Lifetime sport practice and brain metabolism in Amyotrophic Lateral Sclerosis.

OBJECTIVE: To evaluate the metabolic correlates of lifetime sport practice in ALS through brain 18F-FDG-PET. METHODS: 131 patients completed a questionnaire about lifetime exposures, including physical activity related to sports, hobbies and occupations, and underwent brain 18F-FDG-PET. Exposure to sports was expressed as MET (Metabolic Equivalent of Task). We considered only regular practice (at least 2 h/week, for at least three months). We compared brain metabolism between two groups: subjects who did not report regular sport practice during life (N-group) and patients who did (Y-group). The resulting significant clusters were used in each group as seed regions in an interregional correlation analysis (IRCA) to evaluate the impact of lifetime sport practice on brain networks typically involved by the neurodegenerative process of ALS. Each group was compared to healthy controls (HC, n = 40). RESULTS: We found a significant, relative cerebellar hypermetabolism in the N-group compared to the Y-group. The metabolism of such cerebellar cluster resulted correlated to more significant and widespread metabolic changes in areas known to be affected by ALS (i.e. frontotemporal regions and corticospinal tracts) in the N-group as compared to the Y-group, despite the same level of disability as expressed by the ALS FRS-R. Such findings resulted independent of age, sex, site of onset (bulbar/spinal), presence/absence of C9ORF72 expansion, cognitive status and physical activity related to hobbies and occupations. When compared to HC, the N-group showed more widespread metabolic changes than the Y-group in cortical regions known to be relatively hypometabolic in ALS patients as compared to HC. CONCLUSIONS: We hypothesize that patients of the N-group might cope better with the neurodegenerative process, since they show more widespread metabolic changes as compared to the Y-group, despite the same level of disability. Nevertheless, further studies are necessary to corroborate this hypothesis.

Brain Aging, Cardiovascular Diseases, Mixed Dementia, and Frailty in the Oldest Old: From Brain Phenotype to Clinical Expression.

Dementia is an age-related clinical condition, with higher incidence rates in older ages. However, there is some evidence that a reverse epidemiology is also observed. Namely, the cohort analysis of dementia incidence rates by birth in selected populations demonstrated a decreased incidence of dementia in late life across the last twenty years, possibly due to decreased incidence of cardiovascular disorders and increased education and cognitive reserve. In line with that, age is probably a proxy for other pathophysiological processes rather than a strictly causative factor for the onset of dementia, especially in oldest old persons. The present narrative review provides an update on the clinical interplay between the spectrum of brain aging, cardiovascular morbidity, dementia pathologies, and their clinical expression in the oldest old patients. Available evidence suggests that vascular prevention in the perspective of dementia largely involve middle ages, with an apparent reverse epidemiology in oldest old. Similarly, the present findings underline how cognitive resilience and frailty may be key relevant mediators in the modulation of the clinical expression of brain mixed neuropathologies in persons over 85 years old, providing a new integrated conceptual framework.

Serum osteopontin negatively impacts on intima-media thickness in patients with systemic lupus erythematosus.

BACKGROUND: Ultrasound evaluation of carotid intima-media thickness (cIMT) has been extensively used for potentially improving cardiovascular (CV) risk stratification in several patients' categories. Subjects with systemic lupus erythematosus (SLE) have been investigated by both imaging and molecular biomarker approaches with contrasting results. Here, we focused on the role of osteopontin (OPN) as biomarker of subclinical atherosclerosis associated with SLE. MATERIALS AND METHODS: Eighty females (age 18-65 years) affected by SLE and eighty age-matched healthy female controls without a clinical history of CV disease underwent ultrasound evaluation of cIMT and blood sample assay of high-sensitivity C-reactive protein (hs-CRP) and OPN. RESULTS: Healthy controls and SLE patients significantly differed for CV risk factors (ie, waist circumference, hypertension and dyslipidaemia) and the inflammatory status. Noteworthy, an opposite association between cIMT and OPN was observed in the two study groups. Whereas OPN was positively associated with mean cIMT (r = 0.364; P = 0.001) in SLE patients, a negative correlation was found in healthy controls. Furthermore, in SLE patients increased circulating levels of OPN were associated with the use of hydroxychloroquine and the positivity for the anti-dsDNA autoantibodies. At linear regression analysis, only OPN remained independently associated with cIMT also after adjustment for age, smoking pack-year, Heart SCORE, disease length and steroid therapy length. CONCLUSIONS: These results indicate that serum OPN levels were strongly associated with subclinical atherosclerosis in patients with LES and it might be a useful CV biomarker that requires additional validation in larger trials.

Cortical Network Topology in Prodromal and Mild Dementia Due to Alzheimer's Disease: Graph Theory Applied to Resting State EEG.

Graph theory analysis on resting state electroencephalographic rhythms disclosed topological properties of cerebral network. In Alzheimer's disease (AD) patients, this approach showed mixed results. Granger causality matrices were used as input to the graph theory allowing to estimate the strength and the direction of information transfer between electrode pairs. The number of edges (degree), the number of inward edges (in-degree), of outgoing edges (out-degree) were statistically compared among healthy controls, patients with mild cognitive impairment due to AD (AD-MCI) and AD patients with mild dementia (ADD) to evaluate if degree abnormality could involve low and/or high degree vertices, the so called hubs, in both prodromal and over dementia stage. Clustering coefficient and local efficiency were evaluated as measures of network segregation, path length and global efficiency as measures of integration, the assortativity coefficient as a measure of resilience. Degree, in-degree and out-degree values were lower in AD-MCI and ADD than the control group for non-hubs and hubs vertices. The number of edges was preserved for frontal electrodes, where patients' groups showed an additional hub in F3. Clustering coefficient was lower in ADD compared with AD-MCI in the right occipital electrode, and it was positively correlated with mini mental state examination. Local and global efficiency values were lower in patients' than control groups. Our results show that the topology of the network is altered in AD patients also in its prodromal stage, begins with the reduction of the number of edges and the loss of the local and global efficiency.

Free water elimination improves test-retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects.

Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics, there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects. Hum Brain Mapp 38:12-26, 2017. © 2016 Wiley Periodicals, Inc.

A PET/CT approach to spinal cord metabolism in amyotrophic lateral sclerosis.

PURPOSE: In amyotrophic lateral sclerosis, functional alterations within the brain have been intensively assessed, while progression of lower motor neuron damage has scarcely been defined. The aim of the present study was to develop a computational method to systematically evaluate spinal cord metabolism as a tool to monitor disease mechanisms. METHODS: A new computational three-dimensional method to extract the spinal cord from (18)F-FDG PET/CT images was evaluated in 30 patients with spinal onset amyotrophic lateral sclerosis and 30 controls. The algorithm identified the skeleton on the CT images by using an extension of the Hough transform and then extracted the spinal canal and the spinal cord. In these regions, (18)F-FDG standardized uptake values were measured to estimate the metabolic activity of the spinal canal and cord. Measurements were performed in the cervical and dorsal spine and normalized to the corresponding value in the liver. RESULTS: Uptake of (18)F-FDG in the spinal cord was significantly higher in patients than in controls (p < 0.05). By contrast, no significant differences were observed in spinal cord and spinal canal volumes between the two groups. (18)F-FDG uptake was completely independent of age, gender, degree of functional impairment, disease duration and riluzole treatment. Kaplan-Meier analysis showed a higher mortality rate in patients with standardized uptake values above the fifth decile at the 3-year follow-up evaluation (log-rank test, p < 0.01). The independence of this value was confirmed by multivariate Cox analysis. CONCLUSION: Our computational three-dimensional method enabled the evaluation of spinal cord metabolism and volume and might represent a potential new window onto the pathophysiology of amyotrophic lateral sclerosis.

Neurophysiological assessment of Alzheimer's disease individuals by a single electroencephalographic marker.

Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer's disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients' cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2-4 Hz) and low-frequency alpha (8-10.5 Hz) rhythms. Results showed 77.2% of sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty". EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects.

Recommendations from the Italian Interdisciplinary Working Group (AIMN, AIP, SINDEM) for the utilization of amyloid imaging in clinical practice.

Positron emission tomography (PET) of brain amyloid is a technology that has been approved by Food and Drug Administration and European Medical Agency, but its clinical utility in medical practice requires careful definition. To provide guidance to italian dementia care practitioners, patients, and caregivers, a group of experts from "Associazione Italiana di Medicina Nucleare" (AIMN), "Associazione Italiana di Psicogeriatria" (AIP) and "Società Italiana per lo Studio delle Demenze" (SINDEM) convened the Italian Interdisciplinary Working Group on Amyloid Imaging. The Working Group considered a range of clinical scenarios in which amyloid PET should be recommended. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these recommendations. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific recommended use criteria were agreed to define the types of patients and clinical circumstances in which amyloid PET could be used. Both correct and incorrect uses were considered and formulated. Because both dementia care and amyloid-PET technology are in active development, these recommendations will require periodic reassessment.

A survey of FDG- and amyloid-PET imaging in dementia and GRADE analysis.

PET based tools can improve the early diagnosis of Alzheimer's disease (AD) and differential diagnosis of dementia. The importance of identifying individuals at risk of developing dementia among people with subjective cognitive complaints or mild cognitive impairment has clinical, social, and therapeutic implications. Within the two major classes of AD biomarkers currently identified, that is, markers of pathology and neurodegeneration, amyloid- and FDG-PET imaging represent decisive tools for their measurement. As a consequence, the PET tools have been recognized to be of crucial value in the recent guidelines for the early diagnosis of AD and other dementia conditions. The references based recommendations, however, include large PET imaging literature based on visual methods that greatly reduces sensitivity and specificity and lacks a clear cut-off between normal and pathological findings. PET imaging can be assessed using parametric or voxel-wise analyses by comparing the subject's scan with a normative data set, significantly increasing the diagnostic accuracy. This paper is a survey of the relevant literature on FDG and amyloid-PET imaging aimed at providing the value of quantification for the early and differential diagnosis of AD. This allowed a meta-analysis and GRADE analysis revealing high values for PET imaging that might be useful in considering recommendations.