AMPLITUDE OF LOW FREQUENCY FLUCTUATION AT DIFFERENT FREQUENCY BANDS IN EARLY AMNESTIC MILD COGNITIVE IMPAIRMENT: RESULTS FROM ADNI

We used resting-state functional magnetic resonance imaging(fMRI)to determine whether there are any abnormalities in different frequency bands between amplitude of low-frequency fluctuations(ALFF)and fractional ALFF(fALFF)and between 10 early amnestic mild cognitive impairment(EMCI)patients and eight normal controls participating in the Alzheimer’s Disease Neuroimaging Initiative(ADNI).We showed widespread difference in ALFF/fALFF between two frequency bands(slow-4:0.027-0.073 Hz,slow-5:0.01-0.027 Hz)in many brain areas including posterior cingulate cortex(PCC),medial prefrontal cortex(MPFC),suprasellar cistern(SC)and ambient cistern(AC).Compared to the normal controls,the EMCI patients showed increased ALFF values in PCu,cerebellum,occipital lobe and cerebellum posterior lobe in frequency band slow-4.While in frequency band slow-5,the EMCI patients showed decreased ALFF values in temporal lobe,left cerebrum and middle temporal gyrus5.Moreover,the EMCI patients showed increased fALFF values in frontal lobe and inferior frontal gyrus in band slow-5.While in frequency band slow-4,the EMCI patients showed decreased fALFF values in limbic lobe,cingulate gyrus and corpus callosum.These results demonstrated that EMCI patients had widespread abnormalities of amplitude of LFF in different frequency bands.

Alterations of brain local functional connectivity in amnestic mild cognitive impairment

Background:Resting-state functional magnetic resonance imaging studies using a regional homogeneity(ReHo)method have reported that amnestic mild cognitive impairment(aMCI)was associated with abnormalities in local functional connectivity.However,their results were not conclusive.Methods:Seed-based d Mapping was used to conduct a coordinate-based meta-analysis to identify consistent ReHo alterations in aMCI.Results:We identified 10 studies with 11 datasets suitable for inclusion,including 378 patients with aMCI and 435 healthy controls.This meta-analysis identified significant ReHo alterations in patients with aMCI relative to healthy controls,mainly within the default mode network(DMN)(bilateral posterior cingulate cortex[PCC],right angular gyrus,bilateral middle temporal gyri,and left parahippocampal gyrus/hippocampus),executive control network(right superior parietal lobule and dorsolateral prefrontal cortex),visual network(right lingual gyrus and left middle occipital gyrus),and sensorimotor network(right paracentral lobule/supplementary motor area,right postcentral gyrus and left posterior insula).Significant heterogeneity of ReHo alterations in the bilateral PCC,left parahippocampal gyrus/hippocampus,and right superior parietal lobule/angular gyrus was observed.Exploratory meta-regression analyses indicated that general cognitive function,gender distribution,age,and education level partially contributed to this heterogeneity.Conclusions:This study provides provisional evidence that aMCI is associated with abnormal ReHo within the DMN,executive control network,visual network,and sensorimotor network.These local functional connectivity alterations suggest coexistence of functional deficits and compensation in these networks.These findings contribute to the modeling of brain functional connectomes and to a better understanding of the neural substrates of aMCI.Confounding factors merit much attention and warrant future investigations.

Advances in longitudinal studies of amnestic mild cognitive impairment and Alzheimer's disease based on multi-modal MRI techniques

Amnestic mild cognitive impairment （aMCI） is a prodromal stage of Alzheimer＇s disease （AD）, and 75%-80% of aMCI patients finally develop AD. So, early identification of patients with aMCI or AD is of great significance for prevention and intervention. According to cross-sectional studies, it is known that the hippocampus, posterior cingulate cortex, and corpus callosum are key areas in studies based on structural MRI （sMRI）, functional MRI （fMRI）, and diffusion tensor imaging （DTI） respectively. Recently, longitudinal studies using each MRI modality have demonstrated that the neuroimaging abnormalities generally involve the posterior brain regions at the very beginning and then gradually affect the anterior areas during the progression of aMCI to AD. However, it is not known whether follow-up studies based on multi-modal neuroimaging techniques （e.g., sMRI, fMRI, and DTI） can help build effective MRI models that can be directly applied to the screening and diagnosis of aMCI and AD. Thus, in the future, large-scale multi-center follow-up studies are urgently needed, not only to build an MRI diagnostic model that can be used on a single person, but also to evaluate the variability and stability of the model in the general population. In this review, we present longitudinal studies using each MRI modality separately, and then discuss the future directions in this field.

Characteristics of Agraphia in Chinese Patients with Alzheimer＇s Disease and Amnestic Mild Cognitive Impairment

Background： Patients with Alzheimer＇s disease （AD） manifest progressive decline in writing abilities. Most studies on agraphia in AD have been performed in the alphabetic system, such as English. However, these findings may not be applicable to other written language systems. The unique features of the Chinese written script could affect the patterns of agraphia in Chinese AD patients. The aim of this study was to explore the features of writing errors in Chinese patients with AD and amnestie mild cognitive impairment （a-MCI）, as well as to study the relationship between their writing errors and neuropsychological functions. Methods： In this study, we performed an observational study in a group of subjects including 17 AD patients, 14 patients with a-MCI, and 16 elderly healthy controls. We analyzed the writing errors in these subjects and also studied the relationship between their writing errors and neuropsychological functions. Results： Our study showed that in patients whose mother tongue is Chinese, writing ability was comparatively well preserved in the MCI phase but significantly impaired when the disease progressed to the stage of AD. The writing errors showed corresponding increase with the severity of cognition decline, both in the types of errors and rate of occurrence. Analysis of the writing errors showed that word substitution and unintelligible words were the most frequent error types that occurred in all the three study groups. The occurrence rate of unintelligible words was significantly higher in the AD group compared with the a-MCI group （P = 0.024） and control group （P = 0.018）. In addition, the occurrence rates of word substitution were also significantly higher in AD （P = 0.013） and a-MCI groups （P = 0.037） than that of control group. However, errors such as totally no response, visuospatial impairment, paragraph agraphia, ideograph, and perseverative writing errors were only seen in AD group. Besides, we also found a high occurrence rate of visuoconstructional errors （13.3%） in our AD group. Conclusions： Our study confirmed that agraphia is an important feature in patients with AD. The writing error profile in patients whose native language is Chinese was unique compared to patients using the alphabetic language system.

Interhemispheric functional connectivity for Alzheimer's disease and amnestic mild cognitive impairment based on the triple network model

The purpose of this study was to explore the differences in interhemispheric functional connectivity in patients with Alzheimer’s disease(AD) and amnestic mild cognitive impairment(aMCI) based on a triple network model consisting of the default mode network(DMN), salience network(SN), and executive control network(ECN). The technique of voxel-mirrored homotopic connectivity(VMHC) analysis was applied to explore the aberrant connectivity of all patients. The results showed that:(1) the statistically significant connections of interhemispheric brain regions included DMN-related brain regions(i.e. precuneus, calcarine, fusiform, cuneus, lingual gyrus, temporal inferior gyrus, and hippocampus), SN-related brain regions(i.e. frontoinsular cortex), and ECN-related brain regions(i.e. frontal middle gyrus and frontal inferior);(2) the precuneus and frontal middle gyrus in the AD group exhibited lower VMHC values than those in the aMCI and healthy control(HC) groups, but no significant difference was observed between the a MCI and HC groups; and(3) significant correlations were found between peak VMHC results from the precuneus and Mini Mental State Examination(MMSE) and Montreal Cognitive Scale(MOCA) scores and their factor scores in the AD, a MCI, and AD plus aMCI groups, and between the results from the frontal middle gyrus and MOCA factor scores in the a MCI group. These findings indicated that impaired interhemispheric functional connectivity was observed in AD and could be a sensitive neuroimaging biomarker for AD. More specifically, the DMN was inhibited, while the SN and ECN were excited. VMHC results were correlated with MMSE and MOCA scores, highlighting that VMHC could be a sensitive neuroimaging biomarker for AD and the progression from aMCI to AD.

Can multi-modal neuroimaging evidence from hippocampus provide biomarkers for the progression of amnestic mild cognitive impairment?

Impaired structure and function of the hippocampus is a valuable predictor of progression from amnestic mild cognitive impairment（a MCI） to Alzheimer＇s disease（AD）. As a part of the medial temporal lobe memory system,the hippocampus is one of the brain regions affected earliest by AD neuropathology,and shows progressive degeneration as a MCI progresses to AD. Currently,no validated biomarkers can precisely predict the conversion from a MCI to AD. Therefore,there is a great need of sensitive tools for the early detection of AD progression. In this review,we summarize the specifi c structural and functional changes in the hippocampus from recent a MCI studies using neurophysiological and neuroimaging data. We suggest that a combination of advanced multi-modal neuroimaging measures in discovering biomarkers will provide more precise and sensitive measures of hippocampal changes than using only one of them. These will potentially affect early diagnosis and disease-modifying treatments. We propose a new sequential and progressive framework in which the impairment spreads from the integrity of fibers to volume and then to function in hippocampal subregions. Meanwhile,this is likely to be accompanied by progressive impairment of behavioral and neuropsychological performance in the progression of a MCI to AD.

Analysis of entropies based on empirical mode decomposition in amnesic mild cognitive impairment of diabetes mellitus

EEG characteristics that correlate with the cognitive functions are important in detecting mild cognitive impairment(MCI)in T2DM.To investigate the complexity between aMCI group and age-matched non-aMCI control group in T2DM,six entropies combining empirical mode decomposition(EMD),including Approximate entropy(ApEn),Sample entropy(SaEn),Fuzzy entropy(FEn),Permutation entropy(PEn),Power spectrum entropy(PsEn)and Wavelet entropy(WEn)were used in the study.A feature extraction technique based on maximization of the area under the curve(AUC)and a support vector machine(SVM)were subsequently used to for features selection and classi¯cation.Finally,Pearson's linear correlation was employed to study associations between these entropies and cognitive functions.Compared to other entropies,FEn had a higher classification accuracy,sensitivity and specificity of 68%,67.1% and 71.9%,respectively.Top 43 salient features achieved classification accuracy,sensitivity and speci¯city of 73.8%,72.3% and 77.9%,respectively.P4,T4 and C4 were the highest ranking salient electrodes.Correlation analysis showed that FEn based on EMD was positively correlated to memory at electrodes F7,F8 and P4,and PsEn based on EMD was positively correlated to Montreal cognitive assessment(MoCA)and memory at electrode T4.In sum,FEn based on EMD in righttemporal and occipital regions may be more suitable for early diagnosis of the MCI with T2DM.

Abnormal characterization of dynamic functional connectivity in Alzheimer’s disease

Numerous studies have shown abnormal brain functional connectivity in individuals with Alzheimer’s disease(AD)or amnestic mild cognitive impairment(aMCI).However,most studies examined traditional resting state functional connections,ignoring the instantaneous connection mode of the whole brain.In this case-control study,we used a new method called dynamic functional connectivity(DFC)to look for abnormalities in patients with AD and aMCI.We calculated dynamic functional connectivity strength from functional magnetic resonance imaging data for each participant,and then used a support vector machine to classify AD patients and normal controls.Finally,we highlighted brain regions and brain networks that made the largest contributions to the classification.We found differences in dynamic function connectivity strength in the left precuneus,default mode network,and dorsal attention network among normal controls,aMCI patients,and AD patients.These abnormalities are potential imaging markers for the early diagnosis of AD.

Impaired Parahippocampal Gyrus-Orbitofrontal Cortex Circuit Associated with Visuospatial Memory Deficit as a Potential Biomarker and Interventional Approach for Alzheimer Disease

The parahippocampal gyrus-orbitofrontal cortex(PHG-OFC)circuit in humans is homologous to the postrhinal cortex(POR)-ventral lateral orbitofrontal cortex(vlOFC)circuit in rodents.Both are associated with visuospatial malfunctions in Alzheimer’s disease(AD).However,the underlying mechanisms remain to be elucidated.In this study,we explored the relationship between an impaired POR-vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice,and investigated alterations of the PHG-OFC circuit by multi-domain magnetic resonance imaging(MRI)in patients on the AD spectrum.We demonstrated that an impaired glutamatergic POR-vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice.Moreover,MRI measurements of the PHG-OFC circuit had an accuracy of 77.33%for the classification of amnestic mild cognitive impairment converters versus non-converters.Thus,the PHG-OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD,thereby providing a potential predictor for AD progression and a promising interventional approach for AD.