Prodromal Stage Of Alzheimer Research Articles

Compensation versus deterioration across functional networks in amnestic mild cognitive impairment subtypes.

Functional connectivity studies to detect neurophysiological correlates of amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer's disease, have generated contradictory results in terms of compensation and deterioration, as most of the studies did not distinguish between the different aMCI subtypes: single-domain aMCI (sd-aMCI) and multiple-domain aMCI (md-aMCI). The present study aimed to characterize the neurophysiological correlates of aMCI subtypes by using resting-state functional magnetic resonance imaging. The study included sd-aMCI (n = 29), md-aMCI (n = 26), and control (n = 30) participants. The data were subjected to independent component analysis (ICA) to explore the default mode network (DMN) and the fronto-parietal control network (FPCN). Additionally, seed-based and moderation analyses were conducted to investigate the connectivity of the medial temporal lobe and functional networks. aMCI subtypes presented differences in functional connectivity relative to the control group: sd-aMCI participants displayed increased FPCN connectivity and reduced connectivity between the posterior parahippocampal gyrus (PHG) and medial structures; md-aMCI participants exhibited lower FPCN connectivity, higher anterior PHG connectivity with frontal structures and lower posterior PHG connectivity with central-parietal and temporo-occipital areas. Additionally, md-aMCI participants showed higher posterior PHG connectivity with structures of the DMN than both control and sd-aMCI participants, potentially indicating more severe cognitive deficits. The results showed gradual and qualitative neurofunctional differences between the aMCI subgroups, suggesting the existence of compensatory (sd-aMCI) and deterioration (md-aMCI) mechanisms in functional networks, mainly originated in the DMN. The findings support consideration of the subgroups as different stages of MCI within the Alzheimer disease continuum.

Modeling multiple-criterion diagnoses by heterogeneous-instance logistic regression.

Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) that causes a significant burden in caregiving and medical costs. Clinically, the diagnosis of MCI is determined by the impairment statuses of five cognitive domains. If one of these cognitive domains is impaired, the patient is diagnosed with MCI, and if two out of the five domains are impaired, the patient is diagnosed with AD. In medical records, most of the time, the diagnosis of MCI/AD is given, but not the statuses of the five domains. We may treat the domain statuses as missing variables. This diagnostic procedure relates MCI/AD status modeling to multiple-instance learning, where each domain resembles an instance. However, traditional multiple-instance learning assumes common predictors among instances, but in our case, each domain is associated with different predictors. In this article, we generalized the multiple-instance logistic regression to accommodate the heterogeneity in predictors among different instances. The proposed model is dubbed heterogeneous-instance logistic regression and is estimated via the expectation-maximization algorithm because of the presence of the missing variables. We also derived two variants of the proposed model for the MCI and AD diagnoses. The proposed model is validated in terms of its estimation accuracy, latent status prediction, and robustness via extensive simulation studies. Finally, we analyzed the National Alzheimer's Coordinating Center-Uniform Data Set using the proposed model and demonstrated its potential.

Alterations in Gray Matter Structural Networks in Amnestic Mild Cognitive Impairment: A Source-Based Morphometry Study.

Amnestic mild cognitive impairment (aMCI), considered as the prodromal stage of Alzheimer's disease, is characterized by isolated memory impairment and cerebral gray matter volume (GMV) alterations. Previous structural MRI studies in aMCI have been mainly based on univariate statistics using voxel-based morphometry. We investigated structural network differences between aMCI patients and cognitively normal older adults by using source-based morphometry, a multivariate approach that considers the relationship between voxels of various parts of the brain. Ninety-one aMCI patients and 80 cognitively normal controls underwent structural MRI and neuropsychological assessment. Spatially independent components (ICs) that covaried between participants were estimated and a multivariate analysis of covariance was performed with ICs as dependent variables, diagnosis as independent variable, and age, sex, education level, and site as covariates. aMCI patients exhibited reduced GMV in the precentral, temporo-cerebellar, frontal, and temporal network, and increased GMV in the left superior parietal network compared to controls (pFWER < 0.05, Holm-Bonferroni correction). Moreover, we found that diagnosis, more specifically aMCI, moderated the positive relationship between occipital network and Mini-Mental State Examination scores (pFWER < 0.05, Holm-Bonferroni correction). Our results showed GMV alterations in temporo-fronto-parieto-cerebellar networks in aMCI, extending previous results obtained with univariate approaches.

Allostatic load measures in older adults with subjective cognitive decline and mild cognitive impairment: A cross-sectional analysis from the Brazilian Memory and Aging Study

IntroductionAn increasing body of research suggests that stress and allostatic load are related to cognitive dysfunction and neurodegeneration. Objectivesto determine the relationship between allostatic load (AL) and cognitive status in older adults classified with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). MethodologyUsing the Brazilian Memory and Aging Study (BRAMS) database, we analyzed data from 57 older adults with SCD and MCI. Blood neuroendocrine (cortisol, DHEA-s), inflammatory (C-reactive protein, fibrinogen), metabolic (HbA1c, HDL-cholesterol, total cholesterol, creatinine), and cardiovascular (blood pressure, waist/hip ratio) were transformed into an AL index. ResultsDespite a significant difference in the univariate analysis between waist/hip ratio (0.94 in the MCI group vs. 0, 88 in the SCD group, p = 0.03), total cholesterol levels (194 vs. 160, p = 0.02), and AL index (36.9 % in the MCI group vs. 27.2 % in the SCD group, p = 0.04), AL was not associated with SCD or MCI in the multivariate analysis. ConclusionOur data suggest that different profiles of AL in MCI compared to individuals with SCD could be due to cofounding factors. These findings need to be confirmed in longitudinal studies investigating profiles of AL changes at preclinical and prodromal stages of Alzheimer’s disease.

A Strategy for Allowing Earlier Diagnosis and Rigorous Evaluation of BACE1 Inhibitors in Preclinical Alzheimer's Disease.

Given continued failure of BACE1 inhibitor programs at symptomatic and prodromal stages of Alzheimer's disease (AD), clinical trials need to target the earlier preclinical stage. However, trial design is complex in this population with negative diagnosis of classical hippocampal amnesia on standard memory tests. Besides recent advances in brain imaging, electroencephalogram, and fluid-based biomarkers, new cognitive markers should be established for earlier diagnosis that can optimize recruitment to BACE1 inhibitor trials in presymptomatic AD. Notably, accelerated long-term forgetting (ALF) is emerging as a sensitive cognitive measure that can discriminate between asymptomatic individuals with high risks for developing AD and healthy controls. ALF is a form of declarative memory impairment characterized by increased forgetting rates over longer delays (days to months) despite normal storage within the standard delays of testing (20-60 min). Therefore, ALF may represent a harbinger of preclinical dementia and the impairment of systems memory consolidation, during which memory traces temporarily stored in the hippocampus become gradually integrated into cortical networks. This review provides an overview of the utility of ALF in a rational design of next-generation BACE1 inhibitor trials in preclinical AD. I explore potential mechanisms underlying ALF and relevant early-stage biomarkers useful for BACE1 inhibitor evaluation, including synaptic protein alterations, astrocytic dysregulation and neuron hyperactivity in the hippocampal-cortical network. Furthermore, given the physiological role of the isoform BACE2 as an AD-suppressor gene, I also discuss the possible association between the poor selectivity of BACE1 inhibitors and their side effects (e.g., cognitive worsening) in prior clinical trials.

Shared and Specific Changes of Cortico-Striatal Functional Connectivity in Stable Mild Cognitive Impairment and Progressive Mild Cognitive Impairment.

Mild cognitive impairment (MCI), the prodromal stage of Alzheimer's disease, has two distinct subtypes: stable MCI (sMCI) and progressive MCI (pMCI). Early identification of the two subtypes has important clinical significance. We aimed to compare the cortico-striatal functional connectivity (FC) differences between the two subtypes of MCI and enhance the accuracy of differential diagnosis between sMCI and pMCI. We collected resting-state fMRI data from 31 pMCI patients, 41 sMCI patients, and 81 healthy controls. We chose six pairs of seed regions, including the ventral striatum inferior, ventral striatum superior, dorsal-caudal putamen, dorsal-rostral putamen, dorsal caudate, and ventral-rostral putamen and analyzed the differences in cortico-striatal FC among the three groups, additionally, the relationship between the altered FC within the MCI subtypes and cognitive function was examined. Compared to sMCI, the pMCI patients exhibited decreased FC between the left dorsal-rostral putamen and right middle temporal gyrus, the right dorsal caudate and right inferior temporal gyrus, and the left dorsal-rostral putamen and left superior frontal gyrus. Additionally, the altered FC between the right inferior temporal gyrus and right putamen was significantly associated with episodic memory and executive function. Our study revealed common and distinct cortico-striatal FC changes in sMCIs and pMCI across different seeds; these changes were associated with cognitive function. These findings can help us understand the underlying pathophysiological mechanisms of MCI and distinguish pMCI and sMCI in the early stage potentially.

A lack of drebrin causes olfactory impairment.

Olfactory deficit often occurs during the prodromal stage of Alzheimer's disease (AD). Although olfactory deficit is a useful measure for screening AD-related amnestic disorder, little is known about the cause of this deficit. Human and animal studies indicate that loss of the actin binding protein, drebrin, is closely related to cognitive dysfunction in AD. We hypothesized that the olfactory deficit in AD is caused by the loss of drebrin from the spine. To verify this hypothesis, we performed the buried food test in two types of drebrin knockout mice, such as drebrin-double (E and A) knockout (DXKO) mice, and drebrin A-specific knockout (DAKO) mice. The DXKO mice spent a significantly longer time to find food compared with the wild-type (WT) littermates. In contrast, the DAKO mice, in which drebrin E rather than drebrin A is expressed in the postsynaptic sites of mature neurons, spent an equivalent time trying to find food compared to that of the WT. The DXKO mice showed comparable food motivation and sensory functions other than olfaction, including visual and auditory functions. These results indicate that drebrin is necessary for normal olfactory function. Further study is needed to determine whether it is necessary for normal olfaction to express drebrin E during the developmental stage or to have drebrin (whether E or A) present after maturation.

CORRELATES OF MILD BEHAVIORAL IMPAIRMENT IN OLDER ADULTS WITH COGNITIVE DECLINE

Abstract Implementing early interventions in individuals with subjective cognitive decline and mild cognitive impairment during preclinical and prodromal stage of Alzheimer’s dementia spectrum, addresses modifiable risk factors thereby reducing potential dementia. Mild behavioral impairment (MBI) is considered as a potential predictor and prognostic marker for dementia. However, comprehensive reviews on how MBI is associated with other factors in these at-risk groups are limited. This scoping review identified and mapped associated factors of MBI on health outcomes among older adults with subjective cognitive decline and mild cognitive impairment. Following Joanna Briggs Institute methodology, we sourced studies from databases including PubMed (MEDLINE), CINAHL, Web of Science, EMBASE, PsycINFO, Cochrane, and SCOPUS, focusing on English-language publications published between January 2003 and July 2023. A total of 36 studies met the inclusion criteria. We classified MBI correlates identified from these studies into three categories: neurocognitive, physical, and psychosocial. Neurocognitive functions such as objective cognitive decline and progression to Alzheimer’s disease showed distinct health outcomes related to the MBI. Biomarkers including brain atrophy, beta-amyloid, and p-tau were found to be associated with MBI. Frailty, low gait speed, and hearing loss were physical functional outcomes associated with MBI. Studies on psychosocial aspects with MBI were limited, except one study demonstrating the relationship between caregiver burdens and MBI severity. This review underscores the importance of taking into account MBI and its correlates for developing tailored care approaches to prevent functional decline and improving health outcomes among older adults with subjective cognitive decline and mild cognitive impairment.

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 &gt; .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 &gt; .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.

Late positive potential component and cognitive functioning in occipital area of Mild Cognitive Impairment

AbstractBackgroundMild Cognitive Impairment (MCI) is a prodromal stage of Alzheimer’s disease and other dementias (Langa &amp; Levine, 2014). It has been suggested that a late event‐related potential (ERP) called the late positive potential (LPP) is related to cognitive functioning including sustained attention and reaction time in people with MCI (Waninger et al., 2018). The LPP in the occipital area was also suggested to be a biomarker of MCI (Liu et al., 2022). However, it remains unclear whether LPP in the occipital area is related to cognitive functioning.MethodWe collected EEG of 50 people with MCI (mean age 72.44±7.96; education: 5.52±1.07) by using a 20‐channel EEG recording system while participants performed the simple vigilance task (SVT). Their reaction time (ms) was taken as a measure of sustained attention. Vienna Reaction Time Task (VRTT) (Schuhfried GmbH, Moedling, Austria) was used to measure processing speed and inhibition while separating motor action (measured as a motor time) and cognitive processing (measured as a reaction time). Mini‐Mental State Examination (MMSE) was used to measure the severity of cognitive impairment (mean score: 26.20±2.44). Correlation analysis was used to analyze the liner relationship between the average LPP amplitude in the occipital areas (Oz, O1, and O2; time window: 400 to 800 ms after stimulus presentation), reaction time on the three versions of the VRTT, and reaction time on the SVT.ResultWe found significant correlations between reaction time on the SVT and motor time on VRTT (S1: p = 0.015; S2: p = 0.075; S3: p = 0.021;), but we found no significant correlations between reaction time on the SVT and VRTT (ps &gt; 0.193), no significant correlations between LPP amplitude in the occipital areas and reaction time on any of the tasks (SVT: p &gt; 0.056, VRTT: ps &gt; 0.288) or between LPP amplitude and motor time on any version of the VRTT (ps &gt; 0.500).ConclusionOur preliminary results indicate that LPP amplitude measured over the occipital area was not significantly associated with sustained attention or inhibition.

Alzheimer’s Disease genetic risk factor APoE 4 impact auditory processing in young adults

AbstractBackgroundRecent studies have suggested that prodromal stages of Alzheimer’s Disease (AD) are accompanied with central auditory system dysfunction, which may be used as early indicators of disease onset and progression. In AD patients of 60 years old and more and in APOE4 carriers, atypical patterns of oscillatory entrainment to repetitive sound transients have been reported and suggested as potential neuromarkers of AD. Whether such alterations of auditory functions relate to genetic risk factor of AD (APOE4) at an early age (&lt;30) is unknown.MethodWe used EEG recordings to measure auditory responses to repetitive sounds (1 second click trains presented at various frequencies (10‐250Hz) in 32 young neurotypical participants). To test whether auditory responsivity is affected by AD risk factor, we compared auditory brain responses from 17 APOE3 (age mean = 21.6, sd = 1.8) and 17 APOE4 carriers (age mean = 23.6, sd = 4.9).ResultComparing the magnitude of auditory event related potentials (ERP) we observed that APOE4 carriers exhibit slightly attenuated P2 and P3 ERP responses as well as delayed N1 and P2 ERP responses compared to APOE3 carriers. Focusing on Auditory Steady State Response (ASSR) power across frequencies (10‐90Hz), we observed that APOE3 carriers exhibit reliably larger neural entrainment than APOE4 carriers (Cohens’ d = 0.8, ‘large’ effect size). This difference was sustained across the peristimulus time course and did vary across stimulus frequencies.ConclusionOverall, these results suggest that central auditory differences can be detected very early in at‐risk populations. Studying these signals could help identify early AD pathology and provide an entry point for therapeutic interventions against neurodegeneration.

LAS‐Face‐ Name Associative Memory Exam: Discriminant validity for the detection of associative memory disorders in people with mild cognitive impairment in Argentina

AbstractBackgroundThe Latin American Spanish version of the Face‐Name Associative Memory Exam (LAS‐FNAME) is a validated version of the test that has been used to detect subtle cognitive changes in cognitively unimpaired adults at increased risk for Alzheimer’s disease (AD). Performance in this test has also been associated with markers of brain pathology in cognitively unimpaired older adults at increased risk for AD due to genetic factors or subjective cognitive decline (Papp et al., 2014;Vila‐Castelar et al., 2020). However, this test has not yet been used for the detection of Mild Cognitive Impairment (MCI) in the Latin American population. This study aims to analyze the discriminative validity and diagnostic performance of the LAS FNAME for the detection of verbal associative memory disorders in patients with MCI.MethodWe recruited 30 patients with MCI according to Petersen’s criteria (2010) and 20 healthy controls matched by age, sex and educational level. All participants completed the LAS‐FNAME, which consists of 12 learning trials of novel pairs of face‐names (immediate learning), followed by a delayed recall condition, and a neuropsychological assessment that included: Montreal Cognitive Assessment (MoCA), Craft Story 21, Multifactorial Memory Questionnaire (MMQ‐S) and a Functional Activity Questionnaire (FAQ).ResultThe groups did not differ in age, sex or education (p = 0.25, p = 0.54, p = 0.54). The age range was 61 to 86 years (M = 74.66; SD = 6.65) and the education range was 7 to 18 years (M = 14.63; SD = 3.41). The LAS‐FNAME showed an ability to discriminate against healthy controls from patients with MCI, both in its immediate (AUC = 0.81) and delayed (AUC = 0.79) conditions. The predictive ability was superior than a screening measure (MoCA, AUC = 0.74). The sensitivity and specificity was 68.4% and 89.3%, respectively. The LAS‐FNAME also showed evidence of concurrent validity with a standard memory test (Craft Story 21) in both immediate (r = 0.52, p&lt;0.01) and delayed (r = 0.63, p&lt;0.01) conditions, and reliability was excellent (α = 0.91).ConclusionPerformance on the LAS‐FNAME was able to distinguish MCI patients from healthy controls, suggesting that the LAS‐FNAME can detect early cognitive changes in prodromal stages of Alzheimer’s disease in Spanish‐speaking individuals.

A short‐hybrid scale for detecting anosognosia from the prodromal stage of Alzheimer’s disease

AbstractBackgroundWhile not originally developed for this purpose, evidence suggests that the Healthy Aging Brain Care Monitor questionnaire (HABC‐M; Monahan et al, 2012, 2014) may be a valuable instrument for assessing unawareness of cognitive decline (i.e., anosognosia) from preclinical stages of Alzheimer’s disease (AD) (Cacciamani et al, 2017). This is relevant because anosognosia may delay AD diagnosis and therapeutic interventions, with adverse consequences for patients and caregivers. However, several open questions remain: What is the actual effectiveness of this instrument across the AD spectrum? How do the cognitive, functional, and psychological subscales of the HABC‐M differ in their sensitivity to anosognosia in AD? Does the caregiver burden subscale provide additional information about AD patient’s anosognosia? The present study aimed to address these specific questions.MethodsThe HABC‐M was administered to 60 participants (30 AD patients and 30 healthy controls) and their partners (caregivers/informants). A measure of self‐awareness was then estimated by computing the discrepancy scores between the participants and their partners for the different subscales of HABC‐M (with the exception of the caregiver burden subscale, which is a caregiver‐exclusive questionnaire). To evaluate whether these measures can discriminate between patients at different stages of AD and controls, we fit linear models adjusted for age, sex, and education, and computed receiver operating characteristic curves.ResultsAll HABC‐M discrepancy scores, as well as the caregiver burden score, were able to discriminate controls from patients in distinct AD stages. For best performance, the area‐under‐curve for the HABC‐M cognitive subscale discriminated prodromal AD versus controls with a value 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden score raised it to 0.94 [0.86;0.99].ConclusionThe HABC‐M cognitive subscale (six items) can detect anosognosia from the earliest stages of AD. Separately, the caregiver burden subscale (four items) may corroborate the suspicion of anosognosia. A short‐hybrid scale combining these 10 items, instead of the 31 items of the total HABC‐M questionnaire, could provide a practical and efficient instrument for detection of anosognosia in the clinical setting. Importantly, such an instrument could further contribute to a timely AD diagnosis.

Fluid Biomarkers of Neurodegeneration in Mild Cognitive Impairment: A Meta‐Analysis

AbstractBackgroundMild cognitive impairment (MCI) is a well‐established prodromal stage of Alzheimer’s disease and is often accompanied by early signs of neurodegeneration (e.g., neuronal loss) that may influence subsequent prognosis. To facilitate a better characterization of the underlying neuropathology, a thorough investigation of proteins associated with neurodegenerative processes in MCI is needed. Thus, the present study systematically assessed the available literature to quantitatively evaluate cerebrospinal fluid (CSF) and peripheral blood concentrations of biomarkers related to neurodegeneration in individuals with MCI compared to healthy controls (HCs).MethodOriginal peer‐reviewed articles that assessed the following CSF and/or peripheral biomarkers: neurofilament light chain (NFL), total‐tau (T‐tau), glial fibrillary acidic protein (GFAP), heart‐type fatty acid binding protein (HFABP), neuron‐specific enolase (NSE), and S100 calcium‐binding protein B (S100B) in both MCI and HCs were included for meta‐analysis. Standardized mean differences (SMDs) and 95% confidence intervals were calculated using a random‐effects model. Heterogeneity was assessed using the I2 statistic.ResultA total of 109 study cohorts were included in the meta‐analysis. In CSF, concentrations of NFL (MCI n = 2771, HC n = 4263, SMD [95% CI] = 0.69 [0.56, 0.83], p &lt; 0.001), GFAP (MCI n = 513, HC n = 1620, SMD [95% CI] = 0.41 [0.08, 0.74], p = 0.02), and HFABP (MCI n = 363, HC n = 245, SMD [95% CI] = 0.57 [0.23, 0.55], p &lt; 0.001) were elevated in MCI. In peripheral blood, concentrations of NFL (MCI n = 6520, HC n = 9439, SMD [95% CI] = 0.41 [0.32, 0.49], p &lt; 0.001), T‐tau (MCI n = 4463, HC n = 5921, SMD [95% CI] = 0.19 [0.09, 0.29], p &lt; 0.001), and GFAP (MCI n = 1758, HC n = 3179, SMD [95% CI] = 0.39 [0.23, 0.55], p &lt; 0.001) were increased in MCI. Significant heterogeneity was identified for all comparisons and was explored through meta regression and subgroup analysis.ConclusionThe present study identified several fluid biomarkers of neurodegeneration in MCI. Importantly, elevated biomarker levels can be detected in both CSF and less‐invasively through peripheral blood. Future studies should focus on assessing the clinical utility of monitoring these biomarkers as they may provide further insight into neuronal and astroglial pathology occurring in the early stages of cognitive decline.

Resting‐state network connectivity changes in prodromal stage of Alzheimer’s disease

AbstractBackgroundAlzheimer Disease (AD), the most common type of dementia, is accompanied by a generalized loss of neurons and cause severe changes in brain’s structure and function. Mild Cognitive Impairment is associated with a higher risk of developing dementia. This clinical classification is particularly relevant because each subtype is linked to a presumed etiology, with the amnestic subtypes (aMCI) considered as a prodromal form of AD (Petersen et al., 2009, 2014). Resting state fMRI functional connectivity (FCrs‐fMRI) analysis is broadly used to detect brain network differences in neurodegenerative diseases such as AD.MethodForty‐five participants were evaluated: patients with aMCI (n = 17), patients with dementia due to AD (n = 14) and healthy controls (HC) (n = 14). All participants received an extensive neuropsychological battery and brain MRI scanning. Resting state functional scans consisted of 240 T2*‐weighted echo planar imaging volumes (repetition time 3000 ms; echo time 60 ms; ip angle 90°; 32 axial slices; matrix 64×64; voxel size 3.3×3.4×4 mm). Additionally, a high‐resolution T1‐weighted magnetization prepared rapid acquisition gradient echo image was acquired. Data analyses were performed using the Functional Connectivity Toolbox (CONN) for Matlab (https://www.nitrc.org/frs/) to identify large‐scale patterns of temporal signal‐intensity coherence, interpreted as functional connectivity (Beckmann et al., 2005). Regions of interests (ROIs) analysis was performed for each participants and among group. Spatial maps of the group independent component analysis were used in a linear model t against each individual fMRI data set.ResultThe Default Mode Network (DMN) showed two regions of lower functional connectivity (FC) in AD when comparing with HC within the precuneus (p&lt;0.001 uncorrected). No regions of FC changes were found in the DMN when comparing aMCI with HC or AD.ConclusionThe changes in FC rsfMRI in adults with AD are specifically related to regions of the DMN.

Brain Age Estimation on a Dementia Cohort Using FLAIR MRI Biomarkers.

The prodromal stage of Alzheimer's disease presents an imperative intervention window. This work focuses on using brain age prediction models and biomarkers from FLAIR MR imaging to identify subjects who progress to Alzheimer's disease (converting mild cognitive impairment) or those who remain stable (stable mild cognitive impairment). A machine learning model was trained to predict the age of normal control subjects on the basis of volume, intensity, and texture features from 3239 FLAIR MRI volumes. The brain age gap estimation (BrainAGE) was computed as the difference between the predicted and true age, and it was used as a biomarker for both cross-sectional and longitudinal analyses. Differences in biomarker means, slopes, and intercepts were investigated using ANOVA and Tukey post hoc test. Correlation analysis was performed between brain age gap estimation and established Alzheimer's disease indicators. The brain age prediction model showed accurate results (mean absolute error = 2.46 years) when testing on held out normal control data. The computed BrainAGE metric showed significant differences between the stable mild cognitive impairment and converting mild cognitive impairment groups in cross-sectional and longitudinal analyses, most notably showing significant differences up to 4 years before conversion to Alzheimer's disease. A significant correlation was found between BrainAGE and previously established Alzheimer's disease conversion biomarkers. The BrainAGE metric can allow clinicians to consider a single explainable value that summarizes all the biomarkers because it considers many dimensions of disease and can determine whether the subject has normal aging patterns or if he or she is trending into a high-risk category using a single value.

Topological properties analysis and identification of mild cognitive impairment based on individual morphological brain network connectome.

Mild cognitive impairment is considered the prodromal stage of Alzheimer's disease. Accurate diagnosis and the exploration of the pathological mechanism of mild cognitive impairment are extremely valuable for targeted Alzheimer's disease prevention and early intervention. In all, 100 mild cognitive impairment patients and 86 normal controls were recruited in this study. We innovatively constructed the individual morphological brain networks and derived multiple brain connectome features based on 3D-T1 structural magnetic resonance imaging with the Jensen-Shannon divergence similarity estimation method. Our results showed that the most distinguishing morphological brain connectome features in mild cognitive impairment patients were consensus connections and nodal graph metrics, mainly located in the frontal, occipital, limbic lobes, and subcortical gray matter nuclei, corresponding to the default mode network. Topological properties analysis revealed that mild cognitive impairment patients exhibited compensatory changes in the frontal lobe, while abnormal cortical-subcortical circuits associated with cognition were present. Moreover, the combination of multidimensional brain connectome features using multiple kernel-support vector machine achieved the best classification performance in distinguishing mild cognitive impairment patients and normal controls, with an accuracy of 84.21%. Therefore, our findings are of significant importance for developing potential brain imaging biomarkers for early detection of Alzheimer's disease and understanding the neuroimaging mechanisms of the disease.

26 Religious Stress Coping, Memory, and Markers of Brain Pathology in Individuals with Autosomal Dominant Alzheimer’s Disease from the Colombia-Boston Biomarker Study

Objective:High levels of stress may increase risk for Alzheimer’s disease (AD) dementia. Religious coping practices to deal with stress (i.e., prayer, having faith, attending religious services) may reduce risk of dementia. Studying religious stress coping in cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia later in life, may inform us about the role of religious coping in modifying the clinical trajectory from preclinical to clinical stages of the disease. We examined religious stress coping in cognitively unimpaired mutation carriers from the world’s largest ADAD kindred and its relation to markers of brain pathology and memory.Participants and Methods:16 cognitively unimpaired Presenilin-1 E280A mutation carriers and 19 age and education-matched noncarrier family members from the Colombia-Boston (COLBOS) Biomarker Study were included. A subsample (n=26; 13 cognitively unimpaired carriers) underwent amyloid and tau PET imaging. Participants completed the Coping Strategies Questionnaire (CAE) that includes a subscale used to assess religious stress coping, where a higher score indicates more coping, and underwent memory testing using the Free and Cued Selective Reminding Test (FCSRT). The Geriatric Depression Scale (GDS) was used to assess depression. Mann-Whitney U tests were used to examine group differences in religious stress coping, brain pathology (i.e., cortical amyloid-beta, entorhinal and precuneus tau), memory, and depression. Nonparametric correlations were used to examine associations among religious stress coping, age, education, depression, memory, and pathology.Results:Carriers had poorer FCSRT immediate free recall than noncarriers (U=84.5, p=.024). There was no difference between groups in CAE religious stress coping, other FCSRT memory scores, nor GDS score (all p&gt;.05). Compared to non-carriers, carriers had more cortical amyloid (U=152.0, p&lt;.001) and more precuneus tau (U=123.0, p=.05). In carriers, religious stress coping was positively associated with education (r=.57, p=.022), FCSRT immediate free recall (a=.75, p&lt;.001), FCSRT cued recall (a=.50, p=.047), and FCSRT delayed recall (r=.52, p=.038). After controlling for education, religious stress coping remained positively associated with FCSRT immediate free recall (r=.65, p=.009), but not other FCSRT memory scores (all p&gt;.05). Religious stress coping was not associated with age or GDS score regardless of controlling for education (all p&gt;.05). In carriers, religious stress coping was negatively associated with entorhinal tau (r=-.73, p=.005) and precuneus tau burden (r=-.58, p=.037). The association between religious stress coping and entorhinal tau remained significant after controlling for education (r=-.67, p=.016), but not precuneus tau (p&gt;.05). Religious stress coping was not associated with cortical amyloid regardless of controlling for education in carriers (all p&gt;.05). None of the associations with brain pathology or memory were significant in the non-carrier group.Conclusions:Religious stress coping was associated with better memory performance and a low AD pathology burden in individuals at genetic risk for developing AD dementia. Future studies with independent and larger samples should further examine religious stress coping strategies and their associations with other AD-related biomarkers, as well as with other risk and protective factors to better understand their role at the preclinical and prodromal stages of Alzheimer’s disease.

Detecting Anosognosia from the Prodromal Stage of Alzheimer's Disease.

Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer's disease (AD). Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia. The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects' estimation of their performances in a computerized experiment. The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis.