Stability of neural encoding moderates the contribution of sleep and repeated testing to memory consolidation.

There is evidence suggesting that online consolidation during retrieval-mediated learning interacts with offline consolidation during subsequent sleep to transform memory. Here we investigate whether this interaction persists when retrieval-mediated learning follows post-training sleep and whether the direction of this interaction is conditioned by the quality of encoding resulting from manipulation of the amount of sleep on the previous night. The quality of encoding was determined by computing the degree of similarity between EEG-activity patterns across restudy of face pairs in two groups of young participants, one who slept the last 4 h of the pre-training night, and another who slept 8 h. The offline consolidation was assessed by computing the degree of coupling between slow oscillations (SOs) and spindles (SPs) during post-training sleep, while the online consolidation was evaluated by determining the degree of similarity between EEG-activity patterns recorded during the study phase and during repeated recognition of either the same face pair (i.e., specific similarity) or face pairs sharing sex and profession (i.e., categorical similarity) to evaluate differentiation and generalization, respectively. The study and recognition phases were separated by a night of normal sleep duration. Mixed-effects models revealed that the stability of neural encoding moderated the relationship between sleep- and retrieval-mediated consolidation processes over left frontal regions. For memories showing lower encoding stability, the enhanced SO-SP coupling was associated with increased reinstatement of category-specific encoding-related activity at the expense of content-specific activity, whilst the opposite occurred for memories showing greater encoding stability. Overall, these results suggest that offline consolidation during post-training sleep interacts with online consolidation during retrieval the next day to favor the reorganization of memory contents, by increasing specificity of stronger memories and generalization of the weaker ones.

Atrophy of Basal Forebrain Initiates with Tau Pathology in Individuals at Risk for Alzheimer's Disease.

Evidence suggests that the basal forebrain (BF) cholinergic system degenerates early in the course of Alzheimer's disease (AD), likely due to the vulnerability of BF cholinergic neurons to tau pathology. However, it remains unclear whether the presence of tauopathy is the only requirement for initiating the BF degeneration in asymptomatic subjects at risk for AD (AR-AD), and how BF structural deficits evolve from normal aging to preclinical and prodromal AD. Here, we provide human in vivo magnetic resonance imaging evidence supporting that abnormal cerebrospinal fluid levels of phosphorylated tau (T+) are selectively associated with bilateral volume loss of the nucleus basalis of Meynert (nbM, Ch4) in AR-AD individuals. Spreading of atrophy to medial septum and vertical limb of diagonal band Broca (Ch1-Ch2) occurred in both preclinical and prodromal AD. With the exception of A+, all groups revealed significant correlations between volume reduction of BF cholinergic compartments and atrophy of their innervated regions. Overall, these results support the central role played by tauopathy in instigating the nbM degeneration in AR-AD individuals and the necessary coexistence of both AD proteinopathies for spreading damage to larger BF territories, thus affecting the core of the BF cholinergic projection system.

Aging-Related Changes in Cognition and Cortical Integrity are Associated With Serum Expression of Candidate MicroRNAs for Alzheimer Disease.

Evidence has shown that microRNAs (miRNAs) are involved in molecular pathways responsible for aging and prevalent aging-related chronic diseases. However, the lack of research linking circulating levels of miRNAs to changes in the aging brain hampers clinical translation. Here, we have investigated if serum expression of brain-enriched miRNAs that have been proposed as potential biomarkers in Alzheimer's disease (AD) (miR-9, miR-29b, miR-34a, miR-125b, and miR-146a) are also associated with cognitive functioning and changes of the cerebral cortex in normal elderly subjects. Results revealed that candidate miRNAs were linked to changes in cortical thickness (miR-9, miR-29b, miR-34a, and miR-125b), cortical glucose metabolism (miR-29b, miR-125b, and miR-146a), and cognitive performance (miR-9, miR-34a, and miR-125b). While both miR-29b and miR-125b were related to aging-related structural and metabolic cortical changes, only expression levels of miR-125b were associated with patterns of glucose consumption shown by cortical regions that correlated with executive function. Together, these findings suggest that serum expression of AD-related miRNAs are biologically meaningful in aging and may play a role as biomarkers of cerebral vulnerability in late life.

Volume Loss of the Nucleus Basalis of Meynert is Associated with Atrophy of Innervated Regions in Mild Cognitive Impairment.

Extensive research suggests that basal forebrain (BF) cholinergic neurons are selectively vulnerable to Alzheimer's disease (AD). However, it remains unknown whether volume loss of BF cholinergic compartments parallels structural changes of their innervated regions in prodromal AD. To this aim, we have correlated volume of each BF compartment with cortical thickness and hippocampus/amygdala volume in 106 healthy older (HO) adults and 106 amnestic mild cognitive impairment (aMCI) patients. Correlations were limited to regions affected by atrophy in aMCI. The volume of the nucleus basalis of Meynert (NBM/Ch4) was positively correlated with thickness of the temporal cortex in aMCI, and with volume of amygdala in HO and aMCI, separately. Volume of the medial septum/diagonal band of Broca (Ch1-Ch3) was also positively correlated with volume of the hippocampus within the 2 groups. Only correlations between the NBM and their innervated regions showed diagnostic value. Unlike men, aMCI women showed a stronger association between volume of the NBM and thickness of the temporal lobe when compared with HO women. Altogether, these results reveal, for the first time in humans, that atrophy of NBM is associated with structural changes of their innervated regions in prodromal AD, being this relationship more evident in women.

APOE ɛ4 constrains engagement of encoding-related compensatory networks in amnestic mild cognitive impairment.

People with amnestic mild cognitive impairment (aMCI), compared to healthy older adults (HO), benefit less from semantic congruent cues during episodic encoding. The presence of the apolipoprotein E (APOE) ɛ4 makes this congruency benefit smaller, but the neural correlates of this deficit are unknown. Here, we estimated the source generators of EEG oscillatory activity associated with successful encoding of face-location associations preceded by semantically congruent and incongruent cues in HO (N = 26) and aMCI subjects (N = 34), 16 of which were ɛ4 carriers (ɛ4(+) ) and 18 ɛ4 noncarriers (ɛ4(-) ). Source estimation was performed in those spectrotemporal windows where the power of low-alpha, high-alpha, and beta oscillatory activity differed either between congruent and incongruent faces or between groups. Differences in high-alpha and beta-oscillatory dynamics indicated that aMCI ɛ4(+) are unable to activate lateral regions of the temporal lobe involved in associative memory and congruency benefit in HO. Interestingly, and regardless of APOE genotype, aMCI activated additional regions relative to HO, through alpha oscillations. However, only activation in a distributed fronto-temporo-parietal network in ɛ4 noncarriers was paralleled by enhanced memory. On the contrary, the redundant prefrontal activation shown by aMCI ɛ4(+) did not prevent performance from decreasing. These results indicate that the effect of aMCI-related degeneracy on functional networks is constrained by the presence of APOE ɛ4. Whereas individuals with aMCI ɛ4(-) activate attentional, perceptual and semantic compensatory networks, aMCI ɛ4(+) show reduced processing efficiency and capacity.

Sleep deficits in mild cognitive impairment are related to increased levels of plasma amyloid-ß and cortical thinning.

Evidence suggests that amyloid-beta (Aß) depositions parallel sleep deficits in Alzheimer's disease (AD). However, it remains unknown whether impaired sleep and changes in plasma Aß levels are related in amnestic mild cognitive impairment (aMCI) subjects, and whether both markers are further associated with cortical thinning in canonical AD regions. To jointly address this issue, we investigated relationships between changes in physiological sleep and plasma Aß concentrations in 21 healthy old (HO) adults and 21 aMCI subjects, and further assessed whether these two factors were associated with cortical loss in each group. aMCI, but not HO subjects, showed significant relationships between disrupted slow-wave sleep (SWS) and increased plasma levels of Aß42. We also found that shortened rapid-eye movement (REM) sleep in aMCI correlated with thinning of the posterior cingulate, precuneus, and postcentral gyrus; whereas higher levels of Aß40 and Aß42 accounted for grey matter (GM) loss of posterior cingulate and entorhinal cortex, respectively. These results support preliminary relationships between Aß burden and altered sleep physiology observed in animal models of AD amyloidosis, and provide precise cortical correlates of these changes in older adults with aMCI. Taken together, these findings open new research avenues on the combined role of sleep, peripheral Aß levels and cortical integrity in tracking the progression from normal aging to early neurodegeneration.

Predictors of coupling between structural and functional cortical networks in normal aging.

Understanding how the mammalian neocortex creates cognition largely depends on knowledge about large-scale cortical organization. Accumulated evidence has illuminated cortical substrates of cognition across the lifespan, but how topological properties of cortical networks support structure-function relationships in normal aging remains an open question. Here we investigate the role of connections (i.e., short/long and direct/indirect) and node properties (i.e., centrality and modularity) in predicting functional-structural connectivity coupling in healthy elderly subjects. Connectivity networks were derived from correlations of cortical thickness and cortical glucose consumption in resting state. Local-direct connections (i.e., nodes separated by less than 30 mm) and node modularity (i.e., a set of nodes highly interconnected within a topological community and sparsely interconnected with nodes from other modules) in the functional network were identified as the main determinants of coupling between cortical networks, suggesting that the structural network in aging is mainly constrained by functional topological properties involved in the segregation of information, likely due to aging-related deficits in functional integration. This hypothesis is supported by an enhanced connectivity between cortical regions of different resting-state networks involved in sensorimotor and memory functions in detrimental to associations between fronto-parietal regions supporting executive processes. Taken collectively, these findings open new avenues to identify aging-related failures in the anatomo-functional organization of the neocortical mantle, and might contribute to early detection of prevalent neurodegenerative conditions occurring in the late life.

Semantic congruence reverses effects of sleep restriction on associative encoding.

Encoding and memory consolidation are influenced by factors such as sleep and congruency of newly learned information with prior knowledge (i.e., schema). However, only a few studies have examined the contribution of sleep to enhancement of schema-dependent memory. Based on previous studies showing that total sleep deprivation specifically impairs hippocampal encoding, and that coherent schemas reduce the hippocampal consolidation period after learning, we predict that sleep loss in the pre-training night will mainly affect schema-unrelated information whereas sleep restriction in the post-training night will have similar effects on schema-related and unrelated information. Here, we tested this hypothesis by presenting participants with face-face associations that could be semantically related or unrelated under different sleep conditions: normal sleep before and after training, and acute sleep restriction either before or after training. Memory was tested one day after training, just after introducing an interference task, and two days later, without any interference. Significant results were evident on the second retesting session. In particular, sleep restriction before training enhanced memory for semantically congruent events in detriment of memory for unrelated events, supporting the specific role of sleep in hippocampal memory encoding. Unexpectedly, sleep restriction after training enhanced memory for both related and unrelated events. Although this finding may suggest a poorer encoding during the interference task, this hypothesis should be specifically tested in future experiments. All together, the present results support a framework in which encoding processes seem to be more vulnerable to sleep loss than consolidation processes.

Human in vivo evidence of associations between herpes simplex virus and cerebral amyloid-beta load in normal aging.

BACKGROUND: Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aß) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor. METHODS: To shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aß deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers. RESULTS: We showed that increased anti-HSV IgG levels are associated with higher Aß load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aß load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration. CONCLUSIONS: All together, these results suggest that HSV infection is selectively related to cortical Aß deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

Characterization of Extracellular Vesicles from Human Saliva: Effects of Age and Isolation Techniques.

Salivary extracellular vesicles (EVs) represent an attractive source of biomarkers due to the accessibility of saliva and its non-invasive sampling methods. However, the lack of comparative studies assessing the efficacy of different EV isolation techniques hampers the use of salivary EVs in clinical settings. Moreover, the effects of age on salivary EVs are largely unknown, hindering the identification of salivary EV-associated biomarkers across the lifespan. To address these questions, we compared salivary EV concentration, size mode, protein concentration, and purity using eight EV isolation techniques before and after magnetic bead immunocapture with antibodies against CD9, CD63, and CD81. The effects of age on salivary EVs obtained with each isolation technique were further investigated. Results showed higher expression of CD63 on isolated salivary EVs compared to the expression of CD81 and flotillin-1. Overall, magnetic bead immunocapture was more efficient in recovering salivary EVs with Norgen's Saliva Exosome Purification Kit and ExoQuick-TC ULTRA at the cost of EV yield. Regardless of age, Invitrogen Total Exosome Isolation Solution showed the highest level of protein concentration, whereas Izon qEVOriginal-70nm columns revealed the highest purity. This study provides the first comprehensive comparison of salivary EVs in younger and older adults using different EV isolation techniques, which represents a step forward for assessing salivary EVs as a source of potential biomarkers of tissue-specific diseases throughout the life cycle.

Working memory processes are mediated by local and long-range synchronization of alpha oscillations.

Different cortical dynamics of alpha oscillations (8-13 Hz) have been associated with increased working memory load, which have been mostly interpreted as a neural correlate of functional inhibition. This study aims at determining whether different manifestations of load-dependent amplitude and phase dynamics in the alpha band can coexist over different cortical regions. To address this question, we increased information load by manipulating the number and spatial configuration of domino spots. Time-frequency analysis of EEG source activity revealed (i) load-independent increases of both alpha power and interregional alpha-phase synchrony within task-irrelevant, posterior cortical regions and (ii) load-dependent decreases of alpha power over areas of the left pFC and bilateral posterior parietal cortex (PPC) preceded in time by load-dependent decreases of alpha-phase synchrony between the left pFC and the left PPC. The former results support the role of alpha oscillations in inhibiting irrelevant sensorimotor processing, whereas the latter likely reflect release of parietal task-relevant areas from top-down inhibition with load increase. This interpretation found further support in a significant latency shift of 15 msec from pFC to the PPC. Together, these results suggest that amplitude and phase alpha dynamics in both local and long-range cortical networks reflect different neural mechanisms of top-down control that might be crucial in mediating the different working memory processes.

Cortical amyloid-beta burden is associated with changes in intracortical myelin in cognitively normal older adults.

Amyloid-beta (Aß) aggregates and myelin breakdown are among the earliest detrimental effects of Alzheimer's disease (AD), likely inducing abnormal patterns of neuronal communication within cortical networks. However, human in vivo evidence linking Aß burden, intracortical myelin, and cortical synchronization is lacking in cognitively normal older individuals. Here, we addressed this question combining 18F-Florbetaben-PET imaging, cortical T1-weigthed/T2-weighted (T1w/T2w) ratio maps, and resting-state functional connectivity (rs-FC) in cognitively unimpaired older adults. Results showed that global Aß burden was both positively and negatively associated with the T1w/T2w ratio in different cortical territories. Affected cortical regions were further associated with abnormal patterns of rs-FC and with subclinical cognitive deficits. Finally, causal mediation analysis revealed that the negative impact of T1w/T2w ratio in left posterior cingulate cortex on processing speed was driven by Aß burden. Collectively, these findings provide novel insights into the relationship between initial Aß plaques and intracortical myelin before the onset of cognitive decline, which may contribute to monitor the efficacy of novel disease-modifying strategies in normal elderly individuals at risk for cognitive impairment.

Effects of semantic relatedness on age-related associative memory deficits: the role of theta oscillations.

Growing evidence suggests that age-related deficits in associative memory are alleviated when the to-be-associated items are semantically related. Here we investigate whether this beneficial effect of semantic relatedness is paralleled by spatio-temporal changes in cortical EEG dynamics during incidental encoding. Young and older adults were presented with faces at a particular spatial location preceded by a biographical cue that was either semantically related or unrelated. As expected, automatic encoding of face-location associations benefited from semantic relatedness in the two groups of age. This effect correlated with increased power of theta oscillations over medial and anterior lateral regions of the prefrontal cortex (PFC) and lateral regions of the posterior parietal cortex (PPC) in both groups. But better-performing elders also showed increased brain-behavior correlation in the theta band over the right inferior frontal gyrus (IFG) as compared to young adults. Semantic relatedness was, however, insufficient to fully eliminate age-related differences in associative memory. In line with this finding, poorer-performing elders relative to young adults showed significant reductions of theta power in the left IFG that were further predictive of behavioral impairment in the recognition task. All together, these results suggest that older adults benefit less than young adults from executive processes during encoding mainly due to neural inefficiency over regions of the left ventrolateral prefrontal cortex (VLPFC). But this associative deficit may be partially compensated for by engaging preexistent semantic knowledge, which likely leads to an efficient recruitment of attentional and integration processes supported by the left PPC and left anterior PFC respectively, together with neural compensatory mechanisms governed by the right VLPFC.

Effects of network resolution on topological properties of human neocortex.

Graph theoretical analyses applied to neuroimaging datasets have provided valuable insights into the large-scale anatomical organization of the human neocortex. Most of these studies were performed with different cortical scales leading to cortical networks with different levels of small-world organization. The present study investigates how resolution of thickness-based cortical scales impacts on topological properties of human anatomical cortical networks. To this end, we designed a novel approach aimed at determining the best trade-off between small-world attributes of anatomical cortical networks and the number of cortical regions included in the scale. Results revealed that schemes comprising 540-599 regions (surface areas spanning between 250 and 275 mm(2)) at sparsities below 10% showed a superior balance between small-world organization and the size of the cortical scale employed. Furthermore, we found that the cortical scale representing the best trade-off (599 regions) was more resilient to targeted attacks than atlas-based schemes (Desikan-Killiany atlas, 66 regions) and, most importantly, it did not differ that much from the finest cortical scale tested in the present study (1494 regions). In summary, our study confirms that topological organization of anatomical cortical networks varies with both sparsity and resolution of cortical scale, and it further provides a novel methodological framework aimed at identifying cortical schemes that maximize small-worldness with the lowest scale resolution possible.

Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy.

Little attention has been paid to cortical integrity in patients with minimal hepatic encephalopathy (MHE), although cognitive functions affected in early stages of liver disease are mainly allocated in different neocortical structures. Here we used cortical surface-based analysis techniques to investigate if patterns of cortical thinning accompany the mildest form of HE. To aim this goal, cortical thickness obtained from high-resolution 3T magnetic resonance imaging (MRI) was measured in patients with no MHE (NMHE), MHE, and healthy controls. Further correlation analyses were performed to examine whether scores in the critical flicker frequency (CFF) test, and blood ammonia levels accounted for the loss of cortical integrity in different stages of liver disease. Finally, we assessed group differences in volume of different subcortical regions and their potential relationships with CFF scores/blood ammonia levels. Results showed a focal thinning of the superior temporal cortex and precuneus in MHE patients when compared with NMHE and controls. Relationships between blood ammonia levels and cortical thickness of the calcarine sulcus accounted for impaired visual judgment in patients with MHE when compared to NMHE. Regression analyses between cortical thickness and CFF predicted differences between controls and the two groups of HE patients, but failed to discriminate between patients with NMHE and MHE. Taking together, these findings provide the first report of cortical thinning in MHE patients, and they yield novel insights into the neurobiological basis of cognitive impairment associated with early stages of liver diseases.

Effects of non-modifiable risk factors of Alzheimer's disease on intracortical myelin content.

BACKGROUND: Non-modifiable risk factors of Alzheimer's disease (AD) have lifelong effects on cortical integrity that could be mitigated if identified at early stages. However, it remains unknown whether cortical microstructure is affected in older individuals with non-modifiable AD risk factors and whether altered cortical tissue integrity produces abnormalities in brain functional networks in this AD-risk population. METHODS: Using relative T1w/T2w (rT1w/T2w) ratio maps, we have compared tissue integrity of normal-appearing cortical GM between controls and cognitively normal older adults with either APOE4 (N = 50), with a first-degree family history (FH) of AD (N = 52), or with the co-occurrence of both AD risk factors (APOE4+FH) (N = 35). Additionally, individuals with only one risk factor (APOE4 or FH) were combined into one group (N = 102) and compared with controls. The same number of controls matched in age, sex, and years of education was employed for each of these comparisons. Group differences in resting state functional connectivity (rs-FC) patterns were also investigated, using as FC seeds those cortical regions showing significant changes in rT1w/T2w ratios. RESULTS: Overall, individuals with non-modifiable AD risk factors exhibited significant variations in rT1w/T2w ratios compared to controls, being APOE4 and APOE4+FH at opposite ends of a continuum. The co-occurrence of APOE4 and FH was further accompanied by altered patterns of rs-FC. CONCLUSIONS: These findings may have practical implications for early detection of cortical abnormalities in older populations with APOE4 and/or FH of AD and open new avenues to monitor changes in cortical tissue integrity associated with non-modifiable AD risk factors.

Linking Plasma Amyloid Beta and Neurofilament Light Chain to Intracortical Myelin Content in Cognitively Normal Older Adults.

Evidence suggests that lightly myelinated cortical regions are vulnerable to aging and Alzheimer's disease (AD). However, it remains unknown whether plasma markers of amyloid and neurodegeneration are related to deficits in intracortical myelin content, and whether this relationship, in turn, is associated with altered patterns of resting-state functional connectivity (rs-FC). To shed light into these questions, plasma levels of amyloid-ß fragment 1-42 (Aß1-42) and neurofilament light chain (NfL) were measured using ultra-sensitive single-molecule array (Simoa) assays, and the intracortical myelin content was estimated with the ratio T1-weigthed/T2-weighted (T1w/T2w) in 133 cognitively normal older adults. We assessed: (i) whether plasma Aß1-42 and/or NfL levels were associated with intracortical myelin content at different cortical depths and (ii) whether cortical regions showing myelin reductions also exhibited altered rs-FC patterns. Surface-based multiple regression analyses revealed that lower plasma Aß1-42 and higher plasma NfL were associated with lower myelin content in temporo-parietal-occipital regions and the insular cortex, respectively. Whereas the association with Aß1-42 decreased with depth, the NfL-myelin relationship was most evident in the innermost layer. Older individuals with higher plasma NfL levels also exhibited altered rs-FC between the insula and medial orbitofrontal cortex. Together, these findings establish a link between plasma markers of amyloid/neurodegeneration and intracortical myelin content in cognitively normal older adults, and support the role of plasma NfL in boosting aberrant FC patterns of the insular cortex, a central brain hub highly vulnerable to aging and neurodegeneration.

Pre-diabetes is associated with altered functional connectivity density in cortical regions of the default-mode network.

Insulin resistance and glucose dysregulation are associated with patterns of regional brain hypometabolism characteristic of Alzheimer's disease (AD). As predicted by evidence linking brain glucose metabolism to brain functional connectivity, type 2 diabetes is accompanied by altered functional connectivity density (FCD) in regions highly vulnerable to AD, but whether these alterations start at earlier stages such as pre-diabetes remain to be elucidated. Here, in addition to assessing whether pre-diabetes leads to a functional reorganization of densely connected cortical areas (hubs), we will assess whether such reorganization is conditioned by sex and/or insulin resistance, and contributes to improved cognition. One hundred and forty-four cognitively unimpaired middle-aged and older adults (55-78 years, 79 females), 73 with normoglycemia and 71 with pre-diabetes, underwent resting-state fMRI scanning. We first computed FCD mapping on cortical surfaces to determine the number of short- and long-range functional connections of every vertex in the cortex, and next used hubs showing aberrant FCD as seeds for the resting-state functional connectivity (rs-FC) calculation. ANCOVAs and linear multiple regression analyses adjusted by demographic and cardiometabolic confounders using frequentist and Bayesian approaches were applied. Analyses revealed higher long-range FCD in the right precuneus of pre-diabetic females and lower short-range FCD in the left medial orbitofrontal cortex (mOFC) of pre-diabetic individuals with higher insulin resistance. Although the mOFC also showed altered rs-FC patterns with other regions of the default mode network in pre-diabetic individuals, it was FCD of the precuneus and mOFC, and not the magnitude of their rs-FC, that was associated with better planning abilities and Mini-Mental State Examination (MMSE) scores. Results suggest that being female and/or having high insulin resistance exacerbate pre-diabetes-induced alterations in the FCD of hubs of the default-mode network that are particularly vulnerable to AD pathology. These changes in brain network organization appear to be compensatory for pre-diabetic females, likely assisting them to maintain cognitive functioning at early stages of glucose dysregulation.

Semantic congruence enhances memory of episodic associations: role of theta oscillations.

Growing evidence suggests that theta oscillations play a crucial role in episodic encoding. The present study evaluates whether changes in electroencephalographic theta source dynamics mediate the positive influence of semantic congruence on incidental associative learning. Here we show that memory for episodic associations (face-location) is more accurate when studied under semantically congruent contexts. However, only participants showing RT priming effect in a conceptual priming test (priming group) also gave faster responses when recollecting source information of semantically congruent faces as compared with semantically incongruent faces. This improved episodic retrieval was positively correlated with increases in theta power during the study phase mainly in the bilateral parahippocampal gyrus, left superior temporal gyrus, and left lateral posterior parietal lobe. Reconstructed signals from the estimated sources showed higher theta power for congruent than incongruent faces and also for the priming than the nonpriming group. These results are in agreement with the attention to memory model. Besides directing top-down attention to goal-relevant semantic information during encoding, the dorsal parietal lobe may also be involved in redirecting attention to bottom-up-driven memories thanks to connections between the medial-temporal and the left ventral parietal lobe. The latter function can either facilitate or interfere with encoding of face-location associations depending on whether they are preceded by semantically congruent or incongruent contexts, respectively, because only in the former condition retrieved representations related to the cue and the face are both coherent with the person identity and are both associated with the same location.

Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer's disease.

Neuropathological studies suggest that the basal forebrain cholinergic system (BFCS) is affected in Alzheimer's disease (AD), but there is no in vivo evidence of early damage to this system in subjects at high risk of developing AD. Here, we found that mild cognitive impairment (MCI) patients exhibited significant volume reduction of the nucleus basalis of Meynert (NbM) using recently developed probabilistic maps of the BFCS space. In addition, volumes of different magnocellular compartments varied significantly with regional gray matter atrophy in regions known to be affected by AD and were found to correlate with cognitive decline in MCI patients. Bilateral reductions of the horizontal nucleus of the diagonal band of Broca (Ch3) and frontal lobe (medial frontal, orbital, subcallosal gyrus, anterior cingulate, and middle frontal gyrus) were significantly associated with a global decline in cognitive status, whereas volume reduction of the posterior compartment of Ch4 (NbM) and temporal lobe (including hippocampus, entorhinal cortex, and amygdala) were associated with impaired delayed recall in MCI patients. These findings establish, for the first time, a link between degeneration of specific cholinergic compartments of the BFCS and cognitive-related deficits in subjects at high risk of developing AD.