An Exploratory Study of Sleep-Wake Differences of Autonomic Activity in Patients with Mild Cognitive Impairment: The Role of Melatonin as a Modulating Factor.

Purpose: The objective of the present study was to assess sleep-wake differences of autonomic activity in patients with mild cognitive impairment (MCI) compared to control subjects. As a post-hoc objective, we sought to evaluate the mediating effect of melatonin on this association. Patients and Methods: A total of 22 MCI patients (13 under melatonin treatment) and 12 control subjects were included in this study. Sleep-wake periods were identified by actigraphy and 24hr-heart rate variability measures were obtained to study sleep-wake autonomic activity. Results: MCI patients did not show any significant differences in sleep-wake autonomic activity when compared to control subjects. Post-hoc analyses revealed that MCI patients not taking melatonin displayed lower parasympathetic sleep-wake amplitude than controls not taking melatonin (RMSSD -7 ± 1 vs 4 ± 4, p = 0.004). In addition, we observed that melatonin treatment was associated with greater parasympathetic activity during sleep (VLF 15.5 ± 0.1 vs 15.1 ± 0.1, p = 0.010) and in sleep-wake differences in MCI patients (VLF 0.5 ± 0.1 vs 0.2 ± 0.0, p = 0.004). Conclusion: These preliminary findings hint at a possible sleep-related parasympathetic vulnerability in patients at prodromal stages of dementia as well as a potential protective effect of exogenous melatonin in this population.

Oculomotor Abnormalities during Reading in the Offspring of Late-Onset Alzheimer's Disease.

INTRODUCTION: Eye movement patterns during reading are well defined and documented. Each eye movement ends up in a fixation point, which allows the brain to process the incoming information and program the following saccade. In this work, we investigated whether eye movement alterations during a reading task might be already present in middle-aged, cognitively normal offspring of late-onset Alzheimer's disease (O-LOAD). METHODS: 18 O-LOAD and 18 age-matched healthy individuals with no family history of LOAD participated in the study. Participants were seated in front of a 20-inch LCD monitor, and single sentences were presented on it. Eye movements were recorded with an eye tracker with a sampling rate of 1000 Hz. RESULTS: Analysis of eye movements during reading revealed that O-LOAD displayed more fixations, shorter saccades, and shorter fixation durations than controls. CONCLUSION: The present study shows that O-LOAD experienced alterations in their eye movements during reading. O-LOAD eye movement behavior could be considered an initial sign of oculomotor impairment. Hence, the evaluation of eye movement during reading might be a useful tool for monitoring well-defined cognitive resources.

Childhood adversity modulation of central autonomic network components during cognitive regulation of emotion in major depressive disorder and borderline personality disorder.

Adverse childhood experiences (ACEs) have lifelong effects on emotional behavior and are frequent in Borderline Personality Disorder (BPD) and Major Depressive Disorder (MDD). The Central Autonomic Network (CAN), which modulates heart rate variability (HRV), comprises brain regions that mediate emotion regulation processes. However, it remains unclear the effect of ACEs on CAN dynamics and its relationship with HRV in these disorders. We studied the effects of ACEs on the brain and HRV simultaneously, during regulation of psychological stress in 19 BPD, 20 MDD and 20 healthy controls (HC). Participants underwent a cognitive reappraisal task during fMRI with simultaneous ECG acquisition. ACEs exposure was associated with increased activity of CAN and salience network components in patients with MDD compared to BPD during cognitive reappraisal. A brain-autonomic coupling was found in BPD relative to HC during emotion regulation, whereby greater activity of left anterior cingulate and medial superior frontal gyrus areas was coupled with increased HRV. Results suggest that ACEs exposure is associated with a distinct activation of the CAN and salience network regions governing responses to psychological stress in MDD compared to BPD. These alterations may constitute a distinctive neurobiological mechanism for abnormal emotion processing and regulation related to ACEs in MDD.

An fMRI study of cognitive reappraisal in major depressive disorder and borderline personality disorder.

BACKGROUND: One common denominator to the clinical phenotypes of borderline personality disorder (BPD) and major depressive disorder (MDD) is emotion regulation impairment. Although these two conditions have been extensively studied separately, it remains unclear whether their emotion regulation impairments are underpinned by shared or distinct neurobiological alterations. METHODS: We contrasted the neural correlates of negative emotion regulation across an adult sample of BPD patients (n = 19), MDD patients (n = 20), and healthy controls (HCs; n = 19). Emotion regulation was assessed using an established functional magnetic resonance imaging cognitive reappraisal paradigm. We assessed both task-related activations and modulations of interregional connectivity. RESULTS: When compared to HCs, patients with BPD and MDD displayed homologous decreased activation in the right ventrolateral prefrontal cortex (vlPFC) during cognitive reappraisal. In addition, the MDD group presented decreased activations in other prefrontal areas (i.e., left dorsolateral and bilateral orbitofrontal cortices), while the BPD group was characterized by a more extended pattern of alteration in the connectivity between the vlPFC and cortices of the visual ventral stream during reappraisal. CONCLUSIONS: This study identified, for the first time, a shared neurobiological contributor to emotion regulation deficits in MDD and BPD characterized by decreased vlPFC activity, although we also observed disorder-specific alterations. In MDD, results suggest a primary deficit in the strength of prefrontal activations, while BPD is better defined by connectivity disruptions between the vlPFC and temporal emotion processing regions. These findings substantiate, in neurobiological terms, the different profiles of emotion regulation alterations observed in these disorders.

Amyloid and anatomical correlates of executive functioning in middle-aged offspring of patients with late-onset Alzheimer's disease.

A traditional hallmark of cognitive impairment associated with late-onset Alzheimer´s disease (LOAD) is episodic memory impairment. However, early alterations have been identified in brain regions associated with executive function in asymptomatic, middle-age offspring of patients with LOAD (O-LOAD) compared to those with no family history. We hypothesized that executive function among O-LOAD would correlate with structural and amyloid brain imaging differently from those without a family history of LOAD (control subjects, CS). Executive function, cortical thickness, and in-vivo Aß deposits were quantified in 30 O-LOAD and 25 CS. Associations were observed among O-LOAD only. Cortical thickness in the left lateral orbitofrontal cortex was positively associated with Design Fluency. The Stroop Color and Word Test, correlated positively with right rostral mid-frontal cortex thickness. Trails Making Test-B was inversely related to left medial orbitofrontal thickness. Tower of London total time was positively associated with ß-amyloid deposition in the right precuneus. These results support previous evidence that early executive dysfunction might reflect subtle, early changes in persons at risk of LOAD and suggests that executive function alterations deserve further exploration in the LOAD literature.

Coping with Antarctic demands: Psychological implications of isolation and confinement.

Working in extreme environments requires a wide range of cognitive, psychological and social competences. Antarctica represents one of the most challenging habitats to work in due to its aridity, extremely cold weather, and isolated conditions. This study aimed to assess mood variations and coping strategies, as well as their possible modulation by group dynamics in a crew at the Belgrano II Argentine Antarctic Station throughout 1 year of confinement. Thirteen members of the Argentine Army completed emotional, coping and social dynamics questionnaires bimonthly in March, May, July, September and November. Results showed a significant decline in social dynamics scales, evidenced by decreases in perceived peer and hierarchical support. Additionally, coping strategies displayed a drop in mature defence throughout the expedition. A positive correlation was found between social support and recovery from stress. Our results highlight the importance of interpersonal relationships in psychological adjustment to isolation and extreme environments.

Falls Risk, Circadian Rhythms and Melatonin: Current Perspectives.

Aging is associated with weakening of the circadian system. The circadian amplitude of most physiological variables is reduced, while the circadian phase becomes more labile and tends to occur earlier with advancing age. As the incidence of falls in older persons could follow circadian variations, a better understanding of conditions in which falls occur can lead to the implementation of countermeasures (such as adjusting the scheduling of hospital staff, or changing the timing of anti-hypertensive medication if falls are related to undesirable circadian patterns of blood pressure and/or heart rate). This includes knowing the times of the day, days of the week, and times of the year when falls are more likely to occur at home or in the hospital. Additionally, the links between aging processes and factors associated with an increased risk of developing autonomic dysfunction are well established. A strong association between heart rate variability indexes and aging has been shown. Circadian rhythms of autonomous nervous system activity may play important role for maintenance of orthostatic tolerance. Whether one is concerned with disease prediction and prevention or maintenance of healthy aging, the study of circadian rhythms and the broader time structure underlying physiopathology is helpful in terms of screening, early diagnosis and prognosis, as well as the timely institution of prophylactic and/or palliative/curative treatment. Timing the administration of such treatment as a function of circadian (and other) rhythms also could lead to reduction of falls in older persons. Finally, a prominent circadian rhythm characterizes melatonin, which peaks during the night. The circadian amplitude of melatonin decreases as a function of age, raising the questions whether such a decrease in the circadian amplitude of melatonin relates to a higher risk of falls and, if so, whether melatonin supplementation may be an effective countermeasure. This narrative review assesses the relationships between fall risk and the potential role circadian rhythms and melatonin play in mitigating this risk. We aim to provide healthcare workers adequate information about fall risk in older persons, including the potential role of the circadian rhythms and/or melatonin, as well as to lay foundations for future fall prevention interventional studies.

Disrupted functional connectivity of the locus coeruleus in healthy adults with parental history of Alzheimer's disease.

Prevention and early treatment strategies for Alzheimer's disease (AD) are hampered by the lack of research biomarkers. Neuropathological changes in the Locus Coeruleus (LC) are detected early in AD, and noradrenaline plays a neuroprotective role in LC projecting areas. We assessed functional connectivity (FC) of the brainstem in asymptomatic individuals at familial risk for AD hypothesizing that FC of the LC will be decreased in relation to not-at-risk individuals. Thirty-one offspring of patients with late-onset AD (O-LOAD) (22 females; mean age ± SD = 50.36 ± 8.32) and 28 healthy controls (HC) (20 females; mean age ± SD = 53.90 ± 8.44) underwent a neurocognitive evaluation and a resting-state functional magnetic resonance imaging acquisition. In FC analyses we evaluated whole-brain global connectivity of the brainstem area, and subsequently assessed seed-to-voxel FC patterns from regions showing between-group differences. O-LOAD individuals scored worse in neurocognitive measures of memory and overall functioning (pFDR<0.05). In imaging analyses, we observed that O-LOAD individuals showed decreased global connectivity in a cluster encompassing the left LC (peak = -4, -34, -32, pTFCE<0.05). Seed-to-voxel analyses revealed that this finding was largely explained by decreased connectivity between the LC and the cerebellar cortex. Moreover, FC between the LC and the left cerebellum correlated positively with delayed recall scores. FC between the LC and the cerebellar cortex is decreased in the healthy offspring of patients with LOAD, such connectivity measurements being associated with delayed memory scores. The assessment of FC between the LC and the cerebellum may serve as a biomarker of AD vulnerability.

White matter fiber density abnormalities in cognitively normal adults at risk for late-onset Alzheimer's disease.

Tau accumulation affecting white matter tracts is an early neuropathological feature of late-onset Alzheimer's disease (LOAD). There is a need to ascertain methods for the detection of early LOAD features to help with disease prevention efforts. The microstructure of these tracts and anatomical brain connectivity can be assessed by analyzing diffusion MRI (dMRI) data. Considering that family history increases the risk of developing LOAD, we explored the microstructure of white matter through dMRI in 23 cognitively normal adults who are offspring of patients with Late-Onset Alzheimer's Disease (O-LOAD) and 22 control subjects (CS) without family history of AD. We also evaluated the relation of white matter microstructure metrics with cortical thickness, volumetry, in vivo amyloid deposition (with the help of PiB positron emission tomography -PiB-PET) and regional brain metabolism (as FDG-PET) measures. Finally we studied the association between cognitive performance and white matter microstructure metrics. O-LOAD exhibited lower fiber density and fractional anisotropy in the posterior portion of the corpus callosum and right fornix when compared to CS. Among O-LOAD, reduced fiber density was associated with lower amyloid deposition in the right hippocampus, and greater cortical thickness in the left precuneus, while higher mean diffusivity was related with greater cortical thickness of the right superior temporal gyrus. Additionally, compromised white matter microstructure was associated with poorer semantic fluency. In conclusion, white matter microstructure metrics may reveal early differences in O-LOAD by virtue of parental history of the disorder, when compared to CS without a family history of LOAD. We demonstrate that these differences are associated with lower fiber density in the posterior portion of the corpus callosum and the right fornix.

Executive functioning in cognitively normal middle-aged offspring of late-onset Alzheimer's disease patients.

Episodic memory deficits are traditionally seen as the hallmark cognitive impairment during the prodromal continuum of late-onset Alzheimer's disease (LOAD). Previous studies identified early brain alterations in regions subserving executive functions in asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD), suggesting that premature episodic memory deficits could be associated to executive dysfunction in this model. We hypothesized that O-LOAD would exhibit reduced executive performance evidenced by increased errors and decreased strategy use on an episodic memory task. We assessed 32 asymptomatic middle-aged O-LOAD and 28 age-equivalent control subjects (CS) with several tests that measure executive functions and the Rey Auditory Verbal Learning Test (RAVLT) to measure memory performance. All tests were scored using both traditional and process scores (quantification of errors and strategies underlying overall performance). T-tests were used to compare performance between both groups and Spearman correlations were implemented to measure associations between variables. O-LOAD participants exhibited decreased executive performance compared to CS as it relates to initiation time (Tower of London), mental switching (Trail Making Test B), and interference effects (Stroop Word-Color condition). Traditional RAVLT measures showed a poorer performance by O-LOAD and RAVLT process scores revealed increased interference effects on this group. Positive correlations (rs) were found between the executive measures and several RAVLT measures for O-LOAD but not for CS. In conclusion, O-LOAD participants exhibited early subtle cognitive changes in executive processing. Observed memory difficulties may be associated in part to executive deficits suggesting an interplay between memory and executive functions. Process score impairments were observed earlier than clinical decline on neuropsychological scores in this at-risk cohort and might be useful cognitive markers of preclinical LOAD.

Brain Structural and Amyloid Correlates of Recovery From Semantic Interference in Cognitively Normal Individuals With or Without Family History of Late-Onset Alzheimer's Disease.

Failure to recover from proactive semantic interference (frPSI) has been shown to be more sensitive than traditional cognitive measures in different populations with preclinical Alzheimer's disease. The authors sought to characterize the structural and amyloid in vivo correlates of frPSI in cognitively normal offspring of patients with late-onset Alzheimer's disease (O-LOAD), compared with individuals without a family history of neurodegenerative disorders (CS). The authors evaluated the LASSI-L, a test tapping frPSI and other types of semantic interference and delayed recall on the RAVLT, along with 3-T MRI volumetry and positron emission tomography Pittsburgh compound B, in 27 O-LOAD and 18 CS with equivalent age, sex, years of education, ethnicity, premorbid intelligence, and mood symptoms. Recovery from proactive semantic interference (frPSI) and RAVLT delayed recall were lower in O-LOAD cases. Structural correlates of both cognitive dimensions were different in CS and O-LOAD, involving brain regions concerned with autonomic, motor, and motivational control in the former, and regions traditionally implicated in Alzheimer's disease in the latter. Better recovery from retroactive semantic interference was associated with less amyloid load in the left temporal lobe in O-LOAD but not CS. In middle-aged cognitively normal individuals with one parent affected with LOAD, frPSI was impaired compared with persons without a family history of LOAD. The neuroimaging correlates of such cognitive measure in those with one parent with LOAD involve Alzheimer's-relevant brain regions even at a relatively young age.

Cortical thickness, brain metabolic activity, and in vivo amyloid deposition in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer's disease.

The natural history of preclinical late-onset Alzheimer's disease (LOAD) remains obscure and has received less attention than that of early-onset AD (EOAD), in spite of accounting for more than 99% of cases of AD. With the purpose of detecting early structural and functional traits associated with the disorder, we sought to characterize cortical thickness and subcortical grey matter volume, cerebral metabolism, and amyloid deposition in persons at risk for LOAD in comparison with a similar group without family history of AD. We obtained 3T T1 images for gray matter volume, FDG-PET to evaluate regional cerebral metabolism, and PET-PiB to detect fibrillar amyloid deposition in 30 middle-aged, asymptomatic, cognitively normal individuals with one parent diagnosed with LOAD (O-LOAD), and 25 comparable controls (CS) without family history of neurodegenerative disorders (CS). We observed isocortical thinning in AD-relevant areas including posterior cingulate, precuneus, and areas of the prefrontal and temporoparietal cortex in O-LOAD. Unexpectedly, this group displayed increased cerebral metabolism, in some cases overlapping with the areas of cortical thinning, and no differences in bilateral hippocampal volume and hippocampal metabolism. Given the importance of age in this sample of individuals potentially developing early AD-related changes, we controlled results for age and observed that most differences in cortical thickness and metabolism became nonsignificant; however, greater deposition of ß-amyloid was observed in the right hemisphere including temporoparietal cortex, postcentral gyrus, fusiform inferior and middle temporal and lingual gyri. If replicated, the present observations of morphological, metabolic, and amyloid changes in cognitively normal persons with family history of LOAD may bear important implications for the definition of very early phenotypes of this disorder.

Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer's Disease.

BACKGROUND: We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer's disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. OBJECTIVE: To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. METHODS: We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. RESULTS: Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. CONCLUSION: The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations.

Relationship between Cognitive and Sleep-wake Variables in Asymptomatic Offspring of Patients with Late-onset Alzheimer's Disease.

Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep-wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 ± 0.4 vs. 8.6 ± 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler's vocabulary 51.4 ± 1.3 vs. 44.3 ± 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 ± 0.47 h vs. 3.8 ± 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep-wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.