Differentiating between Alzheimer’s disease, amnestic mild cognitive impairment, and normal aging via diffusion kurtosis imaging

Diffusion kurtosis imaging can be used to assess pathophysiological changes in tissue structure and to diagnose central nervous system diseases. However, its sensitivity in assessing hippocampal differences between patients with Alzheimer’s disease and those with amnestic mild cognitive impairment has not been characterized. Here, we examined 20 individuals with Alzheimer’s disease (11 men and 9 women, mean 73.2 ± 4.49 years), 20 with amnestic mild cognitive impairment (10 men and 10 women, mean 71.55 ± 4.77 years), and 20 normal controls (11 men and 9 women, mean 70.45 ± 5.04 years). We conducted diffusion kurtosis imaging, using a 3.0 T magnetic resonance scanner, to compare hippocampal differences among the three groups. The results demonstrated that the right hippocampal volume and bilateral mean kurtosis were remarkably smaller in individuals with Alzheimer’s disease compared with those with amnestic mild cognitive impairment and normal controls. Further, the mean kurtosis was lower in the amnestic mild cognitive impairment group compared with the normal control group. The mean diffusion in the left hippocampus was lower in the Alzheimer’s disease group than in the amnestic mild cognitive impairment and normal control groups, while the mean diffusion in the right hippocampus was lower in the Alzheimer’s disease group than in the normal control group. Fractional anisotropy was similar among the three groups. These results verify that bilateral mean kurtosis and mean diffusion are sensitive to the diagnosis of Alzheimer’s disease and amnestic mild cognitive impairment. This study was approved by the Ethics Review Board of Affiliated Sixth People’s Hospital of Shanghai Jiao Tong University, China on May 4, 2010 (approval No. 2010(C)-6).

Study of brain morphology change in Alzheimer’s disease and amnestic mild cognitive impairment compared with normal controls

Background With an aggravated social ageing level, the number of patients with Alzheimer's disease (AD) is gradually increasing, and mild cognitive impairment (MCI) is considered to be an early form of Alzheimer's disease. How to distinguish diseases in the early stage for the purposes of early diagnosis and treatment is an important topic. Aims The purpose of our study was to investigate the differences in brain cortical thickness and surface area among elderly patients with AD, elderly patients with amnestic MCI (aMCI) and normal controls (NC). Methods 20 AD patients, 21 aMCIs and 25 NC were recruited in the study. FreeSurfer software was used to calculate cortical thickness and surface area among groups. Results The patients with AD had less cortical thickness both in the left and right hemisphere in 17 of the 36 brain regions examined than the patients with aMCI or NC. The patients with AD also had smaller cerebral surface area both in the left and right hemisphere in 3 of the 36 brain regions examined than the patients with aMCI or NC. Compared with the NC, the patients with aMCI only had slight atrophy in the inferior parietal lobe of the left hemisphere, and no significant difference was found. Conclusion AD, as well as aMCI (to a lesser extent), is associated with reduced cortical thickness and surface area in a few brain regions associated with cognitive impairment. These results suggest that cortical thickness and surface area could be used for early detection of AD.

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.

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.

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.

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.

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.

Spanish Version of Test MIS (*) with Delayed Memory Recall Normative Values and Results in a Population with Mild Cognitive Impairment

Background: Cognitive impairment becomes more common with ageing and may benefit from intervention. In a Spanish speaking population, detection of cognitive impairment by a general practitioner in Primary Care can be a problem, as many of the standard tests target English speaking populations. The Memory Impairment Screen (MIS-A) is a validated test using English words to detect Alzheimer’s Disease (AD) and other dementias. We have modified this test to suit a Spanish speaking population and added a new component, delayed recall. We have called our new test the Memory Impairment Screen with Delayed Recall (MIS-D). Objectives: 1) To test a Spanish version of MIS-A and MIS-D. 2) To assess the discriminative validity of MIS-D as a screening tool for the amnestic variant of Mild Cognitive Impairment (aMCI) in a group of Spanish speaking people aged 65 years old and over. Methods: A case-control study of a cohort of 739 native Spanish speaking residents of Buenos Aires aged 65 years old and over, of whom 436 were healthy controls and 303 had a diagnosis of aMCI. Measurements: Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NVP) were estimated for MIS-D and MIS-A. Results: Normative values for MIS-A and MIS-D were obtained from the control population. Both age and education significantly affected these values (p < 0.0001). Control participants showed significant differences for both modalities, MIS-A and MIS-D. The cut-off for MIS-A should be 7.5 and for MIS-D, 5.5. Comparison between control population and aMCI population using ROC curve gave a result of 5.5 in MIS-D, with 97% specificity and 76% sensitivity. Conclusion: MIS-D was positively predictive of aMCI, with 97% specificity and 76% sensitivity in a sample of Spanish speaking patients aged 65 years old and over in Buenos Aires.

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.

Cognitive and Functional Profiles in Mild-to-Moderate Alzheimer’s Disease and Mild Cognitive Impairment Compared to Healthy Elderly

Background: Amnestic mild cognitive impairment (aMCI) and mild-to-moderate Alzheimer’s disease (AD) are clinically distinct but impact cognitive and functional ability similarly. Comprehensive assessment of cognitive and functional deficits may prove useful in informing differential diagnosis in early stages of dementia and in informing endpoint selection in therapeutic AD trials. Objective: The objective of this study was to characterize patterns of cognitive and functional impairment in aMCI and mild-to-moderate AD subjects compared to cognitively intact healthy elderly (HE). Methods: Thirty-one healthy elderly, 20 aMCI and 19 AD participants were administered a cognitive test battery that included the ADAS-Cog and functional assessments. Z-scores were calculated for all endpoints based on the HE reference group. Results: Cognitive deficits were observed in AD and aMCI participants relative to the referent group. On average, aMCI participants performed 1 - 2 standard deviations below HE on cognitive tests, and AD participants performed 2 - 3 standard deviations below HE. Domain-specific functional deficits among AD participants (z- score -0.4 to -6.4) were consistently greater than those of aMCI participants (z-score 0 to -1.7). Conclusion: This study provides further support for comprehensive assessment and monitoring of cognitive and functional domain scores in the diagnosis and treatment of aMCI and mild AD. Domain-specific cognitive scores may be more useful than composite scores in characterizing impairment and decline. Measuring domains such as attention, processing speed and executive function may increase the sensitivity of detecting disease progression and therapeutic effects, particularly in mild-moderate AD where memory decline may be too slow to detect drug effects during a typical clinical trial.

Regional patterns of atrophy on MRI in Alzheimer’s disease: Neuropsychological features and progression rates in the ADNI cohort

Background: Discrete clinical and pathological subtypes of Alzheimer’s disease (AD) with variable presentations and rates of progression are well known. These subtypes may have specific patterns of regional brain atrophy, which are identifiable on MRI scans. Methods: To examine distinct regions which had distinct underlying patterns of cortical atrophy, factor analytic techniques applied to structural MRI volumetric data from cognitively normal (CN) (n = 202), amnestic mild cognitive impairment (aMCI) (n = 333) or mild AD (n = 146) subjects, in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database was applied. This revealed the existence of two neocortical (NeoC-1 and NeoC-2), and a limbic cluster of atrophic brain regions. The frequency and clinical correlates of these regional patterns of atrophy were evaluated among the three diagnostic groups, and the rates of progression from aMCI to AD, over 24 months were evaluated. Results: Discernable patterns of regional atrophy were observed in about 29% of CN, 55% of aMCI and 83% of AD subjects. Heterogeneity in clinical presentation and APOE ε4 frequency were associated with regional patterns of atrophy on MRI scans. The most rapid progression rates to dementia among aMCI subjects (n = 224), over a 24-month period, were in those with NeoC-1 regional impairment (68.2%), followed by the Limbic regional impairment (48.8%). The same pattern of results was observed when only aMCI amyloid positive subjects were examined. Conclusions: The neuroimaging results closely parallel findings described recently among AD patients with the hippocampal sparing and limbic subtypes of AD neuropathology at autopsy. We conclude that NeoC-1, Limbic and other patterns of MRI atrophy may be useful markers for predicting the rate of progression of aMCI to AD and could have utility selecting individuals at higher risk for progression in clinical trials.

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.