Amnestic Mild Cognitive Impairment Group Research Articles

Identification of amnestic mild cognitive impairment by structural and functional MRI using a machine-learning approach

ObjectiveThe importance of early treatment for mild cognitive impairment (MCI) has been extensively shown. However, classifying patients presenting with memory complaints in clinical practice as having MCI vs normal results is difficult. Herein, we assessed the feasibility of applying a machine learning approach based on structural volumes and functional connectomic profiles to classify the cognitive levels of cognitively unimpaired (CU) and amnestic MCI (aMCI) groups. We further applied the same method to distinguish aMCI patients with a single memory impairment from those with multiple memory impairments. MethodsFifty patients with aMCI were enrolled and classified as having either verbal or visual-aMCI (verbal or visual memory impairment), or both aMCI (verbal and visual memory impairments) based on memory test results. In addition, 26 CU patients were enrolled in the control group. All patients underwent structural T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. We obtained structural volumes and functional connectomic profiles from structural and functional MRI, respectively, using graph theory. A support vector machine (SVM) algorithm was employed, and k-fold cross-validation was performed to discriminate between groups. ResultsThe SVM classifier based on structural volumes revealed an accuracy of 88.9% at classifying the cognitive levels of patients with CU and aMCI. However, when the structural volumes and functional connectomic profiles were combined, the accuracy increased to 92.9%. In the classification of verbal or visual-aMCI (n = 22) versus both aMCI (n = 28), the SVM classifier based on structural volumes revealed a low accuracy of 36.7%. However, when the structural volumes and functional connectomic profiles were combined, the accuracy increased to 53.1%. ConclusionStructural volumes and functional connectomic profiles obtained using a machine learning approach can be used to classify cognitive levels to distinguish between aMCI and CU patients. In addition, combining the functional connectomic profiles with structural volumes results in a better classification performance than the use of structural volumes alone for identifying both “aMCI versus CU” and “verbal- or visual-aMCI versus both aMCI” patients.

Connectivity changes in two-channel prefrontal ERP associated with early cognitive decline in the elderly population: beta band responses to the auditory oddball stimuli.

This study utilized recent advancements in electroencephalography (EEG) technology that enable the measurement of prefrontal event-related potentials (ERPs) to facilitate the early detection of mild cognitive impairment (MCI). We investigated two-channel prefrontal ERP signals obtained from a large cohort of elderly participants and compare among cognitively normal (CN), subjective cognitive decline (SCD), amnestic MCI (aMCI), and nonamnestic MCI (naMCI) groups. Signal processing and ERP component analyses, specifically adapted for two-channel prefrontal ERP signals evoked by the auditory oddball task, were performed on a total of 1,754 elderly participants. Connectivity analyses were conducted to assess brain synchronization, especially in the beta band involving the phase locking value (PLV) and coherence (COH). Time-frequency, time-trial, grand average, and further statistical analyses of the standard and target epochs were also conducted to explore differences among the cognition groups. The MCI group's response to target stimuli was characterized by greater response time variability (p < 0.001) and greater variability in the P300 latency (p < 0.05), leading to less consistent responses than those of the healthy control (HC) group (CN+SCD subgroups). In the connectivity analyses of PLV and COH waveforms, significant differences were observed, indicating a loss of synchronization in the beta band in response to standard stimuli in the MCI group. In addition, the absence of event-related desynchronization (ERD) indicated that information processing related to readiness and task performance in the beta band was not efficient in the MCI group. Furthermore, the observed decline in the P200 amplitude as the standard trials progressed suggests the impaired attention and inhibitory processes in the MCI group compared to the HC group. The aMCI subgroup showed high variability in COH values, while the naMCI subgroup showed impairments in their overall behavioral performance. These findings highlight the variability and connectivity measures can be used as markers of early cognitive decline; such measures can be assessed with simple and fast two-channel prefrontal ERP signals evoked by both standard and target stimuli. Our study provides deeper insight of cognitive impairment and the potential use of the prefrontal ERP connectivity measures to assess early cognitive decline.

Correlation between cerebral hemodynamic functional near-infrared spectroscopy and positron emission tomography for assessing mild cognitive impairment and Alzheimer's disease: An exploratory study.

This study was performed to investigate the usefulness of functional near-infrared spectroscopy (fNIRS) by conducting a comparative analysis of hemodynamic activation detected by fNIRS and positron emission tomography (PET) and magnetic resonance imaging (MRI) in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Participants were divided into four groups: the subjective memory impairment (SMI), amnestic MCI (aMCI), non-amnestic MCI (naMCI), and AD groups. We recorded the hemodynamic response during the semantic verbal fluency task (SVFT) using a commercial wireless continuous-wave NIRS system. The correlation between the parameters of the neuroimaging assessments among the groups was analyzed. Region of interest-based comparisons showed that the four groups had significantly different hemodynamic responses during SVFT in the bilateral dorsolateral prefrontal cortex (DLPFC). The linear mixed effect model result indicates that the mean ΔHbO2 from the bilateral DLPFC regions showed a significant positive correlation to the overall FDG-PET after controlling for age and group differences in the fNIRS signals. Amyloid PET signals tended to better differentiate the AD group from other groups, and fNIRS signals tended to better differentiate the SMI group from other groups. In addition, a comparison between the group pairs revealed a mirrored pattern between the hippocampal volume and hemodynamic response in the DLPFC. The hemodynamic response detected by fNIRS showed a significant correlation with metabolic and anatomical changes associated with disease progression. Therefore, fNIRS may be considered as a screening tool to predict the hemodynamic and metabolic statuses of the brain in patients with MCI and AD.

Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer's Disease.

Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer's disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer's Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1-6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

The mean diffusivity of forceps minor is useful to distinguish amnestic mild cognitive impairment from mild cognitive impairment caused by cerebral small vessel disease.

In recent years, the desire to make a more fine-grained identification on mild cognitive impairment (MCI) has become apparent, the etiological diagnosis of MCI in particular. Nevertheless, new methods for the etiological diagnosis of MCI are currently insufficient. The objective of this study was to establish discriminative measures for amnestic mild cognitive impairment (a-MCI) and MCI caused by cerebral small vessel disease (CSVD). In total, 20 normal controls (NCs), 33 a-MCI patients, and 25 CSVD-MCI patients performed comprehensive neuropsychological assessments concerning global cognitive function and five cognitive domains as well as magnetic resonance imaging scan with diffusion tensor imaging (DTI). Diffusion parameters including fractional anisotropy and mean diffusivity of 20 major white matter metrics were obtained by ROI-based analyses. The neuropsychological tests and diffusion measurements were compared and binary logistic regression was used to identify the best differential indicator for the two MCI subgroups. The discriminating power was calculated by receiver operating characteristic analysis. Amnestic mild cognitive impairment group showed significant impairment in memory and language function, while CSVD-MCI group revealed more deficits in multi-cognitive domains of memory, language, attention and executive function than controls. Compared to the a-MCI, CSVD-MCI was significantly dysfunctional in the executive function. The CSVD-MCI group had decreased fractional anisotropy and increased mean diffusivity values throughout widespread white matter areas. CSVD-MCI presented more severe damage in the anterior thalamic radiation, forceps major, forceps minor and right inferior longitudinal fasciculus compared with a-MCI group. No significant neuropsychological tests were found in the binary logistic regression model, yet the DTI markers showed a higher discriminative power than the neuropsychological tests. The Stroop test errors had moderate potential (AUC = 0.747; sensitivity = 76.0%; specificity = 63.6%; P = 0.001; 95% CI: 0.617-0.877), and the mean diffusivity value of forceps minor demonstrated the highest predictive power to discriminate each MCI subtype (AUC = 0.815; sensitivity = 88.0%; specificity = 72.7%; P < 0.001; 95% CI: 0.698-0.932). The mean diffusivity of forceps minor may serve as an optimal indicator to differentiate between a-MCI and CSVD-MCI.

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease.

Objective:Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer’s disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer’s disease.Methods:We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer’s disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping.Results:We found that the probable Alzheimer’s disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration.Conclusions:Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Prospective memory and depression symptoms in mild cognitive impairment

AbstractBackgroundProspective memory involves executing an intended action in the future. This cognitive ability declines in mild cognitive impairment (MCI) and Alzheimer’s disease and affects everyday functioning. Prospective memory is usually assessed by asking participants to execute a single action in the future. We developed a complex prospective memory test that involves selecting the correct action to execute based on the context of the situation. In this study, we examined both types of prospective memory and their relationships with depression symptoms. Prospective memory involves significant cognitive effort, which could be dampened by depression symptoms.MethodParticipants included healthy controls (n= 58) and persons with amnestic MCI (n= 28) and non‐amnestic MCI (n= 36). Before testing, all participants were informed that they should request a pill after completing each of 10 neuropsychological tests that would be administered. Simple prospective memory was assessed using the total number of correct requests. They were also told that if the most recent test involved memorization, they should request one pill, and if it did not, they should request two pills. The number of correct contingency‐based requests was used to assess complex prospective memory. The Geriatric Depression Scale (GDS) was used to measure depressive symptoms.ResultAnalyses of variance revealed that the amnestic MCI group performed significantly worse in simple prospective memory compared to both the controls and the non‐amnestic MCI group. The same pattern was found for complex prospective memory. We found that GDS scores did not predict prospective memory in any group.ConclusionOverall, we found that older adults with objective memory deficits (amnestic MCI) had difficulties with both simple and complex prospective memory, while those with no memory impairment (controls and non‐amnestic MCI) performed better on these tests. Importantly, depressive symptoms were not associated with performance on prospective memory tests for any of the groups. These findings suggest that prospective memory tests are useful for assessing MCI and are resistant to the impact of depressive symptoms.

A Graph Theory Approach to Clarifying Aging and Disease Related Changes in Cognitive Networks.

In accordance with the physiological networks that underlie it, human cognition is characterized by both the segregation and interdependence of a number of cognitive domains. Cognition itself, therefore, can be conceptualized as a network of functions. A network approach to cognition has previously revealed topological differences in cognitive profiles between healthy and disease populations. The present study, therefore, used graph theory to determine variation in cognitive profiles across healthy aging and cognitive impairment. A comprehensive neuropsychological test battery was administered to 415 participants. This included three groups of healthy adults aged 18–39 (n = 75), 40–64 (n = 75), and 65 and over (n = 70) and three patient groups with either amnestic (n = 75) or non-amnestic (n = 60) mild cognitive impairment or Alzheimer’s type dementia (n = 60). For each group, cognitive networks were created reflective of test-to-test covariance, in which nodes represented cognitive tests and edges reflected statistical inter-nodal significance (p < 0.05). Network metrics were derived using the Brain Connectivity Toolbox. Network-wide clustering, local efficiency and global efficiency of nodes showed linear differences across the stages of aging, being significantly higher among older adults when compared with younger groups. Among patients, these metrics were significantly higher again when compared with healthy older controls. Conversely, average betweenness centralities were highest in middle-aged participants and lower among older adults and patients. In particular, compared with controls, patients demonstrated a distinct lack of centrality in the domains of semantic processing and abstract reasoning. Network composition in the amnestic mild cognitive impairment group was similar to the network of Alzheimer’s dementia patients. Using graph theoretical methods, this study demonstrates that the composition of cognitive networks may be measurably altered by the aging process and differentially impacted by pathological cognitive impairment. Network alterations characteristic of Alzheimer’s disease in particular may occur early and be distinct from alterations associated with differing types of cognitive impairment. A shift in centrality between domains may be particularly relevant in identifying cognitive profiles indicative of underlying disease. Such techniques may contribute to the future development of more sophisticated diagnostic tools for neurodegenerative disease.

Working Memory Training in Amnestic and Non-amnestic Patients With Mild Cognitive Impairment: Preliminary Findings From Genotype Variants on Training Effects.

Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations in APOE-epsilon (APOE-ε) and LMX1A genotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped for APOE-ε and LMX1A completed 4 weeks/20–25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups (p < 0.0001), but at 16 weeks the effects only remained in the naMCI group. Better performance was found after training for the naMCI patients with LMX1A-AA genotype and for the APOE-ε4 carriers. Only the naMCI-APOE-ε4 group showed improved Executive Function at 16 weeks. WMT improved working memory and some non-trained cognitive functions in individuals with MCI. The naMCI group had greater training gain than aMCI group, especially in those with LMX1A-AA genotype and among APOE-ε4-carriers. Further research with larger sample sizes for the subgroups and longer follow-up evaluations is warranted.

Atrophy and cognitive profiles in older adults with temporal lobe epilepsy are similar to mild cognitive impairment.

Epilepsy incidence and prevalence peaks in older adults yet systematic studies of brain ageing and cognition in older adults with epilepsy remain limited. Here, we characterize patterns of cortical atrophy and cognitive impairment in 73 older adults with temporal lobe epilepsy (>55 years) and compare these patterns to those observed in 70 healthy controls and 79 patients with amnestic mild cognitive impairment, the prodromal stage of Alzheimer's disease. Patients with temporal lobe epilepsy were recruited from four tertiary epilepsy surgical centres; amnestic mild cognitive impairment and control subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Whole brain and region of interest analyses were conducted between patient groups and controls, as well as between temporal lobe epilepsy patients with early-onset (age of onset <50 years) and late-onset (>50 years) seizures. Older adults with temporal lobe epilepsy demonstrated a similar pattern and magnitude of medial temporal lobe atrophy to amnestic mild cognitive impairment. Region of interest analyses revealed pronounced medial temporal lobe thinning in both patient groups in bilateral entorhinal, temporal pole, and fusiform regions (all P < 0.05). Patients with temporal lobe epilepsy demonstrated thinner left entorhinal cortex compared to amnestic mild cognitive impairment (P = 0.02). Patients with late-onset temporal lobe epilepsy had a more consistent pattern of cortical thinning than patients with early-onset epilepsy, demonstrating decreased cortical thickness extending into the bilateral fusiform (both P < 0.01). Both temporal lobe epilepsy and amnestic mild cognitive impairment groups showed significant memory and language impairment relative to healthy control subjects. However, despite similar performances in language and memory encoding, patients with amnestic mild cognitive impairment demonstrated poorer delayed memory performances relative to both early and late-onset temporal lobe epilepsy. Medial temporal lobe atrophy and cognitive impairment overlap between older adults with temporal lobe epilepsy and amnestic mild cognitive impairment highlights the risks of growing old with epilepsy. Concerns regarding accelerated ageing and Alzheimer's disease co-morbidity in older adults with temporal lobe epilepsy suggests an urgent need for translational research aimed at identifying common mechanisms and/or targeting symptoms shared across a broad neurological disease spectrum.

Serum metabolomic profiling in patients with Alzheimer disease and amnestic mild cognitive impairment by GC/MS.

The aim of this study was to characterize the serum metabolic profiles of patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (AMCI) using metabolomics based on gas chromatography-mass spectrometry (GC/MS). Serum samples were collected from patients with AD (n = 30) and AMCI (n = 32), and normal healthy controls (NOR, n = 40). Metabolite profiles were performed with GC/MS in conjunction with multivariate statistical analysis, and possible biomarker metabolites were identified. Thirty-one kinds of endogenous metabolites could be identified simultaneously. Eleven components were chosen as biomarker metabolites between AD and NOR groups, and these metabolites were closely related to seven biological pathways: arginine and proline metabolism, phenylalanine metabolism, β-alanine metabolism, primary bile acid synthesis, glutathione metabolism, starch and sucrose metabolism, and steroid hormone biosynthesis. Meanwhile, 10 components were chosen as biomarker metabolites between AMCI and NOR groups and seven biological pathways were closely related: arginine and proline metabolism, phenylalanine metabolism, citrate cycle, alanine, aspartate and glutamate metabolism, taurine and hypotaurine metabolism, starch and sucrose metabolism, and steroid hormone biosynthesis. Our study distinguished serum metabotypes between AD, AMCI and NOR patients successfully. The implementation of this metabolomic strategy may help to develop biochemical insight into the metabolic alterations in AD/AMCI and will be helpful for the further understanding of pathogenesis.

Neural Compensatory Response During Complex Cognitive Function Tasks in Mild Cognitive Impairment: A Near-Infrared Spectroscopy Study

The present pilot study was aimed at conducting a comparative analysis of the level of activation in the prefrontal cortex among a normal elderly group and amnestic and nonamnestic mild cognitive impairment (MCI) groups and investigating the presence of neural compensatory mechanisms according to types of MCI and different cognitive tasks. We performed functional near-infrared spectroscopy (fNIRS) along with cognitive tasks, including two-back test, Korean color word Stroop test, and semantic verbal fluency task (SVFT), to investigate hemodynamic response and the presence of neural compensation and neuroplasticity in the prefrontal cortex of patients with amnestic and nonamnestic MCI compared with a healthy elderly group. During the two-back test, there was no significant difference in the bilateral region-of-interest (ROI) analysis in the three groups. During the Stroop test, right-sided hyperactivation compared to the left side during the task was shown in the nonamnestic MCI and normal groups with statistical significance. Mean acc∆HbO2 on the right side was highest in the nonamnestic MCI group (0.30 μM) followed by the normal group (0.07 μM) and the amnestic MCI group (-0.10 μM). Otherwise, intergroup ROI analysis of acc∆HbO2 in these activated right sides showed no significant difference. During the VFT test, there was no significant difference in the bilateral region-of-interest analysis in the three groups. The highest mean acc∆HbO2 was shown in the normal group (0.79 μM) followed by the nonamnestic MCI group (0.52 μM) and the amnestic MCI group (0.21 μM). Otherwise, there was no significant difference between groups. The hemodynamic response during fNIRS showed different findings according to MCI types and cognitive tasks. Among the three tasks, the Stroop test showed results that were suggestive of neural compensatory mechanisms in the prefrontal cortex in nonamnestic MCI.

Instrumental Activities of Daily Living, Neuropsychiatric Symptoms, and Neuropsychological Impairment in Mild Cognitive Impairment.

Neuropsychological deficits, neuropsychiatric symptoms, and problems with instrumental activities of daily living are common in participants with mild cognitive impairment (MCI). To assess how subtle to mildly impaired instrumental activities of daily living (IADLs) might be related to neuropsychological abilities (including executive control and episodic memory) and neuropsychiatric symptoms (including apathy and depression) among participants with a diagnosis of MCI. Participants were evaluated for MCI and possible dementia at an outpatient memory clinic on the basis of a comprehensive neuropsychological evaluation, a geriatric psychiatry evaluation, a magnetic resonance image of the brain, and serum studies to evaluate for a possible reversible cause of cognitive decline. A series of stepwise regression analyses were conducted whereby IADL ability was the dependent variable and neuropsychological abilities, such as executive control and episodic memory, or neuropsychiatric symptoms, including apathy and depression, were the independent or predictor variables. The presence and severity of neuropsychiatric symptoms was assessed using a modified version of the Neuropsychiatric Inventory (mNPI). Participants were grouped by MCI diagnosis status (amnestic MCI, combined dysexecutive/mixed MCI, and no MCI). Twenty-six participants were in the amnestic MCI group, 19 in the combined dysexecutive/mixed MCI group, and 36 participants did not meet criteria for MCI (non-MCI group). Groups did not differ in age, education, Mini-Mental State Examination performance, IADL abilities, estimated premorbid general intellectual abilities, or mNPI ratings for apathy and depression. Stepwise regression analyses found a robust relationship between mild IADL impairment and greater apathy (R=0.497, r21,69=0.247, P<.001; β=-0.497, P<.001). Depression did not enter the final model. A weaker-but statistically significant-relationship was found between mild IADL impairment and worse executive control test performance (R=0.271, r21,68=0.073, P<.023; β=0.271, P<.23). Episodic memory did not enter the final model. When both apathy and executive control were assessed as related to IADL impairment, only apathy entered the final model (R=0.497, R21,69=0.247, P<.001; β=-0.497, P<.001). Mildly impaired IADL functioning can negatively affect quality of life. Moreover, apathy may be amenable to treatment. In a primary geriatric care setting, neuropsychiatric symptoms and neuropsychological abilities should be routinely assessed.

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).

Examining differences in neuropsychiatric symptom factor trajectories in empirically derived mild cognitive impairment subtypes

The aim of this study was to examine neuropsychiatric symptom (NPS) factor severity progression over time in empirically derived (ED) mild cognitive impairment (MCI) subtypes. Participants in the Alzheimer's Disease Neuroimaging Initiative study diagnosed with MCI by Alzheimer's Disease Neuroimaging Initiative protocol using conventional clinical (CC) criteria (n=788) were reclassified using cluster analysis as amnestic, dysnomic, dysexecutive MCI, or cluster-derived normal (CC-Normal) using empirical criteria. Cognitively normal (CN) participants (n=207) were also identified. The Neuropsychiatric Inventory-Questionnaire (NPI-Q) was administered from baseline through 48-month follow-up. Exploratory factor analysis was completed to determine the NPI-Q factor structure at 6-month follow-up. Multilevel modeling was used to determine NPI-Q symptom severity factor and apathy symptom progression over time by cognitive subtype. The exploratory factor analysis revealed that the NPI-Q consisted of 2 factors: hyperactivity/agitation and mood symptoms. Using clinical and empirical criteria, all MCI groups were identified as having more severe hyperactivity/agitation symptoms than CN participants. However, only the amnestic MCI group identified using empirical criteria showed an increase in symptom severity over time relative to CN participants. Mood factor and apathy symptoms were found to be more severe in dysexecutive and amnestic groups in both models. Similarly, both models identified a significant worsening of mood and apathy symptoms over time for dysexecutive and amnestic groups relative to CN participants. This study provides further support that empirical criteria aid in examining the progression of clinical characteristics associated with MCI. Further, it helps to identify which MCI subtypes may be at higher risk for NPS progression.

Dissociable Effects of Aging and Mild Cognitive Impairment on Bottom-Up Audiovisual Integration.

Effective audiovisual sensory integration involves dynamic changes in functional connectivity between superior temporal sulcus and primary sensory areas. This study examined whether disrupted connectivity in early Alzheimer's disease (AD) produces impaired audiovisual integration under conditions requiring greater corticocortical interactions. Audiovisual speech integration was examined in healthy young adult controls (YC), healthy elderly controls (EC), and patients with amnestic mild cognitive impairment (MCI) using McGurk-type stimuli (providing either congruent or incongruent audiovisual speech information) under conditions differing in the strength of bottom-up support and the degree of top-down lexical asymmetry. All groups accurately identified auditory speech under congruent audiovisual conditions, and displayed high levels of visual bias under strong bottom-up incongruent conditions. Under weak bottom-up incongruent conditions, however, EC and amnestic MCI groups displayed opposite patterns of performance, with enhanced visual bias in the EC group and reduced visual bias in the MCI group relative to the YC group. Moreover, there was no overlap between the EC and MCI groups in individual visual bias scores reflecting the change in audiovisual integration from the strong to the weak stimulus conditions. Top-down lexicality influences on visual biasing were observed only in the MCI patients under weaker bottom-up conditions. Results support a deficit in bottom-up audiovisual integration in early AD attributable to disruptions in corticocortical connectivity. Given that this deficit is not simply an exacerbation of changes associated with healthy aging, tests of audiovisual speech integration may serve as sensitive and specific markers of the earliest cognitive change associated with AD.

The characteristic of cognitive dysfunction in remitted late life depression and amnestic mild cognitive impairment

Remitted late life depression exhibits persistent cognitive impairments and enhances the risk of dementia. This study aimed to examine the characteristics of cognitive dysfunction in remitted late life depression and amnestic mild cognitive impairment (MCI). Remitted late life depression (n=61), amnestic MCI (n=61) and age-education-matched controls (n=65) were evaluated with a battery of neuropsychological tests grouped into executive function, memory, processing speed, attention and visuospatial domains. Compared with control subjects, amnestic MCI individuals showed more severe cognitive impairments in all domains, while remitted late life depression individuals performed worse in executive function and memory. The pattern of cognitive profiles significantly differed between remitted late life depression and amnestic MCI groups, which might be mainly attributed to worse impairments in memory and executive function in amnestic MCI individuals. Executive function was the core impaired cognitive domain mediating the influence of predictors on other cognitions in both remitted late life depression and amnestic MCI groups, which indicated a possible etiopathogenic mechanism underlying the conversion to dementia.

Participant–Informant Relationships Affect Quality of Life Ratings in Incipient and Clinical Alzheimer Disease

Clinical trials in incipient and clinical Alzheimer disease (AD) often include informant-reported outcomes. Whereas informant reports in AD dementia may be modulated by the nature of participant-informant relationships, whether informant type affects reporting at earlier disease stages is less certain. We sought to determine the effects of participant-informant relationships on informant assessments of quality of life (QOL), functional abilities, and behavioral symptoms in individuals with normal cognition (NC), mild cognitive impairment (MCI), and mild-to-moderate AD dementia. Cross-sectional. Easton Center for Alzheimer Disease Research at the University of California, Los Angeles. A total of 399 individuals who met criteria for NC (N = 100), MCI [amnestic (N = 125) and nonamnestic (N = 61)], and AD (N = 113). Participants were subdivided into groups based on informant-participant relationships (spouse versus other). We examined informant effects on the Quality of Life-Alzheimer's Disease (QOL-AD) scale, the Functional Activities Questionnaire (FAQ), and the Neuropsychiatric Inventory (NPI). After adjustments for demographic and cognitive factors, spouse informants reported higher participant QOL in the amnestic MCI and AD groups than did other informants. No informant effects were seen on QOL-AD ratings in the nonamnestic MCI or NC groups or on the FAQ or NPI in the MCI and AD groups. Participant-informant relationships may modulate informant responses on subjective measures such as the QOL-AD in both incipient and clinical AD. Clinical trials that use informant measures may need to address these effects.

Cortical Amyloid Burden Differences Across Empirically-Derived Mild Cognitive Impairment Subtypes and Interaction with APOE ɛ4 Genotype.

We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

Disrupted white matter integrity is associated with cognitive deficits in patients with amnestic mild cognitive impairment: An atlas-based study.

Objective:This study investigated white matter integrity in patients with amnestic mild cognitive impairment by diffusion tensor imaging.Methods:A total of 83 patients with amnestic mild cognitive impairment and 85 elderly healthy controls underwent neuropsychological testing and a diffusion tensor imaging scan. Whole-brain white matter data were parcellated into 50 regions based on the anatomical ICBM-DTI-81 atlas, and regional diffusion metrics consisting of fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity were calculated for each region. Diffusion tensor imaging indices were compared between groups, and it was determined that between-group differences were significantly correlated with neurocognitive performance.Results:Relative to the healthy controls group, the amnestic mild cognitive impairment group exhibited poorer cognitive performance in all neuropsychological tests except the complex figure test (p = 0.083) and showed decreased mean fractional anisotropy in the fornix, increased mean diffusivity in the fornix and bilateral uncinate fasciculus, elevated axial diffusivity in the fornix and genu of corpus callosum, and elevated radial diffusivity in the fornix and bilateral uncinate fasciculus (p < 0.05). Behaviorally, integrity of the bilateral uncinate fasciculus was correlated positively with episodic memory function, while left uncinate fasciculus integrity was positively associated with language function in the amnestic mild cognitive impairment group (p < 0.05).Conclusion:White matter abnormalities in neural pathways associated with memory were correlated with neurocognitive deficiencies in amnestic mild cognitive impairment. Given that amnestic mild cognitive impairment is putatively a prodromal syndrome for Alzheimer’s disease, this study furthers our understanding of the white matter changes associated with Alzheimer’s disease pathogenesis in the predementia stage.