (P < 0.01). The percentage of patients with a PSA threshold less than 1.0 ng/mL for performing PET/CT was higher in the years 2014 to 2019 (n = 341, 25% of cases) than during the previous period (n = 148, 16%; in 2008-2013). When used for staging purposes, receiver operating characteristic analysis showed that PSA levels of 9.2, 16.4, and 16.6 ng/mL were the optimal cutoffs for distinguishing between positive and negative PET/CT findings for local disease, lymph node involvement, and metastasis, respectively. In the restaging setting, a PSA level of 1.27 ng/mL was the optimal cutoff for distinguishing between a positive and negative PET/CT scan. CONCLUSIONS: F-choline PET/CT can help identify early recurrences, even in the case of low PSA levels (<1 ng/mL). Our data suggest that important improvements have been made in the interpretation of F-choline images and in patient selection in the last 5 years.

The Brain Metabolic Correlates of the Main Indices of Neuropsychological Assessment in Alzheimer's Disease.

BACKGROUND: The study aimed to investigate the relationships between F-18 fluorodeoxyglucose (18F)FDG uptake and neuropsychological assessment in Alzheimer's disease (AD). METHODS: We evaluated 116 subjects with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a brain PET/CT with (18F)FDG, cerebrospinal fluid (CSF) assay, mini-mental state examination (MMSE) and further neuropsychological tests: Rey auditory verbal learning test, immediate recall (RAVLT immediate); Rey auditory verbal learning test, delayed recall (RAVLT, delayed); Rey complex figure test, copy (RCFT, copy); Rey complex figure test, delayed recall (RCFT, delayed); Raven's colored progressive matrices (RCPM); phonological word fluency test (PWF) and Stroop test. We performed the statistical analysis by using statistical parametric mapping (SPM12; Wellcome Department of Cognitive Neurology, London, UK). RESULTS: A significant relationship has been reported between (18F)FDG uptake and RAVLT immediate test in Brodmann area (BA)37 and BA22 and with RCFT, copy in BA40, and BA7. We did not find any significant relationships with other tests. CONCLUSION: In the AD population, brain (18F)FDG uptake is moderately related to the neuropsychological assessment, suggesting a limited impact on statistical data analysis of glucose brain metabolism.