Normal Cognition Research Articles

Serum Bile Acids Improve Prediction of Alzheimer's Progression in a Sex-Dependent Manner.

Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4219 samples collected from 1180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n=660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n=578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.

Association between health-related quality of life and heart rate variability in elderly individuals with cognitive impairment in Korea: cross-sectional study

BackgroundCognitive impairment, a characteristic and prior stage of dementia, is a serious public health concern in Korea a country with rapidly aging population. In a neurovisceral integration model, cognitive ability is connected to emotional and autonomic regulation via an interconnection in the brain, which may be associated with health-related quality of life (HRQoL).MethodsThis study investigated the association between the HRQoL and the autonomic nervous system (ANS) via EuroQoL-5 Dimension (EQ-5D) and heart rate variability (HRV) among 417 patients who visited the Neurology Department in Veterans Health Service Medical Center, Seoul, South Korea.ResultsThe mean age of 275 patients in the cognitive impairment group (CIG) was higher than that of 142 patients in the normal cognition group (NCG) (74.85 years vs. 72.96 years, p < 0.001). In a generalized linear model with a beta coefficient (β), an increase in HRQoL was associated with higher HRV levels was observed only in CIG (CIG: the standard deviation of all NN intervals (SDNN) (ln, ms): β = 0.02, p = 0.007; Total power spectral density (TP) (ln, ms2): β = 0.01, p = 0.007; High frequency (HF) (ln, ms2): β = 0.01, p = 0.015; Low frequency (LF) (ln, ms2): β = 0.01, p = 0.003) (NCG: SDNN (ln, ms): β = 0.01, p = 0.214; TP (ln, ms2): β = 0.01, p = 0.144; HF (ln, ms2): β = 0.00, p = 0.249; LF (ln, ms2): β = 0.01, p = 0.294).ConclusionsWe found a significant association between HRQoL and HRV in Korean elders with cognitive impairment. However, this study is cross-sectional, so we cannot define direct causation. Further studies are needed to support our findings and to elucidate the biological mechanisms underlying these associations, especially in people cognitively impaired.

The static balance ability on soft and hard support surfaces in older adults with mild cognitive impairment

Objective This study aimed to assess the static balance ability of the older adults with mild cognitive impairment (MCI) while standing on soft and hard support surfaces. Methods Forty older adults participated in this study (21 in the MCI group and 19 in the control group). Participants were required to perform balance tests under four conditions of standing: standing on a hard support surface with eyes open, standing on a soft support surface with eyes open, standing on a hard support surface with eyes closed, and standing on a soft support surface with eyes closed. Each test was measured in three trials and each trial lasted 30 seconds. Participants were asked to take off their shoes and place their feet in a parallel position with a 20-centimeter distance for bipedal support. The trajectories of the center of pressure (COP) were measured using a Kistler force platform with a frequency of 1000 Hz to assess balance while standing in both groups, with larger COP trajectories indicating poorer static balance in older adults. Results With eyes open, the displacement of COP in the anterior-posterior direction(D-ap) (hard support surface: P = 0.003) and the 95% confidence ellipse area(95%AREA-CE) (soft support surface: P = 0.001, hard support surface: P &lt; 0.001) of the COP in the MCI group standing on hard and soft support surfaces were significantly larger than the control group. The 95%AREA-CE (P &lt; 0.001) of the COP in the MCI group on the soft support surface was significantly larger than on the hard support surface. With eyes closed, the root mean square distance(RDIST), root mean square distance-ML(RDISTml), and 95%AREA-CE of the COP were no significant between-group differences when standing on hard support surfaces. However, the RDIST (P = 0.014), RDISTml (P = 0.014), and 95%AREA-CE (P = 0.001) of the COP in the MCI group on the soft support surfaces were significantly larger than the control group. The 95%AREA-CE (P &lt; 0.001), RDIST (P &lt; 0.001), and RDISTml (P &lt; 0.001) of the COP in the MCI group on the soft support surface were significantly larger than the hard support surface. Conclusion With eyes open, the older adults with MCI showed poorer static balance ability compared to the older adults with normal cognition on soft and hard support surfaces. With eyes closed, the older adults with MCI showed poorer static balance on soft support surfaces, but no differences on hard support surfaces compared with the older adults with normal cognition. With eyes open and closed, the older adults with MCI showed poorer static balance on soft support surfaces as compared to hard support surfaces.

Relationship between reaction time variability on go/no go tasks and neuropsychological functioning in younger and older adults

ABSTRACT Introduction Early detection of cognitive impairment in older adults is important for the prevention of dementia. Intra-individual variability in reaction time (IIV-RT) during go/no-go tasks can be used for the early detection of cognitive impairment in older adults living in the community. This study aimed to determine the relationship between IIV-RT and cognitive function during go/no-go tasks and the cutoff values for determining the risk of cognitive impairment in community-dwelling older adults. Methods This study included 31 older adults without cognitive impairment, 15 community-dwelling older adults with cognitive impairment, and 34 healthy young adults. All participants performed a go/no-go task to assess the IIV-RT. Additionally, older adults underwent neuropsychological testing. Based on the results of the Japanese version of the Montreal Test of Cognitive Abilities (MoCA-J), older adults were divided into those with normal cognition and those with cognitive impairment. Results There were significant differences in the IIV-RT among groups, including a higher IIV in the cognitively impaired group than in young adults and cognitively normal older adults. Moreover, the IIV-RT was correlated with the MoCA-J (r = −0.531, p < 0.001), Trail Making Test Part A (r = 0.571, p < 0.001), and Verbal Fluency Test scores (r = −0.442, p = 0.002). Receiver operating curve analysis showed that the area under the curve for IIV-RT was 0.935, and the cutoff value at which the IIV-RT identified cognitive impairment was 25.37%. Conclusions These findings indicate that the IIV-RT during go/no-go tasks is a useful early indicator of cognitive impairment in community-dwelling older adults.

Elevated Homocysteine Levels and Hypertension Relate to Cognitive Impairment via Increased White Matter Hyperintensity Volume.

Recent studies have identified a relationship between elevated homocysteine levels and hypertension (HTN) with Alzheimer's disease (AD), but its pathogenesis remains unclear. To evaluate elevated homocysteine levels and HTN as risk factors for cognitive impairment (CI) and determine their relationship with white matter hyperintensity (WMH) volume. A total of 521 subjects were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and divided into two groups according to the diagnostic criteria of the ADNI database. The CI group included 370 subjects, consisting of 122 with AD and 248 with mild CI, while the cognitively normal (CN) group contained 151 subjects. The history of HTN, homocysteine levels, WMH volume and Mini-Mental State Examination (MMSE) scores were analyzed. The study found that patients with CI had higher homocysteine levels than those with CN. Additionally, WMH volume was significantly correlated with homocysteine levels in CI patients, and MMSE scores decreased as WMH volume increased. Further analysis revealed that CI patients with HTN had significantly higher homocysteine levels than those without HTN. Furthermore, the correlation between WMH volume and homocysteine levels was significant only in CI patients with HTN and not in those without HTN. In CN patients, there was no correlation between WMH volume and homocysteine levels in either the HTN or non-HTN groups, and no difference was observed in homocysteine levels. It is indicated that elevated homocysteine levels in conjunction with HTN are associated with the increased volume of WMHs and CI.

Brain Dynamics Complexity as a Signature of Cognitive Decline in Parkinson's Disease.

Higuchi's fractal dimension (FD) captures brain dynamics complexity and may be a promising method to analyze resting-state functional magnetic resonance imaging (fMRI) data and detect the neuronal interaction complexity underlying Parkinson's disease (PD) cognitive decline. The aim was to compare FD with a more established index of spontaneous neural activity, the fractional amplitude of low-frequency fluctuations (fALFF), and identify through machine learning (ML) models which method could best distinguish across PD-cognitive states, ranging from normal cognition (PD-NC), mild cognitive impairment (PD-MCI) to dementia (PDD). Finally, the aim was to explore correlations between fALFF and FD with clinical and cognitive PD features. Among 118 PD patients age-, sex-, and education matched with 35 healthy controls, 52 were classified with PD-NC, 46 with PD-MCI, and 20 with PDD based on an extensive cognitive and clinical evaluation. fALFF and FD metrics were computed on rs-fMRI data and used to train ML models. FD outperformed fALFF metrics in differentiating between PD-cognitive states, reaching an overall accuracy of 78% (vs. 62%). PD showed increased neuronal dynamics complexity within the sensorimotor network, central executive network (CEN), and default mode network (DMN), paralleled by a reduction in spontaneous neuronal activity within the CEN and DMN, whose increased complexity was strongly linked to the presence of dementia. Further, we found that some DMN critical hubs correlated with worse cognitive performance and disease severity. Our study indicates that PD-cognitive decline is characterized by an altered spontaneous neuronal activity and increased temporal complexity, involving the CEN and DMN, possibly reflecting an increased segregation of these networks. Therefore, we propose FD as a prognostic biomarker of PD-cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study.

Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer's disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. The goal of this study was to study human GE180 from the perspective of the previous animal observations. With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed. 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

Altered metabolism in right basal ganglia associated with asymptomatic neurocognitive impairment in HIV-infected individuals

BackgroundOnly few studies have focused on the metabolite differences between asymptomatic neurocognitive impairment (ANI) and cognitively normal people living with HIV (PLWH). The current study aims to examine whether brain metabolisms in basal ganglia (BG) by magnetic resonance spectroscopy (MRS) were potential to discriminate ANI from cognitively normal PLWH. MethodsAccording to neuropsychological (NP) test, 80 PLWH (37.4 ± 10.2 years) were divided into ANI group (HIV-ANI, n = 31) and NP normal group (HIV-normal, n = 49). Brain metabolisms by MRS from right BG were compared between groups, including N-acetylaspartate and N-acetyl aspartylglutamate (tNAA), creatine and phosphocreatine (tCr), and choline-containing compounds (tCho). A total value of three metabolites were introduced. All brain metabolisms were evaluated as its percentage of total. Furthermore, correlations between MRS and NP and clinical measures were evaluated. A logistic regression model was applied, and the AUC values for the model and the continuous factors were compared using receiver operating curve (ROC) analysis. ResultsCompared to HIV-normal group, tNAA/total was lower and tCr/total was higher in the HIV-ANI group (P < 0.05). Both tNAA/total and tCr/total values were correlated with NP score (P < 0.05), especially in verbal fluency, speed of information processing, learning, and recall (P < 0.05). The logistic model included BG-tCr/total, current CD4 and infection years of PLWH. The AUC value for the BG-tCr/total was 0.696 and was not significantly lower than that for logistic model (P < 0.01). ConclusionThe altered brain metabolites in the right BG were found in the ANI group compared to PLWH with normal cognition, and further associated with NP deficits. The current findings indicated that brain metabolites assessed by MRS has the potential to discriminate ANI from cognitively normal PLWH.

Correlation between gut microbiome and cognitive impairment in patients undergoing peritoneal dialysis

BackgroundGrowing evidence has demonstrated that patients undergoing peritoneal dialysis (PD) are more likely to experience cognitive impairment than patients with non-dialysis end-stage renal disease (ESRD); however, the underlying mechanisms remain unclear. This study aimed to identify the role and predictive significance of gut microbiome alterations in PD-associated cognitive impairment.MethodsA total of 29 non-dialysis ESRD patients and 28 PD patients were enrolled in this study and divided into subgroups according to the Montreal Cognitive Assessment (MoCA). Faecal samples were analyzed using 16 S rRNA. Mini-Mental State Examination (MMSE) and MoCA scores were used to assess the degree of cognitive impairment in patients.ResultsThe 16 S rRNA analysis demonstrated differences in gut microbiome abundance and structure between PD and non-dialysis ESRD patients and between PD patients with cognitive impairment (PCI) and PD patients with normal cognition (PNCI). At family and genus levels, Prevotellaceae exhibited the greatest structure difference, while Lactobacillus exhibited the greatest abundance difference between PCI and PNCI. Altered microbiota abundance significantly correlated with cognitive function and serum indicators in PD. In addition, different modules related to fatty acid, lipid, pantothenate, and coenzyme A biosynthesis, and tyrosine and tryptophan metabolism were inferred from 16 S rRNA data between PCI and PNCI. Both groups could be distinguished using models based on the abundance of Lactobacillaceae (Area under curve [AUC] = 0.83), Actinomycetaceae (AUC = 0.798), and Prevotellaceae (AUC = 0.778) families and Lactobacillus (AUC = 0.848) and Actinomyces (AUC = 0.798) genera.ConclusionGut microbiome evaluation could aid early cognitive impairment diagnosis in patients undergoing PD.

Radiomics models based on cortical damages for identification of multiple sclerosis with cognitive impairment

BackgroundCognitive impairment (CI) is a common symptom in multiple sclerosis (MS) patients. Cortical damages can be closely associated with cognitive network dysfunction and clinically significant CI in MS. So, in this study, We aimed to develop a radiomics model to efficiently identify the MS patients with CI based on clinical data and cortical damages. MethodsOne hundred and eighteen patients with MS were divided into CI and normal cognitive (NC) cohorts (62/56) as defined by the Montreal Cognitive Assessment (MoCA). All participants were randomly divided into train and test sets with a ratio of 7:3. The radiomic features were selected by using the least absolute shrinkage and selection operator (LASSO) method. The discrimination models were built with the support vector machines (SVM) by the clinical data, radiomic features, and merge data, respectively. And the patients were further divided according to each cognitive domain including memory, visuospatial, language, attention and executive, and each domain model was applied by the most suitable classifier. ResultsA total of 2298 features were extracted, of which 36 were finally selected. The merge model showed the greatest performance with the area under the curve (AUC) of 0.86 (95 % confidence interval: 0.81–0.91), accuracy (ACC) of 0.78, sensitivity of 0.79 and specificity of 0.77 in test cohort. However, although the visuospatial domain model showed the highest AUC of 0.71 (95 % confidence interval: 0.61–0.81) among five domain models, other domain models did not meet satisfactory results with a relatively low AUC, ACC, sensitivity and specificity. ConclusionsThe radiomics model based on clinical data and cortical damages had a great potential to identify the MS patients with CI for clinical cognitive assessment.

Impact of the COVID‐19 Pandemic on Dementia Research Participants

AbstractBackgroundThe impact of COVID‐19 on Alzheimer’s disease and related dementias (ADRD) research participation is not fully known. Individual differences in stress and coping may impact research findings (Goldfarb, 2020). It is possible that participants with questionable cognitive impairment (QCI) may be more vulnerable to stress and loss to follow up. The objective of this study is to examine the differential impact of the COVID‐19 pandemic on dementia research participants among individuals with varying degrees of cognitive impairment.MethodThe COVID‐19 impact survey was mailed to participants of the UC Davis Alzheimer’s Disease Research Center (ADRC) in August 2020. The survey asked questions related to feelings about the pandemic and how it impacted willingness to participate in research. Fisher’s exact test was used to compare responses across diagnostic groups. All analyses were conducted using SAS software, version 9.4.ResultOf 115 participants (69.6% female, 52.2% non‐White), 38 had normal cognition, 38 had questionable cognitive impairment (QCI; defined as having one or more neuropsychological tests that was slightly low but did not rise to the threshold of impairment), 16 had mild cognitive impairment (MCI), and 22 had dementia (Table 1). Overall, 9% of the participants were very or extremely worried about getting COVID‐19, 19% felt very or extremely isolated, 36% felt the pandemic had been very or extremely disruptive. The pandemic changed willingness to participate in research at least a little for 50% and very much or extremely for 13%. Impaired participants (either MCI or dementia) were less concerned about getting COVID‐19 and felt less isolated than those with normal cognition or QCI (Table 2). A higher percentage of those with QCI (vs. normal cognition or impaired groups) felt that the pandemic was very or extremely disruptive. Although not statistically significant, a higher percentage of those with QCI also reported that the pandemic changed their willingness to participate in in‐person research very much or extremely.ConclusionThe COVID‐19 pandemic was more disruptive to participants with QCI than participants with normal or impaired cognition. More research is needed to evaluate the impact of the pandemic on dementia research participants.

Impaired ability to smile in Alzheimer’s disease is associated with reduced brain volume of nucleus accumbens and pallidum, revealed by artificial intelligence

AbstractBackgroundPatients tend to lose the ability to smile during the clinical course of dementia. However, details of such impairment remain obscure presumably due to difficulty of quantifying facial expression. Feature extraction is now automated as a result of recent developments in artificial intelligence (AI). The authors applied a model to quantify impaired smile expression in patients with Alzheimer disease (AD). The relationship between the expression of a smile and subcortical volumes was also investigated.MethodThis study included 280 and 190 participants with AD and with normal cognition (NC), respectively. The faces of the participants were photographed as they smiled or maintained a neutral expression. Subcortical brain volume was assessed in 210 and 90 of those with AD and NC, respectively, using MRI and the FSL‐FIRST algorithm. Datasets of the photographs were prepared with combinations of smiling and neutral expression in NC and AD, smiling in AD and NC, and neutral expression in AD and NC, then binary discrimination proceeded using the VGG‐Face convolutional neural network (CNN).ResultThe accuracy of discriminating a smile from a neutral expression was of 92.3% in NC, and 61.2% in AD, indicating that a considerable proportion of patients with AD have difficulties forming a natural smile. 48.5% of smile AD were classified as negative in NC dataset. The smile/neutral‐NC scores for AD were robustly associated with the volume of the bilateral nucleus accumbens (right, r = 0.51, p = 2.59 × 10−15; left, r = 0.493, p = 2.89 × 10−14) and the bilateral pallidum (right, r = 0.266, p = 0.0000981; left, r = 0.256, p = 0.000174). The accuracy of discriminating between AD and NC was 95.2% with smile and 90.1% with a neutral expression, respectively (p = 0.0045). The neutral‐AD/NC score inversely correlated with the results of the MMSE (p = 1.62 × 10−7), but not with smile/neutral‐NC or smile‐AD/NC scores.ConclusionThe ability to form smile was impaired in AD and associated with nucleus accumbens and pallidum shrinkage. Such impairment enhanced the accuracy of facial discrimination between AD and NC, whereas a neutral expression was associated with cognitive function.

Associations of Neighborhood Disadvantage, Cardiometabolic Risk, and Cognition in a Community‐Dwelling Cohort

AbstractBackgroundSocial determinants of health (SDoH) are important environmental factors in cardiometabolic risk and cognitive aging. Area Deprivation Index (ADI) is a measure of neighborhood‐level socioeconomic disadvantage and has been studied in normal cognition (NC), but relatively less is known about impact in those with mild cognitive impairment (MCI).MethodThis study explores, in participants with NC and MCI enrolled in the Wake Forest ADRC Clinical Core, baseline measures of metabolic risk (Oral Glucose Tolerance Testing of blood glucose 120‐minute post‐challenge; OGTT‐120), cognition (Preclinical Alzheimer’s Cognitive Composite; PACC), demographics (age, education, diagnosis, race, sex), and participant national ADI rank (using baseline home address). Consensus diagnosis of NC and MCI was adjudicated by a panel of experts.ResultDemographics of community‐dwelling adults enrolled as a convenience sample in the Wake Forest ADRC with metabolic and cognitive measures by cognitive status is listed in Table 1. MCI participants, compared with CN, were older, more likely male and white, with lower education and PACC, and higher ADI (higher = more disadvantaged). Significant differences in ADI were observed when participants were stratified by race (Figure 1); post‐hoc tests indicate significantly higher ADI in Black compared to white participants, and to some degree, by higher ADI among Black participants compared with Asian participants. OGTT‐120 in participants with NC (n = 265) and MCI (n = 156) was not significantly associated with ADI national rank (Figure 2A); when controlling for age, sex, education, and diagnosis, there was still no association between OGTT‐120 and ADI. Higher ADI was significantly associated with lower PACC scores in individuals with NC (p = 0.044), but not MCI (Figure 2B); this association remained significant (p = 0.004) independent of age, sex, education, and diagnosis (all covariates p&lt;0.001).ConclusionAmong community‐dwelling older adults, ADI national rank differs by participant race. OGTT‐120 does not correlate with ADI in participants with NC or MCI. PACC scores correlate negatively with ADI national rank in participants with NC, but not MCI; this relationship remained when controlling for covariates. Further analyses are necessary to examine the association between cardiometabolic risk and ADI.

CSF synapse marker changes in predementia Alzheimer´s Disease: AMPA receptor modulators NPTX2 and NPTXR mediate cognition within A/T/N stages

AbstractBackgroundSynapse pathology has been linked to excitotoxicity and glutamate receptor dysregulation (such as AMPAR) in Alzheimer´s Disease (AD) progression. Of the core cerebrospinal fluid (CSF) AD biomarkers for amyloid, tau pathology and neurodegeneration (A/T/N), T/N status is proposed to reflect levels of neuronal plasticity, but fluid biomarkers for precision interventions in subgroups with increased excitotoxicity are lacking. Herein, we assess group differences of 19 CSF synapse markers including the AMPAR‐modulating NPTX, in both cognitively normal (CN) and Mild Cognitive Impairment (MCI) with either A+/T‐/N‐ and A+/T or N+ (A+/T/N+) as compared to CN A‐/T‐/N‐ and assess relationships with verbal memory recall and hippocampal volume.MethodsA/T/N was determined using the CSF Aβ42/40 ratio, p‐tau181 and total‐tau in predementia AD cases (n = 194) and CN participants with normal AD biomarkers (n = 145) in the Dementia Disease Initiation cohort. CSF synapse marker concentrations were determined using mass‐spectrometry (table 1) and ELISA for GAP‐43. Adjusted for age and sex, we compared marker concentrations between CN cases (A+/T‐/N‐ n = 20; A+/T/N+ n = 40) and MCI cases (A+/T‐/N‐ n = 25;A+/T/N+ n = 109) with CN A‐/T‐/N‐ (n = 145) as the reference group. Associations to verbal memory recall and brain imaging were performed in the total sample and respective A/T/N groups adjusted for covariates. Results p&lt;.01 were considered significant.ResultsTop markers based on between‐group results are reported (Table 1 &amp; figure 1‐2 for all markers). Compared to CN A‐/T‐/N‐, 14‐3‐3 ζ/δ concentrations were higher in all A+/T/N+ groups (p&lt;.001), but unaltered in A+/T‐/N‐ groups. In A+/T‐/N‐, NPTX2 concentrations were lower in MCI (p&lt;.001) but not in CN. In A+/T/N+, NPTX2 was higher in CN (p&lt;.001) but not in MCI. 14‐3‐3 ζ/δ was associated with worse memory in the total sample (p&lt;.001) but not in the A+ groups. Lower NPTX2 was associated with worse memory in the total sample (p&lt;.001) and in both A+ groups (p&lt;.01; p&lt;001). Neither 14‐3‐3 ζ/δ nor NPTX2 were significantly associated with hippocampal volume (figure 2).ConclusionOverall, increased 14‐3‐3 ζ/δ was most closely associated with worse memory recall. Lower NPTX2 was linked to poorer cognitive status within A+ groups, suggesting links to AMPAR dysregulation and excitotoxicity.

Amyloid β‐specific T cell response is enhanced in individuals with mild cognitive impairment

AbstractBackgroundNeuroinflammation is a key process in initiating and propagating Alzheimer’s disease (AD). Even though it is widely known that the deposit of amyloid plaques and CSF levels of amyloid distinguishes patients with AD or mild cognitive impairment (MCI) from cognitively normal (CN) individuals, little is known about the role of amyloid‐specific immune response in cognitive decline.MethodUsing a polyfunctionality assay typically used for detecting virus‐specific T cell responses, we tested participants from the Epidemiology of Mild Cognitive Impairment in Taiwan study (EMCIT) and the Taiwan Precision Medicine Initiative of Cognitive impairment and dementia (TPMIC) study to compare the amyloid‐specific T cell responses between CN and MCI individuals. The abilities of T cell response parameters and plasma p‐Tau181 to distinguish MCI from CN were tested.ResultResults from both cohorts showed an enhanced amyloid‐specific T‐cell response in individuals with MCI. In the EMCIT cohort, the individual’s amyloid‐specific CD4+ response frequency of total CD4+ cells was significantly larger in MCI (n = 69, 0.93%) than in CN (n = 69, 0.51%, p &lt; 0.001). CD4+ T cell response discriminated MCI versus CN (area under curve [AUC], 0.72 [0.64‐0.81]) with significantly higher accuracy than p‐Tau181 (AUC: 0.59 [0.5‐0.69], p &lt; 0.01). In the TPMIC cohort, both CD4+ and CD8+ response frequencies were higher in MCI individuals (n = 21, CD4: 1.2%, CD8: 2.02%) than in CN (n = 30, CD4: 0.14%, CD8:0.27%; both p &lt; 0.001). CD4+ T cell response frequency and CD8+ response frequency also outperform p‐Tau181 in their discriminative accuracy of MCI versus NC (CD4+ AUC, 0.97, [0.94‐1.01]; CD8+ AUC, 0.96, [0.92‐1.01]; p‐Tau181 AUC, 0.83, [0.69‐0.96]; both p &lt; 0.05).ConclusionOur study validates the amyloid hypothesis by showing that amyloid‐associated neuroinflammation is involved in the process of neurodegeneration and demonstrated the accuracy of using amyloid‐specific T cell response to discriminate MCI from CN individuals. The TPMIC cohort is an ongoing longitudinal study that includes amyloid PET results and thus we will investigate the prognostic value of amyloid‐T cell response in the future.

Behavioural Deficits and Regional Cerebral Perfusion Map in Cognitively Normal and Pre‐Dementia Stages

AbstractBackgroundOur previous work has shown increased presence of early behavioural impairment in Asian than Western cohorts(Soo et al.,2021). Such impairments include mild behavioural changes, sleep disruptions and higher depression, anxiety and stress, in turn representing an at‐risk state which may predict later development of dementia(Müller‐Spahn,2003;Soo et al.,2021). Additionally, growing evidence illustrates that cerebrovascular changes are a key component in the pathological sequelae and may be detectable years before clinical presentation of dementia (de la Torre,2018). However, the influence of cerebral perfusion on behaviour, especially in pre‐dementia stages remains to be elucidated. Thus, we examined the association between regional grey matter perfusion and behaviour in cognitively normal(CN) and subjects with mild cognitive impairment(MCI) or subjective cognitive decline(SCD). We hypothesized that grey matter perfusion deficits would be related to behaviour impairment even in early stages of SCD/MCI.MethodWe studied 35 CN and 248 pre‐dementia (MCI/SCD) from a community‐based research cohort from the Dementia Research Centre (Singapore) with neuroimaging, neuropsychological and behavioural assessments(Table 1). We investigated the association between regional grey matter perfusion across 31 regions of interest spanning frontal, parietal, temporal and occipital lobes using 2D pulsed Arterial Spin Labelling and performance on the mild behaviour impairment‐checklist(MBI‐C), Pittsburgh Sleep Quality Index(PSQI) and Depression, Anxiety and Stress Scale(DASS). These associations were examined in CN and MCI/SCD groups separately and respective Pearson’s correlation matrices were derived.ResultOverall, greater behavioural impairment on the MBI‐C, DASS and PSQI was associated with hypoperfusion across multiple grey matter regions. This association was stronger in CN than in the pre‐dementia group. Specifically, among CN, hypoperfusion in the frontal, parietal and occipital lobes related most strongly to greater behavioural impairment, especially MBI‐C and DASS depression(Fig.1). In the MCI+SCD group, only hypoperfusion in the frontal and temporo‐occipital regions related to worse behavioural impairment across the MBI, PSQI and DASS(Fig.2).ConclusionIn this study, we illustrate differential associations between cerebral hypoperfusion and behavioural impairment in CN and MCI/SCD groups, with CN individuals showing more widespread and stronger associations between behavioural impairment and hypoperfusion across the brain. In SCD/MCI, hypoperfusion in frontal and temporo‐occipital regions were associated with behavioural impairment.

Comparison of Vascular Health in Super‐Agers and Cognitively Normal Adults 80 Years and Older

AbstractBackgroundUnraveling factors associated with cognitive resilience and super‐agers might reduce expected increases in Alzheimer’s disease and related dementia (ADRD). Vascular disease can impair the cerebral circulation and increase risk for cognitive decline and ADRD. However, data in persons aged 80+ suggests that maintained vascular health can preserve key brain regions for normal cognition.MethodUsing National Alzheimer’s Coordinating Center (NACC) data from January 2005 ‐ December 2020, we found 9,581 participants age 80+ (white: 8,296 vs. AA: 1,285,p&lt;.0001) at the baseline visit. We defined cognitive groups per global Clinical Dementia Rating (CDR) and Memory subscale scores. Normal cognition (NC) was defined as a global CDR and memory subscale score = 0. To identify super‐agers (SA), we utilized data‐derived cutoffs from cognitive test performances consistent with prior reports. The operationalized definition was created from: 1) Mean Craft delayed recall scores in 50–60‐year‐olds with NC; 2) Craft scores among age 80+ with NC group were standardized to the mean score for age 50‐60 with NC; and 3) Standardized mean scores for non‐memory measures (trail making test‐B, phonemic fluency, and multilingual naming test) for age 80+ with NC. SA were defined as age 80+ with episodic memory performance (Craft scores) ≥ 1 standard deviation (SD) of the standardized mean for the age 50‐60 group and non‐memory scores ≥ 1 SD of the standardized mean for the 80+ age group.ResultWe identified 4.5% (n = 431) SA and 27.7% (n = 2,654) NC (p&lt;.01) to compare vascular variables. Compared to NC, SA were younger (83.5±3.4 vs. 84.7±4.0, p&lt;.01), had more education (16.5±2.8 vs. 15.2±3.1, p&lt;.01), higher diastolic blood pressure (DBP) (73.9±10.5 vs. 71.9±10.5, p&lt;.01), and mean arterial pressure (MAP) (95.5±11.8 vs. 93.5±11.5, p&lt;.01). Pulse pressure (PP) was similar for both groups (67.5±17.1 vs. 68.1±10.5, p = .33).ConclusionOur results suggest that vascular health could impact cognition in aged 80+ adults. SA may have higher cerebral perfusion (CP) per MAP. Although DBP can decrease with aging, higher values in our sample may contribute to CP. The PP in our sample is similar to reported values for healthy 70‐year‐old adults. Further study of vascular health and super‐aging is needed.

Plasma amyloid‐β, total tau, and neurofilament light chain across the Alzheimer clinical spectrum: a population‐based study

AbstractBackgroundPlasma biomarkers have emerged as a promising approach for defining mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We aimed to characterize Alzheimer’s plasma biomarkers across the clinical continuum of AD, and to assess their ability to differentiate between MCI, AD, and normal cognition.MethodThis population‐based study engaged 1446 rural‐dwelling older adults (age≥60 years, 61.0% women) derived from Multimodal Interventions to Delay Dementia and Disability in Rural China study; of these, 902 were defined with normal cognition, 402 with MCI, and 142 with AD according to the international criteria. Plasma amyloid‐beta (Aβ), total‐tau (t‐tau), and neurofilament light chain (NfL) concentrations were analysed using Simoa platform. Data were analysed using the logistic and general linear models, and receiver operating characteristic (ROC) analysis.ResultPlasma concentrations of Aβ40, Aβ42, t‐tau, and NfL were significantly increased with age (P&lt;0.01). Women had higher plasma Aβ2 (age‐adjusted β = 0.62; 95%CI = 0.30‐0.94), Aβ42/Aβ40 ratio (0.19; 0.01‐0.36) and lower NfL concentrations (‐0.11; ‐0.16‐ ‐0.06). Plasma Aβ42 (age‐ and sex‐adjusted β = ‐0.73; ‐1.15‐ ‐0.31) and Aβ42/Aβ40 ratio (‐0.51; ‐0.74‐ ‐0.29) were lower in APOE ε4 carriers than that in non‐carriers. Plasma Aβ40 and Aβ42/Aβ40 ratio showed an increased and decreased trend, respectively, across AD clinical spectrum. Plasma t‐tau and t‐tau/Aβ42 ratio were higher in people with AD than those with MCI or normal cognition. Plasma NfL was increased across the AD clinical continuum and outperformed other Alzheimer’s biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75). However, all of these plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC&lt;0.60). When adding plasma NfL to the basic model that included age, sex, education, and APOE genotype, the AUC was 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition.ConclusionAge, sex, and APOE genotype should be considered in clinical interpretation of Alzheimer’s plasma biomarkers. Plasma Aβ, t‐tau, and NfL concentrations differ across the cognitive continuum, but plasma NfL, which starts to elevate in the early stages of AD development, appears to be superior than plasma Aβ and t‐tau for defining cognitive continuum in old age.

Cerebral perfusion and amyloidosis in the oldest‐old

AbstractBackgroundCerebrovascular contributions to cognitive aging and Alzheimer’s disease (AD) risk represent a growing field in aging research. Studies in the young‐old have demonstrated the critical role of vascular dysregulation (i.e., altered cerebral blood flow) in relation to cognitive decline prior to the appearance of amyloid/tau biomarkers. However, cerebral perfusion has not been well‐studied in the oldest‐old (ages 90 and over), a rapidly growing population that may provide unique insight into resilience and protective factors against dementia in later life. We characterized amyloid and cerebral perfusion profiles of cognitively normal (CN) and cognitively impaired without dementia (CIND) oldest‐old individuals.MethodParticipants were 97 dementia‐free older adults (70 CN and 27 CIND) from the 90+ Study who had available neuroimaging (T1‐MRI, ASL‐MRI, Florbetapir‐PET), demographic, and clinical data. We examined differences between CN and CIND in regional perfusion in areas associated with AD risk (medial temporal lobe, posterior cingulate, precuneus, frontal cortex, inferior parietal lobe) and in amyloid burden using linear regression models controlling for age, sex, education, APOE4 status, and vascular risk factors.ResultCN and CIND groups did not differ in the characteristics compared (Table 1). CIND participants had lower CBF in the posterior cingulate/precuneus than the CN group, but groups did not differ in posterior cingulate/precuneus amyloid SUVR (Figure 1). Additionally, CIND had lower CBF than CN in the inferior parietal lobe but higher CBF in the medial temporal lobe and orbitofrontal cortex (Figure 2).ConclusionCIND individuals had lower regional perfusion in the posterior cingulate/precuneus, but groups did not differ in amyloidosis, highlighting the relationship between cerebrovascular function and cognitive status in the oldest‐old independent of amyloidosis. Our findings complement previously reported posterior cingulate/precuneus hypoperfusion in younger‐old individuals with cognitive impairment and AD. Interestingly, we observed greater medial temporal/frontal perfusion in CIND than CN, similar to previous studies demonstrating initial hyperperfusion preceding hypoperfusion across the CN‐CIND‐Dementia spectrum. This may represent a compensatory vascular mechanism supporting cognition in individuals at greater risk of developing dementia. Future studies will further characterize this cohort with longitudinal perfusion analyses, neuropsychological correlates, and relationships between perfusion and other indices of cerebrovascular dysfunction.

Comparison of plasma and cerebrospinal fluid protein markers and their significance for the characterization of dementia disease status

AbstractBackgroundAlthough Aβ42 and phosphorylated tau (p‐tau) in cerebrospinal fluid (CSF) are valuable to diagnose Alzheimer’s disease (AD), many patients are reluctant to accept lumbar puncture. In addition, there is lack of biomarkers for the different stages of AD dementia. This study sought to compare the plasma and CSF protein markers to characterize dementia status.MethodThis cohort study included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 73 proteins measured in plasma (566 total, 58 cognitively normal (CN), 396 mild cognitive impairment (MCI), and 112 AD) and in CSF (310 total, 92 CN, 149 MCI, and 69 AD). Univariate/multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) were used to identify the protein candidates for the disease classification. The following three models were examined for CN vs. MCI and MCI vs. AD; model 1: proteins only, model 2: proteins adjusted for age, sex, education, and model 3: model 2 plus APOE4 status.ResultNine proteins in plasma and CSF were chosen based on their importance from LASSO. The area under the curve (AUC) for the final multivariate logistic regression including the 9 proteins was calculated for each disease group in plasma [CN vs. MCI: 0.895 (model 1), 0.899 (model 2), 0.921 (model 3), and MCI vs. AD: 0.828 (model 1), 0.842 (model 2), 0.856 (model 3)]. In addition, AUC in CSF [CN vs. MCI: 0.678 (model 1), 0.726 (model 2), 0.770 (model 3) and MCI vs. AD: 0.711 (model 1), 0.738 (model 2), 0.765 (model 3)] was also estimated. We observed that plasma proteins outperformed the CSF proteins to be associated with MCI and AD. Also, plasma proteins were significantly better than the established AD markers, namely CSF Aβ42 and p‐tau in CN vs. MCI [AUC: 0.836 (model 1), 0.842 (model 2), 0.862 (model 3)] and MCI vs. AD [AUC: 0.665 (model 1), 0.673 (model 2), 0.680 (model 3)].ConclusionThis study demonstrates that the combination of plasma proteins could be considered an effective marker for diagnosing AD and its early‐stage symptoms with better performance than the other markers.