Amnestic Type Mild Cognitive Impairment Research Articles

An Atherosclerosis Indicator Hyaluronic Acid: Can Plasma Hyaluronic Acid Be Useful in Diagnosing Alzheimer's Disease?

The aim is to compare the plasma levels of hyaluronic acid (HA) which is closely related to inflam-mation and vascular changes and arterial stiffness (AS) related values in patients with Alzheimer's disease (AD), amnestic type mild cognitive impairment (aMCI), and normal cognitive functions (NCF). Ninety participants were categorized into three groups, patients with AD, MCI, and NCF. Arterial stiffness measurement in the nephrology outpatient clinic, and storage and analysis of plasma samples in the biochemistry laboratory. Of the 90 patients, 32 had NCF, 32 had aMCI, and 26 had AD. Between groups, there was no difference in HA, pulse wave velocity, and augmentation index. The HA level had no statistically significant correlation with any of the other variables. Plasma HA levels will not be useful in the diagnosis of AD. More comprehensive studies with larger number of patients are needed.

P6: Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance: a longitudinal study

P6: Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance: a longitudinal study

Alteration of Visuospatial System as an Early Marker of Cognitive Decline: A Double-Center Neuroimaging Study.

Amnestic-type mild cognitive impairment (a-MCI) represents the prodromal phase of Alzheimer's disease associated with a high conversion rate to dementia and serves as a potential golden period for interventions. In our study, we analyzed the role of visuospatial (VS) functions and networks in the recognition of a-MCI. We examined 78 participants (32 patients and 46 controls) in a double-center arrangement using neuropsychology, structural, and resting-state functional MRI. We found that imaging of the lateral temporal areas showed strong discriminating power since in patients only the temporal pole (F = 5.26, p = 0.034) and superior temporal gyrus (F = 8.04, p < 0.001) showed reduced cortical thickness. We demonstrated significant differences between controls and patients in various neuropsychological results; however, analysis of cognitive subdomains revealed that the largest difference was presented in VS skills (F = 8.32, p < 0.001). Functional connectivity analysis of VS network showed that patients had weaker connectivity between the left and right frontotemporal areas, while stronger local connectivity was presented between the left frontotemporal structures (FWE corrected p < 0.05). Our results highlight the remarkable potential of examining the VS system in the early detection of cognitive decline. Since resting-state setting of functional MRI simplifies the possible automatization of data analysis, detection of VS system alterations might provide a non-invasive biomarker of a-MCI.

Clinical and immunological effects of choline alfoscerate in the treatment of amnestic type Mild Cognitive Impairment

To evaluate the change of a number of clinical and immunological parameters of patients with amnestic type Mild Cognitive Impairment (aMCI) in the course of therapy with Choline alfoscerate (α-GPC) in order to develop a monitoring and predicting system of its effectiveness in people at risk for Alzheimer's disease. Thirty patients with aMCI, aged 56 to 82 years (mean age 68.8±9.4 years), received course therapy with α-GPC in capsules of 400 mg 3 times a day (1200 mg per day) for 3 months. Therapeutic efficacy evaluation according to psychometric tests and scales was carried out three times (0, 45 and 90 days), immunological parameters of leukocyte elastase (LE) and α1-protease inhibitor (α1-PI) were evaluated twice on days 0 and 90 of therapy. A good therapeutic effect over the course treatment with α-GPC, both in terms of cognitive functioning and a number of immunological parameters in patients with aMCI was shown. Significant clinical and immunological correlations included both an improvement in cognitive functions (according to MMSE and the Boston Naming Test) and an increase in LE activity level after the completion of a course of α-GPC therapy, which suggest that an increase in LE functional activity can be considered as a potential marker of a positive therapeutic response to α-GPC treatment in aMCI patients. This study shows high significance of further research in assessing the role of immune mechanisms of α-GPC therapeutic efficacy in aMCI patients and the possibility of using immunological parameters as prognostic markers of its therapeutic effect.

Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance

Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance

Assessing a Sensory-Motor-Cognition Triad in Amnestic Mild Cognitive Impairment With Dichotic Listening While Walking: A Dual-Task Paradigm.

A contemporary topic in aging research relates to the significance of cognitive changes proper to mild cognitive impairment (MCI) to higher risk of falls and gait deteriorations. The present study addresses this question in the amnestic type of MCI (aMCI) by examining a triad of interrelated comorbidities occurring in the MCI condition: attentional impairments, hearing loss and gait disturbances. To this end, we applied a dichotic listening (DL) test during over-ground walking. DL assesses spontaneous and lateralized auditory attention in three conditions (i.e., free report or Non-forced (NF), Forced-Right (FR) ear and Forced-Left (FL) ear). Earlier reports suggest that this dual-task paradigm evoke asymmetric gait effects on healthy controls, which are moderated by degree of hearing loss. Therefore, the aim of the present study was to evaluate the effects of DL on bilateral (data from both limbs) and lateralized (each limb separately) gait outcomes in a group of forty-three aMCI participants (mean = 71.19) and fifty-two healthy older controls (mean = 70.90) by using hearing loss as a covariate in all analyses. Results showed the aMCI group presented overall compromised gait parameters, especially higher gait variability in all DL conditions during lateralized attentional control. These findings were observed bilaterally, and no lateralized effects on gait were observed. Only after controlling for hearing acuity, gait asymmetries on step length variability emerged almost exclusively in healthy controls. It was concluded that hearing loss in the aMCI group together with higher attentional impairments preclude aMCI individuals to properly execute DL and therefore, they do not display gait asymmetries. The present data demonstrate that varied demands on attentional control dependent on hearing acuity affects gait negatively in healthy older adults and aMCI individuals in very different ways. The appearance of asymmetric effects seems to be a perturbation related to normal aging, while the lack of asymmetries but exaggerated gait variability characterizes aMCI. The present findings show the intricate interplay of sensory, cognitive, and motor deteriorations in different group of older adults, which stresses the need of addressing co-occurring comorbidities behind gait perturbations in individuals prone to develop a dementia state.

Comparison of Amyloid Positivity Rate and Accumulation Pattern between Amnestic and Non-Amnestic Type Mild Cognitive Impairment.

ObjectiveWe aimed to compare cerebral beta-amyloid protein (Aβ) positivity rate and amyloid accumulation pattern on amyloid positron emission tomography (PET) between mild cognitive impairment (MCI) subtypes, i.e. amnestic mild cognitive impairment (aMCI) and non-amnestic mild cognitive impairment (naMCI). MethodsThe study participants were 34 naMCI patients and age-, sex- and education-matched 68 aMCI patients (1:2 ratio) who visited the Dementia and Age-Associated Cognitive Decline Clinic of the Seoul National University Hospital. All participants received comprehensive clinical and neuropsychological assessments and [18F] florbetaben PET. ResultsAβ positivity rate of naMCI group (26.5%) was significantly lower than that of aMCI group (64.7%). Among Aβ positive individuals, there was no difference in Aβ accumulation pattern between naMCI and aMCI. ConclusionThe findings suggest that MCI subtypes based on impaired cognitive domains have a differential association with brain Aβ deposition, a core pathology of AD. Amnestic subtype of MCI are more closely associated with cerebral Aβ deposition compared to non-amnestic subtype. In contrast, the pattern of amyloid deposition does not appear to have any difference between the subtypes.

Locus coeruleus connectivity alterations in late-life major depressive disorder during a visual oddball task

The Locus Coeruleus (LC) is the major source of noradrenergic neurotransmission. Structural alterations in the LC have been observed in neurodegenerative disorders and at-risk individuals, although functional connectivity studies between the LC and other brain areas have not been yet performed in these populations. Patients with late-life major depressive disorder (MDD) are indeed at increased risk for neurodegenerative disorders, and here we investigated LC connectivity in late-life MDD in comparison to individuals with amnestic type mild cognitive impairment (aMCI) and healthy controls (HCs). We assessed 20 patients with late-life MDD, 16 patients with aMCI, and 26 HCs, who underwent a functional magnetic resonance scan while performing a visual oddball task. We assessed task-related modulations of LC connectivity (i.e., Psychophysiological Interactions, PPI) with other brain areas. A T1-weighted fast spin-echo sequence for LC localization was also obtained. Patients with late-life MDD showed lower global connectivity during target detection in a cluster encompassing the right caudal LC. Specifically, we observed lower LC connectivity with the left anterior cingulate cortex (ACC), the right fusiform gyrus, and different cerebellar clusters. Moreover, alterations in LC-ACC connectivity correlated negatively with depression severity (i.e., Geriatric Depression Scale and number of recurrences). Reduced connectivity of the LC during oddball performance seems to specifically characterize patients with late-life MDD, but not other populations of aged individuals with cognitive alterations. Such alteration is associated with different measures of disease severity, such as the current presence of symptoms and the burden of disease (number of recurrences).

Application of local gyrification index in the early diagnosis of Alzheimer disease

Objective To evaluate the role of local gyrification index (LGI) in the early diagnosis of Alzheimer disease(AD). Methods Thirty-five amnestic-type mild cognitive impairment patients (aMCI group), 34 mild AD patients (mild AD group) and 33 healthy volunteers (normal control group) were studied. All patients underwent high resolution MRI examination and mini-mental state examination (MMSE). Using surface-based morphometry, the FreeSurfer was employed to access LGI of vertex over every participant′s whole cortical surface, then we calculated the mean LGI (mLGI) of each subject′s left and right hemisphere separately. Taking age, gender and educational year as covariance, analysis of covariance was used to compare the difference of mLGI of left and right brain among 3 groups, then Bonferroni was done between every two groups. Analysis of covariance was applied to compare the difference of LGI of every participant among 3 groups, and Monte Carlo method was employed to perform multiple comparison corrections. The correlations between the MMSE scores and LGIs of the three groups were analyzed. Results Compared with normal control group(left 3.03±0.12,right 3.02±0.13), the mLGI of hemispheres in mild AD group(left 2.94±0.11,right 2.93±0.10) decreased respectively(P 0.05). The difference of mLGI of hemispheres between aMCI group and mild AD group also had no statistical significance(P>0.05). The aMCI group showed decrease of LGI in some brain regions located at the right temporal lobe, bilateral frontal and parietal lobe compared with the normal control group. While compared with aMCI group, decreased LGIs was presented in some brain regions located at bilateral temporal, occipital, frontal lobe and the right parietal lobe of mild AD group. There was a positive correlation between MMSE scores and LGIs of some brain regions in the bilateral temporal, occipital lobe, the left frontal lobe and the right parietal lobe in the three groups. Conclusion LGI is conductive in the early diagnosis of AD and can serve as an imaging marker for monitoring disease progresses. Key words: Alzheimer disease; Mild cognitive impairment; Magnetic resonance imaging; Local gyrification index

Parafoveal vessel loss and correlation between peripapillary vessel density and cognitive performance in amnestic mild cognitive impairment and early Alzheimer's Disease on optical coherence tomography angiography.

PurposePatients with Alzheimer’s Disease (AD) exhibit decreased retinal blood flow and vessel density (VD). However, it is not known whether these changes are also present in individuals with early AD (eAD) or amnestic type mild cognitive impairment (aMCI), an enriched pre-AD population with a higher risk for progressing to dementia. We performed a prospective case-control clinical study to investigate whether optical coherence tomography angiography (OCTA) parameters in the macula and disc are altered in those with aMCI and eAD.MethodsThis is a single center study of 32 participants. Individuals with aMCI/eAD (n = 16) were 1:1 matched to cognitively normal controls (n = 16). We evaluated OCTA images of the parafoveal superficial capillary plexus (SCP) and two vascular layers in the peripapillary region, the radial peripapillary capillary (RPC) and superficial vascular complex (SVC). Outcome vascular and structural parameters included VD, vessel length density (VLD), adjusted flow index (AFI) and structural retinal nerve fiber layer (RNFL) thickness. We compared these parameters between the two groups and examined the correlation between OCTA parameters and cognitive performance on the Montreal Cognitive Assessment (MoCA).ResultsCognitively impaired participants demonstrated statistically significant decrease in parafoveal SCP VD and AFI as compared to controls, but no statistically significant difference in peripapillary parameters. Furthermore, we found a significant positive correlation between MoCA scores for the entire study cohort and both the parafoveal SCP VD and peripapillary RPC VLD.ConclusionOCTA shows significant decline in parafoveal flow and VD in individuals with early cognitive impairment related to AD, suggesting that these parameters could have potential utility as early disease biomarkers. In contrast, the presence of larger vascular channels in the peripapillary region may have obscured subtle capillary changes in that region. Overall, the correlation between vascular OCTA parameters and cognitive performance supports further OCTA studies in this population.

Clinical and neuropsychological profile of persons with mild cognitive impairment, a hospital based study from a lower and middle income country.

Mild Cognitive impairment (MCI) is an important pre-dementia stage to be identified towards prevention. We screened a large number of older adults seeking help at hospital and community towards a diagnosis of MCI and this study describe their clinical and neuropsychological profile. Older adults aged 60 years & above seeking help at NIMHANS outpatient & community services were screened for early cognitive deficits. Persons were diagnosed to have MCI according to Petersen's criteria, after detailed clinical and neuropsychological assessments. Age, gender and education matched healthy controls were recruited for comparison. A total of 7469 older adults were screened during the study period (July 2012-December 2014). Less than 1% (n=56) were diagnosed with MCI. Majority were males, from urban background with an average of 13 years of education. They presented mainly with memory disturbances, more than 75% (n=43) were found to have amnestic type of MCI (aMCI). Of the aMCI subjects, majority (80%) had deficits in more than one cognitive domain. They performed significantly worse (p<0.001) on tests of episodic memory, logical memory, attention and executive functions. Neuropsychiatric symptoms were prevalent in 55% of MCI group and influenced their cognitive scores. The findings suggest that persons with MCI perform worse not only on memory tasks but also on some of the attention and executive functions tasks. As observed in earlier studies, amnestic multiple-domain MCI was the most common type of MCI in this study population. Indigenous assessment tools were of significant value in distinguishing MCI from normal ageing.

Membrane characteristics and vascular cognitive impairment

Objective : to study the clinical phenomenology of vascular cognitive impairment (VCI) in individuals with different rates of passive transmembrane ion transport. Patients and methods. Cognitive functions were evaluated in 372 patients with different clinical variants of moderate VCI after 1, 5, and 10 years of follow-up. Quantile analysis was used to group patients into quartiles according to the ranges in the rate of passive transmembrane ion transport reflecting the genetically determined properties of cell membranes and identified by the study of Na+–Li+ countertransport (NLC) in the erythrocyte membrane. Results. There was initially a monofunctional non-amnestic type in 11.0% of the patients, a monofunctional amnestic type in 16.1%, a multifunctional non-amnestic type in 34.9%, and a multifunctional amnestic type in 37.9%. At the same type, in the patients with high-speed NLC, the number of amnestic VCI types statistically dominated: 77.1% of the patients belonging to IV quartile. After 1 year and 5 years of follow-up, there was an increase in the number of patients with severe cognitive impairment, reaching the degree of dementia (33.2% of all the examinees following 1 year). The patients with high-speed NLC showed a significant predominance of not only the total number of dementias (86.7% of the patients in IV quartile; p<0.001), but also a more unfavorable mixed (disregulatory + Alzheimer's disease) type of dementia (74.7% of the patients in IV quartile; p<0.001). The dysregulatory type of dementia was more common in patients with low- and moderate-speed NLC. 70% of all dementias formed from the multifunctional amnestic type of mild cognitive impairment (MCI). Different types of MCI were observed to be transformed to the prognostically unfavorable multifunctional amnestic type of MCI. The study conducted 10 years later noted the same trends. Conclusion. The NLC speed has been shown to be associated with the VCI profile, which makes this indicator promising for predicting the course of VCI in the early stage of the disease and for choosing a treatment policy.

Cognitive and anatomical correlates of anosognosia in amnestic mild cognitive impairment and early-stage Alzheimer's disease.

Anosognosia is a common feature in Alzheimer's disease (AD). The brain substrates of anosognosia are not fully understood, and less is known about the cognitive substrates of anosognosia in prodromal and early stages of AD. Fourty-seven patients with amnestic-type mild cognitive impairment (aMCI) (n = 26) and early-stage AD (n = 21) were included, and Clinical Insight Rating Scale and Anosognosia Questionnaire for Dementia (AQ-D) were used to assess anosognosia. A detailed neuropsychological battery was administered; each patient underwent a structural magnetic resonance imaging (MRI). Correlation between anosognosia and performance in individual cognitive domains as well as correlation between anosognosia and cortical thickness values in regions of interest were assessed. Performance of the anosognosic patients in Digit Ordering Test (DOT), Digit Span Backwards, and Clock Drawing Test (CDT) was significantly worse compared to non-anosognosic patients in the total study population and in the aMCI subgroup but not in AD group. AQ-D scores negatively correlated with Mini-Mental State Examination (MMSE), California Verbal Learning Test (CVLT), Digit Span Backwards and CDT scores in total group and MMSE, CVLT, DOT, and Digit Span Backwards scores in the aMCI group. No significant correlations were found between cortical thickness measurements and AQ-D scores in any of the patient populations. Anosognosia was associated with episodic memory, working memory, and executive functions in the total population and aMCI group, but no association was found in early-stage AD patients. Anosognosia in the early stages of AD may be related with non-structural changes such as hypoconnectivity rather than structural changes.

The apolipoprotein E gene affects the three-year trajectories of compensatory neural processes in the left-lateralized hippocampal network.

Previous cross-sectional studies that investigated the effects of apolipoprotein E (ApoE) ε4 status on hippocampal networks have shown inconsistent results. Aging is a well-known risk factor for Alzheimer's disease (AD) and could strongly interact with ApoE-related vulnerabilities to affect AD risk. However, no longitudinal data have been published regarding the interaction of the ApoE genotype and aging on hippocampal networks. Fifty-one patients with amnestic-type mild cognitive impairment (aMCI) and 64 matched cognitively normal elderly subjects underwent resting-state fMRI scans and neuropsychological tests at baseline and at a 35-month follow-up. Hippocampal resting-state functional connectivity (FC) data were analyzed utilizing a mixed analysis of covariance with ApoE genotype, time points and disease as fixed factors, controlling for age, sex and years of education. The notable finding was that the FC between the left hippocampus and right frontal regions for ε4 carriers longitudinally increased in the normal subjects, but decreased in aMCI patients, whereas the FC for non-carriers was maintained in normal subjects but increased in aMCI patients. Specifically, the longitudinal increases in hippocampal FC with the right inferior frontal gyrus were positively correlated with the changes in episodic memory test scores in non-carriers with aMCI. The interaction between the ApoE genotype, aging and disease suggested that aging should be considered a key regulator of the impact of the ApoE genotype on the phenotypic variants of AD. These findings also demonstrated that compensatory neural processes were accelerated in genetically high risk individuals, but could be subsequently exhausted with the onset of cognitive impairment.

STRATEGIC MEMORY ALZHEIMER’S REHABILITATION TRAINING (SMART): COGNITIVE PROTECTION AND INTERVENTION FOR AMNESTIC-TYPE MILD COGNITIVE IMPAIRMENT (MCI)

STRATEGIC MEMORY ALZHEIMER’S REHABILITATION TRAINING (SMART): COGNITIVE PROTECTION AND INTERVENTION FOR AMNESTIC-TYPE MILD COGNITIVE IMPAIRMENT (MCI)

Application of cerebral MR perfusion imaging using pulsed arterial spin labeling technique in patients with amnestic-type mild cognitive impairment and mild Alzheimer disease

Objective To study the value of relative cerebral blood flow (rCBF) changes in patients with amnestic-type mild cognitive impairment (aMCI) and mild Alzheimer disease (AD) using MRI pulsed arterial spin labeling (PASL). Methods A prospective study recruited 37 aMCI patients (aMCI group) , 30 mild AD patients (mild AD group) and 30 healthy volunteers (normal control group) from March 2011 to December 2013, MRI using PASL for cerebral perfusion imaging was performed and data of rCBF were collected. Taking age as covariate, analysis of variance (ANONA) was carried out to assess the difference of rCBF among all the three groups, then Bonferroni was done between every two groups. A follow-up examination using PASL was performed in the seventeen patients of the aMCI group. And paired t-test was used for comparing the longitudinal change of their rCBF data. Results Compared with the normal control group, the aMCI group showed significant increase of rCBF in bilateral posterior cingulate cortices and precuneus (cluster number 2 785, P<0.05). While the mild AD group showed decrease of rCBF in the left inferior and superior parietal lobes, the angular, middle frontal lobe, as well as the right superior temporal lobe (cluster number 3 459-5 206, P<0.05). When compared with the aMCI group, the mild AD group showed regional hypoperfusion in bilateral middle frontal lobes, the left precuneus, the right postcentral and inferior parietal lobe (cluster number 3 236-19 863, P<0.05). In the longitudinal study of the 17 aMCI patients, an increased rCBF was found to coexist with reduced rCBF in the left inferior frontal and lateral occipital cortex, bilateral frontal poles and paracingulate gyrus, with hyperperfusion dominated. Increased rCBF was also detected in the left temporal lobe, the angular gyrus and precuneus, while decreased rCBF was present in the left putamen, the operculum and right corpus callosum (P<0.05). Conclusions ASL perfusion imaging is a valuable method for dynamic monitoring of the cerebral perfusion changes in aMCI and AD patients. PASL will assist in finding a useful imaging biomarker for early diagnosis of AD. Key words: Cognition disorders; Alzheimer disease; Magnetic resonance imaging

Changes of gray matter volume and amplitude of low-frequency oscillations in amnestic MCI: An integrative multi-modal MRI study.

Numerous studies have reported that the amnestic-type mild cognitive impairment (aMCI) patients have impaired brain structural integrity and functional alterations separately. To investigate the changes of gray matter and amplitude of low-frequency oscillations in patients with aMCI by combining structural and functional magnetic resonance imaging (fMRI). Thirty-four patients with aMCI and 34 controls were recruited. We adopted optimized voxel-based morphometry to detect regions with gray matter volume (GMV) loss induced by aMCI. Then regional differences in amplitude of slow-4 band (0.027-0.073 Hz) oscillations among these regions between patients and healthy controls were examined. Both slow-4 amplitude of low-frequency fluctuations (ALFF) and slow-4 fractional ALFF (fALFF; the relative amplitude that resides in the low frequencies) were employed. Patients with aMCI demonstrated significant GMV loss in the ventral medial prefrontal cortex (vMPFC), posterior cingulate cortex (PCC), bilateral hippocampus, right superior parietal gyrus, left insula and left middle temporal gyrus (P < 0.01). The patients exhibited significant decreases of slow-4 ALFF in the left hippocampus (P = 0.05) and PCC (P = 0.02), while the decreased slow-4 fALFF was detected in PCC (P = 0.01) and increased slow-4 fALFF in vMPFC (P = 0.03). In PCC, aMCI and controls exhibited significant different GMV-fALFF correlation (P < 0.05), with opposite correlation trend. The correlates between anatomical deficits and functional alterations in aMCI suggest that anatomical and functional deficits are linked to each other. The differences of GMV-fALFF correlations demonstrated altered anatomical-functional relationship in aMCI.

Semantic profiles in mild cognitive impairment associated with Alzheimer's and Parkinson's diseases.

The temporal and the prefrontal cortices have different roles in semantic information processing: the temporal lobe is where knowledge is stored (Graham and Hodges, 1997), whereas the prefrontal cortex is more specifically involved in executive aspects of semantic processing. Relatively little is known about the semantic profiles of mild cognitive impairment (MCI) in Alzheimer's disease (AD) and Parkinson's disease (PD). This observational study investigated naming and semantic questionnaire performances in three groups of subjects: 10 patients with the amnestic-type MCI prodrome of AD (aMCI), 10 patients with early-stage executive-type MCI in PD (MCI-PD), and 10 normal subjects. The MCI-PD subjects demonstrated inferior performances on a semantic questionnaire, whereas the aMCI group displayed modest difficulties in a naming task. These differences may be explained by topographical differences in pathological involvement. Since the frontal areas are more functionally impaired in PD, we hypothesize that the semantic deficit may be a consequence of a deficiency in control of semantic processing. On the other hand, the semantic deficit in aMCI may be related to a lexical-semantic storage dysfunction resulting from pathological involvement of the temporal lobe.

Altered Effective Connectivity of the Default Mode Network in Resting-State Amnestic Type Mild Cognitive Impairment

Amnestic mild cognitive impairment (aMCI) is the transitional, heterogeneous continuum from normal elderly to Alzheimer's disease (AD). Previous studies have shown that brain functional activity in the default mode network (DMN) is impaired in aMCI patients with saliently cognitive and memory decline. However, the effective connectivity among the spatially isolated, but functionally related areas within the DMN in aMCI patients remains largely unknown. The present study examined dysfunctional connectivity of the DMN by combining an independent component analysis (ICA) approach with multivariate Granger causality analysis (mGCA) in 18 aMCI patients and 18 age-matched cognitively normal elderly. Results from mGCA showed decreased effective connectivity occurred among the middle temporal gyrus (MTG), hippocampus (HC) and fusiform gyrus (FG), as well as between the precuneus/posterior cingulate cortex (PreCN/PCC) and HC in patients with aMCI. Such an impaired connectivity was also correlated with patients' cognitive performance of the auditory verbal learning. Moreover, enhanced effective connectivity within frontal cortex emerged, which may maintain memory functions after attenuated connections within DMN activity. These findings may elucidate the dysfunctional processes in brain networks of aMCI patients, highlighting the importance of connectivity changes in the pathophysiology of aMCI.

Association of a GSK-3β Polymorphism with Brain Resting-State Function in Amnestic-Type Mild Cognitive Impairment

The glycogen synthase kinase-3β (GSK-3β) gene has been implicated in Alzheimer's disease (AD). Polymorphisms in this gene are plausible modulators of brain function. However, little is known about the potential role of the GSK-3β rs334558 polymorphism, which has been associated with amnestic mild cognitive impairment (aMCI), which is itself associated with a high risk of AD. In this study, 43 aMCI patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging, and their GSK-3β rs334558 genotypes were evaluated to determine the effect of the risk variant on regional brain activity and functional networks in these subjects. Then, gene-brain-behavior relationships were examined. Compared with the controls, aMCI subjects with the higher risk T allele had more deficits in regional activation of the right superior frontal gyrus (rSFG), while a higher functional connectivity of the rSFG was observed in TT/CT carriers. Further correlative analyses revealed that the increase in rSFG connectivity was robustly positively correlated with non-memory performance in aMCI GSK-3β rs334558 TT/CT carriers. Our findings are the first to show that a clinically significant proportion of resting-state brain function variation in aMCI patients may be explained by genetic variation at the GSK-3βrs334558 locus in ways that are distinguishable from controls.