Alterations in resting-state functional connectivity associated to the age-related decline in time-based prospective memory.

Time-based prospective memory (TBPM) is defined as the ability to remember to perform intended actions at a specific time in the future. TBPM is impaired in aging, and this decline has been associated with white-matter alterations within the superior fronto-occipital fasciculus. In the present study, we used resting-state functional magnetic resonance imaging from 22 healthy young (26 ± 5.2 years) and 23 older (63 ± 6.1 years) participants to investigate how age-related alterations in resting-state functional connectivity are related to TBPM performance, and whether these alterations are associated with the white-matter disruptions we have previously observed with diffusion tensor imaging. Whole-brain analyses revealed lower resting-state functional connectivity in older participants compared with younger ones, which in turn correlated with TBPM performance. These correlations were mainly located in the salience network and the parietal part of the frontoparietal network. Our findings suggest that resting-state functional connectivity alterations contribute to the age-related decline in TBPM.

Brain Substrates of Time-Based Prospective Memory Decline in Aging: A Voxel-Based Morphometry and Diffusion Tensor Imaging Study.

Time-based prospective memory (TBPM) allows us to remember to perform intended actions at a specific time in the future. TBPM is sensitive to the effects of age, but the neural substrates of this decline are still poorly understood. The aim of the present study was thus to better characterize the brain substrates of the age-related decline in TBPM, focusing on macrostructural gray matter and microstructural white matter integrity. We administered a TBPM task to 22 healthy young (26 ± 5.2 years) and 23 older (63 ± 5.9 years) participants, who also underwent volumetric magnetic resonance imaging and diffusion tensor imaging scans. Neuroimaging analyses revealed lower gray matter volumes in several brain areas in older participants, but these did not correlate with TBPM performance. By contrast, an age-related decline in fractional anisotropy in several white-matter tracts connecting frontal and occipital regions did correlate with TBPM performance, whereas there was no significant correlation in healthy young subjects. According to the literature, these tracts are connected to the anterior prefrontal cortex and the thalamus, 2 structures involved in TBPM. These results confirm the view that a disconnection process occurs in aging and contributes to cognitive decline.

Impact of emotionally negative information on attentional processes in normal aging and Alzheimer's disease.

Impairments of emotional processing have been reported in Alzheimer's disease (AD), consistently with the existence of early amygdala atrophy in the pathology. In this study, we hypothesized that patients with AD might show a deficit of orientation toward emotional information under conditions of visual search. Eighteen patients with AD, 24 age-matched controls, and 35 young controls were eye-tracked while they performed a visual search task on a computer screen. The target was a vehicle with implicit (negative or neutral) emotional content, presented concurrently with one, three, or five non-vehicle neutral distractors. The task was to find the target and to report whether a break in the target frame was on the left or on the right side. Both control groups detected negative targets more efficiently than they detected neutral targets, showing facilitated engagement toward negative information. In contrast, patients with AD showed no influence of emotional information on engagement delays. However, all groups reported the frame break location more slowly for negative than for neutral targets (after accounting for the last fixation delay), showing a more difficult disengagement from negative information. These findings are the first to highlight a selective lack of emotional influence on engagement processes in patients with AD. The involvement of amygdala alterations in this behavioral impairment remains to be investigated.

Semantic relatedness and distinctive processing may inflate older adults' positive memory bias.

Emotional stimuli are often more semantically interrelated and relatively distinct than neutral stimuli. These factors can enhance memory for emotional stimuli in young adults, but their effects in older adults-and on the age-related positive memory bias-remain unknown. In the present article, we tested whether item relatedness and distinctiveness affect emotional memory in young adults (Exps. 1 and 2) and the positive memory bias in older adults (Exp. 2). In both experiments, participants studied positive, negative, and neutral pictures and performed free recall after 1 min and 45 min. To manipulate relatedness, the neutral pictures were either as highly interrelated as the emotional pictures ("related neutral") or lower in semantic relatedness ("unrelated neutral"). To manipulate distinctiveness, we had participants process the emotional pictures in either a relatively distinct manner (mixed condition), by studying emotional and neutral pictures at the same time, or in a nondistinctive manner (unmixed condition), by studying and recalling each picture category separately. Overall, higher semantic relatedness (i.e., related-neutral vs. unrelated-neutral pictures) increased memory in both age groups. Distinctiveness did not affect memory in young adults, but it did alter the positive memory bias in older adults. Older adults recalled more positive than negative pictures when the pictures were processed in mixed sets, but not when they were processed in unmixed sets. These findings were consistent across both test delays. This suggests that previous reports, which were often based on mixed designs in which item interrelatedness was not controlled, may have overestimated the size and/or robustness of the positivity bias in older adults.

Compensation patterns and altered functional connectivity in alcohol use disorder with and without Korsakoff's syndrome.

Alcohol use disorder is a chronic disease characterized by an inappropriate pattern of drinking, resulting in negative consequences for the individual's physical, mental and social health. Korsakoff's syndrome is a complication of alcohol use disorder and is characterized by severe memory and executive deficits. The fronto-cerebellar and Papez circuits are structurally affected in patients with alcohol use disorder with and without Korsakoff's syndrome. The first objective of the present study was to measure the effect of chronic and excessive alcohol consumption on resting-state functional connectivity of these two functional brain networks. The second objective was to identify, for the first time, resting-state functional connectivity abnormalities specific to amnesic patients with Korsakoff's syndrome. In the present study, a neuropsychological assessment and a resting-state functional magnetic resonance imaging examination were conducted in 31 healthy controls (43.6 ± 6.1 years) and 46 patients (46.6 ± 9.1 years) with alcohol use disorder including 14 patients with Korsakoff's syndrome (55.5 ± 5.3 years) to examine the effect of chronic and heavy alcohol consumption on functional connectivity of the fronto-cerebellar and the Papez circuits at rest and the specificity of functional connectivity changes in Korsakoff's syndrome compared to alcohol use disorder without Korsakoff's syndrome. The resting-state functional connectivity analyses focused on the nodes of the fronto-cerebellar and Papez circuits and combined region of interest and graph theory approaches, and whether these alterations are associated with the neuropsychological profile. In patients pooled together compared to controls, lower global efficiency was observed in the fronto-cerebellar circuit. In addition, certain regions of the fronto-cerebellar and Papez circuits were functionally hyperconnected at rest, which positively correlated with executive functions. Patients with Korsakoff's syndrome showed lower resting-state functional connectivity, lower local and global efficiency within the Papez circuit compared to those without Korsakoff's syndrome. Resting-state functional connectivity positively correlated with several cognitive scores in patients with Korsakoff's syndrome. The fronto-cerebellar and Papez circuits, two normally well-segregated networks, are functionally altered by alcohol use disorder. The Papez circuit attempts to compensate for deficits in the fronto-cerebellar circuit, albeit insufficiently as evidenced by patients' overall lower cognitive performance. Korsakoff's syndrome is characterized by altered functional connectivity in the Papez circuit known to be centrally involved in memory.

An Impairment of Prospective Memory in Mild Alzheimer's Disease: A Ride in a Virtual Town.

Objective: Research suggests that prospective memory (PM) is impaired from the very early stages of Alzheimer's disease (AD). We sought to further characterize this impairment in patients with mild AD, using a virtual reality (VR) task to provide ecological assessment of PM. Methods: Fifteen cognitively normal older individuals (76.47 years old ± 4.14, MMSE: 28.80 ± 1.21), and 17 patients with mild AD (79.29 years old ± 4.45, MMSE: 22.82 ± 2.83) were asked to recall the prospective and retrospective components of seven intentions in a virtual town task. Six intentions were event-based, where the prospective cue was either highly (three intentions) or weakly (three intentions) associated with the retrospective component. The remaining intention was time-based. All participants completed a neuropsychological assessment of episodic memory, semantic memory and executive functioning. Non-parametric tests were used to compare the two groups on the different intentions types and components. Correlations between cognition and PM scores were then realized to further understand the cognitive correlates of the PM impairment in patients with AD. Results: Overall, patients with Alzheimer disease recalled fewer intentions than controls, with the retrospective component and time-based intentions being the most challenging for them. The strength of the association between the prospective and retrospective components, however, had no effect on their performance. Event-based PM impairment, as well as deficit in the recall of prospective component correlated with memory and executive functions performance. Conclusion: PM is impaired in AD. Both automatic and controlled processes of PM retrieval are disturbed. This study also confirms the reliability of VR for assessing complex cognitive functions such as PM.

Ageing stereotypes and prodromal Alzheimer's disease (AGING): study protocol for an ongoing randomised clinical study.

INTRODUCTION: The number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients' cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI. METHODS AND ANALYSIS: The ongoing study is a 4-year randomised clinical trial comparing patients' physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve. ETHICS AND DISSEMINATION: This protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03138018.