aMCI Patients Research Articles

Clock‐drawing center estimation varies with age and Alzheimer's disease

AbstractBackgroundHealthy, young adults deviate leftward when bisecting horizontal lines and upward when bisecting vertical lines, a phenomenon termed “pseudoneglect”. With aging, there is a reduction in this leftward bias. Alzheimer’s disease (AD) can be associated with neglect. Our research assessed directional bias in healthy controls, patients with amnestic mild cognitive impairment (aMCI), and AD with the digital Clock Drawing Test (dCDT) command test condition.MethodThe sample included 68 cognitively normal older adults (M= 72.08, SD= 5.1), 16 younger healthy adults (M= 31.34, SD= 5.83), 13 patients with aMCI (M= 72.56, SD= 6.00), and 24 patients with AD (M= 80.34, SD= 5.97). dCDT protocols were selected for correct number placement within 30 degrees of ideal and hands directed toward the correct digits. The estimated center of the clock face was determined by the point where clock hands converged. Horizontal and vertical deviations of this estimated center from the actual center in each group were normalized as percentages of the clock face diameter.ResultHorizontal deviation: Younger adults deviated leftward(M= 3.55%, SD = 2.82%) and differed from older controls (p= 0.003) who were near center with leftward deviation (0.31%, SD 2.58%). AD patients deviated leftward (M= 3.77%, SD = 4.58%) relative to older controls (p= 0.008). aMCI patients also deviated leftward (M= 2.18%, SD=2.36%) and differed from older controls (p= 0.047).Vertical deviation: Every group deviated upward relative to center (M= 1.82%, SD= 5.09%; p< 0.001).ConclusionOn average, clock center estimation deviates upward similarly across age and AD related neurodegeneration. Leftward “pseudoneglect” was present in younger clocks and decreased with age. AD and aMCI were associated with greater leftward deviation compared to healthy older adults. Leftward deviation on the dCDT may be a useful marker predicting cognitive impairment in otherwise “normal” clocks.

Performance on autobiographical memory tests measuring contextual details is impaired in subjective cognitive decline and mild cognitive impairment

AbstractBackgroundThe neuropathological hallmarks of Alzheimer’s disease (AD) occur many years prior to the onset of clinical symptoms. Subjective memory decline can occur during this phase, but no standardized, clinically usable neuropsychological tests are currently able to detect such changes. Autobiographical memory (AM) tests tap a brain network affected in “preclinical” AD. The aim of this study was to investigate whether AM test performance was impaired in persons with Subjective Cognitive Decline (SCD) and in persons with Mild Cognitive Impairment (MCI) and mild dementia due to AD.MethodWe included 17 SCD patients diagnosed according to international SCD criteria, 17 amnestic MCI (aMCI) patients, and 17 patients with mild dementia due to AD. A group of 30 healthy controls was also examined. All participants were ≥ 45 years old and had MMSE scores of ≥ 24. AM was assessed using the Columbia Autobiographical Memory Interview – Short Form (CAMI‐SF) and an instrument, which we named the 3 Events Test. Both measure the specificity of AM and the ability to provide details about personal experiences. We also applied cognitive and neuropsychiatric screening tests and a traditional neuropsychological battery.ResultFor the 3 Events Test, a significant effect of group was found. Post‐hoc testing showed that participants with SCD, aMCI, or mild AD produced significantly fewer contextual details than the healthy controls. An ANOVA also showed a significant effect of group for the CAMI‐SF, and post‐hoc testing showed that the aMCI and mild AD groups were able to answer fewer questions or gave less detailed answers compared to the other groups. The total scores on the CAMI‐SF were lower in the SCD group than in the control group, but the difference was not significant.ConclusionAM was compromised in SCD, aMCI, and mild AD, as reflected by lower scores on the 3 Events Test compared to the control group. Thus, AM may be impaired in very early AD – even in the phases where standard episodic memory tests show no decline. AM tests could be useful in the attempt to verify subjective memory problems, and a decline on such a test could indicate later cognitive decline.

Individualized subtypes prognosis of MCI using deep‐learning based jointly optimized clustering‐classification method

AbstractBackgroundThe heterogeneity of Alzheimer’s disease is important theme for studying the epidemiology of the disease. Practically, understanding disease phenotypes helps deciding treatment before proceeding to dementia. Generally, it is known that AD’s subtype can be divided into three.MethodWe used 660 mild cognitive impairment (MCI) patients’ T1‐weighted magnetic resonance images (MRI) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). Inputs are atrophy vectors which mean excluding the positive part and resigned W‐scores calculated from 81,924 vertex‐level cortical‐thicknesses extracted from T1. Unlike existing clustering‐only or separated clustering‐classification models, we used a model which is jointly optimized with respect to both clustering and classification. The model is comprised of three parts: 1) feature extractor, 2) clustering module, and 3) classifier. In first part, we extract important features using simple neural network. Then, we do clustering using the deep‐features and obtain pseudo‐labels in latent space. Finally, we implement classification at last layer with the answers which are assigned from clustering module. It is end‐to‐end training being able to find the solution of combined objective function.ResultsResults were represented from 10 fold cross‐validation. Average log‐likelihood of Gaussian mixture and normalized mutual information of labels between adjacent iterations are used as clustering performance metric, cross‐entropy loss and accuracy as classification. It is difficult for such models to converge according to referenced studies. But, in this study, all the metrics were well‐converged. Atrophy maps show group comparison results of cortical thicknesses between each subtype and cognitive normal (CN) patient with FDR correction and W‐score averaged in each subtype. The demographic table about Aβ positivity and dementia conversion percentages without missing information and neuropsychological test scores table of each subtypes showed that subtype‐I has highest degree of disease severity, then subtype‐II and finally III. External validation with 662 aMCI patients’ data from Samsung Medical Center (SMC) used in similar study represented bigger gap of dementia conversion percentages between subtype‐I and II.ConclusionsIn this study, we made clustering‐classification model for individualized subtype prediction. It is end‐to‐end training method optimizing clustering and classification loss simultaneously. The results showed our model exceeds existing subtype clustering model.

The Influence of MTHFR Polymorphism on Gray Matter Volume in Patients With Amnestic Mild Cognitive Impairment.

The methylenetetrahydrofolate reductase (MTHFR) gene has been associated with Alzheimer’s disease (AD) pathogenesis. Amnestic mild cognitive impairment (aMCI) represents a prodromal stage of dementia and involves a high risk of progression into AD. Although the effects of the apolipoprotein E (APOE) gene on structural alterations in aMCI have been widely investigated, the effects of MTHFR C677T and interaction effects of MTHFR × APOE genotypes on gray matter atrophy in aMCI remain largely unknown. In the present study, 60 aMCI patients and 30 healthy controls were enrolled, and voxel-based morphometry analysis was performed to inspect the effects of diagnosis, different genotypes, and their interactions on gray matter atrophy. The results showed that aMCI patients had significant gray matter atrophy involving the bilateral hippocampus, the right parahippocampal gyrus, and the left superior temporal gyrus compared with healthy controls. Besides, a substantial reduction in gray matter volume was observed in the right hippocampus region in APOE ε4 carriers from the aMCI group, compared with APOE ε4 non-carriers. A significant interaction was found between diagnosis and MTHFR C677T genotype on the right precuneus in healthy controls and aMCI patients not carrying APOE ε4 allele. Our findings may provide new evidence substantiating the genetic effects of MTHFR C677T on brain structural alternation in patients with aMCI.

Serum Adiponectin in Alzheimer's Disease (AD): Association with AD Biomarkers and Cognitive Outcome.

The association between dementia and serum adiponectin has been evaluated in many studies; however, conclusions remain mixed. We investigated the cross-sectional associations of adiponectin with cognitive function and Alzheimer's disease (AD) biomarkers and whether serum adiponectin levels can predict cognitive outcomes. This study included 496 participants from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) with available serum adiponectin levels at baseline and ≥65 years of age. Subjects were stratified based on sex and apolipoprotein ɛ4 (APOE4) carrier status to determine associations between adiponectin and cognitive function. The linear mixed model was used to analyze associations between adiponectin level and cognitive outcome in amnestic mild cognitive impairment (aMCI) patients. Serum adiponectin levels were higher in aMCI and AD than in CN subjects among APOE4 non-carrier males (adiponectin in CN, aMCI, and AD: 0.54±0.24, 0.74±0.25, and 0.85±0.25, respectively, p < 0.001). In this group, serum adiponectin levels were associated with age (p = 0.001), ADAS13 (p < 0.001), memory function (p < 0.001), executive function (p < 0.001), total tau (p < 0.001), and phosphorylated tau (p < 0.001) measures in cerebrospinal fluid (CSF). Higher adiponectin level was not associated with cognitive outcome in aMCI patients in the linear mixed model analysis over 5.3±2.6 years of mean follow-up. Serum adiponectin level was associated with cognitive function and CSF AD biomarkers among APOE4 non-carrier males. However, serum adiponectin level was not associated with longitudinal cognitive function outcome in aMCI.

Acupuncture for amnestic mild cognitive impairment: A pilot multicenter, randomized, parallel controlled trial.

Introduction:Patients with amnesic mild cognitive impairment (aMCI) are more likely to develop Alzheimer disease than corresponding age normal population. Because Alzheimer disease is irreversible, early intervention for aMCI patients seems important and urgent. We have designed a pilot multicenter, randomized, parallel controlled trial to assess the efficacy and safety of acupuncture on aMCI, explore the feasibility of acupuncture in the treatment of aMCI, so as to provide a reference for large-sample clinical trials in the next stage.Method:We designed a pilot multicenter, randomized, parallel controlled trial. This trial aims to test the feasibility of carrying out a large-sample clinical trial. In this trial, 50 eligible patients with aMCI will be included and allocated to acupuncture group (n = 25) or sham acupuncture group (n = 25) at random. Subjects will accept treatment 2 times a week for 12 weeks continuously, with a total of 24 treatment sessions. We will select 6 acupoints (GV20, GV14, bilateral BL18, bilateral BL23). For the clinical outcomes, the primary outcome is Montreal cognitive assessment, which will be assessed from baseline to the end of this trial. And the secondary outcomes are Mini-mental State Examination, Delayed Story Recall, Clinical Dementia Rating scale, Global Deterioration Scale, Activity of Daily Life, Alzheimer Disease Assessment Scale-Cognitive Section, brain magnetic resonance imaging, brain functional magnetic resonance imaging, and event-related potential P300, which will be assessed before and after treatment. In addition, we will assess the safety outcomes from baseline to the end of this trial and feasibility outcome after treatment. We will evaluate neuropsychological assessment scale (Montreal cognitive assessment, Mini-mental State Examination, Alzheimer Disease Assessment Scale-Cognitive Section) at 3 months and 6 months after treatment.Discussion:This pilot trial aims to explore the feasibility of the trial, verify essential information of its efficacy and safety. This pilot study will provide a preliminary basis for carrying out a larger clinical trial of acupuncture on aMCI in near future.

Whole-body vibration exercise and training increase regional CBF in mild cognitive impairment with enhanced cognitive function.

Preclinical and non-medicinal interventions are essential for preventing and treating cognitive decline in patients with mild cognitive impairment (MCI). Whole-body vibration (WBV) exercise is conducted on a platform that generates vertical sinusoidal vibrations, and WBV training may improve regional cerebral blood flow (rCBF) and cognitive function, however, the underlying mechanism remains unclear. The aim of the present study was to investigate whether WBV exercise and a 24-week WBV training protocol increased rCBF and enhanced cognitive function in patients with amnestic MCI (aMCI). [99mTc]-ECD and SPECT studies were performed on 16 aMCI patients at baseline, during WBV exercise, and on 6 of the 16 patients after 24-week WBV training. To diagnose SPECT images and select the patients, a Z-score mapping approach was used, which revealed pathological hypoperfusion in the parietal association cortex, precuneus and/or posterior cingulate gyrus for MCI at baseline. rCBF was semi-quantitatively measured and underestimation in the high flow range was corrected. Since it is difficult to quantitatively measure rCBF during WBV exercise, the rCBFratio was obtained by standardizing with the average of individual mean SPECT counts with correcting underestimation in the high flow range. The rCBFratios at baseline and after WBV training were also obtained in a similar manner. Since the changes in rCBF were regarded as corresponding to the changes in rCBFratio, the ratios were compared. Cognitive function was also evaluated and compared. We found that the rCBFratio changed with an average range of 11.5% during WBV exercise, and similar changes were observed after 24-week WBV training with a 13.0% change, resulting in improved cognitive function (MoCA-J, P = 0.028). The rCBFratio increased in the parietal association cortex and occipital lobes, including the precuneus and posterior cingulate gyrus, at which hypoperfusion was detected at baseline, but decreased in the frontal lobe and anterior cingulate gyrus. The rCBFratio increased on the right side of several motion-suppressive nuclei by WBV exercise; the bilateral red nuclei and right medial globus pallidus by WBV training. WBV exercise and training increase rCBF in aMCI patients, and WBV training enhances cognitive function and may increase the cognitive reserve. Further investigation is necessary.

Specificity of Entorhinal Atrophy MRI Scale in Predicting Alzheimer's Disease Conversion.

We compared entorhinal cortex atrophy (ERICA) score vs. medial temporal atrophy (MTA) score's ability to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) using magnetic resonance imaging (MRI). We hypothesized that ERICA would show higher specificity. Data from 61 aMCI patients were analyzed. Positive ERICA was associated with AD conversion with a sensitivity of 56% (95% CI: 30-80%) and a specificity of 78% (63-89%) vs. 69% (41-89%) SE and 60% (44-74%) SP for the MTA. Results suggest that ERICA is superior to MTA in predicting conversion from aMCI to AD in a small sample of participants.

Peptoid Nanosheet-Based Sensing System for the Diagnosis and Surveillance of Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by progressive cognitive decline. Early diagnosis and dynamic monitoring are essential to the treatment and care of AD but challenging. Here we develop a noninvasive, blood-based AD detection method based on surface plasmonic resonance imaging (SPRi) technique. The functionalized sensing SPRi chips were constructed with self-assembled loop-displaying peptoid nanosheets to improve the detection sensitivity of plasma amyloid β42 (Aβ42). We analyze the plasma from 30 clinically diagnosed AD patients, 29 amnestic cognitive impairment (aMCI) patients, and 30 control individuals and demonstrate that this sensing system can significantly distinguish the three groups with high sensitivity and specificity. In the follow-up studies of the aMCI patients, we find that decrease in the binding signals in the patients correlates with the disease progression into AD whereas the almost unchanged signals correlate with stable disease remaining at aMCI status. These results show the capability of the peptoid-nanosheet-based SRPi sensing system for the early diagnosis and dynamic monitoring of AD.

The protective impact of education on brain structure and function in Alzheimer\u2019s disease

BackgroundThe Cognitive Reserve (CR) theory posits that brains with higher reserve can cope with more cerebral damage to minimize clinical manifestations. The aim of this study was to examine the effect of education (CR proxy) on brain structure and function in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) patients and in cognitively healthy elderly (HC) individuals.MethodsFifty-seven AD patients, 57 aMCI patients and 48 HCs were included to investigate the relationships between education years and gray matter volume (GMV), regional homogeneity (ReHo) and functional connectivity (FC) in brain regions to show associations with both structure and function. Taking the severity of the disease into account, we further assessed the relationships in AD stratified analyses.ResultsIn AD group, the GMV of the dorsal anterior cingulate cortex (dACC) and ReHo in the left inferior temporal cortex (ITC) were inversely associated with education years, after adjustment for age, sex, Mini-Mental State Examination (MMSE), and total intracranial volume or head motion parameters. Seed-based FC analyses revealed that education years were negatively correlated with the FC between the left anterior ITC and left mid frontal cortex as well as right superior frontal cortex and right angular gyrus. Stratified analyses results indicated that this negative relation between education and GMV, ReHo, FC was mainly present in mild AD, which was attenuated in moderate AD and aMCI groups.ConclusionsOur results support the CR theory, and suggest that CR may be protective against AD related brain pathology at the early stage of clinical dementia. These findings could provide the locus of CR-related functional brain mechanisms and a specific time-window for therapeutic interventions to help AD patients to cope better with the brain pathological damage by increasing CR.

Early Microstructure Changes of White Matter Fiber Bundles in Patients with Amnestic Mild Cognitive Impairment Predicts Progression of Mild Cognitive Impairment to Alzheimer's Disease.

Amnestic mild cognitive impairment (aMCI) is the transitional stage between normal aging and Alzheimer's disease (AD). Some aMCI patients will progress into AD eventually, whereas others will not. If the trajectory of aMCI can be predicted, it would enable early diagnosis and early therapy of AD. To explore the development trajectory of aMCI patients, we used diffusion tensor imaging to analyze the white matter microstructure changes of patients with different trajectories of aMCI. We included three groups of subjects:1) aMCI patients who convert to AD (MCI-P); 2) aMCI patients who remain in MCI status (MCI-S); 3) normal controls (NC). We analyzed the fractional anisotropy and mean diffusion rate of brain regions, and we adopted logistic binomial regression model to predicate the development trajectory of aMCI. The fraction anisotropy value is significantly reduced, the mean diffusivity value is significantly increased in the two aMCI patient groups, and the MCI-P patients presented greater changes. Significant changes are mainly located in the cingulum, fornix, hippocampus, and uncinate fasciculus. These changed brain regions significantly correlated with the patient's Mini-Mental State Examination scores. The study predicted the disease trajectory of different types of aMCI patients based on the characteristic values of the above-mentioned brain regions. The prediction accuracy rate can reach 90.2%, and the microstructure characteristics of the right cingulate band and the right hippocampus may have potential clinical application value to predict the disease trajectory.

Functional Brain Networks in Mild Cognitive Impairment Based on Resting Electroencephalography Signals.

The oscillatory patterns of electroencephalography (EEG), during resting states, are informative and helpful in understanding the functional states of brain network and their contribution to behavioral performances. The aim of this study is to characterize the functional brain network alterations in patients with amnestic mild cognitive impairment (aMCI). To this end, rsEEG signals were recorded before and after a cognitive task. Functional connectivity metrics were calculated using debiased weighted phase lag index (DWPLI). Topological features of the functional connectivity network were analyzed using both the classical graph approach and minimum spanning tree (MST) algorithm. Subsequently, the network and connectivity values together with Mini-Mental State Examination cognitive test were used as features to classify the participants. Results showed that: (1) across the pre-task condition, in the theta band, the aMCI group had a significantly lower global mean DWPLI than the control group; the functional connectivity patterns were different in the left hemisphere between two groups; the aMCI group showed significantly higher average clustering coefficient and the remarkably lower global efficiency than the control. (2) Analysis of graph measures under post-task resting state, unveiled that for the percentage change of post-task vs. pre-task in beta EEG, a significant increase in tree hierarchy was observed in aMCI group (2.41%) than in normal control (−3.89%); (3) Furthermore, the classification analysis of combined measures of functional connectivity, brain topology, and MMSE test showed improved accuracy compared to the single method, for which the connectivity patterns and graph metrics were used as separate inputs. The classification accuracy obtained for the case of post-task resting state was 87.2%, while the one achieved under pre-task resting state was found to be 77.7%. Therefore, the functional network alterations in aMCI patients were more prominent during the post-task resting state. This study suggests that the disintegration observed in MCI functional network during the resting states, preceding and following a task, might be possible biomarkers of cognitive dysfunction in aMCI patients.

Amide Proton Transfer-Weighted MRI Might Help Distinguish Amnestic Mild Cognitive Impairment From a Normal Elderly Population.

Objectives: To evaluate whether 3D amide proton transfer weighted (APTw) imaging based on magnetization transfer analysis can be used as a novel imaging marker to distinguish amnestic mild cognitive impairment (aMCI) patients from the normal elderly population by measuring changes in APTw signal intensity in the hippocampus and amygdala.Materials and Methods: Seventy patients with aMCI and 74 age- and sex-matched healthy volunteers were recruited for routine MRI and APT imaging examinations. Magnetic transfer ratio asymmetry (MTRasym) of the amide protons (at 3.5 ppm), or APTw values, were measured in the bilateral hippocampus and amygdala on three consecutive cross-sectional APT images and were compared between the aMCI and control groups. The independent sample t-test was used to evaluate the difference in APTw values of the bilateral hippocampus and amygdala between the aMCI and control groups. Receiver operator characteristic analysis was used to assess the diagnostic performance of the APTw. The paired t-test was used to assess the difference in APTw values between the left and right hippocampus and amygdala, in both the aMCI and control groups.Results: The APTw values of the bilateral hippocampus and amygdala in the aMCI group were significantly higher than those in the control group (left hippocampus 1.01 vs. 0.77% p < 0.001; right hippocampus 1.02 vs. 0.74%, p < 0.001; left amygdala 0.98 vs. 0.70% p < 0.001; right amygdala 0.94 vs. 0.71%, p < 0.001). The APTw values of the left amygdala had the largest AUC (0.875) at diagnosis of aMCI. There was no significant difference in APTw values between the left and right hippocampus and amygdala, in either group. (aMCI group left hippocampus 1.01 vs. right hippocampus 1.02%, p = 0.652; healthy control group left hippocampus 0.77 vs. right hippocampus 0.74%, p = 0.314; aMCI group left amygdala 0.98 vs. right amygdala 0.94%, p = 0.171; healthy control group left amygdala 0.70 vs. right amygdala 0.71%, p = 0.726).Conclusion: APTw can be used as a new imaging marker to distinguish aMCI patients from the normal elderly population by indirectly reflecting the changes in protein content in the hippocampus and amygdala.

White-Matter Hyperintensity Load and Differences in Resting-State Network Connectivity Based on Mild Cognitive Impairment Subtype.

“Mild cognitive impairment” (MCI) is a diagnosis characterised by deficits in episodic memory (aMCI) or in other non-memory domains (naMCI). Although the definition of subtypes is helpful in clinical classification, it provides little insight on the variability of neurofunctional mechanisms (i.e., resting-state brain networks) at the basis of symptoms. In particular, it is unknown whether the presence of a high load of white-matter hyperintensities (WMHs) has a comparable effect on these functional networks in aMCI and naMCI patients. This question was addressed in a cohort of 123 MCI patients who had completed an MRI protocol inclusive of T1-weighted, fluid-attenuated inversion recovery (FLAIR) and resting-state fMRI sequences. T1-weighted and FLAIR images were processed with the Lesion Segmentation Toolbox to quantify whole-brain WMH volumes. The CONN toolbox was used to preprocess all fMRI images and to run an independent component analysis for the identification of four large-scale haemodynamic networks of cognitive relevance (i.e., default-mode, salience, left frontoparietal, and right frontoparietal networks) and one control network (i.e., visual network). Patients were classified based on MCI subtype (i.e., aMCI vs. naMCI) and WMH burden (i.e., low vs. high). Maps of large-scale networks were then modelled as a function of the MCI subtype-by-WMH burden interaction. Beyond the main effects of MCI subtype and WMH burden, a significant interaction was found in the salience and left frontoparietal networks. Having a low WMH burden was significantly more associated with stronger salience-network connectivity in aMCI (than in naMCI) in the right insula, and with stronger left frontoparietal-network connectivity in the right frontoinsular cortex. Vice versa, having a low WMH burden was significantly more associated with left-frontoparietal network connectivity in naMCI (than in aMCI) in the left mediotemporal lobe. The association between WMH burden and strength of connectivity of resting-state functional networks differs between aMCI and naMCI patients. Although exploratory in nature, these findings indicate that clinical profiles reflect mechanistic interactions that may play a central role in the definition of diagnostic and prognostic statuses.

Altered Volume and Structural Connectivity of the Hippocampus in Alzheimer's Disease and Amnestic Mild Cognitive Impairment.

Background: Hippocampal atrophy is a characteristic of Alzheimer’s disease (AD). However, alterations in structural connectivity (number of connecting fibers) between the hippocampus and whole brain regions due to hippocampal atrophy remain largely unknown in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI).Methods: We collected high-resolution structural MRI (sMRI) and diffusion tensor imaging (DTI) data from 36 AD patients, 30 aMCI patients, and 41 normal control (NC) subjects. First, the volume and structural connectivity of the bilateral hippocampi were compared among the three groups. Second, correlations between volume and structural connectivity in the ipsilateral hippocampus were further analyzed. Finally, classification ability by hippocampal volume, its structural connectivity, and their combination were evaluated.Results: Although the volume and structural connectivity of the bilateral hippocampi were decreased in patients with AD and aMCI, only hippocampal volume correlated with neuropsychological test scores. However, positive correlations between hippocampal volume and ipsilateral structural connectivity were displayed in patients with AD and aMCI. Furthermore, classification accuracy (ACC) was higher in AD vs. aMCI and aMCI vs. NC by the combination of hippocampal volume and structural connectivity than by a single parameter. The highest values of the area under the receiver operating characteristic (ROC) curve (AUC) in every two groups were all obtained by combining hippocampal volume and structural connectivity.Conclusions: Our results showed that the combination of hippocampal volume and structural connectivity (number of connecting fibers) is a new perspective for the discrimination of AD and aMCI.

Fluency type index: A neuropsychological marker to predict amnestic mild cognitive impairment progression to Alzheimer's disease

Category fluency (CF), mainly dependent on linguistic functions, reveals a temporal disfunction, while letter fluency (LF), mainly dependent on attentive-executive functions, reveals a prefrontal dysfunction. Fluency Type Index (FTI = adjustedCF – adjustedLF / adjustedCF + adjustedLF) quantifies relative proficiency of each subject on CF and LF. A positive value (FTI+) suggests an attentive-executive deficit and a negative value (FTI-) a semantic deficit, that has been shown to characterize AD. Image 1 The study aims to investigate FTI's ability to predict amnestic Mild Cognitive Impairment (MCI) evolution in Alzheimer's disease (AD) and its correlation with a CSF parameter (Tau/Aβ) in aMCI patients.

Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer\u2019s disease, but not in cerebral amyloid angiopathy

BackgroundNeuroleukin (NLK) is a protein with neurotrophic properties and is present in a proportion of senile plaques and amyloid laden vessels. It has been suggested that NLK is part of a neuroprotective response to amyloid β-induced cell death. The aim of our study was to investigate the value of cerebrospinal fluid (CSF) NLK levels as a biomarker of vascular amyloid deposition in patients with cerebral amyloid angiopathy (CAA) and in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD).MethodsCSF NLK levels were quantified by ELISA in CAA patients (n = 25) and controls (n = 27) and in two independent samples of aMCI patients, AD patients, and controls: (1) From the Radboud University Medical Center (Nijmegen), we included n = 19 aMCI patients, n = 40 AD patients, and n = 32 controls. (2) From the Hospital of Sant Pau (Barcelona), we included n = 33 aMCI patients, n = 17 AD patients, and n = 50 controls.ResultsCSF NLK levels were similar in CAA patients and controls (p = 0.95). However, we found an elevated CSF concentration of NLK in aMCI (p < 0.0001) and AD patients (p < 0.0001) compared to controls in both samples sets. In addition, we found a correlation of CSF NLK with CSF YKL-40 (age-adjusted-spearman-rank-coefficient = 0.82, p < 0.0001) in aMCI/AD patients, a well-known glial marker of neuro-inflammation.ConclusionsWe found that CSF NLK levels are elevated in aMCI and AD patients compared to controls, but are not increased in CAA patients. CSF NLK levels may be related to an increased neuroinflammatory state in early stages of AD, given its association with YKL-40.

Short- and Long-Term Functional Connectivity Differences Associated with Alzheimer’s Disease Progression

Introduction: Progression of amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) is a clinical event with highly variable progression rates varying from 10–15% up to 30–34%. Functional connectivity (FC), the temporal similarity between spatially remote neurophysiological events, has previously been reported to differ between aMCI patients who progress to AD (pMCI) and those who do not (i.e., remain stable; sMCI). However, these reports had a short-term follow-up and do not provide insight into long-term AD progression. Methods: Seventy-nine participants with a baseline and 78 with a 12-month, 51 with a 24-month, and 22 with a +48-month follow-up resting-state fMRI with aMCI diagnosis from the Alzheimer’s Disease Neuroimaging Initiative database were included. FC was assessed using the CONN toolbox. Local correlation and group independent component analysis were utilized to compare regional functional coupling and between-network FC, respectively, between sMCI and pMCI groups. Two-sample t tests were used to test for statistically significant differences between groups, and paired t-tests were used to assess cognitive changes over time. Results: All participants (i.e., 66 sMCI and 19 pMCI) had a baseline and a year follow-up fMRI scan. Progression from aMCI to AD occurred in 19 patients (10 at 12 months, 5 at 24 months, and 4 at >48 months), while 73 MCI patients remained cognitively stable (sMCI). The pMCI and sMCI cognitive profiles were different. More between-network FC than regional functional coupling differences were present between sMCI and pMCI patients. Activation in the salience network (SN) and the default mode network (DMN) was consistently different between sMCI and pMCI patients across time. Discussion: sMCI and pMCI patients have different cognitive and FC profiles. Only pMCI patients showed cognitive differences across time. The DMN and SN showed local correlation and between-network FC differences between the sMCI and pMCI patient groups at multiple moments in time.

Clinical Implications of Amyloid-Beta Accumulation in Occipital Lobes in Alzheimer's Continuum.

A substantial amount of amyloid-beta (Aβ) accumulates in the occipital cortices; however, it draws less attention. We investigated the clinical implications of Aβ accumulation in the occipital lobes in the Alzheimer’s disease (AD) continuum. [18F]-Florbetaben amyloid PET scans were performed in a total of 121 AD or amnestic mild cognitive impairment (aMCI) patients. Of the 121 patients, 74 Aβ positive patients were divided into occipital Aβ positive (OCC+) and occipital Aβ negative (OCC−) groups based on Aβ accumulation in the bilateral occipital lobes. The OCC+ group (41/74, 55.4%) was younger and had a younger age at onset than the OCC− group. The OCC+ group also had an increased standard uptake value ratio in the occipital lobes and greater cortical thinning in relevant areas. The OCC+ group had a higher global deterioration scale, lower performance for the copy, immediate recall, delayed recall, and recognition in Rey–Osterrieth Complex Figure tests than the OCC- group, although both groups had similar disease durations. AD or aMCI patients in the OCC+ group exhibited features noted in early onset AD with relevant neuropsychological and image findings. Occipital Aβ positivity in amyloid PET scans need to be considered as an underestimated marker of early onset AD continuum.

Clinical study of central cholinergic pathway damage in two mild cognitive impairment patients

ObjectivesTo explore the role of the central cholinergic system in amnestic mild cognitive impairment (aMCI) and mild vascular cognitive impairment (vMCI).MethodsTwenty-five aMCI patients and 25 vMCI patients were enrolled in this study, and 25 healthy people were chosen as a control group. All participants performed a set of cognitive function scales and were subjected to a brain MRI. We analyzed differences in neuropsychological damage between groups, as well as the degree of brain atrophy and changes in the microstructure of central cholinergic pathways (CCP) in relation to effects on neuropsychological scores.Results(1) Regarding neuropsychological characteristics of the three groups, scores on the MoCA scale, immediate memory, delayed recall, cued recall, long time prolonged recognition, and CDR-SB of the control group were significantly better than those of the aMCI and vMCI groups. Scores on immediate memory, delayed memory, cued recall, long time delayed recognition, and Forward of Digital Span Test (FDST) in the aMCI group were lower than those in the vMCI group. Compared with the aMCI group, the vMCI group was significantly delayed in Trail Making Test (TMA)-A, TMT-B, and TMT B-A. There were no significant differences in HAMA, HAMD, MMSE, MoCA, the Boston Naming Test (BNT), language fluency or visual scale of posterior atrophy (Koedam score) between the vMCI and aMCI groups. (2) As for microstructure changes in the central cholinergic pathway, vMCI group had a decreased FA value in the cingulum (Cing) of the medial pathway, but an increased MD value in the external capsule (Excap) of the lateral pathway when compared to other two groups. Furthermore, the CingMD value of the vMCI group was higher than that of the control group, but the difference was not obvious when compared to the aMCI group. (3) Last, we researched microstructural changes to CCP, degree of brain atrophy, and neuropsychological scores by using partial correlation analysis for all participants. CingFA was negatively correlated with TMT-B, B-A, and FDST. CingMD was negatively correlated with FDST. ExcapFA was positively correlated with MMSE and Backward of BDST, while ExcapMD was negatively correlated with MMSE and MoCA. Claustrum (Claus)FA was positively related to MoCA and FDST, but was negatively related to TMT-A. ClausMD was negatively correlated with MoCA and language fluency. Koedam score was positively correlated with CDR-SB, ExcapMD, and ClausMD, but negatively correlated with MMSE score and inverse BDST.ConclusionThe central cholinergic system is involved in the cognitive impairment of both aMCI and vMCI, and their mechanisms may be distinct. aMCI patients may present with primary CCP impairment while vMCI patients probably exhibit impairment secondary to vasogenic damage to the cholinergic system projection network. The lateral cholinergic pathway was more severely impaired than the medial pathway in vMCI patients, in addition to being associated with decreased executive and general cognitive functions. The damage to CCP was related to the degree of brain atrophy, and both may be involved in the development and progression of cognitive dysfunction.