Prodromal Stage Of Alzheimer's Disease Research Articles

Impact of transcranial direct current stimulation on white matter microstructure integrity in mild cognitive impairment patients according to effect modifiers as risk factors for Alzheimer's disease.

Little research exists on how individual risk factors for Alzheimer's disease (AD) affect the intermediate phenotype after transcranial direct current stimulation (tDCS), despite the importance of precision medicine-based therapeutic approaches. To determine how an application of sequential tDCS (2 mA/day, left dorsolateral prefrontal cortex, 10 sessions) affects changes in white matter (WM) microstructure integrity in 63 mild cognitive impairment (MCI) patients with effect modifiers such as Aβ deposition, APOE ε4 carrier status, BDNF Val66Met polymorphism status, and sex. We examined individual effect modifier-by-tDCS interactions and multiple effect modifiers-by-tDCS interactions for diffusion metrics. We also evaluated the association between baseline Aβ deposition and changes in WM microstructure integrity following tDCS. We found that APOE ε4 carrier status and sex had a significant interaction with tDCS, resulting in increased fractional anisotropy (FA) in the right uncinate fasciculus (UF) after stimulation. Additionally, we observed multiple effect modifiers-by-tDCS interactions on WM integrity of the right UF, leading to a more pronounced increase in FA values in APOE ε4 carriers and females with Val66 homozygotes. Finally, baseline Aβ deposition was positively associated with a difference in FA of the left cingulum in the hippocampal area, which showed a positive association with the changes in the score for delayed memory. Our study shows the differential impact of individual AD risk factors on changes in the early intermediate phenotype after sequential tDCS in MCI patients. This research emphasizes the importance of precision medicine approaches in tDCS for the prodromal stages of AD.

AT(N) biomarker profiles and Alzheimer's disease symptomology in Down syndrome.

Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [11 C]Pittsburgh compound B) and tau (10 mCi of [18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory. Analyses included 162 adults with DS (aged M=38.84 years, standard deviation=8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. Findings add to understanding of AT(N) biomarker profiles in DS. Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS.

The effect of plasma cortisol on hippocampal atrophy and clinical progression in mild cognitive impairment.

Both elevated cortisol and hippocampal volume have been linked to an increased risk for the development of Alzheimer's disease (AD). This longitudinal study assessed the effects of plasma cortisol on hippocampal atrophy and clinical progression rates in patients with mild cognitive impairment (MCI). Patients with amnestic MCI (n=304) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on availability of baseline plasma cortisol and hippocampal volume measures, assessed at baseline and during follow-ups. We investigated associations between plasma cortisol, hippocampal volume, and risk of clinical progression to AD over a study period of up to 100 months (mean follow-up time 36.8 months) using linear mixed models, Cox proportional hazards models, and Kaplan-Meier estimators. Plasma cortisol predicted greater hippocampal atrophy, such that participants with higher cortisol showed faster decline in hippocampal volume over time (interaction: β=-0.15, p=0.004). Small hippocampal volume predicted a higher risk of clinical progression to AD (haard ratio [HR]=2.15; confidence in terval [CI], 1.64-2.80; p<0.001). A similar effect was not found for cortisol (HR=1.206; CI, 0.82-1.37; p=0.670) and there was no statistical evidence for an interaction between hippocampal volume and cortisol on clinical progression (HR=0.81; CI, 0.57-0.17; p=0.260). Our findings suggest that higher cortisol predicts higher hippocampal atrophy, which in turn is a risk factor for progression to AD. Regulation of the hypothalamic-pituitary-adrenal axis through stress-reducing lifestyle interventions might be a protective factor against hippocampal degeneration at the prodromal stage of AD.

Olfactory memory in mild cognitive impairment and Alzheimer's disease.

Olfaction is impaired in Alzheimer's disease (AD). However, olfactory memory has rarely been examined. As the pathogenesis of AD remains largely unknown, collecting more data regarding the occurrence and progression of its symptoms would help gain more insight into the disease. To investigate olfactory memory and its relationship with verbal memory and other clinical features in patients with early-stage AD. Three groups of participants were enrolled in this study: patients with mild dementia due to AD (MD-AD, N = 30), patients with mild cognitive impairment due to AD (MCI-AD, N = 30), and cognitively normal older participants (CN, N = 30). All participants underwent cognitive evaluation (Clinical Dementia Rating scale, Mini Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale, delayed verbal recall, and verbal fluency tests) and assessment of olfactory immediate and delayed recognition memory. Olfactory immediate and delayed recognition memory scores were significantly lower in the MD-AD group than in the MCI-AD and CN groups. The MCI-AD and CN groups did not differ significantly [in both cases, Kruskal-Wallis test, p < 0.05; post hoc analysis revealed significant differences between the MD-AD and MCI-AD groups and between the MD-AD and CN groups (p < 0.05), and no significant difference between the MCI-AD and CN groups (p > 0.05)]. Verbal immediate recall, delayed recall after 5 min, and delayed recall after 30 min scores were significantly worse in the MD-AD and MCI-AD groups than in the CN group. MD-AD and MCI-AD groups did not differ significantly [in all cases Kruskal-Wallis test, p < 0.05; post hoc analysis revealed significant differences between MD-AD and CN groups, and MCI-AD and CN groups (p < 0.05) and no significant difference between MD-AD and MCI-AD groups (p > 0.05)]. Duration of AD symptoms was a strong predictor of both immediate and delayed olfactory recognition memory scores. Olfactory memory impairment was observed in patients with AD. The changes progress during the course of the disease. However, unlike verbal memory, olfactory memory is not significantly impaired in the prodromal stage of AD.

APOEε4 genotype boosts neurodegenerative structural changes in medial temporal lobe areas in adults with Mild Cognitive Impairment

AbstractBackgroundApolipoprotein E ε4 allele (APOEε4) is considered the major genetic risk factor of Alzheimer´s Disease (AD). Structural magnetic resonance imaging (sMRI) studies demonstrated that, compared to APOEε4 non‐carriers, APOEε4 carriers display structural changes in lateral and medial temporal lobe (MTL). However, the knowledge about the impact of this genotype on hippocampal subfields is still limited. The present sMRI study aimed to evaluate volumetric and cortical thickness differences between adults with mild cognitive impairment (MCI) APOEε4 non‐carriers compared with MCI‐APOEε4 carriers.MethodTwelve MCI‐APOEε4 non‐carriers (mean age: 70.33 years, SD: 5.12) and ten MCI‐APOEε4 carriers (mean age: 72.70 years, SD: 6.38), diagnosed as MCI according Petersen criteria (Petersen, 2004; Albert et al., 2011), underwent neuropsychological assessment, cerebrospinal fluid, genetic and MRI examinations. MRI surface‐based morphometry analyses was conducted with the FreeSurfer software to evaluate volumetric and thickness differences in the hippocampal subfields and its surrounding MTL areas.ResultCompared with MCI‐APOEε4 non‐carriers, the MCI‐APOEε4 carriers group showed a significant reduced volume in several areas of the left hemisphere. Specifically, in this hemisphere volumetric changes were found in the entorhinal cortex, the whole hippocampus and in its head, body and tail; the head of presubiculum, the head and body of subiculum, the CA1, CA3, CA4 subfields, the granulate cell of the molecular layer of dentate gyrus and the molecular layer of the hippocampus. This group also displayed a significant reduced volume in the right body of CA3 subfield.ConclusionThese results suggest that, in MCI adults, the presence of the APOEε4 genotype may have an additional neuropathological impact on the structure of brain regions of the MTL with a critical functional role in episodic memory, the most affected neurocognitive system in Alzheimer’s disease (AD). Particularly, the left MTL would show higher vulnerability to neurodegenerative changes in the prodromal stage of AD.

The time-dependent impact of type 2 diabetes mellitus on incident prodromal Alzheimer's disease: a longitudinal study in 1395 participants.

To investigate the longitudinal impact of type 2 diabetes mellitus (T2DM) on the prodromal and dementia stages of Alzheimer's disease (AD), focusing on diabetes duration and other comorbidities. 1395 dementia-free individuals aged 55-90 years with a maximum 15-year follow-up data were enrolled from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of the incidence of prodromal or dementia stages of AD. Longer T2DM duration (≥5 years) (multi-adjusted HR=2.19, 95% CI=1.05-4.58), but not shorter T2DM duration (<5 years), was associated with a significantly increased risk of incident prodromal AD over a mean follow-up of 4.8 years. APOE ε4 alleles (HR=3.32, 95% CI=1.41-7.79) and comorbid coronary artery disease (CAD) (HR=3.20, 95% CI=1.29-7.95) further increased the risk of incident prodromal AD in patients with T2DM. No significant association was observed between T2DM and conversational risk of progression from prodromal AD to AD dementia. T2DM, which is characterized by a longer duration, increases the incidence risk of prodromal AD but not AD dementia. APOE ε4 allele and comorbid CAD strengthen the relationship between T2DM and prodromal AD. These findings highlight T2DM characteristics and its comorbidities as predictors for accurate prediction of AD and screening of at-risk populations.

Spectral power ratio as a measure of EEG changes in mild cognitive impairment due to Alzheimer’s disease: a case-control study

Adopting preventive strategies in individuals with subclinical Alzheimer’s disease (AD) has the potential to delay dementia onset and reduce healthcare costs. Thus, it is extremely important to identify inexpensive, scalable, sensitive, and specific markers to track disease progression. The electroencephalography spectral power ratio (SPR: the fast to slow spectral power ratio), a measure of the shift in power distribution from higher to lower frequencies, holds potential for aiding clinical practice. The SPR is altered in patients with AD, correlates with cognitive functions, and can be easily implemented in clinical settings. However, whether the SPR is sensitive to pathophysiological changes in the prodromal stage of AD is unclear. We explored the SPR of individuals diagnosed with amyloid-positive amnestic mild cognitive impairment (Aβ+aMCI) and its association with both cognitive function and amyloid load. The SPR was lower in Aβ+aMCI than in the cognitively unimpaired individuals and correlated with executive function scores but not with amyloid load. Hypothesis-generating analyses suggested that aMCI participants with a lower SPR had an increased probability of a positive amyloid positron emission tomography. Future research may explore the potential of this measure to classify aMCI individuals according to their AD biomarker status.

Plasma p-tau181 as a promising non-invasive biomarker of Alzheimer’s Disease pathology in Subjective Cognitive Decline. (P7-6.001)

<h3>Objective:</h3> To explore plasma phosphorylated tau (p-tau) 181 levels in Subjective Cognitive Decline and to investigate its role as a potential biomarker for Alzheimer’s Disease (AD) in Subjective Cognitive Decline (SCD). <h3>Background:</h3> One of the greatest challenges in AD is the discovery of new non-invasive, sensitive and specific biomarkers, which might be useful in the early stages such as SCD. Plasma p-tau181 is becoming increasingly notable in prodromal stages of AD, as a valuable marker for tauopathy, one of the core features of AD. <h3>Design/Methods:</h3> We included 27 SCD patients, who underwent clinical evaluation, neuropsychological assessment, Apolipoprotein E (APOE) genotyping, plasma p-tau181 analysis with SiMoA assay and cerebrospinal fluid (CSF) biomarkers analysis (Aβ1–42, Aβ1–42/1–40, p-tau, t-tau).Patients were rated according to A/T(N) system and classified as carrier of AD pathology (AP+) when A+ was associated with either T+ or N+, or non-carriers (AP−) when they were classified as A− (regardless of T and N classification), or A+/T−/N−. <h3>Results:</h3> Plasma p-tau181 levels were correlated with CSF p-tau (ϱ=0.819, <i>p</i>&lt;0.001) and also with age (ϱ=0.605, <i>p</i>=0.001), CSF Aβ1–42 (ϱ= −0.461, <i>p</i>=0.012), CSF Aβ1–42/1–40 (ϱ= −0.770, <i>p</i>&lt;0.001) and CSF t-tau (ϱ=0.535, <i>p</i>=0.009). A multivariate linear regression analysis showed that plasma p-tau181 were significantly associated only with CSF p-tau levels (<i>p</i>=0.027). When comparing AP+ and AP− subgroups, we found that plasma p-tau181 levels were significantly higher in the former group (2.85±0.53 vs 1.75±.66, <i>p</i>&lt;0.001). A ROC curve analysis demonstrated that plasma p-tau181 was highly accurate for discriminating between AP+ and AP− SCD patients (AUC = 0.908). <h3>Conclusions:</h3> Plasma p-tau181 levels strongly correlated with CSF p-tau. Plasma p-tau showed a high accuracy in differentiating SCD patients who were carriers from SCD patients who were non-carriers of AD pathology. Our preliminary results suggest that plasma p-tau181 might be a promising noninvasive biomarker of AD pathology which might be useful in preclinical stage of AD. <b>Disclosure:</b> Ms. Giacomucci has nothing to disclose. Mr. Mazzeo has nothing to disclose. Dr. Bagnoli has nothing to disclose. Dr. Ingannato has nothing to disclose. Sonia Padiglioni has nothing to disclose. Sandro Sorbi has nothing to disclose. Valentina Bessi has nothing to disclose. Benedetta Nacmias has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier.

Properties of odor identification testing in screening for early-stage Alzheimer’s disease

Odor identification (OI) is impaired in the early stages of Alzheimer’s disease (AD). However, data regarding the diagnostic properties of OI tests are lacking, preventing their clinical use. We aimed to explore OI and determine the accuracy of OI testing in screening for patients with early AD. In total, 30 participants with mild cognitive impairment due to AD (MCI-AD), 30 with mild dementia due to AD (MD-AD), and 30 cognitively normal elderly participants (CN) were enrolled, and cognitive examination (CDR, MMSE, ADAS-Cog 13, and verbal fluency tests) and assessment of OI (Burghart Sniffin’ Sticks odor identification test) were performed. MCI-AD patients scored significantly worse in OI than CN participants, and MD-AD patients had worse OI scores than MCI-AD patients. The ratio of OI to ADAS-Cog 13 score had good diagnostic accuracy in differentiating AD patients from CN participants and in differentiating MCI-AD patients from CN participants. Substitution of ADAS-Cog 13 score with the ratio of OI to ADAS-Cog 13 score in a multinomial regression model improved the classification accuracy, especially of MCI-AD cases. Our results confirmed that OI is impaired during the prodromal stage of AD. OI testing has a good diagnostic quality and can improve the accuracy of screening for early-stage AD.

Early Detection of Alzheimer's Disease-Related Pathology Using a Multi-Disease Diagnostic Platform Employing Autoantibodies as Blood-Based Biomarkers.

Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78-0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93-0.99) and overall accuracy (93.0%). Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD.

The interplay between micro RNAs and genetic liability to Alzheimer‘s Disease on memory trajectories in the general population

Deficits in cognitive function and memory are common early symptoms of neurodegenerative disorders, such as Alzheimer's Disease (AD). Several studies have discussed micro RNAs (miRNAs) as potential epigenetic early detection biomarkers. In a longitudinal general population sample (n = 548) from the Study of Health in Pomerania, we analyzed the associations between 167 baseline miRNA levels and changes in verbal memory scores with a mean follow-up time of 7.4 years. We additionally assessed the impact of an individual‘s genetic liability for AD on verbal memory scores in n = 2,334 subjects and a possible interactions between epigenetic and genetic markers. Results revealed two miRNAs associated with changes in immediate verbal memory over time. In interaction analyses between miRNAs and a polygenic risk score for AD, five miRNAs showed a significant interaction effect on changes in verbal memory. All of these miRNAs have previously been identified in the context of AD, neurodegeneration or cognition. Our study provides candidate miRNAs for a decline in verbal memory as an early symptom of neurodegeneration and AD. Further experimental studies are needed to verify the diagnostic value of these miRNA markers in the prodromal stage of AD.

The β-adrenergic hypothesis of synaptic and microglial impairment in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease originating partly from amyloid β protein-induced synaptic failure. As damaging of noradrenergic neurons in the locus coeruleus (LC) occurs at the prodromal stage of AD, activation of adrenergic receptors could serve as the first line of defense against the onset of the disease. Activation of β2 -ARs strengthens long-term potentiation (LTP) and synaptic activity, thus improving learning and memory. Physical stimulation of animals exposed to an enriched environment (EE) leads to the activation of β2 -ARs and prevents synaptic dysfunction. EE also suppresses neuroinflammation, suggesting that β2 -AR agonists may play a neuroprotective role. The β2 -AR agonists used for respiratory diseases have been shown to have an anti-inflammatory effect. Epidemiological studies further support the beneficial effects of β2 -AR agonists on several neurodegenerative diseases. Thus, I propose that β2 -AR agonists may provide therapeutic value in combination with novel treatments for AD.

Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear. We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression. We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from the Alzheimer's Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer's Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression. We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤0.8. Based on the linkage disequilibrium clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year progression to AD from MCI significantly increased the predictive accuracy. Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway.

Altered Feedback-Related Negativity in Mild Cognitive Impairment

Feedback-related negativity (FRN) is electrical brain activity related to the function of monitoring behavior and its outcome. FRN is generated by negative feedback input, such as punishment or monetary loss, and its potential is distributed maximally over the frontal-central part of the skull. Our previous study demonstrated that FRN latency was delayed and that the amplitude was increased in patients with mild Alzheimer's disease (AD). As mild cognitive impairment (MCI) is considered to be a prodromal stage of AD, we speculated that FRN would also be altered in MCI, as in AD. The aim of this study is to examine whether MCI patients showed changes in FRN during a gambling task. Thirteen MCI patients and thirteen age-matched healthy elderly individuals participated in a simple gambling task and underwent neuro-psychological assessments. The participants were asked to choose one out of two options and randomly received positive or negative feedback to their response. An EEG was recorded during the task, and FRN was obtained by subtracting the positive feedback-related activity from the negative feedback-related activity. The reaction time to probe stimuli was comparable in the two groups. The group comparisons revealed that the FRN amplitude was significantly larger for the MCI group than for the healthy elderly (F(1,24) = 6.4, ηp2 = 0.22, p = 0.019), but there was no group difference in the FRN latency. The FRN amplitude at the frontocentral electrode positively correlated with the mini-mental state examination score (Spearman's rhopartial = 0.41, p = 0.043). The finding of increased FRN amplitude in MCI was consistent with the previous finding in AD. Our findings indicate that monitoring dysfunction might also be involved in the prodromal stage of dementia.

Vitamin D and inflammatory cytokines association in mild cognitive impaired subjects

BackgroundMild cognitive impairment (MCI) is a prodromal stage of Alzheimer’s disease (AD). The association of low Vitamin D and chronic inflammation in the onset of cognitive decline in the elderly population has been established but the variable population-based study is still lacking. MethodologyThe present study aims to investigate the level of plasma Vitamin D, pro-inflammatory cytokines IL-1β, IL-6, TNF-α, cognitive performance, and white matter changes in the elderly population in the North-Eastern part of Uttar Pradesh, India. Results70 participants with (Mean age- 75.14 ± 1.24, Male/Female- 50/20) with an Mini Mental State Examination (MMSE) score of (24.82 ± 1.82) and Montreal Cognitive Assessment Test (MOCA) score (21.83 ± 1.75), were cognitive decline, against the 70 healthy controls (Mean Age-73.18 ± 1.43; Male/Female- 50/20) with MMSE score (28.1 ± 1.5) and MOCA (28.5 ± 1.65), White matter variable Fractional Anisotropy (FA) and Apparent Diffusion Coefficient (ADC) values in MCI subject was found significantly altered in Right temporal lobe, Corpus Callosum (Right) and Hippocampus body (Right), Hippocampus body (left), Hippocampus head (Right) and Hippocampus head (Left)as compared with healthy controls. The level of cytokines IL-1β, IL-6, TNF-α, was significantly high in MCI subjects as compared with controls. Further lower Vitamin D level in plasma was detected in MCI as compared with healthy controls. ConclusionThe result from the present study depicts that chronic inflammation and lower Vitamin D level influences neurodegeneration and decline in cognitive performance in the elderly population. These variables can be used as biomarkers for early identification of AD and interventional strategies can be designed for prevention at the prodromal stage of AD.

Efficacy and safety of Kami‐guibi‐tang for mild cognitive impairment: a pilot, randomized, double‐blind, placebo‐controlled trial

AbstractBackgroundMild cognitive impairment (MCI) is considered an intermediate phase between normal aging and dementia. As the majority of cases of amnestic MCI (aMCI) progress to Alzheimer’s disease (AD), it is considered the prodromal stage of AD, and a treatment target for prevention of further cognitive decline. However, no medications have been shown to have symptomatic or preventive benefits in MCI. Kami‐guibi‐tang (KGT) is a traditional herbal formula used in Korean medicine to treat amnesia, which is reported to increase acetylcholine levels via activation of choline acetyltransferase. The objective of this study was to evaluate the efficacy and safety of KGT in patients with aMCI.MethodThis study was designed as a single‐center, randomized, double‐blind, placebo‐controlled pilot study. Participants diagnosed with aMCI were randomized to receive either KGT or placebo granules for 24 weeks. The efficacy measure was a change in the Seoul Neuropsychological Screening Battery (SNSB) score. The safety measures included the occurrence of adverse events and abnormalities in vital signs and blood chemistry, electrocardiogram (ECG), and brain magnetic resonance imaging (MRI) findings.ResultA total of 16 patients in the KGT group and 14 patients in the placebo group were investigated in the study. The mean score of Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) significantly improved from 1.53 (0.64) points to 1.13 (0.62) points in the KGT group (p = 0.010), whereas it worsened from 1.61 (0.88) points to 1.75 (0.94) points in the placebo group. There was a significant difference in the CDR‐SB scores between the two groups after the intervention (p = 0.045). The total SNSB‐D scores and the scores in the memory domain after the treatment were significantly higher than the baseline values in the KGT group, but not in the placebo group. The frequency of adverse events was not significantly different between the two groups, and there were no abnormalities in vital signs or blood test, ECG, and brain MRI findings after the intervention.ConclusionKGT may provide a safe and effective treatment option for patients with aMCI. Further studies with a larger sample size are needed to validate the findings.

Reduced density of cholinergic fibers in App knock‐in mouse models of Aβ amyloidosis

AbstractBackgroundCholinergic system is critical for learning, memory, attention, and other cognitive functions. Nucleus basalis of Meynert (NBM) is a nucleus containing the cell bodies of cholinergic neurons in the brain and is severely affected by Alzheimer’s disease (AD). Significant loss of forebrain cholinergic projections is evident at prodromal stage of AD, and, along with locus coeruleus (LC), NBM neurons are among the first to display neurofibrillary tangle, suggesting that abnormality in cholinergic system is involved in the early stage of AD pathogenesis. Acetylcholinesterase inhibitors have been used for symptomatic treatment to improve cognitive function, however, mechanisms underlying neurodegeneration in cholinergic system remain elusive. We have previously reported that AppNL‐G‐F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited cognitive deficits, severe neuroinflammation and significant loss of LC noradrenergic fibers accompanied by massive amyloid‐β (Aβ) pathology. In this study, we asked whether and how cholinergic system is altered in AppNL‐G‐F mice.MethodTo ask whether AppNL‐G‐F mice exhibit cholinergic degeneration, we compared the density of vesicular acetylcholine transporter (VAChT)‐positive fibers in the cortex and hippocampus as well as the number of choline acetyltransferase (ChAT)‐positive neurons in the NBM between AppNL‐G‐F and wild‐type (WT) C57BL/6J mice at 24 months of age. We also examined whether tau pathology occurs in the cholinergic system in these mice.ResultHistochemical analyses revealed that 24‐month‐old AppNL‐G‐F mice exhibited significant decreases in the density of VAChT‐positive fibers in the cortex and the hippocampal CA1, the regions associated with learning and memory, compared to WT mice.ConclusionThis study demonstrates that Aβ pathology is sufficient to reduce the density of cholinergic fibers. Quantitative analyses of cell loss and tau accumulation in ChAT‐positive neurons in the NBM are currently underway, and we will present these results at the meeting.

Volumetry of the Olfactory‐Related Structure as a New Biomarker of Individuals at Risk of Alzheimer Disease? Results From the CIMA‐Q Cohort

AbstractBackgroundHippocampal and entorhinal atrophies are used as gold‐standard biomarkers of the prodromal stage of Alzheimer's disease (AD). These atrophies are related to episodic memory deficits found in individuals with mild cognitive impairment (MCI). Olfactory deficits have been identified as clinical biomarkers of AD and found in individuals with MCI. Olfactory‐related structures such as the primary olfactory cortex (POC) were found to be atrophied in patients with AD. The aim of this study was to evaluate if the atrophy of hippocampal and entorhinal regions in individuals with MCI was accompanied with the atrophy of the POC regions.MethodUsing voxel‐based morphometry (VBM), we compared hippocampal, entorhinal and POC’s grey matter volume between a group of 93 participants with memory complaint (mean age: 72.15, SD: 4.74) and a group of 40 patients with MCI (mean age: 72.08, SD: 5.51) from the Consortium for the early identification of Alzheimer's disease–Quebec (CIMA‐Q). VBM analyses were done using the region of interest (ROI) approach with a specific mask combining masks for the hippocampus and the entorhinal cortex from the Neuromorphometrics atlas and a mask for POC structures from Northwestern University (Zhou et al., 2019).ResultVBM analysis reveals smaller bilateral grey matter volume within bilateral hippocampus (left peak: MNI ‐32 −10 ‐22, k = 24, T = 3.78, pFWE corr. = 0.033) (right peak: MNI 30 −8 ‐26, k = 111, T = 4.11, pFWE corr. = 0.016) and right POC (peak: MNI 27 0 ‐14, kE = 20, T = 3.71, pFWE corr. = 0.035) in MCI patients compared to the older participants with memory complaints.ConclusionThe neurodegeneration of olfactory‐related structures seems to occur in the prodromal stage of AD and atrophy of these structures might represent a way to improve the specificity of preclinical AD if combined with hippocampal atrophy.

Deconvolving Cerebrospinal Fluid Soluble TREM2 Signal and Longitudinal Associations with Cognition

AbstractBackgroundCerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer’s disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. We previously found a novel association between high Aβ40 (but not Aβ42) and high sTREM2 levels at baseline and replicated additional associations between a fluid biomarker of blood‐brain barrier (BBB) integrity and CSF biomarkers of neurodegeneration. Therefore, we sought to determine the relative contributions of these biological correlates to CSF sTREM2 levels during the prodromal stages of AD. Additionally we investigated whether the residual variance in sTREM2 level correlated with each biomarker predicted future cognitive performance.MethodLeveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6, male=67%, mild cognitive impairment=47%), previously established associations between baseline CSF sTREM2 concentrations and CSF AD biomarkers (Aβx‐40, total tau, phosphorylated tau, and neurofilament light) and BBB integrity (CSF/plasma albumin ratio) were examined via hierarchical linear regression using sTREM2 as an outcome variable. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status. Baseline CSF sTREM2 levels and corresponding residual components when adjusting for other biomarker levels in independent models were used in longitudinal mixed effects models predicting an episodic memory composite calculated as a z‐score from independent tests. Participants had up to five visits (mean±sd=2.63±1.30 visits).ResultHigh baseline CSF sTREM2 levels predicted slower longitudinal memory decline in VMAP (β=1.442e‐05, p=0.035). Additionally, the component of sTREM2 signal correlated with Aβx‐40 best predicted future memory performance (β=2.217e‐05, p=0.007). Together, Aβx‐40, phosphorylated tau, and the CSF/plasma albumin ratio jointly explained 36% of variance in sTREM2 levels. Aβx‐40 levels and the CSF/plasma albumin ratio explained sTREM2 signal above and beyond established associations with tau (R2=0.21; R2=0.21; and R2=0.17, respectively).ConclusionWe highlight potential contributions of Aβ homeostasis and BBB integrity to elevations in CSF sTREM2, underscoring novel biomarker associations relevant to disease progression. Results suggest that the tight correlation between baseline CSF sTREM2 and Aβx‐40 levels may have notable importance to cognitive trajectory in an aged cohort enriched for mild cognitive impairment.

Novel brain PET imaging agents: Strategies for imaging neuroinflammation in Alzheimer's disease and mild cognitive impairment.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with a concealed onset and continuous deterioration. Mild cognitive impairment (MCI) is the prodromal stage of AD. Molecule-based imaging with positron emission tomography (PET) is critical in tracking pathophysiological changes among AD and MCI patients. PET with novel targets is a promising approach for diagnostic imaging, particularly in AD patients. Our present review overviews the current status and applications of in vivo molecular imaging toward neuroinflammation. Although radiotracers can remarkably diagnose AD and MCI patients, a variety of limitations prevent the recommendation of a single technique. Recent studies examining neuroinflammation PET imaging suggest an alternative approach to evaluate disease progression. This review concludes that PET imaging towards neuroinflammation is considered a promising approach to deciphering the enigma of the pathophysiological process of AD and MCI.