Neural mechanisms of non-pharmacological interventions in patients with mild cognitive impairment and Alzheimer's disease: An ALE meta-analysis.

Objective To investigate platelet α and β secretase activities and the amounts of platelet soluble fragment of APP (sAPPα) produced by α-secretase in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods The neurological functions of 48 non-demented patients, 42 MCI and 40 AD patients were evaluated by neuropsychological examinations. The platelet α and β secretase activities and sAPPα production in each group were measured by fluorescence and Western blotting analysis respectively. Results The α secretase activities in non-demented, MCI and AD group were 100.0%±10.6%, 78.2%±9.4% and 61.8%±7.2% respectively. As compared with non-demented group, the α secretase activities in MCI and AD group were decreased (F=22.935, P=0.001). The α secretase activity in AD group was significantly lower than MCI group. The β secretase activities in non-demented, MCI and AD group were 100.0%±11.2%, 145.8%±12.7% and 189.8%±14.2% respectively. The β secretase activities in MCI and AD group were significantly higher than that in non-demented group (F=16.368, P=0.001). The β secretase activity in AD group was significantly decreased as compared with MCI group. The sAPPα amounts in MCI group and AD group were all decreased as compared with that in control group; the sAPPα amount in AD patients was significantly decreased as compared with that in MCI group. Conclusions The platelet α secretase activity and its production sAPPα in MCI and AD patients are decreased, while β secretase activity is increased, as compared with that in control group; the altered α and β secretase activities may participate in the pathogenesis of MCI and AD patients and may have diagnostic potential for them. Key words: Cognition disorders; Alzheimer disease; Amyloid precursor protein secretases

To compare the sex differences on brain stem auditory evoked potentials (BAEP) and P300 in the elderly patients with mild cognitive impairment (MCI) and the patients with Alzheimer's disease (AD). Thirty-eight elderly patients with MCI, 26 cases of AD and 20 health controls (HC) were examined with BAEP, P300 . Sex difference of the variables was compared inter-and intra-groups. Significant sex differences of BAEP were found in the latency period wave III, V of left side in the MCI group (P <0.01), in the latency period wave IV, V of left side in HC group (P<0.01), and no such differences were found in AD group. The females had longer latency period in P300 measurement than males in MCI group (P <0.01), but there were no significant differences within AD or HC groups. The males showed significant differences in wave I, II in left side between the MCI and AD groups. The males also showed significant difference in wave I, III approximate, equals V in left side, wave IV in right side between AD and HC groups, and so did the females in wave I approximate, equals V in both sides. The males had significant difference in the left wave III, IV and right wave I, IV, V between MCI and HC groups, and so did the females in right side wave I, II, V. In P300, longer latency waves were found in AD group than in MCI group. Both sexes showed significant differences in the latency of Fz, Cz, Pz between AD and HC groups, but no significant differences were found in the latency of Fz, Cz, Pz in the females between the MCI and HC groups. Sex differences were found in the examination of both BAEP and P300 in MCI group, but not in AD group. The people of same sex have different expression of BAEP and P300 among MCI, AD and HC groups, suggesting the sex difference should be considered in the differential diagnosis.

High Activities of BACE1 in Brains with Mild Cognitive Impairment

Background/Aims Language changes are the earliest signs and symptoms of mild cognitive impairment and Alzheimer's disease. The aim of this study was to explore the language difference performance between people with mild cognitive impairment, people with Alzheimer's disease and healthy individuals as a control group. To accomplish this aim, the language profile of both mild cognitive impairment and Alzheimer's disease needs to be characterised to determine which feature is more affected by both mild cognitive impairment and Alzheimer's disease among expressive language, receptive language, executive function and memory performance. Methods This case-control prospective study involved 90 participants. The Mini-Mental Status Examination and the Functional Assessment Staging Tool were used to classify the participants into three groups: people with mild cognitive impairment, people with Alzheimer's disease and healthy individuals as a control group. Then, the language performance of patients in the mild cognitive impairment and Alzheimer's disease groups was investigated and compared with those of the control group by using the Barnes Language Assessment. The groups were reassessed 6 months later to see if there was any change in language ability. Results The results showed that the mild cognitive impairment group and Alzheimer's disease group had significant decreases in expressive language (P&gt;0.01), executive function (P&gt;0.01), receptive language (P&gt;0.01) and memory skills (P&gt;0.01) from baseline to the reassessment at 6 months. Conclusions Language deficits, especially expressive language deficits, could appear before impairment in executive function, receptive language and verbal episodic memory in participants with mild cognitive impairment or Alzheimer's disease. Speech and language therapists can use the findings of this study to design and implement treatment programmes.

This study describes conversations between persons living with mild cognitive impairment (MCI), Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and their family caregivers, and the possible contributions of sensory loss. Conversations (N=130) between a participant (60% male) and a family caregiver (75% female; spouses) in the COMPASS-ND study were analyzed. Conversations were transcribed verbatim, segmented into communication units (c-units), and analyzed using the trouble-source repair (TSR) paradigm that includes analyses of communication breakdowns, repair initiators, and repair strategies. A one-way analysis of variance was conducted to evaluate between-group differences among sensory and communication variables. The AD group had poorer hearing than the MCI and PD groups. Both AD and MCI groups had poorer vision than the PD group. The MCI group used significantly more c-units than the AD and PD groups. The mean proportion of the TSR sequences was 13% across all groups, but with significantly more sequences in the AD and PD groups than the MCI group. Notably, the proportion of trouble sources created by caregivers was significantly greater for conversations in the AD group than the MCI or PD groups. The proportion of repair initiators used was significantly greater for the AD group than the MCI or PD groups. The intersection of cognition and sensory variables will be illustrated using three case studies. The findings highlight the active participation of persons living with AD and sensory loss in signalling misunderstandings created by caregivers. However, the interface between cognitive and sensory abilities influences the communication among both conversational partners.

Objective:Prospective memory (PM) is the ability to execute a planned action in the future (e.g., remembering to take medication before going to bed). Prior work has suggested that PM failure can account for 50-80% of reported memory problems. Research has also shown that PM becomes increasingly impaired in the Alzheimer's disease (AD) process. To our knowledge, most PM studies use PM accuracy as a measure of PM performance. However, examining the speed of the response as it relates to the AD process remains relatively unexplored. In this study, we examined both PM accuracy and speed in healthy aging, mild cognitive impairment (MCI), and AD.Participants and Methods:Participants included healthy older controls (N=65), persons with MCI (N=70), and persons with AD (N=11). The PM task was embedded within a working memory task as PM demands often occur during an ongoing activity in everyday life. For the working memory component of the PM task, participants were shown a series of words and asked to continuously monitor the words while maintaining the last 3 in memory. All words were displayed within 1 of 6 background patterns. For the PM component, participants were asked to press "1" on the keyboard whenever they were shown a particular background pattern on the screen. PM abilities were measured using the median response time and total accuracy.Results:Age was correlated with PM accuracy. An ANCOVA, controlling for age, and examining the impact of diagnosis on PM accuracy, was significant. Post-hoc tests revealed a trend toward the AD and MCI groups being less accurate than healthy controls. In contrast to accuracy, age was not related to PM speed. An ANOVA examining the impact of diagnosis on PM accuracy found that the AD group responded faster than healthy controls. The MCI group did not show differences in speed from the healthy control and AD groups.Conclusions:Overall, the pattern of results differed in accuracy and speed of PM performance. There was a trend for the MCI and AD groups being less accurate than the controls, with no difference in performance between the MCI and AD groups. However, the AD group responded more quickly than the controls, which may have impacted their accuracy. These findings indicate that PM performance differences among groups can be detected by examining speed and not just accuracy. As speed appears to be an essential aspect involved in PM performance, future research should consider incorporating speed as a measure of PM performance when examining PM differences in populations.

PurposeTo compare the retinal nerve fiber layer (RNFL) as well as the macula volume and thickness in the eyes of age-matched healthy controls with no cognitive disabilities with those of elderly people with mild cognitive impairment (MCI) or Alzheimer disease (AD). We used optical coherence tomography (OCT) to determine the effectiveness of the above quantities for early diagnosis of MCI or AD.MethodsNinety eyes were considered in this study, split between 30 normal eyes, 30 eyes from patients with MCI, and 30eyes from patients with AD. All subjects underwent ophthalmologic and cognitive examinations, and measurements of the RNFL thickness as well as macular volume and thickness were taken for all patients using OCT.ResultsThe mean RNFL thickness upon OCT was significantly thinner in the AD group than in the MCI group (p = 0.01). The RNFL was thinner in the superior quadrant in patients with AD when compared to the healthy controls (p = 0.03). The RNFL thicknesses in the inferior, nasal, and temporal quadrants did not differ significantly between the groups. Measurements in the 12 clock-hour zones revealed that zone 11 had a significantly thinner RNFL in the AD group as compared with the healthy control group (p = 0.02). In zone 2, the MCI group had a significantly thinner RNFL than the AD group (p = 0.03).ConclusionsOur OCT findings revealed a neuroanatomic difference in the RNFL thickness among the three groups, i.e., the AD, MCI, and healthy control groups. This suggests that a change in average RNFL thickness could be a meaningful index for diagnosing early AD.

Unraveling novel biomarkers for mild cognitive impairment (MCI) was highlighted in the prevention and modification of Alzheimer's disease (AD). Inconsistent results for comparison between MCI patients and healthy controls (HC) were obtained from previous neuroimaging studies. An activation likelihood estimation (ALE) meta-analysis was made for multimodal neuroimaging in MCI. After initial research and step-by-step exclusions procedures, n = 101 articles (MCI, n = 2681; HC, n = 2941, respectively) were included in the study. It detected MCI related gray matter atrophy in the bilateral medial temporal lobe and white matter abnormality in the left posterior cingulate, parahippocampal gyrus, thalamus, caudate, and bilateral precuneus. It revealed MCI-related decreased resting-state activity in the left superior temporal gyrus, right posterior cingulate/precuneus, and uncus and hyperactivation in the inferior parietal lobule and superior parietal lobule compared to HC. Task-related functional neuroimaging studies indicated MCI-related hypoactivation in the left inferior parietal lobule, right posterior cingulate, and bilateral precuneus and hyperactivation in the left middle frontal gyrus, superior parietal lobule, insula, superior temporal gyrus, and right inferior frontal gyrus. Via this ALE meta-analysis, we obtained these key regions suffering from different kinds of deficits in MCI. These regional abnormalities in MRI studies might serve as biomarkers for early diagnosis of MCI.

At present, Alzheimer's disease (AD) lacks effective treatment means, and early diagnosis and intervention are the keys to treatment. Therefore, for mild cognitive impairment (MCI) and AD patients, blood sample analysis using the 4D nonstandard (label-free) proteomic in-depth quantitative analysis, looking for specific protein marker expression differences, is important. These marker levels change as AD progresses, and the analysis of these biomarkers changes with this method, which has the potential to show the degree of disease progression and can be used for the diagnosis and preventive treatment of MCI and AD. Patients were recruited according to the inclusion and exclusion criteria and divided into three groups according to scale scores. Elderly patients diagnosed with AD were selected as the AD group (n = 9). Patients diagnosed with MCI were classified into the MCI group (n = 10). Cognitively healthy elderly patients were included in the normal cognition control group (n = 10). Patients' blood samples were used for 4D label-free proteomic in-depth quantitative analysis to identify potential blood biomarkers. The sample size of each group was expanded (n = 30), and the selected biomarkers were verified by enzyme-linked immunosorbent assay (ELISA) to verify the accuracy of the proteomic prediction. Six specific blood markers, namely, APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8, were detected by 4D label-free proteomic quantitative analysis. These markers showed a statistically significant upregulation trend in the MCI and AD groups compared with the normal cognition control group (P < 0.05). ELISA results showed that the levels of these six proteins in the MCI group were significantly higher than those in the normal cognition control group, and the levels of these six proteins in the AD group were significantly higher than those in the MCI group (P < 0.05). The plasma levels of APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8 in cognitively healthy elderly patients and patients with MCI and AD were significantly different and, more importantly, showed a trend of increasing expression. These results indicate that these six human plasma markers have important diagnostic and therapeutic potential in the identification of cognitive impairment and have value for in-depth research and clinical application.

Brain age is a machine learning-derived estimate that captures lower brain volume. Previous studies have found that brain age is significantly higher in mild cognitive impairment and Alzheimer's disease (AD) compared to healthy controls. Few studies have investigated changes in brain age longitudinally in MCI and AD. We hypothesized that individuals with MCI and AD would show heightened brain age over time and across the lifespan. We also hypothesized that both MCI and AD would show faster rates of brain aging (higher slopes) over time compared to healthy controls. We utilized data from an archival dataset, mainly Alzheimer's disease Neuroimaging Initiative (ADNI) 1 with 3Tesla (3 T) data which totaled 677 scans from 183 participants. This constitutes a secondary data analysis on existing data. We included control participants (healthy controls or HC), individuals with MCI, and individuals with AD. We predicted brain age using a pre-trained model and tested for accuracy. We investigated cross-sectional differences in brain age by group [healthy controls or HC, mild cognitive impairment (MCI), and AD]. We conducted longitudinal modeling of age and brain age by group using time from baseline in one model and chronological age in another model. We predicted brain age with a mean absolute error (MAE) < 5 years. Brain age was associated with age across the study and individuals with MCI and AD had greater brain age on average. We found that the MCI group had significantly higher rates of change in brain age over time compared to the HC group regardless of individual chronologic age, while the AD group did not differ in rate of brain age change. We replicated past studies that showed that MCI and AD had greater brain age than HC. We additionally found that this was true over time, both groups showed higher brain age longitudinally. Contrary to our hypothesis, we found that the MCI, but not the AD group, showed faster rates of brain aging. We essentially found that while the MCI group was actively experiencing faster rates of brain aging, the AD group may have already experienced this acceleration (as they show higher brain age). Individuals with MCI may experience higher rates of brain aging than AD and controls. AD may represent a homeostatic endpoint after significant neurodegeneration. Future work may focus on individuals with MCI as one potential therapeutic option is to alter rates of brain aging, which ultimately may slow cognitive decline in the long-term.

BackgroundCallosal Angle (CA) and Evans Index (EI) are considered as imaging biomarkers to diagnose normal-pressure hydrocephalus using traditional MR measurement methods.ObjectiveThe current study aimed to evaluate the differential diagnostic value of CA and EI in Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD).MethodsFive-hundred and two subjects were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, which included 168 Normal Controls (NC), 233 MCI and 101 AD patients. The structural MR images were interactively applied with multiplanar reconstruction to measure the CA and EI.ResultsCA presented no significant difference among NC, MCI and AD groups (H value = 3.848, P value = 0.146), and EI demonstrated higher value in MCI and AD groups than that in NC groups (P = 0.000 and 0.001, respectively). MCI group had significant larger EI (0.29±0.04) than (0.27±0.03) NC group in 70-75 years old sub-groups. ROC showed that the area under the curve was 0.704±0.045 for NC-MCI in 70-75 years old groups. The correlation analysis indicated that EI was significantly negatively related to MMSE scores of MCI patients (r = -0.131, P = 0.046).ConclusionEI might serve as a screening imaging biomarker for MCI in 70-75 years old patients, and show limited differential value for the diagnosis of AD. CA could present no diagnostic value for MCI and AD in the current study.

Mild cognitive impairment (MCI) has emerged as an identifiable condition and in many cases is a transitional state preceding diagnosable Alzheimer disease (AD). Neurobiological and neuroimaging characteristics of amnestic-type MCI have been investigated, but few comprehensive neuropsychiatric studies have been reported. The aim of this preliminary study was to define the neuropsychiatric features of the amnestic-type MCI and compare them with those of mild AD and normal controls. The Neuropsychiatric Inventory (NPI) was used to assess the neuropsychiatric symptoms in three age and education comparable groups, i.e., 28 MCI, 124 mild AD, and 50 normal subjects. Individual subscores of the 10 NPI symptoms and total NPI scores were compared between the MCI patients and the other 2 groups. The results of this preliminary investigation showed that MCI patients frequently manifested neuropsychiatric symptoms. The most common symptoms in the MCI group were dysphoria (39%), apathy (39%), irritability (29%), and anxiety (25%). There were significant differences in apathy, dysphoria, irritability, anxiety, agitation, and aberrant motor behavior between the MCI and control groups; in contrast, only delusions were significantly less common in MCI compared with mild AD. There was a significant difference between the MCI and control groups on total NPI scores (p = 0.001), but not between the MCI and mild AD groups (p = 0.304). Amnestic MCI is associated with significant neuropsychiatric symptoms, especially mood disturbances and apathy. Psychotic symptoms are significantly more common in the early stage of AD than in MCI. These results are derived from a limited clinical sample and require confirmation in longitudinal community-based investigations.

Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer's disease

The ability to read irregularly spelled words is commonly used to estimate premorbid intelligence, as this ability has been thought to be resistant to early effects of neurodegenerative disorders. However, studies evaluating decline of this skill in Alzheimer's disease (AD) have produced conflicting results. Irregular word reading was assessed three times over 36 months in a large (N = 995) sample, including healthy control, AD, and Mild Cognitive Impairment (MCI) groups. At baseline, MCI and AD groups read correctly an average of 3.01 and 7.39 fewer words, respectively, than healthy controls. The MCI group's performance remained stable during the study, but the AD group declined. Importantly, the observed decline was likely an underestimate, as significant numbers of the AD participants (42.6%) could not complete the task at follow-up. Use of alternate (e.g., demographics-based) methods is advised to augment or replace word pronunciation in estimating premorbid intelligence in individuals with even mild AD. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Objective To explore changes in glycogen synthase kinase-3 (GSK-3) levels in the lymphocytes of patients with mild cognition impairment (MCI) and Alzheimer's disease (AD). Methods GSK-3 activity was measured by 32P liquid scintillography in a control group, an MCI group and an AD group. The expressions of GSK-3βat Ser9 and total GSK-3β were determined by western blotting. Results GSK-3 levels were significantly higher in the AD and MCI groups than in the control group. The phosphorylation of GSK-3βat Ser9 was significantly lower in the AD and MCI groups compared with the control group, but there was no difference in the phosphorylation of total GSK-3β among the three groups. Conclusions Higher GSK-3 activity in the lymphocytes might have value in the diagnosis of MCI and early AD. Key words: Mild cognitive impairment; Alzheimer's disease; Lymphocytes; Glycogen synthase kinase-3