DTI measures in crossing-fibre areas: Increased diffusion anisotropy reveals early white matter alteration in MCI and mild Alzheimer's disease

High Activities of BACE1 in Brains with Mild Cognitive Impairment

Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Disease

IC-P-068: Diffusion tensor imaging of normal appearing white matter in MCI and AD

Whilst there is evidence implicating small vessel cerebrovascular disease in the pathogenesis of Alzheimer's disease (AD), its specific contribution to the pathophysiology of AD remains unclear. The burden of small vessel cerebrovascular disease visualized as white matter hyperintensity (WMH) and its association with medial temporal atrophy (MTA) at different stages of AD was studied. One hundred and sixty-five cognitively normal (CN) community controls, 103 mild cognitive impairment (MCI) patients, 141 mild AD patients and 68 moderate-severe AD patients were studied. Clinical, cognitive and risk factor data were collected, and WMH and MTA were quantified by trained raters. The Jonckheere-Terpstra test for ordered alternatives was used to study the association between WMH and MTA in different stages of AD. The burden of total WMH increased significantly with increasing severity of AD, even after correcting for confounders. The proportion of CN, MCI, mild AD and moderate-severe AD subjects with severe burden of WMH was 6.7%, 9.7%, 28.4%, and 39.7%, respectively. A strong positive association between WMH severity and MTA was evident amongst MCI (P = 0.011) and mild AD (P = 0.003) subjects, but not in CN (P = 0.953) and moderate-severe AD subjects (P = 0.301). The burden of WMH increased significantly from the stage of CN to MCI to AD. The association between WMH and MTA was greatest at the stage of MCI and mild AD. This has implications on the strategy to slow the progression of AD, where measures to reduce WMH, including control of vascular risk factors, need to be optimized at the stage of MCI and mild AD.

To the Editor: Alzheimer disease (AD) is the most common form of dementia, and the central pathogenic event is the abnormal accumulation of amyloid β–protein (Aβ) in extracellular amyloid deposits and cerebral blood vessels.1 AD is a complex and genetically heterogeneous disease. Mild cognitive impairment (MCI), a cognitive disorder in the transition between normal cognition and AD, is a known risk factor for AD, with a conversion rate of ≈10% per year.2 Apolipoprotein E (apoE), a lipid transporter, has been found to be contained in amyloid plaques. The apoE4 isoform or APOE e4 allele is associated with the development of AD1 and an increased risk of MCI.3 Cholesterol has also been identified as a risk factor for AD1,4 and MCI.5 A direct role of cholesterol in the pathogenesis of AD has been suggested by studies in transgenic animal models of AD: cholesterol feeding increases Aβ accumulation and accelerates AD-related pathology,6 whereas cholesterol lowering with statin reduces Aβ pathology.7 Although CAD is a prevalent finding in AD,8 whether or not plasma lipoprotein subfractions are associated with MCI and AD has not yet been investigated. The separation and determination of lipoprotein subfractions are generally labor-intensive and time-consuming. Recently, however, the research group of Schmitz and coworkers developed a new automated technique to separate and quantify lipoprotein subfractions in minutes using capillary isotachophoresis (cITP).9,10 Therefore, in the present study, we investigated the associations among lipoprotein subfractions as determined by cITP, apoE phenotype, MCI, and AD. Twenty-eight patients with MCI, 47 patients with AD, and 26 nondemented control subjects were evaluated at the Neurology Department of Fukuoka …

Cortical sources of resting eyes-closed alpha rhythms are typically abnormal in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects. Here we tested the hypothesis of a progressive impairment of cortical alpha reactivity to eye-opening across amnesic MCI and mild AD subjects, reflecting another aspect of the impairment of cortical neural synchronization. Resting electroencephalography (EEG) data were recorded in 36 normal elderly subjects (Nold), 91 amnesic MCI, and 31 mild AD subjects during eyes-closed and -open conditions. EEG sources were estimated by LORETA software. In the eye-closed condition, posterior alpha 1 (8-10.5 Hz) sources were lower in MCI and AD than Nold subjects. The opposite was true for occipital delta sources (2-4 Hz). Reactivity to the eyes-open condition showed posterior alpha 1 and alpha 2 (10.5-13 Hz) sources was high in the Nold, intermediate in the MCI, and low in the AD subjects. Furthermore, occipital alpha 1 reactivity across MCI and AD subjects was correlated to the cognitive impairment as revealed by Mini-Mental State Examination score. In conclusion, at least at group level, the continuum across amnesic MCI and mild AD status is related to an impaired reactivity of cortical neuronal synchronization to eyes opening at alpha rhythms.

The study objective is to evaluate the use of qEEG data for the cross-sectional differentiation of mild cognitive impairment (MCI) from mild Alzheimer's disease (AD) and in the longitudinal prediction of cognitive decline in MCI. Eighty-eight subjects with MCI and 42 subjects with mild probable AD were enrolled. Baseline EEGs were recorded using a 32-channel system with electrode positioning according to the international 10-20 system. Digitalized EEG data were further studied by quantitative spectral analysis. Study subjects were followed up for 1 year and reassessed psychometrically. An increase of the total ADAS-cog score of >or= 4 points was regarded as a significant cognitive decline. Using this cut-off, MCI subjects were sub-grouped into stable MCI (s-MCI) and progressing MCI (p-MCI). AD subjects and p-MCI subjects were differentiated from s-MCI subjects by a reduction of alpha power over posterior leads. Reduction of alpha power and mean frequency were significantly correlated with poorer cognitive performance in psychometric tests. Baseline values of alpha power over posterior leads had the highest positive predictive power for MCI and AD (69-80%) and predicted cognitive decline in MCI within a 1-year follow up. qEEG revealed decreased alpha activity in progressing MCI and mild AD prior to an increase of slow wave activity, which typically occurs in advancing AD. This finding may reflect an affection of thalamo-cortical relay activity and cortical connectivity in the early disease course of AD. Reduced alpha activity in MCI subjects at baseline may have prognostic value regarding future cognitive decline.

It has been suggested that mild cognitive impairment (MCI) patients deteriorate faster than the healthy elderly population and have an increased risk of developing dementia. Certain blood molecular biomarkers have been identified as prognostic markers in Alzheimer's disease (AD). The present study was aimed to assess the status of the platelet amyloid precursor protein (APP) metabolism in MCI and AD subjects and establish to what extent any variation could have a prognostic value suggestive of predictive AD in MCI patients. Thirty-four subjects diagnosed with MCI and 45 subjects with AD were compared to 28 healthy elderly individuals for assessing for protein levels of APP, β-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and a disintegrin and metalloproteinase-10 (ADAM-10) by western blot, and for the enzyme activities of BACE1 and γ-secretase by using specific fluorogenic substrates, in samples of platelets. A similar pattern in the healthy elderly and MCI patients was found for BACE1 and PS1 levels. A reduction of APP levels in MCI and AD patients compared with healthy elderly individuals was found. Augmented levels of ADAM-10 in both MCI and AD were displayed in comparison with age-matched control subjects. The ratio ADAM-10/BACE1 was higher for the MCI group versus AD group. Whereas BACE1 and PS1 levels were only increased in AD regarding to controls, BACE1 and γ-secretase activities augmented significantly in both MCI and AD groups. Finally, differences and similarities between MCI and AD patients were observed in several markers of platelet APP processing. Larger sample sets from diverse populations need to be analyzed to define a signature for the presence of MCI or AD pathology and to early detect AD at the MCI stage.

Background: The Alzheimer's Disease Functional Assessment and Change Scale (ADFACS) is a functional assessment instrument widely used in clinical research. Aims: To test the diagnostic and concurrent validity of the Spanish version of this scale and to describe the functional deficit pattern for mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. Methods: The ADFACS, the Interview for Deterioration in Daily Living Activities in Dementia (IDDD), and the Mini Mental State Examination (MMSE) were administered to 146 control subjects (CS) and 165 patients (67 MCI and 98 AD). Nonparametric tests were used to compare the diagnostic groups. Cronbach's α and correlations with the MMSE and the IDDD were calculated. Sensitivity, specificity and predictive values were studied. Results: The ADFACS had a high internal consistency (α = 0.95). Three cutoff points of 1, 4, and 17 were provided to separate CS and MCI patients, MCI and mild AD patients, and mild AD and moderate AD patients, respectively. The ADFACS strongly correlated with functional (IDDD, 0.927) and cognitive (MMSE, 0.747) measures. A similar pattern of dysfunction, but in different grades, was found for the MCI and AD groups. Conclusion: The ADFACS is a reliable, valid, and sensitive instrument to assess functional abilities; it is useful in dementia assessment for elderly populations.

Introduction: The Montreal Cognitive Assessment (MoCA) is a cognitive screening test widely used in clinical practice and suited for the detection of Mild Cognitive Impairment (MCI). The aims were to evaluate the psychometric properties of the Persian MoCA as a screening test for mild cognitive dysfunction in Iranian older adults and to assess its accuracy as a screening test for MCI and mild Alzheimer disease (AD). Method: One hundred twenty elderly with a mean age of 73.52 ± 7.46 years participated in this study. Twenty-one subjects had mild AD (MMSE score ≤21), 40 had MCI, and 59 were cognitively healthy controls. All the participants were administered the Mini-Mental State Examination (MMSE) to evaluate their general cognitive status. Also, a battery of comprehensive neuropsychological assessments was administered. Results: The mean score on the Persian version of the MoCA and the MMSE were 19.32 and 25.62 for MCI and 13.71 and 22.14 for AD patients, respectively. Using an optimal cutoff score of 22 the MoCA test detected 86% of MCI subjects, whereas the MMSE with a cutoff score of 26 detected 72% of MCI subjects. In AD patients with a cutoff score of 20, the MoCA had a sensitivity of 94% whereas the MMSE detected 61%. The specificity of the MoCA was 70% and 90% for MCI and AD, respectively. Discussion: The results of this study show that the Persian version of the MoCA is a reliable screening tool for detection of MCI and early stage AD. The MoCA is more sensitive than the MMSE in screening for cognitive impairment, proving it to be superior to MMSE in detecting MCI and mild AD.

ROI-based diffusion tensor analysis for the differential diagnosis of mild cognitive impairment and Alzheimer's disease

Background: Cognitive performance is relatively well preserved during early cognitive impairment owing to compensatory mechanisms.Methods: We explored functional near-infrared spectroscopy (fNIRS) alongside a semantic verbal fluency task (SVFT) to investigate any compensation exhibited by the prefrontal cortex (PFC) in Mild Cognitive Impairment (MCI) and mild Alzheimer's disease (AD). In addition, a group of healthy controls (HC) was studied. A total of 61 volunteers (31 HC, 12 patients with MCI and 18 patients with mild AD) took part in the present study.Results: Although not statistically significant, MCI exhibited a greater mean activation of both the right and left PFC, followed by HC and mild AD. Analysis showed that in the left PFC, the time taken for HC to achieve the activation level was shorter than MCI and mild AD (p = 0.0047 and 0.0498, respectively); in the right PFC, mild AD took a longer time to achieve the activation level than HC and MCI (p = 0.0469 and 0.0335, respectively); in the right PFC, HC, and MCI demonstrated a steeper slope compared to mild AD (p = 0.0432 and 0. 0107, respectively). The results were, however, not significant when corrected by the Bonferroni-Holm method. There was also found to be a moderately positive correlation (R = 0.5886) between the oxygenation levels in the left PFC and a clinical measure [Mini-Mental State Examination (MMSE) score] in MCI subjects uniquely.Discussion: The hyperactivation in MCI coupled with a better SVFT performance may suggest neural compensation, although it is not known to what degree hyperactivation manifests as a potential indicator of compensatory mechanisms. However, hypoactivation plus a poorer SVFT performance in mild AD might indicate an inability to compensate due to the degree of structural impairment.Conclusion: Consistent with the scaffolding theory of aging and cognition, the task-elicited hyperactivation in MCI might reflect the presence of compensatory mechanisms and hypoactivation in mild AD could reflect an inability to compensate. Future studies will investigate the fNIRS parameters with a larger sample size, and their validity as prognostic biomarkers of neurodegeneration.

Is directionality of electroencephalographic (EEG) synchronization abnormal in amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD)? And, do cerebrovascular and AD lesions represent additive factors in the development of MCI as a putative preclinical stage of AD? Here we reported two studies that tested these hypotheses. EEG data were recorded in normal elderly (Nold), amnesic MCI, and mild AD subjects at rest condition (closed eyes). Direction of information flow within EEG electrode pairs was performed by directed transfer function (DTF) at δ (2–4 Hz), θ (4–8 Hz), α1 (8–10 Hz), α2 (10–12 Hz), β1 (13–20 Hz), β2 (20–30 Hz), and γ (30–40 Hz). Parieto-to-frontal direction was stronger in Nold than in MCI and/or AD subjects for α and β rhythms. In contrast, the directional flow within interhemispheric EEG functional coupling did not discriminate among the groups. More interestingly, this coupling was higher at θ, α1, α2, and β1 in MCI with higher than in MCI with lower vascular load. These results suggest that directionality of parieto-to-frontal EEG synchronization is abnormal not only in AD but also in amnesic MCI, supporting the additive model according to which MCI state would result from the combination of cerebrovascular and neurodegenerative lesions.

Positron emission tomography (PET) scans are commonly used to diagnose Alzheimer's disease (AD) by detecting β-amyloid (Aβ) deposition in the cortex; however, brain amyloid plaque load (BAPL) scores based on the visual interpretation of experts are highly subjective. In the current retrospective study, voxel-based processing of [18F] Florbetaben ([18F] FBB) Aβ PET scans was used to compare images from patients with AD, patients with mild cognitive impairment (MCI), and healthy controls (HCs). The aim of our study was to highlight the gray matter voxels that were higher uptake than white matter and perform group comparison of the numbers of these voxels among AD, MCI and HC subjects. This was a cross-sectional study investigating Aβ PET of AD, MCI and HC subjects from the Global Alzheimer's Association Information Network (GAAIN) database and from Taipei Veterans General Hospital (TVGH) between October 2019 and December 2021. The determination of diagnosis (AD, MCI and HC) from GAAIN database was referred from the notes of this database and that from TVGH was referred from the medical records. Aβ PET scans were processed using statistical parametric mapping software. This analysis identified gray matter voxels presenting [18F] FBB uptake intensity exceeding 98% of the maximal uptake intensity in white matter (i.e., positive gray matter voxels). Comparison of numbers of positive gray matter voxels among AD, MCI and HC subjects was performed by analysis of variance (ANOVA) (Kruskal-Wallis) test. Whole brain observations revealed significant differences between AD patients, MCI patients, and elderly HC subjects in terms of the number of positive gray matter voxels (P=0.0281). In addition, more number of positive gray matter voxels were observed in AD patients than in elderly HC subjects (P=0.036). Most of the elderly HC subjects exhibited no positive gray matter voxels. Our preliminary analysis of [18F] FBB Aβ PET scans demonstrates proof-of-concept, suggesting that positive gray matter voxels could be used to differentiate among AD, MCI, and HC subjects.

BackgroundScreening for clinical trials identifies persons with clinical symptoms of Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD) but no amyloid on PET. We compared blood biomarkers and proteomics in these screen failures with cognitively normal, amyloid PET negative persons and with amyloid PET positive MCI or mild AD patients.MethodWe analyzed data from 296 persons with clinical symptoms of MCI or mild AD from the Bio‐Hermes study who were amyloid PET negative (MCI + AD AB‐); we compared them with 313 Bio‐Hermes participants who were cognitively normal and amyloid PET negative (CN AB‐) and with 258 amyloid PET positive persons with clinical MCI or mild AD (MCI + AD AB+). Measures included regional amyloid PET, plasma A‐beta40 and 42, total tau, p‐tau 181, p‐tau 217, NfL, GFAP, a panel of 69 cytokines (Fireplex) and 7596 proteins from the Somalogic panel.ResultRelative to the CN AB‐ group, the MCI + AD AB‐ group were older, more cognitvely and functionally impaired, had slightly less education and were more likely to be non‐white; the groups did not differ in gender or APOE4 rates. The groups did not differ on amyloid SUVR, p‐tau 217, t‐tau or GFAP. NfL was higher in MCI + AD AB‐ persons compared with CN AB‐ persons (Table 1 and 2). After using a False Discovery Rate adjustment there were no Somalogic proteins significantly different in MCI + AD AB‐ participants vs CN AB‐ participants. Several proteins were different in amyloid PET positive persons compared with amyloid PET negative parsons (Figure 1).ConclusionNfL data indicate very significant neurodegeneration in symptomatic but amyloid PET negative clinical trial screen failures. Biomarkers reflecting amyloid and tau were not different and the proteomics profile did not find specific abnormalities in amyloid negative, symptomatic persons.