Amnestic Mild Cognitive Impairment Patients Research Articles

Non-Alzheimer's amnestic mild cognitive impairment with medial temporal hypometabolism.

The increasing use of Alzheimer's disease (AD) biomarkers has led to the recognition of a subgroup of non-AD amnestic mild cognitive impairment (aMCI) patients who have medial temporal hypometabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET). In this academic memory-clinic-based consecutive series, 16 non-AD aMCI patients and 28 AD controls matched for sex, age, and baseline Mini-Mental State Examination (MMSE) were followed for a median duration of 4.5 years. Our primary outcome was the MMSE decline rate over the subsequent years. We also determined the final diagnosis over time. FDG-PET showed more pronounced medial temporal hypometabolism in non-AD cases and more inferior parietal lobule hypometabolism in AD controls. MMSE decline was slower in non-AD (β=-0.51) than in AD (β=-2.00) patients. Five non-AD cases developed frontotemporal dementia years after symptom onset, and one developed dementia with Lewy bodies. Non-AD aMCI patients with medial temporal hypometabolism show slower cognitive decline. Non-AD aMCI with medial temporal hypometabolism shows slower cognitive decline than AD.FDG-PET revealed distinct metabolic patterns between non-AD aMCI and AD patients.Approximately one-third of non-AD aMCI cases developed frontotemporal dementia.Comprehensive diagnostic biomarkers are crucial for non-AD aMCI characterization.

Improved Accuracy of the Addenbrooke's Cognitive Examination-Revised in the Diagnosis of Mild Cognitive Impairment, Mild Dementia Due to Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Mokken Scale Analysis.

The Addenbrooke's Cognitive Examination-Revised (ACE-R) is an accessible cognitive tool that supports the early detection of mild cognitive impairment (MCI), Alzheimer's disease (AD), and behavioral variant frontotemporal dementia (bvFTD). To investigate the diagnostic efficacy of the ACE-R in MCI, AD, and bvFTD through the identification of novel coefficients for differentiation between these diseases. We assessed 387 individuals: 102 mild AD, 37 mild bvFTD, 87 with amnestic MCI patients, and 161 cognitively unimpaired controls. The Mokken scaling technique facilitated the extraction out of the 26 ACE-R items that exhibited a common latent trait, thereby generating the Mokken scales for the AD group and the MCI group. Subsequently, we performed logistic regression, integrating each Mokken scales with sociodemographic factors, to differentiate between AD and bvFTD, as well as between AD or MCI and control groups. Ultimately, the Receiver Operating Characteristic curve analysis was employed to assess the efficacy of the coefficient's discrimination. The AD-specific Mokken scale (AD-MokACE-R) versus bvFTD exhibited an Area Under the Curve (AUC) of 0.922 (88% sensitivity and specificity). The AD-MokACE-R versus controls achieved an AUC of 0.968 (93% sensitivity, 94% specificity). The MCI-specific scale (MCI-MokACE-R) versus controls demonstrated an AUC of 0.859 (78% sensitivity, 79% specificity). The ACE-R's capacity is enhanced through statistical methods and demographic integration, allowing for accurate differentiation between AD and bvFTD, as well as between MCI and controls. This new method not only reinforces its clinical value in early diagnosis but also surpasses traditional approaches noted in prior studies.

Effect of APOE ɛ4 Status on Brain Amyloid‐β and Cognitive Function in Amnestic and Nonamnestic Mild Cognitive Impairment: A [18F] Florbetapir PET‐CT Study

AbstractMild cognitive impairment (MCI) is recognized as a predementia syndrome caused by multiple etiologies and nonmemory symptoms in MCI have recently gained increasing attention. However, the pattern of Aβ deposition and the effect of APOE (apolipoprotein E, APOE) ε4 on cognitive impairment in amnestic MCI (aMCI) and nonamnestic MCI (naMCI) patients has not been demonstrated. In this work, the amyloid‐β (Aβ) load by [18F]florbetapir PET imaging and cognitive performance is compared by comprehensive neuropsychological scales in participants with different MCI types or different APOE ε4 carriage status. According to the Aβ positivity and results of voxel‐wise analysis, higher Aβ loads are observed in aMCI patients than naMCI patients, especially aMCI patients with APOE ε4. Additionally, it is observed that memory domain Z scores show a strong negative correlation with global florbetapir SUVR in the aMCI group (r = – 0.352, p < 0.001) but not in the naMCI group (r = –0.016, p = 0.924). Moreover, this correlation is independent of APOE e4 carriage status. This study aims to identify high‐risk groups at an early stage of AD(Alzheimer's Disease, AD) through cognitive performance and APOE ε4 carrier status, which can be important for guiding clinical intervention trials.

Distinguishable neural circuit mechanisms associated with the clinical efficacy of rTMS in aMCI patients.

Repetitive transcranial magnetic stimulation is used in early-stage Alzheimer's disease to slow progression, but heterogeneity in response results in different treatment outcomes. The mechanisms underlying this heterogeneity are unclear. This study used resting-state neuroimaging to investigate the variability in episodic memory improvement from angular gyrus repetitive transcranial magnetic stimulation and tracked the neural circuits involved. Thirty-four amnestic mild cognitive impairment patients underwent angular gyrus repetitive transcranial magnetic stimulation (4weeks, 20Hz, 100% resting motor threshold) and were divided into high-response and low-response groups based on minimal clinically important differences in auditory verbal learning test scores. Baseline and pre/post-treatment neural circuit activities were compared. Results indicated that the orbital middle frontal gyrus in the orbitofrontal cortex network and the precuneus in the default mode network had higher local activity in the low-response group. After treatment, changes in local and remote connectivity within brain regions of the orbitofrontal cortex, default mode network, visual network, and sensorimotor network showed opposite trends and were related to treatment effects. This suggests that the activity states of brain regions within the orbitofrontal cortex and default mode network could serve as imaging markers for early cognitive compensation in amnestic mild cognitive impairment patients and predict the aftereffects of repetitive transcranial magnetic stimulation response.

Episodic memory network characteristics in patients with amnestic mild cognitive impairment accompanied by executive function impairment.

To explore the functional connectivity (FC) characteristics of the episodic memory network (EMN) in amnestic mild cognitive impairment (aMCI) patients with different levels of executive function (EF). This study included 76 participants from the Alzheimer's Disease Neuroimaging Initiative database, comprising 23 healthy controls (HCs) and 53 aMCI patients. Based on EF levels, aMCI patients were categorized into aMCI-highEF and aMCI-lowEF groups. Cognitive function scores, pathological markers (cerebrospinal fluid β-amyloid, total tau protein, phosphorylated tau protein, AV45-PET, and FDG-PET), and functional magnetic resonance imaging were collected and compared among the three groups. Seed-based FC analysis was used to examine differences in the EMN among the groups, and partial correlation analysis was employed to investigate the relationship between changes in FC and cognitive function scores as well as pathological markers. Compared to the aMCI-highEF group, the aMCI-lowEF group exhibited more severe cognitive impairment, decreased cerebral glucose metabolism, and elevated AV45 levels. Significant FC differences in the left superior temporal gyrus (STG) of the EMN were observed among the three groups. Post hoc analysis revealed that the aMCI-lowEF group had increased FC in the left STG compared to the HCs and aMCI-highEF groups, with statistically significant differences. Correlation analysis showed a significant negative correlation between the differences in FC in the left STG of aMCI-highEF and aMCI-lowEF groups and Rey Auditory Verbal Learning Test forgetting scores. Receiver operator characteristic curve analysis indicated an area under the curve of 0.741 for distinguishing between aMCI-highEF and aMCI-lowEF groups based on FC of left STG, with a sensitivity of 0.808 and a specificity of 0.667. aMCI-lowEF exhibits characteristic changes in FC within the EMN, providing theoretical support for the role of EF in mediating EMN alterations and, consequently, impacting episodic memory function.

1009 Association of Circadian Rhythm with 27-Hydroxycholesterol in Amnestic Mild Cognitive Impairment (aMCI) Patients

1009 Association of Circadian Rhythm with 27-Hydroxycholesterol in Amnestic Mild Cognitive Impairment (aMCI) Patients

Sex differences in functional connectivity and the predictive role of the connectome-based predictive model in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline. Sex differences in the progression of AD exist, but the neural mechanisms are not well understood. The purpose of the current study was to explore sex differences in brain functional connectivity (FC) at different stages of AD and their predictive ability on Montreal Cognitive Assessment (MoCA) scores using connectome-based predictive modeling (CPM). Resting-state functional magnetic resonance imaging was collected from 81 AD patients (44 females), 78 amnestic mild cognitive impairment patients (44 females), and 92 healthy controls (50 females). The FC analysis was conducted and the interaction effect between sex and group was investigated using two-factor variance analysis. The CPM was used to predict MoCA scores. There were sex-by-group interaction effects on FC between the left dorsolateral superior frontal gyrus and left middle temporal gyrus, left precuneus and right calcarine fissure surrounding cortex, left precuneus and left middle occipital gyrus, left middle temporal gyrus and left precentral gyrus, and between the left middle temporal gyrus and right cuneus. In the CPM, the positive network predictive model significantly predicted MoCA scores in both males and females. There were significant sex-by-group interaction effects on FC between the left precuneus and left middle occipital gyrus, and between the left middle temporal gyrus and right cuneus could predict MoCA scores in female patients. Our results suggest that there are sex differences in FC at different stages of AD. The sex-specific FC can further predict MoCA scores at individual level.

Exploring the impact of intensified multiple session tDCS over the left DLPFC on brain function in MCI: a randomized control trial

Transcranial direct current stimulation combined with cognitive training (tDCS-cog) represents a promising approach to combat cognitive decline among healthy older adults and patients with mild cognitive impairment (MCI). In this 5-day-long double-blinded randomized trial, we investigated the impact of intensified tDCS-cog protocol involving two trains of stimulation per day on working memory (WM) enhancement in 35 amnestic and multidomain amnestic MCI patients. Specifically, we focused to improve WM tasks relying on top-down attentional control and hypothesized that intensified tDCS would enhance performance of visual object matching task (VOMT) immediately after the stimulation regimen and at a 1-month follow-up. Secondarily, we explored whether the stimulation would augment online visual working memory training. Using fMRI, we aimed to elucidate the neural mechanisms underlying the intervention effects by analyzing BOLD activations during VOMT. Our main finding revealed no superior after-effects of tDCS-cog over the sham on VOMT among individuals with MCI as indicated by insignificant immediate and long-lasting after-effects. Additionally, the tDCS-cog did not enhance online training as predicted. The fMRI analysis revealed brain activity alterations in right insula that may be linked to tDCS-cog intervention. In the study we discuss the insignificant behavioral results in the context of the current evidence in tDCS parameter space and opening the discussion of possible interference between trained cognitive tasks.

Quantitative EEG Spectral and Connectivity Analysis for Cognitive Decline in Amnestic Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is considered to be the borderline of cognitive changes associated with aging and very early dementia. Cognitive functions in MCI can improve, remain stable or progress to clinically probable AD. Quantitative electroencephalography (qEEG) can become a useful tool for using the analytical techniques to quantify EEG patterns indicating cognitive impairment. The aim of our study was to assess spectral and connectivity analysis of the EEG resting state activity in amnestic MCI (aMCI) patients in comparison with healthy control group (CogN). 30 aMCI patients and 23 CogN group, matched by age and education, underwent equal neuropsychological assessment and EEG recording, according to the same protocol. qEEG spectral analysis revealed decrease of global relative beta band power and increase of global relative theta and delta power in aMCI patients. Whereas, decreased coherence in centroparietal right area considered to be an early qEEG biomarker of functional disconnection of the brain network in aMCI patients. In conclusion, the demonstrated changes in qEEG, especially, the coherence patterns are specific biomarkers of cognitive impairment in aMCI. Therefore, qEEG measurements appears to be a useful tool that complements neuropsychological diagnostics, assessing the risk of progression and provides a basis for possible interventions designed to improve cognitive functions or even inhibit the progression of the disease.

Differences between sub-second and supra-second durations for the assessment of timing deficits in amnestic mild cognitive impairment

Previous studies have often reported timing deficits in older adults with different degrees of cognitive decline, however, the exact nature of impairments in time perception is still to be elucidated. In particular, it is unclear if the deficits are more pronounced for short or long intervals, consistent with notions that different cognitive processes and neuroanatomical areas are involved in the processing of durations of different ranges. The present study aims to further investigate timing abilities in amnestic mild cognitive impairment (aMCI) patients and age-matched controls. Participants were asked to decide whether an acoustic event occurred within the first or the second half of a reference duration. The results revealed a bias towards larger PSE values and reduced precision in aMCI patients compared to healthy controls. Further analyses showed that the bias towards larger PSE values correlated with memory performance, especially when sub-second durations were tested. Overall, the results demonstrate that memory deficits in aMCI patients coincide with changes in time perception in the sub-second interval range.

Electrical field strength from anodal prefrontal tDCS determines degree of white matter integrity changes in amnestic MCI patients

AbstractBackgroundAn electrical field (EF) strength induced by tDCS affects a therapeutic effect. Additionally, sequential tDCS has improved white matter integrity in cognitively impaired patients. However, researchers have not evaluated the impact of EF strength on white matter integrity in the prodromal stage of dementia. This study aimed to elucidate the effect of EF strength from prefrontal anodal tDCS on white matter integrity change and the modulating role of relevant genetic and pathologic factors in this effect in amnestic mild cognitive impairment (MCI) patients.MethodIn 55 amnestic MCI patients, we delivered anodal‐tDCS (2 mA/day, five times/week, for two weeks) over the left dorsolateral prefrontal cortex (DLPFC), calculated the EF strength for the left inferior frontal gyrus and DLPFC through the stimulation navigation program analysis. Additionally, we assessed the white matter integrity by diffusion tensor imaging before and after two weeks of stimulation; finally, we evaluated the modulating factors: amyloid‐beta (Aβ) deposition, APOE ε4‐allele status, and BDNF polymorphism.ResultAs the EF intensity in the left inferior frontal gyrus increased, the range of changes in white matter integrity significantly increased in left anterior thalamic radiation, corticospinal tract, inferior fronto‐occipital fasciculus, and inferior longitudinal fasciculus. Additionally, we found that greater change in white matter integrity was observed with higher regional EF strength in the APOE ε4 non‐carriers and BDNF MET non‐carrier, which could be attributed to an interaction between these modulating factors and EF intensity in the left anterior thalamic radiation and right uncinate fasciculus.ConclusionThese findings provide evidence for the precision‐medicine‐based application of tDCS in the prodromal stage of dementia, inducing the optimized therapeutic effect.

Developing Topics.

Amyloid-negative amnestic mild cognitive impairment (MCI) patients have a conversion rate to dementia of approximately 10% within 2 years. This study aimed to investigate whether brain age, calculated using quantitative data obtained from brain magnetic resonance imaging (MRI) artificial intelligence (AI) software can be an important factor in predicting the conversion of dementia in amyloid-negative amnestic MCI patients. We conducted a retrospective cohort study of patients with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain MRI, and [18F]-florbetaben (FBB) positron emission tomography (PET) scan. Conversion to dementia was determined by a neurologist based on a clinical interview with a detailed neuropsychological test or a decline in the Korean version of the Mini-Mental State Examination score of more than 4 points per year combined with impaired activities of daily living. Brain age was determined through volumetric assessment of 12 distinct brain regions using commercially available segmentation software, Neurophet AQUA. During the follow-up period, 38% (35/91) of patients converted to dementia from amnestic MCI. 73% (66/91) of patients had a higher brain age than their actual chronological age. In the conversion group, all participants except three (91%, 32/35) had a brain age older than their chronological age. Conversely, the conversion rate to dementia was significantly lower in the group with a younger brain age than their actual age. The subjects were divided into eight groups based on sex, education level, and brain age. When defining the 'survival' as the non-conversion of MCI to dementia, these groups significantly differed in survival probability with a p-value of 0.036. The low-educated female group with a higher brain age than their actual age had the lowest survival rate of all groups. Our findings suggest that MRI-based brain age used in this study can contribute to predicting conversion to dementia in patients with amyloid-negative amnestic MCI.

NG‐001: A novel multi‐domain digital cognitive intervention for cognitive symptoms in mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is a prodromal stage of Alzheimer’s disease that offers a window for early intervention prior to dementia onset. The cognitive impairment observed in MCI includes declines across several cognitive domains, including memory, processing speed, and executive function. Emerging evidence supports a multidomain intervention to improve cognitive performance. Therefore, we aim to investigate the utility of a novel, scalable multi‐domain digital intervention as a therapeutic solution to prevent or reverse cognitive decline.Method30 amnestic MCI patients were enrolled in a pilot open‐label clinical trial of a 10‐week digital therapeutic intervention using NG‐001 delivered via a tablet. 27 participants completed the trial and their data were analyzed. NG‐001 consisted of weekly 1‐hour trainings spread across several domains: cognitive games; physical exercise; mindfulness (e.g., yoga and meditation); health literacy; and reminiscence therapy. The outcome composite scores were calculated from the Neuropsychological Test Battery including Overall Cognition, Processing Speed, Executive Functioning, Overall Memory as well as Immediate and Delayed Memory. Composites were calculated into Z‐scores based on normative data from age and education‐adjusted reference groups. Changes in the Z‐scores were then assessed using paired Wilcoxon signed ranked tests (two‐tailed) and the effect size was calculated using Hedges’ g.ResultCompared to baseline, at post‐intervention, MCI patients showed significant improvements in Overall Cognition (‐0.440 to ‐0.213, g = 0.352), Overall Memory (‐0.587 to ‐0.132, g = 0.407), Immediate Memory (‐0.549 to ‐0.030, g = 0.512) and Delayed Memory (‐0.626 to ‐0.233, g = 0.305). There were no significant changes in Processing Speed or in Executive Functioning (ps > .05).ConclusionNG‐001 significantly improved memory (both immediate and delayed) for amnestic MCI patients, indicating its potential as a form of digital therapeutics for early intervention of memory impairment in MCI. Further research is needed to investigate the mechanisms involved in this improvement, and whether modifications can be made to extend its facilitatory effect to other cognitive domains such as executive functioning and language.

NG‐001: A novel multi‐domain digital cognitive intervention for cognitive symptoms in mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is a prodromal stage of Alzheimer’s disease that offers a window for early intervention prior to dementia onset. The cognitive impairment observed in MCI includes declines across several cognitive domains, including memory, processing speed, and executive function. Emerging evidence supports a multidomain intervention to improve cognitive performance. Therefore, we aim to investigate the utility of a novel, scalable multi‐domain digital intervention as a therapeutic solution to prevent or reverse cognitive decline.Method30 amnestic MCI patients were enrolled in a pilot open‐label clinical trial of a 10‐week digital therapeutic intervention using NG‐001 delivered via a tablet. 27 participants completed the trial and their data were analyzed. NG‐001 consisted of weekly 1‐hour trainings spread across several domains: cognitive games; physical exercise; mindfulness (e.g., yoga and meditation); health literacy; and reminiscence therapy. The outcome composite scores were calculated from the Neuropsychological Test Battery including Overall Cognition, Processing Speed, Executive Functioning, Overall Memory as well as Immediate and Delayed Memory. Composites were calculated into Z‐scores based on normative data from age and education‐adjusted reference groups. Changes in the Z‐scores were then assessed using paired Wilcoxon signed ranked tests (two‐tailed) and the effect size was calculated using Hedges’ g.ResultCompared to baseline, at post‐intervention, MCI patients showed significant improvements in Overall Cognition (‐0.440 to ‐0.213, g = 0.352), Overall Memory (‐0.587 to ‐0.132, g = 0.407), Immediate Memory (‐0.549 to ‐0.030, g = 0.512) and Delayed Memory (‐0.626 to ‐0.233, g = 0.305). There were no significant changes in Processing Speed or in Executive Functioning (ps > .05).ConclusionNG‐001 significantly improved memory (both immediate and delayed) for amnestic MCI patients, indicating its potential as a form of digital therapeutics for early intervention of memory impairment in MCI. Further research is needed to investigate the mechanisms involved in this improvement, and whether modifications can be made to extend its facilitatory effect to other cognitive domains such as executive functioning and language.

Clinical and biomarker characteristics of amnestic MCI patients exhibiting a temporo‐limbic FDG‐PET pattern suggestive of LATE

AbstractBackgroundWe have recently described a specific temporo‐limbic FDG‐PET signature that characterizes autopsy‐confirmed cases with limbic age‐related TDP‐43 encephalopathy (LATE), and have demonstrated its clinical utility for differential diagnosis of amnestic dementia patients. Here we assessed the utility of this pattern for patient stratification at a predementia disease stage, and further used tau‐PET data to study the degree to which this “LATE‐specific” FDG‐PET signature may correspond to a limbic‐predominant AD subtype.MethodIndividual FDG‐PET scans of 909 amnestic MCI (aMCI) patients from the ADNI cohort were screened for hypometabolic patterns being suggestive of LATE (sLATE) or typical AD (sAD) using automated pattern‐matching to autopsy‐confirmed pathology‐specific FDG‐PET signatures. sLATE and sAD patients were compared on clinical features, APOE4 genotype, and CSF biomarkers. Tau‐PET scans ([18F]Flortaucipir) were available in a smaller subsample (30%) and were analyzed for tau‐positivity using an FDA‐approved visual interpretation method as well as entorhinal SUVR (positivity‐threshold: SUVR = 2.1).Result734 aMCI patients showed evidence of significant regional hypometabolism, and of these 92 had a pronounced temporo‐limbic hypometabolic pattern classified as sLATE, whereas 68 had a classical temporo‐parietal pattern classified as sAD(Fig‐1). Compared to sAD, sLATE patients had similar MMSE and memory scores but more preserved executive function scores, and they showed generally slower cognitive decline over follow‐up (p<0.001)(Fig‐2). They were also significantly older (d = 0.83, p = 0.01), less often APOE4 carriers (39% vs 64%, p<0.001), and had less abnormal CSF Aß42 (d = 0.60, p = 0.001) and p‐tau181 levels (d = ‐0.40, p = 0.01). With regards to tau‐PET, 9/30 sLATE (30%) and 9/10 sAD (90%) patients were visually positive and similar proportions were seen for entorhinal SUVR (40% vs 90%).ConclusionThe majority of amnestic MCI patients exhibiting a LATE‐typical temporo‐limbic FDG‐PET pattern show clinical and biomarker features that deviate from prodromal AD. A smaller subset of these patients shows elevated tau‐PET signal and could thus represent a limbic‐predominant AD subtype.

Clinical and biomarker characteristics of amnestic MCI patients exhibiting a temporo‐limbic FDG‐PET pattern suggestive of LATE

AbstractBackgroundWe have recently described a specific temporo‐limbic FDG‐PET signature that characterizes autopsy‐confirmed cases with limbic age‐related TDP‐43 encephalopathy (LATE), and have demonstrated its clinical utility for differential diagnosis of amnestic dementia patients. Here we assessed the utility of this pattern for patient stratification at a predementia disease stage, and further used tau‐PET data to study the degree to which this “LATE‐specific” FDG‐PET signature may correspond to a limbic‐predominant AD subtype.MethodIndividual FDG‐PET scans of 909 amnestic MCI (aMCI) patients from the ADNI cohort were screened for hypometabolic patterns being suggestive of LATE (sLATE) or typical AD (sAD) using automated pattern‐matching to autopsy‐confirmed pathology‐specific FDG‐PET signatures. sLATE and sAD patients were compared on clinical features, APOE4 genotype, and CSF biomarkers. Tau‐PET scans ([18F]Flortaucipir) were available in a smaller subsample (30%) and were analyzed for tau‐positivity using an FDA‐approved visual interpretation method as well as entorhinal SUVR (positivity‐threshold: SUVR≥2.1).Result734 aMCI patients showed evidence of significant regional hypometabolism, and of these 92 had a pronounced temporo‐limbic hypometabolic pattern classified as sLATE, whereas 68 had a classical temporo‐parietal pattern classified as sAD(Fig‐1). Compared to sAD, sLATE patients had similar MMSE and memory scores but more preserved executive function scores, and they showed generally slower cognitive decline over follow‐up (p<0.001)(Fig‐2). They were also significantly older (d = 0.83, p = 0.01), less often APOE4 carriers (39% vs 64%, p<0.001), and had less abnormal CSF Aβ42 (d = 0.60, p = 0.001) and p‐tau181 levels (d = ‐0.40, p = 0.01). With regards to tau‐PET, 9/30 sLATE (30%) and 9/10 sAD (90%) patients were visually positive and similar proportions were seen for entorhinal SUVR (40% vs 90%).ConclusionThe majority of amnestic MCI patients exhibiting a LATE‐typical temporo‐limbic FDG‐PET pattern show clinical and biomarker features that deviate from prodromal AD. A smaller subset of these patients shows elevated tau‐PET signal and could thus represent a limbic‐predominant AD subtype.

The molar ratio between PAI‐1 and BDNF is increased in Alzheimer’s disease patients with full dementia and negatively correlates with MMSE score

AbstractBackgroundIn a previous study, we demonstrated that the enzyme plasminogen activator inhibitor‐1 (PAI‐1), which inhibits plasmin synthesis in the central nervous system (CNS), is increased in the serum of patients with Alzheimer’s disease (AD). In addition to reducing the accumulation of Ab, plasmin in the CNS regulates the synthesis of the trophic factor brain‐derived neurotrophic factor (BDNF) which appears to be altered in the brain of patients with AD. We investigated whether BDNF serum levels in AD and amnestic mild cognitive impairment (aMCI) patients are altered compared to cognitively healthy controls. Moreover, we examined the PAI‐1/BDNF ratio in these patient groups and correlated with cognitive scores as measured by Mini‐Mental State Examination (MMSE).Method40 AD, 40 aMCI and 10 healthy controls were recruited. Venous blood was collected and BDNF serum concentration were quantified by sandwich ELISAs. Comparisons among the experimental groups (AD dementia, aMCI patients, and cognitively healthy controls) on BDNF serum levels were performed using univariate analyses of variance (ANOVA). Pearson correlation coefficients were calculated to explore relationships between biochemical and clinical data. The level of statistical significance was set at p<0.05.ResultThe results showed that BDNF serum levels are decreased in AD as compared to aMCI patients (p < .05). In addition, there was a positive correlation between PAI‐1 and BDNF serum levels (r = .190, p < .05). Furthermore, PAI‐1/BDNF ratio was significantly increased in AD patients as compared to aMCI (p < .001) and controls (p < .001). Lastly, PAI‐1/BDNF ratio negatively correlated with MMSE score (r = ‐.508, p < .001).ConclusionThese data suggest that in AD a reduction of plasmin caused by PAI‐1 may negatively affect the production of BDNF and promote disease progression. Our results also demonstrate that the PAI‐1/BDNF ratio is increased in AD patients compared with aMCI and controls. They also suggest that this ratio could be used as a marker of AD in a state of overt cognitive impairment, as supported by the strong negative correlation between PAI‐1/BDNF ratio and MMSE.

MiR‐431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice

AbstractBackgroundSynaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRNAs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. Our previous miRNA assay data have shown that miR‐431 is downregulated in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice. However, the potential role of miR‐431 in AD has not been fully defined.MethodLv‐miR‐431 (1×109 TU/ml, 2 µl), Lv‐Smad4 (1×109 TU/ml, 2 µl) or AAV‐sh‐Smad4 (5×1012 GC/ml, 200 nl) was slowly injected into the bilateral hippocampus of APP/PS1 mice. The behavioral or electrophysiological tests were performed 1 month following the injection, and the mice were then sacrificed for other experiments. QRT‐PCR was used to detect the expression of miR‐431 in plasma and hippocampus. Golgi staining and electron microscopy were performed to evaluate the synaptic structure. Western blot was employed to test the levels of synaptic associated proteins. Immunofluorescence staining and ELISA were utilized to assess hippocampal Aβ levels. Cut&Tag assay and ChIP were used to explore and confirm the potential targets of Smad4.ResultThe level of miR‐431 was downregulated in the plasma of amnestic mild cognitive impairment (aMCI) and AD patients, and it was also decreased in the hippocampus and plasma of APP/PS1 mice. MiR‐431 overexpression in the hippocampus ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it didn’t affect the Aβ levels. Smad4 was identified as a target of miR‐431, and Smad4 overexpression reversed the protective effects of miR‐431 in APP/PS1 mice. Furthermore, Smad4 knockdown modulated the expression of synaptic proteins including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice.ConclusionMiR‐431 attenuates synaptic impairment at least partially by Smad4 inhibition and miR‐431/Smad4 may be a potential therapeutic target for AD treatment.

Mapping High‐Frequency Conductivity Using MRI in the Brains of Alzheimer’s Disease Patients

AbstractBackgroundPrevious studies reported increased concentrations of metallic ions and imbalanced Na+ and K+ ions in patients with Alzheimer’s disease (AD) and the increased mobility of protons by microstructural disruptions in AD. The purposes of this study were: 1)to apply a high‐frequency conductivity (HFC) mapping technique using a clinical 3T MRI system and 2)to compare HFC values among participant groups.MethodThis prospective study included 74 participants (23 AD patients, 27 amnestic mild cognitive impairment (MCI) patients, and 24 cognitively normal (CN) elderly people) to explore the clinical application of HFC mapping in the brain. For the brain MREPT images, a multi‐echo turbo spin‐echo pulse sequence was used. A homemade software was used to map the HFC at the Larmor frequency of 128 MHz at 3T. We performed statistical analyses to 1) compare HFC maps between the three participant groups and 2) to evaluate the association of HFC maps with Mini‐Mental State Examination (MMSE) scores.ResultThe HFC value was higher in the AD group than in the CN and MCI groups. MMSE scores were negatively associated with HFC values, but age was positively associated with HFC values. The HFC value in the insula has a high area under the ROC curve (AUC) value to differentiate AD patients from the CN participants (Sensitivity (SE) = 82, Specificity (SP) = 97, AUC = 0.902, p < 0.0001), better than GMV in hippocampus (SE = 79, SP = 83, AUC = 0.880, p < 0.0001).ConclusionHFC values were significantly increased in the AD group compared to the CN group and increased with age and disease severity. HFC values of the insula along with the GMV of the hippocampus can be used as an imaging biomarker to improve the differentiation of AD from CN.

Fastball ‐ a new functional biomarker of cognitive impairment

AbstractBackgroundFastball provides a new, rapid, objective EEG method for assessing cognitive function. Fastball is culturally, linguistically and educationally independent. Participants do not need to understand the task, or provide any response, and tasks take just minutes to complete. Fastball has recently been shown to be sensitive to memory deficits in Alzheimer’s disease (Stothart et al., Brain, 2021), and we present the latest findings in Mild Cognitive Impairment (MCI) patients.MethodHealthy older adult controls (n = 56, ACE‐III = 96+‐3) and MCI patients (n = 46, ACE‐III = 82+‐10) completed a Fastball task designed to measure their recognition memory at baseline and at 12 month follow up. All EEG data were collected in patients' homes using low‐cost portable EEG. They also completed the ACE‐III and the Delayed Match to Sample 48, a validated neuropsychological measure of recognition memory.ResultBetween group comparisons, controlling for individual differences in EEG response magnitude, showed amnestic MCI patients had significantly reduced Fastball responses compared to non‐amnestic MCI patients (p = .002) and healthy older adult controls (p = .005). Fastball scores correlated with the ACE‐III memory subscale (r(46) = .44, p = 0.002) and no other ACE‐III subscale, demonstrating sensitivity and specificity to memory dysfunction. Fastball scores also correlated with performance on the Delayed Match to Sample 48 abstract subscale (r(46) = .37, p = .011). 12 month follow up is underway and data will be presented at AAIC 2023.ConclusionFastball is a passive, rapid measure of memory dysfunction in Alzheimer’s disease that we have now demonstrated to be sensitive to early memory dysfunction in Mild Cognitive Impairment. Fastball data can be reliably collected in patients' homes using low‐cost portable EEG, and the approach holds great potential as a future diagnostic tool.