Normal Cognition Group Research Articles

Individuals from Memory Clinic were Associated with Severer Amyloid Deposition in the Chinese Population in Urban Cities

AbstractBackgroundAmyloid deposition is considered the initial pathology in Alzheimer’s disease (AD), investigation of amyloid pathology and the risk factor for amyloid pathology and cognitive declines in the Chinese population is critical for personalized management. However, the prevalence of amyloid deposition and the risk factors for amyloid pathology are unknown in the Chinese population.MethodParticipants were recruited from urban communities and memory clinics in Shanghai and Zhengzhou, China. A total of 246 AD individuals, 274 Mild cognitive impairment (MCI) individuals, and 506 Normal cognition (NC) individuals were identified: 106 AD, 156 MCI and 506 NC from the Community‐based cohort (COMC) as well as 140 AD and 118 MCI from the Clinic‐based cohort (CLIC). Amyloid positivity and deposition were analyzed based on amyloid positron emission tomography (PET) scans. We also performed a partial least squares (PLS) analysis to evaluate the associations of cohort, age, sex, education level, and ApoE genotype with amyloid qualification, quantification results and global cognition in all 1026 participants.ResultAcross the two cohorts, the AD group displayed the significantly highest rate of amyloid positivity (211/246, 85.8%), followed by the MCI (122/274, 44.5%) and NC groups (136/506, 26.9%, all P < 0.001). Participants from the CLIC displayed a higher rate of amyloid positivity than those from the COMC in the MCI (68/118, 57.6% vs. 54/156, 34.6%, P < 0.001) and AD groups (128/140, 91.4% vs. 83/106, 78.3%, P = 0.006). MCI (SUVr: 1.37 ± 0.25 vs. 1.25 ± 0.18, P < 0.001), Aß+ MCI (SUVr: 1.48 ± 0.27 vs. 1.37 ± 0.24, P = 0.03) and AD individuals (SUVr: 1.47 ± 0.23 vs. 1.39 ± 0.23, P = 0.01) in the CLIC displayed significantly greater amyloid deposition than those in the COMC. According to the PLS model, we found that the CLIC was significantly associated with positive amyloid deposition and severer amyloid deposition.ConclusionWe found that individuals from CLIC displayed a higher amyloid positive rate and severer amyloid deposition. Specifically, in a PLS model, The CLIC, was strongly associated with amyloid pathology.

Using plasma ptau181 in Lewy Body Disease spectrum for the identification of Alzheimer’s disease co‐pathology

AbstractBackgroundLewy body disease (LBD) patients frequently present with Alzheimer’s disease (AD) co‐pathology, which influences disease progression, cognitive decline, and brain atrophy. AD‐related pathology can be identified with new blood‐based biomarkers like plasma phosphorylated‐tau181 (ptau181).We aimed to determine whether plasma ptau181 helps identify AD‐related co‐pathology in LBD, and whether plasma ptau181 is associated with clinical features, and AD cerebrospinal (CSF) biomarkers.MethodFrom a total of 632 Stanford research participants, we selected 245: 115 cognitively normal (CN), 47 Parkinson’s disease (PD) with normal cognition, 47 on the LBD spectrum (31 MCI and 16 dementia), and 36 on the AD spectrum (14 MCI and 22 dementia). Plasma ptau181 levels were measured with Lumipulse G fully automated platform by Fujirebio with Lumipulse G Assays. A subset of the participants had available AD CSF biomarkers (N = 201) and/or 18F‐Florbetaben PET imaging (N = 73). Diagnostic accuracy was evaluated with area‐under‐the‐curve (AUC) values from receiver‐operating characteristic (ROC) analyses. Linear regression models adjusted for confounding factors were used to analyze effects of baseline plasma ptau181 levels on global cognition (MoCA), global function (CDR‐SOB), motor function (UPDRS Part III), and functional disability (Hoehn and Yahr).ResultPlasma ptau181 levels were higher in the LBD spectrum group compared to CN and PD with normal cognition groups, but lower than in the AD spectrum group.Plasma ptau181 levels predicted CSF ptau181/Aβ42 ratio in LBD spectrum patients with an AUC = 0.87. Including age, sex, years of education, and APOE E4 genotype levels improved the prediction of the model (AUC = 0.94).In the LBD spectrum group, males and females showed similar plasma ptau181 levels, and we found no association between plasma ptau181 levels with age, sex, years of education, MoCA, CDR‐SOB, UPDRS Part III, or Hoehn and Yahr. Nevertheless, plasma ptau181 levels were associated with CSF ptau181 levels and amyloid‐β42/40 after controlling for age and sex.ConclusionPlasma ptau181 levels help identify LBD patients with AD co‐pathology, and are associated with AD CSF biomarkers. These findings support the use of plasma ptau181 as a screening tool for AD co‐pathology in patients with LBD and cognitive impairment.

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.

Temporal lobe function during memory encoding in older individuals prior to the onset of cognitive impairment

AbstractBackgroundPrevious studies have shown that resting state brain function begins to change in the years leading up to the development of cognitive impairment. This study examines temporal lobe function during memory encoding approximately 2.5 years before the onset of cognitive impairment in Baltimore Longitudinal Study of Aging (BLSA) participants.MethodBLSA participants with subsequent memory impairment (Subsequently Impaired (SI), n = 22, mean age = 83.6, time to impairment = 2.5 ± 1.1 SD years post‐scan) and age, sex, and education matched cognitively normal participants (Cognitively Normal (CN), n = 64, mean age = 84.9) performed a face‐scene encoding task during fMRI scanning. Group differences in task performance and brain activation patterns were examined during encoding trials they later remembered, and trials they later forgot during the recognition phase of the task.ResultThe SI group performed more poorly than the CN group during the recognition phase of the task. Both CN and SI activated the occipitotemporal visual pathway during memory encoding. Yet relative to CN participants, the SI group showed decreased activation of the hippocampus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus during encoding of face‐scene pairs. This decreased activation was seen during both encoding of pairs they later remembered and pairs they forgot during recognition.ConclusionBoth memory dysfunction and decreased temporal lobe activity during encoding begin before the onset of clinically evident cognitive impairment. In the SI group, the decreased temporal lobe activation was seen regardless of whether they later remembered or forgot the face‐scene pairs during the recognition task. This suggests that those who go on to develop impairment have an overall weaker functional response in temporal lobe regions during memory encoding. Further examination of the functional connectivity of these regions may help to determine if differences in brain network characteristics are related to subsequently remembered or forgotten visual stimuli during encoding. This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.

Basal forebrain nuclei volume is associated with hematoencephalic barrier dysfunction in early Alzheimer’s disease

AbstractBackgroundHematoencephalic barrier (HEB) is a protective layer of cells that separates the circulatory system from the brain. Its dysfunction is one of the possible mechanisms leading to the development of Alzheimer’s disease (AD), a progressive neurodegenerative disease and a leading cause of dementia worldwide. The albumin quotient (QAlb), the ratio between cerebrospinal fluid (CSF) and serum albumin concentrations, is a frequently used measure of HEB breakdown. Elevated levels of QAlb were previously reported in early AD. Here we explored the relationship between QAlb and volumes of the hippocampus and entorhinal cortex (EC) subregions and basal forebrain (BF) nuclei, the brain structures affected early in the course of AD.Method92 participants, including 20 AD biomarker negative cognitively normal (CN), 42 AD biomarker positive with mild cognitive impairment (AD‐MCI) and 30 AD biomarker positive with mild dementia (AD‐DEM), from the Czech Brain Aging Study underwent structural MRI and CSF sampling. CSF levels of amyloid beta 1‐42, total tau, phosphorylated tau 181 and QAlb, as well as volumes of the hippocampal subregions (i.e., head, body and tail), anterolateral and posteromedial EC and BF nuclei were obtained. Associations between regional brain volumes, normalized to total intracranial volume, and QAlb were assessed using MANOVA controlled for gender and age.ResultIn the AD‐MCI group, volumes of the anterior and posterior parts of the nucleus basalis of Meynert (NBM), one of the BF nuclei, were positively associated with QAlb levels (β = 0.317 and 0.345, p = 0.045 and 0.029, respectively). There were no other significant associations of regional brain volumes with QAlb in CN, AD‐MCI or AD‐DEM groups. All measured volumes, except for BF nuclei of medial septum in AD‐DEM (p = 0.058), were smaller in AD‐MCI and AD‐DEM v.s. CN group (p<0.05). There were no differences in volumes between AD‐MCI and AD‐DEM groups. QAlb did not differ between groups.ConclusionOur results show that severity of HEB dysfunction is associated with increased volume of the NBM in individuals with AD‐MCI, suggesting a link between HEB dysfunction and early pathological changes in the BF nuclei.

Temporal lobe function during memory encoding in older individuals prior to the onset of cognitive impairment

AbstractBackgroundPrevious studies have shown that resting state brain function begins to change in the years leading up to the development of cognitive impairment. This study examines temporal lobe function during memory encoding approximately 2.5 years before the onset of cognitive impairment in Baltimore Longitudinal Study of Aging (BLSA) participants.MethodsBLSA participants with subsequent memory impairment (Subsequently Impaired (SI), n = 22, mean age = 83.6, time to impairment = 2.5 ± 1.1 SD years post‐scan) and age, sex, and education matched cognitively normal participants (Cognitively Normal (CN), n = 64, mean age = 84.9) performed a face‐scene encoding task during fMRI scanning. Group differences in task performance and brain activation patterns were examined during encoding trials they later remembered, and trials they later forgot during the recognition phase of the task.ResultsThe SI group performed more poorly than the CN group during the recognition phase of the task. Both CN and SI activated the occipitotemporal visual pathway during memory encoding. Yet relative to CN participants, the SI group showed decreased activation of the hippocampus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus during encoding of face‐scene pairs. This decreased activation was seen during both encoding of pairs they later remembered and pairs they forgot during recognition.ConclusionsBoth memory dysfunction and decreased temporal lobe activity during encoding begin before the onset of clinically evident cognitive impairment. In the SI group, the decreased temporal lobe activation was seen regardless of whether they later remembered or forgot the face‐scene pairs during the recognition task. This suggests that those who go on to develop impairment have an overall weaker functional response in temporal lobe regions during memory encoding. Further examination of the functional connectivity of these regions may help to determine if differences in brain network characteristics are related to subsequently remembered or forgotten visual stimuli during encoding.This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.

Artificial neural network application to characterize patients with Alzheimer ’s disease and Mild Cognitive Impairment from Cognitive Normal.

AbstractBackgroundThis study aimed to build an artificial neural network model to differentiate patients with various diagnosis, including Alzheimer’s disease (AD), mild cognitive impairment (MCI) from cognitive normal (CN) using structural MRI images.MethodsMRI T1 image of 580 participants (97 AD, 291 MCI and 192 CN) were downloaded from ADNI, which is a publicly available database. The MPRAGE T1W MRI were pre‐processed by SPM software, including re‐orientation, segmentation and normalized to the whole brain mask template. 3D slicer software with pyradiomics extension were employed to extract the 107 radiomics features within the brain. Also, 45 brain regional volumes were segmented and calculated using Freesurfer. The AD, MCI and CN groups were divided into a training group and a validation group based on 70:30 ratio. Ten‐fold cross validation were performed to minimize the chance of overfitting. Three feed forward neural network model were built using the neural network toolbox of MATLAB, with one model using 107 radiomics alone (R model), one with 45 brain regional volumes (V Model) and the last one with both radiomics and volumes features (R+V model).ResultsThe receiver operating characteristics (ROC) curves showed that the V model and the R+V model achieved excellent accuracy, with 96.6% and 94.8% respectively. The area under the curve (AUC) was 99.6% and 97.9% respectively.ConclusionThe neural network model can accurately differentiate AD, MCI from HC. The application is practical and can be fully automatic, which can be used for dementia screening.

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

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

Lower serum vitamin D aggravates hippocampal neurodegeneration related with amyloid pathology

AbstractBackgroundPrevious studies reported the associations between vitamin D deficiency and increased risk of Alzheimer’s disease (AD) dementia in older adults, but little is known how vitamin D is involved in the pathophysiology of AD. Thus, we aimed to examine the association and interaction of serum vitamin D level with in vivo AD pathologies including beta‐amyloid (Aβ) and neurodegeneration in nondemented older adults.MethodNondemented older adults consisting of cognitively normal and mild cognitive impairment groups were recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25(OH)D, and multimodal brain imaging including Pittsburgh compound‐B (PiB) positron emission tomography and magnetic resonance imaging at baseline. Global PiB retention was measured for Aβ biomarker, and hippocampal volume adjusted for intracranial volume (HVa) was used for neurodegeneration biomarker. Age, sex, apolipoprotein E (APOE) e4 positivity was controlled as covariates in all analyses.ResultA total 428 participants (mean age [SD]: 70.54 [7.97], female [N, %]: 182 [43%]) were included for analysis. Serum 25(OH)D levels were directly associated neither Aβ deposition nor HVa. However, serum 25(OH)D level had significant moderation effect on the association between Aβ and hippocampal neurodegeneration, in that lower serum 25(OH)D level significantly exacerbate the negative association between global Aβ retention and HVa (β = 34.612, p = 0.008) (Figure).ConclusionThe present findings suggest that lower serum vitamin D level may increase AD dementia risk by aggravating Aβ‐related neurodegeneration.

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.

Medial temporal lobe gray matter microstructure alterations provide improved sensitivity to detect neurodegeneration associated with Alzheimer’s disease biomarkers

AbstractBackgroundDespite the strengths conventional structural imaging measures to detect atrophy, cross‐sectional relationships between neurodegeneration and Alzheimer’s disease (AD) biomarkers in early stages is limited. Neurite orientation dispersion and density imaging (NODDI) measures microstructural alterations that are unique from conventional structural metrics. Alterations in microstructure have been detected in individuals with AD compared to cognitively normal individuals, but there is sparse data regarding the relationship between these metrics and AD biomarkers. Here we sought to characterize how NODDI metrics in the medial temporal lobe (MTL) are associated with plasma AD biomarkers.MethodOne‐hundred and sixty‐seven cognitively normal (CN) individuals, 47 individuals with mild cognitive impairment, and 16 individuals with AD underwent diffusion and T1w imaging. T1w images were segmented using the ASHS‐T1 protocol to form anterior and posterior MTL ROIs. Multi‐shell DTI data were collected in 113 non‐collinear directions with 1.5mm isotropic voxels, were pre‐processed using a custom pipeline, and fit with voxel‐wise NODDI models. ANTs was used to linearly register NODDI and T1w images to allow transformation of MTL ROIs to diffusion space. Stepwise‐regression models examined relationships between anterior and posterior MTL NODDI metrics with plasma biomarkers in CN and impaired (MCI/AD) groups after accounting for MTL volume.ResultNODDI metrics of intracellular volume fraction (icVf) and orientation dispersion index (ODI) were decreased, and isometric volume fraction (isoVf) was increased in cognitively impaired compared to CN. Amyloid positivity was associated with decreased ODI and increased isoVf in cognitively impaired individuals. While posterior MTL volume predicted plasma p‐Tau‐181, inclusion of NODDI metrics subsumed this effect (F‐change>7.54, p<0.0067), and reduced ODI was the best predictor of plasma pTau‐181 within cognitively impaired individuals, while isoVf best predicted pTau‐181 across all individuals. Posterior MTL volume did not predict plasma GFAP, but inclusion of ODI and icVf both significantly predicted plasma GFAP in both CN and impaired individuals (F‐change>12.68, p<.001). Anterior MTL icVf predicted both pTau‐181 and GFAP.ConclusionMicrostructural alterations measured by NODDI appear more closely linked to AD‐related molecular measures and, thus, may provide a more sensitive cross‐sectional measure of neurodegeneration of the MTL compared to conventional macrostructural metrics.

Assessment of brain oxygen extraction fraction between normal cognition and mild cognitive impairment in an elderly cohort using quantitative BOLD

AbstractBackgroundThis study is to quantify oxygen extraction fraction (OEF), an important physiological biomarker for brain hemodynamic impairment, in the elderly cohort using non‐invasive quantitative BOLD (qBOLD) modeling, which is an MRI method for assessment of hemodynamic and metabolic properties.Methods56 participants (75.4±7.0yo, 37F), including 46 cognitively normal (CN) individuals (75.2±7.3yo, 29F) and 10 mild‐cognitive‐impairment (MCI) patients (76.0±6.1yo, 7F), were recruited from UC Davis Alzheimer’s Disease Research Center cohort. MRI scans were acquired on a 3T scanner (Siemens Tim Trio) with a 32‐channel head coil, including an Asymmetric Spin Echo (ASE) scan (TR/TE, 2800/66ms; 2.3×2.3.x1.3mm3 resolution; FOV, 224mm; 13 values of the spin echo displacement time, from 0 to 52ms) and a T1‐weighted MPRAGE. T1‐weighted images were segmented into regions of interest (ROI), including gray matter (GM), white matter (WM), and cortical lobes (frontal, parietal, occipital, temporal) using FSL FAST. ASE signal curves were preprocessed and fit to two‐compartment qBOLD model with Variational Bayesian framework to estimate deoxygenated blood volume (DBV) and transverse relaxation rate (R2 ’), which are used to quantify OEF with known physiological constants (Cherukara et al., NeuroImage 2019). Average OEF values were calculated and compared for each ROI between CN and MCI groups using pairwise t‐tests with Bonferroni correction. The correlation between OEF and age were assessed using a linear mixed effects model that accounted for subject clustering.ResultsCompared to CN, reduced DBV and increased OEF were observed throughout most of the brain on the group average level in MCI (Figure 1). In regional analysis, we observed a trend of increased OEF in MCI compared to CN in several ROIs, which was significant in the occipital lobe (p = 0.007) (Figure 2). In Figure 3, OEF was inversely correlated with age in the parietal lobe for CN (p = 0.026). In contrast, there was a positive trend of association between OEF and age for MCI across all regions.ConclusionThis study showed that age has an association with brain oxygen extraction that are differently affected by normal aging and MCI. Higher brain OEF in MCI individuals may reflect changes in oxygen metabolism because of underlying pathology, including vascular injury and compensation for hypoperfusion.

Assessment of brain oxygen extraction fraction between normal cognition and mild cognitive impairment in an elderly cohort using quantitative BOLD

AbstractBackgroundThis study is to quantify oxygen extraction fraction (OEF), an important physiological biomarker for brain hemodynamic impairment, in the elderly cohort using non‐invasive quantitative BOLD (qBOLD) modeling, which is an MRI method for assessment of hemodynamic and metabolic properties.Method56 participants (75.4±7.0yo, 37F), including 46 cognitively normal (CN) individuals (75.2±7.3yo, 29F) and 10 mild‐cognitive‐impairment (MCI) patients (76.0±6.1yo, 7F), were recruited from UC Davis Alzheimer’s Disease Research Center cohort. MRI scans were acquired on a 3T scanner (Siemens Tim Trio) with a 32‐channel head coil, including an Asymmetric Spin Echo (ASE) scan (TR/TE, 2800/66ms; 2.3×2.3.x1.3mm3 resolution; FOV, 224mm; 13 values of the spin echo displacement time, from 0 to 52ms) and a T1‐weighted MPRAGE. T1‐weighted images were segmented into regions of interest (ROI), including gray matter (GM), white matter (WM), and cortical lobes (frontal, parietal, occipital, temporal) using FSL FAST. ASE signal curves were preprocessed and fit to two‐compartment qBOLD model with Variational Bayesian framework to estimate deoxygenated blood volume (DBV) and transverse relaxation rate (R2’), which are used to quantify OEF with known physiological constants (Cherukara et al., NeuroImage 2019). Average OEF values were calculated and compared for each ROI between CN and MCI groups using pairwise t‐tests with Bonferroni correction. The correlation between OEF and age were assessed using a linear mixed effects model that accounted for subject clustering.ResultCompared to CN, reduced DBV and increased OEF were observed throughout most of the brain on the group average level in MCI (Figure 1). In regional analysis, we observed a trend of increased OEF in MCI compared to CN in several ROIs, which was significant in the occipital lobe (p = 0.007) (Figure 2). In Figure 3, OEF was inversely correlated with age in the parietal lobe for CN (p = 0.026). In contrast, there was a positive trend of association between OEF and age for MCI across all regions.ConclusionThis study showed that age has an association with brain oxygen extraction that are differently affected by normal aging and MCI. Higher brain OEF in MCI individuals may reflect changes in oxygen metabolism because of underlying pathology, including vascular injury and compensation for hypoperfusion.

Medial temporal lobe gray matter microstructure alterations provide improved sensitivity to detect neurodegeneration associated with Alzheimer’s disease biomarkers

AbstractBackgroundDespite the strengths conventional structural imaging measures to detect atrophy, cross‐sectional relationships between neurodegeneration and Alzheimer’s disease (AD) biomarkers in early stages is limited. Neurite orientation dispersion and density imaging (NODDI) measures microstructural alterations that are unique from conventional structural metrics. Alterations in microstructure have been detected in individuals with AD compared to cognitively normal individuals, but there is sparse data regarding the relationship between these metrics and AD biomarkers. Here we sought to characterize how NODDI metrics in the medial temporal lobe (MTL) are associated with plasma AD biomarkers.MethodOne‐hundred and sixty‐seven cognitively normal (CN) individuals, 47 individuals with mild cognitive impairment, and 16 individuals with AD underwent diffusion and T1w imaging. T1w images were segmented using the ASHS‐T1 protocol to form anterior and posterior MTL ROIs. Multi‐shell DTI data were collected in 113 non‐collinear directions with 1.5mm isotropic voxels, were pre‐processed using a custom pipeline, and fit with voxel‐wise NODDI models. ANTs was used to linearly register NODDI and T1w images to allow transformation of MTL ROIs to diffusion space. Stepwise‐regression models examined relationships between anterior and posterior MTL NODDI metrics with plasma biomarkers in CN and impaired (MCI/AD) groups after accounting for MTL volume.ResultNODDI metrics of intracellular volume fraction (icVf) and orientation dispersion index (ODI) were decreased, and isometric volume fraction (isoVf) was increased in cognitively impaired compared to CN. Amyloid positivity was associated with decreased ODI and increased isoVf in cognitively impaired individuals. While posterior MTL volume predicted plasma p‐Tau‐181, inclusion of NODDI metrics subsumed this effect (F‐change>7.54, p<0.0067), and reduced ODI was the best predictor of plasma pTau‐181 within cognitively impaired individuals, while isoVf best predicted pTau‐181 across all individuals. Posterior MTL volume did not predict plasma GFAP, but inclusion of ODI and icVf both significantly predicted plasma GFAP in both CN and impaired individuals (F‐change>12.68, p<.001). Anterior MTL icVf predicted both pTau‐181 and GFAP.ConclusionMicrostructural alterations measured by NODDI appear more closely linked to AD‐related molecular measures and, thus, may provide a more sensitive cross‐sectional measure of neurodegeneration of the MTL compared to conventional macrostructural metrics.

The Effects of Sex and APOE4 Genotype on Longitudinal Changes in White Matter Integrity Differ by Diagnostic Group Along the Spectrum of Alzheimer’s Disease

AbstractBackgroundSex and APOE ε4 (APOE4) are well‐established risk factors for Alzheimer’s disease (AD), with female ε4‐carriers at greatest risk. Uncovering the neurobiological substrates of sex and genetic effects in AD is critical to improve prevention, intervention, and treatment monitoring. While changes to white matter (WM) integrity are commonly noted in the progression of AD, it is unclear if these changes are further modulated by sex and APOE4 status. In the current study, we examined the effects of sex and APOE4 carrier status on WM integrity, both cross‐sectionally and longitudinally, across the AD continuum.MethodA total of 457 participants (233 cognitively normal (CN), 167 mild cognitive impairment (MCI), and 57 AD; 223 females; 187 APOE ε4‐carriers) was selected from the ADNI database, based on the availability two diffusion MRI (dMRI) sessions. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA). Annualized FA change maps were created to measure voxel‐wise WM change over time. The effect of sex, APOE4‐carrier status, diagnosis, and their interactions, on cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age.ResultAt baseline, females exhibited greater FA than males in the fornix, right inferior fronto‐occipital fasciculus, left inferior and superior longitudinal fasciculus, while males showed greater FA in the left corticospinal tract. Additionally, there were widespread differences across the skeleton by diagnosis, with FA decreasing stepwise across the continuum (CN>MCI>AD). There were no APOE4‐related differences in baseline WM integrity. Longitudinally, a three‐way interaction between diagnosis, APOE4, and sex emerged within the corpus collasum, left anterior thalamic radiation, left corticospinal tract, left uncinate fasciculus, and left inferior and superior longitudinal fasciculus. Posthoc analyses revealed that within the AD group, but not CN or MCI groups, females underwent greater WM degeneration than males among nonε4‐carriers, while males showed greater WM degeneration than females among ε4‐carriers.ConclusionThese findings suggest that increased risk associated with sex and APOE4 genotype may change and interact with the progression of AD. Future studies are warranted to examine the contribution of cerebrovascular risk factors to AD progression in male ε4‐carriers.

Correlations of p‐tau217, p‐tau181 and tau levels between CSF and plasma that are measured by fully automated immunoassay platform

AbstractBackgroundCerebrospinal fluid (CSF)‐based ATN classification (A: β‐amyloid (Aβ) deposition, T: pathogenic tau accumulation, N: neurodegeneration) is being widely accepted for the characterization of Alzheimer’s disease (AD). However, for the implementation of ATN classification in clinical practice, blood‐based biomarker is preferable in terms of specimen collection ease. Therefore, we have developed the blood‐based biomarker assays that correlate well with CSF levels. We have previously demonstrated that the plasma tau and phosphorylated tau at threonine‐181 (p‐tau181) immunoassays can significantly differentiate between AD, mild cognitive impairment (MCI), and cognitively normal (CN) groups. Here, we evaluated the correlation of biomarker levels between CSF and plasma utilizing the biomarker panel with addition of phosphorylated tau at threonine‐217 (p‐tau217) immunoassay.MethodWe have measured p‐tau217, p‐tau181 and tau using commercially available specimens on a fully automated immunoassay platform, HISCLTM analyzer. The platform can achieve high degree of sensitivity, requires only 30 µl of sample and 17 minutes to complete the measurement per assay. The bio‐analytical performance for the immunoassays was evaluated by measuring lower limit of quantification (LLOQ). The developed immunoassays were used to measure the paired CSF and plasma specimens from AD (n = 10), MCI (n = 35) and CN (n = 9) groups.ResultThe quantitative sensitivity for p‐tau217, p‐tau181 and tau were sufficient to measure plasma specimens in all groups. The plasma biomarker levels were significantly different between the AD and CN groups for all the biomarkers. We have found good correlations of biomarker levels between CSF and plasma for p‐tau217 (rs = 0.594, p < 0.01), p‐tau181 (rs = 0.453, p < 0.01) and tau (rs = 0.326, p < 0.05).ConclusionOur results indicated the possibility of detecting plasma p‐tau217, p‐tau181 and tau levels which may reflect the CSF levels. In addition to these assays, we have also developed plasma Ab and neurofilament light chain assays that had demonstrated good correlation with CSF levels. Thus, all the plasma assays developed on the HISCL analyzer could assess ATN classification. The blood‐based biomarker panel using our fully automated assay will accelerate research in the dementia field and may help in appropriate diagnosis of patients with dementia in routine clinical practice.

Cognitive decline in elderly patients with type 2 diabetes is associated with glycated albumin, ratio of Glycated Albumin to glycated hemoglobin, and concentrations of inflammatory and oxidative stress markers

ObjectiveTo investigate the correlations of cognitive function with glycated albumin (GA), the ratio of GA to glycated hemoglobin (GA/HbA1c), and the concentrations of interleukin-6 (IL-6) and superoxide dismutase (SOD) in elderly patients with type 2 diabetes mellitus (T2DM). MethodsA total of 44 elderly T2DM patients were evaluated for cognitive function using the mini-mental state examination (MMSE) and the Montreal cognitive assessment (MoCA). Patients were then divided into two groups based on the MMSE and MoCA scores: a cognitive dysfunction group and a normal cognitive function group. The correlations of the MMSE and MoCA scores with GA/HbA1c, GA, IL-6, and SOD were analyzed. Logistic regression analysis was used to identify independent influential factors for cognitive dysfunction. The predictive value of GA and GA/HbA1c for cognitive dysfunction in elderly T2DM patients was evaluated by receiver operating characteristic (ROC) curve analysis. ResultsAmong these patients, 28 had cognitive impairment. They had significantly higher GA/HbA1c, increased GA and IL-6 levels, and lower SOD concentrations than the normal cognitive function group (all P < 0.05). GA/HbA1c was negatively correlated with the MMSE (r = −0.430, P = 0.007) and MoCA (r = −0.432, P = 0.007) scores. SOD was positively correlated with the MMSE (r = 0.585, P=0.014) and MoCA (r = 0.635, P=0.006) scores. IL-6 was negatively correlated with the MoCA score (r = −0.421, P=0.015). Age and GA/HbA1c were independent factors contributing to cognitive dysfunction. The areas under the ROC curves of GA and GA/HbA1c for the diagnosis of cognitive dysfunction were 0.712 and 0.720, respectively. ConclusionsGA and GA/HbA1c are related to cognitive dysfunction in elderly patients with T2DM.

Association of Pork Intake with Cognitive Performance in Older Adults Enrolled in the National Health and Nutrition Examination Survey (NHANES), 2011-2014 Data Cycles.

Pork provides higher levels of several nutrients important for cognitive maintenance in older adults. A pilot clinical study suggests the addition of moderate amounts of pork to a Mediterranean-style diet improves cognition in older adults. There is an absence of observational research that isolates effects of pork from other red meats. To examine the relationship of pork intake on cognitive performance in older adults. Cross-sectional data from the U.S. National Health and Nutrition Examination Survey (NHANES) 2011-2014 cycles were used in these analyses. Pork intake was assessed using data from two non-consecutive 24-h dietary recalls. Cognitive function was assessed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning, CERAD Delayed Recall, Animal Fluency, and Digital Substitution tests. Statistical analyses were adjusted for sample weighting and survey design variables to account for the complex design. Student t-tests (continuous variables) and Pearson chi-squared tests (categorical variables) were employed to compare participant characteristics between the low and normal cognitive performance groups. Logistic regression was used to determine the relationship of pork intake (low, medium, and high) with prevalence of low cognitive performance, with the non-consumer group as the referent category. Pork intake was not beneficially or detrimentally associated performance on the any of the cognitive tests in both the crude and multivariate models (p > 0.05). Prospective cohort investigations and larger/longer-term clinical trials are needed to fully elucidate effects of pork intake on cognition in older adults.

Cognitive impairment and outcomes in older adults with non-ST-elevation acute coronary syndrome

ObjectiveThis study aimed to explore the prognostic impact of cognitive impairment on the long-term risk of major adverse cardiovascular events (MACEs) in older patients with non-ST-elevation acute coronary syndrome (NSTEACS)...

Effects of carotid revascularization on cognitive function and brain functional connectivity in carotid stenosis patients with cognitive impairment: a pilot study.

Carotid stenosis can lead to both cognitive impairment (CI) and ischemic stroke. Although carotid revascularization surgery, which includes carotid endarterectomy (CEA) and carotid artery stenting (CAS), can prevent future strokes, its effect on cognitive function is controversial. In this study, the authors examined resting-state functional connectivity (FC) in carotid stenosis patients with CI undergoing revascularization surgery, with a particular focus on the default mode network (DMN). Twenty-seven patients with carotid stenosis who were scheduled to undergo CEA or CAS between April 2016 and December 2020 were prospectively enrolled. A cognitive assessment, including the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Japanese version of the Montreal Cognitive Assessment (MoCA), as well as resting-state functional MRI, was performed 1 week preoperatively and 3 months postoperatively. For FC analysis, a seed was placed in the region associated with the DMN. The patients were divided into two groups according to the preoperative MoCA score: a normal cognition (NC) group (MoCA score ≥ 26) and a CI group (MoCA score < 26). The difference in cognitive function and FC between the NC and CI groups was investigated first, and then the change in cognitive function and FC after carotid revascularization was investigated in the CI group. There were 11 and 16 patients in the NC and CI groups, respectively. The FC of the medial prefrontal cortex with the precuneus and that of the left lateral parietal cortex (LLP) with the right cerebellum were significantly lower in the CI group than in the NC group. In the CI group, significant improvements were found in MMSE (25.3 vs 26.8, p = 0.02), FAB (14.4 vs 15.6, p = 0.01), and MoCA scores (20.1 vs 23.9, p = 0.0001) after revascularization surgery. Significantly increased FC of the LLP with the right intracalcarine cortex, right lingual gyrus, and precuneus was observed after carotid revascularization. In addition, there was a significant positive correlation between the increased FC of the LLP with the precuneus and improvement in the MoCA score after carotid revascularization. These findings suggest that carotid revascularization, including CEA and CAS, might improve cognitive function based on brain FC in the DMN in carotid stenosis patients with CI.