Functional segregation loss over time is moderated by APOE genotype in healthy elderly

We investigated the influence of the apolipoprotein E‐?4 allele (APOE‐?4) on longitudinal age‐related changes in brain functional connectivity (FC) and cognition, in view of mixed cross‐sectional findings. One hundred and twenty‐two healthy older adults (aged 58–79; 25 APOE‐?4 carriers) underwent task‐free fMRI scans at baseline. Seventy‐eight (16 carriers) had at least one follow‐up (every 2 years). Changes in intra‐ and internetwork FCs among the default mode (DMN), executive control (ECN), and salience (SN) networks, as well as cognition, were quantified using linear mixed models. Cross‐sectionally, APOE‐?4 carriers had lower functional connectivity between the ECN and SN than noncarriers. Carriers also showed a stronger age‐dependent decrease in visuospatial memory performance. Longitudinally, carriers had steeper increase in inter‐ECN‐DMN FC, indicating loss of functional segregation. The longitudinal change in processing speed performance was not moderated by APOE‐?4 genotype, but the brain–cognition association was. In younger elderly, faster loss of segregation was correlated with greater decline in processing speed regardless of genotype. In older elderly, such relation remained for noncarriers but reversed for carriers. APOE‐?4 may alter aging by accelerating the change in segregation between high‐level cognitive systems. Its modulation on the longitudinal brain–cognition relationship was age‐dependent.     

Common and distinct brain networks underlying verbal and visual creativity

Creativity is imperative to the progression of human civilization, prosperity, and well‐being. Past creative researches tends to emphasize the default mode network (DMN) or the frontoparietal network (FPN) somewhat exclusively. However, little is known about how these networks interact to contribute to creativity and whether common or distinct brain networks are responsible for visual and verbal creativity. Here, we use functional connectivity analysis of resting‐state functional magnetic resonance imaging data to investigate visual and verbal creativity‐related regions and networks in 282 healthy subjects. We found that functional connectivity within the bilateral superior parietal cortex of the FPN was negatively associated with visual and verbal creativity. The strength of connectivity between the DMN and FPN was positively related to both creative domains. Visual creativity was negatively correlated with functional connectivity within the precuneus of the pDMN and right middle frontal gyrus of the FPN, and verbal creativity was negatively correlated with functional connectivity within the medial prefrontal cortex of the aDMN. Critically, the FPN mediated the relationship between the aDMN and verbal creativity, and it also mediated the relationship between the pDMN and visual creativity. Taken together, decreased within‐network connectivity of the FPN and DMN may allow for flexible between‐network coupling in the highly creative brain. These findings provide indirect evidence for the cooperative role of the default and executive control networks in creativity, extending past research by revealing common and distinct brain systems underlying verbal and visual creative cognition. Hum Brain Mapp 38:2094–2111, 2017. © 2017 Wiley Periodicals, Inc.     

Reduced executive and default network functional connectivity in cigarette smokers

Altered functional connectivity has been associated with acute and chronic nicotine use. Connectivity alterations, specifically in the right and left executive control networks (RECN/LECN) and the default mode network (DMN), may contribute to the addiction cycle. The objective of this study was to determine if executive control network (ECN) and DMN connectivity is different between non‐smokers and smokers and whether reductions in connectivity are related to chronic cigarette use. The RECN, LECN, and DMN were identified in resting state functional magnetic resonance imaging data in 650 subjects. Analyses tested for group differences in network connectivity strength, controlling for age and alcohol use. There was a significant group effect on LECN and DMN connectivity strength with smokers (n = 452) having lower network strengths than non‐smokers (n = 198). Smokers had lower connectivity than non‐smokers associated with key network hubs: the dorsolateral prefrontal cortex, and parietal nodes within ECNs. Further, ECN connectivity strength was negatively associated with pack years of cigarette use. Our data suggest that chronic nicotine use negatively impacts functional connectivity within control networks that may contribute to the difficulty smokers have in quitting. Hum Brain Mapp 36:872–882, 2015. © 2014 Wiley Periodicals, Inc.     

Altered memory‐related functional connectivity of the anterior and posterior hippocampus in older adults at increased genetic risk for Alzheimer's disease

The hippocampal complex is affected early in Alzheimer's disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOE?4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired‐associates memory task to examine differences in task‐dependent functional connectivity of the anterior and posterior hippocampus in nondemented APOE?4 carriers (n = 34, 18F) and noncarriers (n = 46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOE?4‐mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context‐dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOE?4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOE?4 carriers showed strong negative connectivity changes compared to noncarriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOE?4 and are consistent with the anterior‐to‐posterior theory of AD progression in the hippocampus. Hum Brain Mapp 37:366–380, 2016. © 2015 Wiley Periodicals, Inc.     

Precuneus degeneration in nondemented elderly individuals with APOE ɛ4: Evidence from structural and functional MRI analyses

Neurodegenerative diseases such as Alzheimer's disease (AD) have been recognized to exhibit disease‐specific brain vulnerability patterns. Apolipoprotein E (APOE ) ?4 allele imparts a high genetic risk of developing AD. Whether the APOE ?4 allele damages the brain when cognitive functions are still intact is important to understand, especially for possible early detection and intervention. This study aimed to examine the selective degeneration pattern associated with the APOE ?4 allele in the brains of cognitively normal elderly subjects. We enrolled 35 cognitively healthy ?4 carriers and 40 non‐carriers (53 to 81 years old) to evaluate group differences in cortical thickness and brain activation during a memory‐encoding task. We also assessed the functional connectivity of the brain regions with both structural and functional damages. The results from the neuropsychological tests showed that the performances of ?4 carriers and non‐carriers were comparable. Primarily, we found that the precuneus exhibited thinner cortical thickness and decreased deactivation during memory encoding. Furthermore, the connectivity analyses show that carriers exhibited damaged connectivity of the precuneus to several regions in the default mode network and the attention/executive control network. Our study reveals the degeneration pattern of the ?4 allele, which could be used as a potential biomarker for early detection for possible interventions and treatments. Hum Brain Mapp 38:271–282, 2017 . © 2016 Wiley Periodicals, Inc.     

Temporal lobe functional activity and connectivity in young adult APOE ɛ4 carriers

BackgroundWe sought to determine if the APOE ε4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTLs) during successful memory encoding in young adults.MethodsTwenty-four healthy young adults, i.e., 12 carriers and 12 noncarriers of the APOE ε4 allele, were scanned in a subsequent-memory paradigm, using event-related functional magnetic resonance imaging. The neuroanatomic correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTLs, as well as whole-brain functional connectivity with the MTLs, were assessed.ResultsIn the absence of demographic or performance differences, APOE ε4 allele carriers exhibited greater bilateral MTL activity relative to noncarriers while accomplishing the same encoding task. Moreover, whereas ε4 carriers demonstrated a greater functional connectivity of ESA-related MTL activity with the posterior cingulate and other peri-limbic regions, reductions in overall connectivity were found across the anterior and posterior cortices.ConclusionsThese results suggest that the APOE ?4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTLs to other regions implicated in memory encoding. Enhanced functional connectivity of the MTLs with the posterior cingulate in young adult ε4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer's disease, long before late-onset dementia is a practical risk or consideration. These functional connectivity differences may also reflect pleiotropic effects of APOE during early development.     

Functional connectivity with distinct neural networks tracks fluctuations in gain/loss framing susceptibility

Multiple large‐scale neural networks orchestrate a wide range of cognitive processes. For example, interoceptive processes related to self‐referential thinking have been linked to the default‐mode network (DMN); whereas exteroceptive processes related to cognitive control have been linked to the executive‐control network (ECN). Although the DMN and ECN have been postulated to exert opposing effects on cognition, it remains unclear how connectivity with these spatially overlapping networks contribute to fluctuations in behavior. While previous work has suggested the medial‐prefrontal cortex (MPFC) is involved in behavioral change following feedback, these observations could be linked to interoceptive processes tied to DMN or exteroceptive processes tied to ECN because MPFC is positioned in both networks. To address this problem, we employed independent component analysis combined with dual‐regression functional connectivity analysis. Participants made a series of financial decisions framed as monetary gains or losses. In some sessions, participants received feedback from a peer observing their choices; in other sessions, feedback was not provided. Following feedback, framing susceptibility—indexed as the increase in gambling behavior in loss frames compared to gain frames—was heightened in some participants and diminished in others. We examined whether these individual differences were linked to differences in connectivity by contrasting sessions containing feedback against those that did not contain feedback. We found two key results. As framing susceptibility increased, the MPFC increased connectivity with DMN; in contrast, temporal‐parietal junction decreased connectivity with the ECN. Our results highlight how functional connectivity patterns with distinct neural networks contribute to idiosyncratic behavioral changes. Hum Brain Mapp 36:2743–2755, 2015. © 2015 Wiley Periodicals, Inc .     

APOE influences working memory in non‐demented elderly through an interaction with SPON1 rs2618516

Exploring how risk genes cumulatively impair brain function in preclinical phase (i.e., in cognitively normal elderly) could provide critical insights into the pathophysiology of Alzheimer's disease (AD). Working memory impairment has always been a considerable cognitive deficit in AD, which is likely under complex genetic control. Though, the APOE ?4 allele could damage the working memory performance in normal elderly, dissociable results have been reported. This allele may exert specific effects in contexts with other genetic variants. The rs2618516 in the spondin 1 gene (SPON1) has been associated with AD risk and brain structure in the elderly. SPON1 may interact with APOE through processing the amyloid precursor protein and suppressing amyloid‐β levels. Using neuropsychological tasks from 710 individuals, we found significant SPON1 × APOE genotype interactions in working memory and executive function performances. Moreover, such interaction was also found in regional brain activations based on functional magnetic resonance imaging data with the n‐back working memory task performed in a sub‐cohort of 64 subjects. The effects of ?4 allele on activation of right inferior frontal gyrus, triangular part (IFGtriang.R) were modulated by rs2618516 in a working memory task. Furthermore, lower IFGtriang.R activation was associated with better cognitive functions. Moreover, the IFGtriang.R activation could mediate the impacts of SPON1 × APOE interactions on working memory performance. These findings suggested the importance of weighing APOE effects on brain activation under the working memory task within the context of the SPON1 genotype.     

Altered intra‐ and inter‐network functional coupling of resting‐state networks associated with motor dysfunction in stroke

Motor functions are supported through functional integration across the extended motor system network. Individuals following stroke often show deficits on motor performance requiring coordination of multiple brain networks; however, the assessment of connectivity patterns after stroke was still unclear. This study aimed to investigate the changes in intra‐ and inter‐network functional connectivity (FC) of multiple networks following stroke and further correlate FC with motor performance. Thirty‐three left subcortical chronic stroke patients and 34 healthy controls underwent resting‐state functional magnetic resonance imaging. Eleven resting‐state networks were identified via independent component analysis (ICA). Compared with healthy controls, the stroke group showed abnormal FC within the motor network (MN), visual network (VN), dorsal attention network (DAN), and executive control network (ECN). Additionally, the FC values of the ipsilesional inferior parietal lobule (IPL) within the ECN were negatively correlated with the Fugl‐Meyer Assessment (FMA) scores (hand + wrist). With respect to inter‐network interactions, the ipsilesional frontoparietal network (FPN) decreased FC with the MN and DAN; the contralesional FPN decreased FC with the ECN, but it increased FC with the default mode network (DMN); and the posterior DMN decreased FC with the VN. In sum, this study demonstrated the coexistence of intra‐ and inter‐network alterations associated with motor‐visual attention and high‐order cognitive control function in chronic stroke, which might provide insights into brain network plasticity following stroke.     

Structural core of the executive control network: A high angular resolution diffusion MRI study

Executive function (EF) is a set of cognitive capabilities considered essential for successful daily living, and is negatively affected by ageing and neurodegenerative conditions. Underpinning EF performance are functional nodes in the executive control network (ECN), while the structural connectivity underlying this network is not well understood. In this paper, we evaluated the structural white matter tracts that interconnect the ECN and investigated their relationship to the EF performance. Using high‐angular resolution diffusion MRI data, we performed tractography analysis of structural connectivity in a cognitively normal cohort (n = 140), specifically targeting the connectivity between ECN nodes. Our data revealed the presence of a strongly‐connected “structural core” of the ECN comprising three components: interhemispheric frontal connections, a fronto‐parietal subnetwork and fronto‐striatal connections between right dorsolateral prefrontal cortex and right caudate. These pathways were strongly correlated with EF performance (p = .003). Post‐hoc analysis of subregions within the significant ECN connections showed that these effects were driven by a highly specific subset of interconnected cortical regions. The structural core subnetwork of the functional ECN may be an important feature crucial to a better future understanding of human cognition and behaviour.     

Gender differences in healthy aging and Alzheimer's Dementia: A 18F‐FDG‐PET study of brain and cognitive reserve

Cognitive reserve (CR) and brain reserve (BR) are protective factors against age‐associated cognitive decline and neurodegenerative disorders. Very limited evidence exists about gender effects on brain aging and on the effect of CR on brain modulation in healthy aging and Alzheimer's Dementia (AD). We investigated gender differences in brain metabolic activity and resting‐state network connectivity, as measured by ¹⁸F‐FDG‐PET, in healthy aging and AD, also considering the effects of education and occupation. The clinical and imaging data were retrieved from large datasets of healthy elderly subjects (HE) (225) and AD patients (282). In HE, males showed more extended age‐related reduction of brain metabolism than females in frontal medial cortex. We also found differences in brain modulation as metabolic increases induced by education and occupation, namely in posterior associative cortices in HE males and in the anterior limbic‐affective and executive networks in HE females. In AD patients, the correlations between education and occupation levels and brain hypometabolism showed gender differences, namely a posterior temporo‐parietal association in males and a frontal and limbic association in females, indicating the involvement of different networks. Finally, the metabolic connectivity in both HE and AD aligned with these results, suggesting greater efficiency in the posterior default mode network for males, and in the anterior frontal executive network for females. The basis of these brain gender differences in both aging and AD, obtained exploring cerebral metabolism, metabolic connectivity and the effects of education and occupation, is likely at the intersection between biological and sociodemographic factors. Hum Brain Mapp 38:4212–4227, 2017. © 2017 Wiley Periodicals, Inc.     

From hippocampus to whole‐brain: The role of integrative processing in episodic memory retrieval

Multivariate functional connectivity analyses of neuroimaging data have revealed the importance of complex, distributed interactions between disparate yet interdependent brain regions. Recent work has shown that topological properties of functional brain networks are associated with individual and group differences in cognitive performance, including in episodic memory. After constructing functional whole‐brain networks derived from an event‐related fMRI study of memory retrieval, we examined differences in functional brain network architecture between forgotten and remembered words. This study yielded three main findings. First, graph theory analyses showed that successfully remembering compared to forgetting was associated with significant changes in the connectivity profile of the left hippocampus and a corresponding increase in efficient communication with the rest of the brain. Second, bivariate functional connectivity analyses indicated stronger interactions between the left hippocampus and a retrieval assembly for remembered versus forgotten items. This assembly included the left precuneus, left caudate, bilateral supramarginal gyrus, and the bilateral dorsolateral superior frontal gyrus. Integrative properties of the retrieval assembly were greater for remembered than forgotten items. Third, whole‐brain modularity analyses revealed that successful memory retrieval was marginally significantly associated with a less segregated modular architecture in the network. The magnitude of the decreases in modularity between remembered and forgotten conditions was related to memory performance. These findings indicate that increases in integrative properties at the nodal, retrieval assembly, and whole‐brain topological levels facilitate memory retrieval, while also underscoring the potential of multivariate brain connectivity approaches for providing valuable new insights into the neural bases of memory processes. Hum Brain Mapp 38:2242–2259, 2017. © 2017 Wiley Periodicals, Inc.     

Three subsystems of the inferior parietal cortex are differently affected in mild cognitive impairment

The Inferior parietal cortex (IPC), including the intraparietal sulcus (IPS), angular gyrus (AG), and supramarginal gyrus (SG), plays an important role in episodic memory, and is considered to be one of the specific neuroimaging markers in predicting the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, it is still unclear whether the connectivity of the IPC is impaired in MCI patients. In the present study, we used resting state fMRI to examine the functional connectivity of the three subdivisions of the IPC in MCI patients after controlling the impact of regional grey matter atrophy. It was found that, using IPS, AG, and SG as seeds of functional connectivity, three canonical functional networks could be correspondingly traced, i.e., executive control network (ECN), default mode network (DMN), and salience network (SN), and the three networks are differently altered in MCI patients. In contrast to the healthy controls, it was found that in MCI patients: 1) AG connectivity was significantly reduced within the DMN; 2) IPS showed decreased connectivity with the right inferior frontal gyrus while showing increased connectivity with the left frontal regions within the ECN; and 3) SG displayed decreased connectivity with a distribution of regions including the frontal and parietal regions, and increased connectivity with some sub-cortical areas within the SN. Moreover, the connectivity within the three networks was correlated with episodic memory and general cognitive impairment in MCI patients. These results extend well beyond the DMN, and further suggest that MCI is associated with alteration of large-scale functional brain networks.     

Memory performance and fMRI signal in presymptomatic familial Alzheimer's disease

Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late‐onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation‐carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD‐relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes. Hum Brain Mapp 34:3308–3319, 2013. © 2012 Wiley Periodicals, Inc.     

Disrupted brain network topology in pediatric posttraumatic stress disorder: A resting‐state fMRI study

Children exposed to natural disasters are vulnerable to the development of posttraumatic stress disorder (PTSD). Recent studies of other neuropsychiatric disorders have used graph‐based theoretical analysis to investigate the topological properties of the functional brain connectome. However, little is known about this connectome in pediatric PTSD. Twenty‐eight pediatric PTSD patients and 26 trauma‐exposed non‐PTSD patients were recruited from 4,200 screened subjects after the 2008 Sichuan earthquake to undergo a resting‐state functional magnetic resonance imaging scan. Functional connectivity between 90 brain regions from the automated anatomical labeling atlas was established using partial correlation coefficients, and the whole‐brain functional connectome was constructed by applying a threshold to the resultant 90 * 90 partial correlation matrix. Graph theory analysis was then used to examine the group‐specific topological properties of the two functional connectomes. Both the PTSD and non‐PTSD control groups exhibited “small‐world” brain network topology. However, the functional connectome of the PTSD group showed a significant increase in the clustering coefficient and a normalized characteristic path length and local efficiency, suggesting a shift toward regular networks. Furthermore, the PTSD connectomes showed both enhanced nodal centralities, mainly in the default mode‐ and salience‐related regions, and reduced nodal centralities, mainly in the central‐executive network regions. The clustering coefficient and nodal efficiency of the left superior frontal gyrus were positively correlated with the Clinician‐Administered PTSD Scale. These disrupted topological properties of the functional connectome help to clarify the pathogenesis of pediatric PTSD and could be potential biomarkers of brain abnormalities. Hum Brain Mapp 36:3677–3686, 2015. © 2015 Wiley Periodicals, Inc .     

Cognitive and default‐mode resting state networks: Do male and female brains “rest” differently?

Variability in human behavior related to sex is supported by neuroimaging studies showing differences in brain activation patterns during cognitive task performance. An emerging field is examining the human connectome, including networks of brain regions that are not only temporally‐correlated during different task conditions, but also networks that show highly correlated spontaneous activity during a task‐free state. Both task‐related and task‐free network activity has been associated with individual task performance and behavior under certain conditions. Therefore, our aim was to determine whether sex differences exist during a task‐free resting state for two networks associated with cognitive task performance (executive control network (ECN), salience network (SN)) and the default mode network (DMN). Forty‐nine healthy subjects (26 females, 23 males) underwent a 5‐min task‐free fMRI scan in a 3T MRI. An independent components analysis (ICA) was performed to identify the best‐fit IC for each network based on specific spatial nodes defined in previous studies. To determine the consistency of these networks across subjects we performed self‐organizing group‐level ICA analyses. There were no significant differences between sexes in the functional connectivity of the brain areas within the ECN, SN, or the DMN. These important findings highlight the robustness of intrinsic connectivity of these resting state networks and their similarity between sexes. Furthermore, our findings suggest that resting state fMRI studies do not need to be controlled for sex. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Topological graph kernel on multiple thresholded functional connectivity networks for mild cognitive impairment classification

Recently, brain connectivity networks have been used for classification of Alzheimer's disease and mild cognitive impairment (MCI) from normal controls (NC). In typical connectivity‐networks‐based classification approaches, local measures of connectivity networks are first extracted from each region‐of‐interest as network features, which are then concatenated into a vector for subsequent feature selection and classification. However, some useful structural information of network, especially global topological information, may be lost in this type of approaches. To address this issue, in this article, we propose a connectivity‐networks‐based classification framework to identify accurately the MCI patients from NC. The core of the proposed method involves the use of a new graph‐kernel‐based approach to measure directly the topological similarity between connectivity networks. We evaluate our method on functional connectivity networks of 12 MCI and 25 NC subjects. The experimental results show that our proposed method achieves a classification accuracy of 91.9%, a sensitivity of 100.0%, a balanced accuracy of 94.0%, and an area under receiver operating characteristic curve of 0.94, demonstrating a great potential in MCI classification, based on connectivity networks. Further connectivity analysis indicates that the connectivity of the selected brain regions is different between MCI patients and NC, that is, MCI patients show reduced functional connectivity compared with NC, in line with the findings reported in the existing studies. Hum Brain Mapp 35:2876–2897, 2014. © 2013 Wiley Periodicals, Inc.     

Cerebral atrophy,apolipoprotein E ɛ4, and rate of decline in everyday function among patients with amnestic mild cognitive impairment

BackgroundPatients with amnestic mild cognitive impairment (MCI) demonstrate decline in everyday function. In this study, we investigated whether whole brain atrophy and apolipoprotein E (APOE) genotype are associated with the rate of functional decline in MCI.MethodsParticipants were 164 healthy controls, 258 MCI patients, and 103 patients with mild Alzheimer's disease (AD), enrolled in the Alzheimer's Disease Neuroimaging Initiative. They underwent brain MRI scans, APOE genotyping, and completed up to six biannual Functional Activities Questionnaire (FAQ) assessments. Random effects regressions were used to examine trajectories of decline in FAQ across diagnostic groups, and to test the effects of ventricle-to-brain ratio (VBR) and APOE genotype on FAQ decline among MCI patients.ResultsRate of decline in FAQ among MCI patients was intermediate between that of controls and mild AD patients. Patients with MCI who converted to mild AD declined faster than those who remained stable. Among MCI patients, increased VBR and possession of any APOE ?4 allele were associated with faster rate of decline in FAQ. In addition, there was a significant VBR by APOE ?4 interaction such that patients who were APOE ?4 positive and had increased atrophy experienced the fastest decline in FAQ.ConclusionsFunctional decline occurs in MCI, particularly among patients who progress to mild AD. Brain atrophy and APOE ?4 positivity are associated with such declines, and patients who have elevated brain atrophy and are APOE ?4 positive are at greatest risk of functional degradation. These findings highlight the value of genetic and volumetric MRI information as predictors of functional decline, and thus disease progression, in MCI.     

Prefrontal network dysfunctions in rapid eye movement sleep behavior disorder

IntroductionResting-state functional connectivity magnetic resonance imaging (rsfcMRI) of rapid eye movement (REM) sleep behavior disorder (RBD) may provide an early biomarker of α-synucleinopathy. However, few rsfcMRI studies have examined cognitive networks. To elucidate brain network changes in RBD, we performed rsfcMRI in patients with polysomnography-confirmed RBD and healthy controls (HCs), with a sufficiently large sample size in each group.MethodsWe analyzed rsfcMRI data from 50 RBD patients and 70 age-matched HCs. Although RBD patients showed no motor signs, some exhibited autonomic and cognitive problems. Several resting-state functional networks were extracted by group independent component analysis from HCs, including the executive-control (ECN), default-mode (DMN), basal ganglia (BGN), and sensory-motor (SMN) networks. Functional connectivity (FC) was compared between groups using dual regression analysis. In the RBD group, correlation analysis was performed between FC and clinical/cognitive scales.ResultsPatients with RBD showed reduced striatal-prefrontal FC in ECN, consistent with executive dysfunctions. No abnormalities were found in DMN. In the motor networks, we identified reduced midbrain-pallidum FC in BGN and reduced motor and somatosensory cortex FC in SMN.ConclusionWe found abnormal ECN and normal DMN as a possible hallmark of cognitive dysfunctions in early α-synucleinopathies. We replicated abnormalities in BGN and SMN corresponding to subclinical movement disorder of RBD. RsfcMRI may provide an early biomarker of both cognitive and motor network dysfunctions of α-synucleinopathies.