Late-Life Depression: Modifications of Brain Resting State Activity.

Late-life depression (LLD) is a common emotional and mental disability in the elderly population characterized by the presence of depressed mood, the loss of interest or pleasure in daily activities, and other depression symptoms. It has a serious effect on the quality of life of elderly individuals and increases their risk of developing physical and mental diseases. It is an important area of research, given the growing elderly population. Brain functional connectivity modifications represent one of the neurobiological biomarker for LLD even if to date remains poorly understood. In our study, we enrolled 10 elderly patients with depressive symptoms compared to 11 age-matched healthy controls. All participants were evaluated by means of neuropsychological tests and underwent the same functional magnetic resonance imaging (fMRI) protocol to evaluate modifications of brain resting state functional connectivity. Between-group differences were observed for the Geriatric Depression Scale and Hamilton Depression Rating Scale, with higher scores for patients with LLD. Voxel-wise, 1-way analysis of variance revealed between-group differences in left frontoparietal network (lFPN) and sensory motor network (SMN): Increased intrinsic connectivity in the LLD group was observed in the left dorsolateral prefrontal cortex and in the left superior parietal lobule of the lFPN and increased intrinsic connectivity in the LLD group was observed in the bilateral primary somatosensory cortex of the SMN. Our findings support the use of resting state fMRI as a potential biomarker for LLD; even if to confirm the relationship between brain changes and the pathophysiology of LLD, longitudinal neuroimaging studies are required.

Effects of non-pharmacological or pharmacological interventions on cognition and brain plasticity of aging individuals.

Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia.

Characterization of resting state activity in MCI individuals.

Objectives. Aging is the major risk factor for Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI). The aim of this study was to identify novel modifications of brain functional connectivity in MCI patients. MCI individuals were compared to healthy elderly subjects. Methods. We enrolled 37 subjects (age range 60-80 y.o.). Of these, 13 subjects were affected by MCI and 24 were age-matched healthy elderly control (HC). Subjects were evaluated with Mini Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and prose memory (Babcock story) tests. In addition, with functional Magnetic Resonance Imaging (fMRI), we investigated resting state network (RSN) activities. Resting state (Rs) fMRI data were analyzed by means of Independent Component Analysis (ICA). Subjects were followed-up with neuropsychological evaluations for three years. Results. Rs-fMRI of MCI subjects showed increased intrinsic connectivity in the Default Mode Network (DMN) and in the Somatomotor Network (SMN). Analysis of the DMN showed statistically significant increased activation in the posterior cingulate cortex (PCC) and left inferior parietal lobule (lIPL). During the three years follow-up, 4 MCI subjects converted to AD. The subset of MCI AD-converted patients showed increased connectivity in the right Inferior Parietal Lobule (rIPL). As for SMN activity, MCI and MCI-AD converted groups showed increased level of connectivity in correspondence of the right Supramarginal Gyrus (rSG). Conclusions. Our findings indicate alterations of DMN and SMN activity in MCI subjects, thereby providing potential imaging-based markers that can be helpful for the early diagnosis and monitoring of these patients.

Acute effects of modafinil on brain resting state networks in young healthy subjects.

BACKGROUND: There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects. METHODOLOGY: A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven's Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; NCT01684306; http://clinicaltrials.gov/ct2/show/NCT01684306. PRINCIPAL FINDINGS: Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p<0.04) and Dorsal Attention (DAN; p<0.04) networks. No modifications in structural connectivity were observed. CONCLUSIONS AND SIGNIFICANCE: Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01684306 http://clinicaltrials.gov/ct2/show/NCT01684306.

Combination training in aging individuals modifies functional connectivity and cognition, and is potentially affected by dopamine-related genes.

BACKGROUND: Aging is a major co-risk factor in many neurodegenerative diseases. Cognitive enrichment positively affects the structural plasticity of the aging brain. In this study, we evaluated effects of a set of structured multimodal activities (Combination Training; CT) on cognitive performances, functional connectivity, and cortical thickness of a group of healthy elderly individuals. CT lasted six months. METHODOLOGY: Neuropsychological and occupational performances were evaluated before and at the end of the training period. fMRI was used to assess effects of training on resting state network (RSN) functional connectivity using Independent Component Analysis (ICA). Effects on cortical thickness were also studied. Finally, we evaluated whether specific dopamine-related genes can affect the response to training. PRINCIPAL FINDINGS: Results of the study indicate that CT improves cognitive/occupational performances and reorganizes functional connectivity. Intriguingly, individuals responding to CT showed specific dopamine-related genotypes. Indeed, analysis of dopamine-related genes revealed that carriers of DRD3 ser9gly and COMT Val158Met polymorphisms had the greatest benefits from exposure to CT. CONCLUSIONS AND SIGNIFICANCE: Overall, our findings support the idea that exposure to a set of structured multimodal activities can be an effective strategy to counteract aging-related cognitive decline and also indicate that significant capability of functional and structural changes are maintained in the elderly.