bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal [18F]RO948 PET SUVR is associated with Aβ accumulation and baseline tau pathology
Authors: Leuzy Antoine , Klein Gregory , Ossenkoppele Rik , Mattsson Niklas , Janelidze Shorena , Palmqvist Sebastian , Strandberg Olof , Coloma Preciosa M , Borroni Edilio , Stomrud Erik , Smith Ruben , Hansson Oskar
Published: December 2020

Background

Alzheimer’s disease (AD) is defined by amyloid‐β (Aβ) and tau pathology. Specifically, Aβ and tau are thought to interact, with Aβ mediating the spread of tau. We here aimed to examine the association between cross‐sectional Aβ and tau‐PET with change in tau‐PET SUVR.

Methods

51 subjects from the ongoing BioFINDER‐2 longitudinal sub‐study were included: 23 cognitively unimpaired (CU; 9 Aβ‐negative,14 Aβ‐positive), 21 with MCI (3 Aβ‐negative,18 Aβ‐positive) and 7 AD with dementia (all Aβ‐positive). Aβ‐status was based on CSF Aβ42/Aβ40. Aβ (CU, MCI only, by design) and tau‐PET (all subjects) were performed using [18F]flutemetamol and [18F]RO948, respectively. Subjects underwent a targeted follow‐up of ∼12‐months (mean=13.2±2.6) with [18F]RO948. FreeSurfer (v.6.0) was used to calculate mean‐SUVR values for tau‐PET across four predefined ROIs reflecting Braak‐stages I‐VI (inferior cerebellar cortex as reference). For Aβ‐PET SUVR, a cortical meta‐ROI was used (composite white‐matter reference region). The association between longitudinal and cross‐sectional findings was assessed using linear regression with subject specific slopes for tau‐PET and tau and Aβ‐PET SUVR at baseline as predictors (adjusted for age, sex, interscan‐interval).

Results

Largest longitudinal change and effect‐sizes followed a group/Braak ROI specific pattern (Figure 1): I‐II (entorhinal cortex) for Aβ‐positive CU (+3.14%, effect‐size 0.72), III‐IV (amygdala, fusiform gyrus, inferior/middle temporal cortex, and parahippocampus) for Aβ‐positive MCI (+3.62%, effect‐size 0.61) and V‐VI (neocortical) for AD dementia (+3.98%, effect‐size 0.58). No significant increases were seen across Aβ‐negative subjects. Regression models in CU and MCI subjects (no AD dementia due absence of Aβ‐PET) showed that increases in tau‐PET SUVR were related to both Aβ‐PET and tau‐PET SUVR at baseline. However, when incorporating both measures as predictors, Aβ‐PET remained significant only in Aβ‐positive CU subjects. Plotting change in tau‐PET as a function of change in Aβ‐PET (Figure 2) revealed a seeming threshold effect whereby tau pathology accelerated around an Aβ‐PET SUVR of 0.65.

Conclusion

Initial results with longitudinal [18F]RO948 indicate that it is able to capture the progression of early tau pathology in Aβ‐positive CU subjects, as well as cortical increases in subjects with cognitive impairment. A critical burden of Aβ appears to be a prerequisite for increases in tau pathology.
Effect‐modifying role of education and crystalized intelligence on the association of amyloid pathology and cognitive function
Authors: Udeh‐Momoh Chinedu T. , Zheng Bang , Price Geraint J. , Watermeyer Tam J. , de Jager Celeste A. , Robb Catherine , Giannakopoulou Parthenia , Su Bowen , Saad Ziad , Fogle Michael , Ford Jamie , Ritchie Craig W. , Baker David , Novak Gerald P. , Ahmadi‐Abhari Sara , Middleton Lefkos T.
Published: December 2020

Background

Cognitive reserve factors reflecting innate (crystallized intelligence) and derived (educational attainment) cognitive capacity are shown to be associated with preservation of cognitive function and delayed decline. Yet little information is available on how these static measures of reserve themselves are associated with cerebral amyloid burden and influence its effect on neurocognitive performance.

Methods

In the deeply‐phenotyped CHARIOT:PRO substudy, 501 cognitively healthy individuals aged 60‐85 years had available information on ApoE genotype (carrier vs non‐carrier), brain PET‐scan/CSF‐derived amyloid load (positive vs negative), education attainment, premorbid intelligence measured by the National Adult Reading Test (NART), and cognitive performance via the multi‐domain Repeatable Battery Assessment of Neuropsychological Status (RBANS) measured at two time‐points (average 3.5 months apart). Linear mixed models were used to independently examine the effect modifying role of education and intelligence as measures of cognitive reserve on the association of amyloid status and cognitive function.

Results

There was an effect modification in the association of amyloid status and global cognition (total RBANS score) by both intelligence and Education in mutually adjusted models accounting for age, sex and ApoE. The effect modification was more pronounced for intelligence. RBANS total score was lower in participants who were amyloid positive (vs negative) among those with lower than median intelligence quotient (mean difference in RBANS Z‐score by amyloid status ‐0.2 (95% CI ‐0.35, ‐0.04)). The inverse association between amyloid positivity and global cognition disappeared among those with higher than median intelligence (mean difference in RBANS Z‐score by amyloid status 0.01 (95% CI ‐0.16, 0.18)), P‐value for interaction <0.001. Correspondingly, mean difference in RBANS Z‐score for amyloid positivity (vs negativity) was ‐0.18 (95% CI ‐0.36, 0.00) for participants with below median education, and ‐0.07 (95% CI ‐0.24, 0.09) for participants with above median education attainment, P‐value for interaction 0.19. Further adjustment for body mass index, smoking, physical activity, systolic blood pressure and diabetes did not have a remarkable effect on the findings.

Conclusions

Our results support the hypothesis that although education and intelligence are both associated with higher cognitive reserve, crystalized intelligence provides more resilience against the neurodegenerative effect of amyloid pathology on global cognition.
Subjective versus objective cognitive assessment in an ethnically diverse cohort of oldest‐old individuals: The LifeAfter90 Study
Authors: Corrada Maria M.M. , Kawas Claudia H. , DeCarli Charles , Gilsanz Paola , Glymour M. Maria , Mayeda Elizabeth Rose , Mungas Dan M. , Whitmer Rachel A.
Published: December 2020

Background

The ability to measure cognition accurately in ethnically diverse populations is important. However, information about cognition in the oldest‐old (people aged 90+) comes almost exclusively from cohorts of highly educated Caucasian individuals. We studied the association between self‐rated cognition and objectively measured cognition among the first 610 participants enrolled in an ongoing multi‐ethnic oldest‐old cohort.

Method

LifeAfter90 participants are long‐time members of the Kaiser Permanente Northern California Health Care System without a dementia diagnosis in their medical record at recruitment. Evaluations are every six months and include the Everyday Cognition (ECog) and Spanish and English Neuropsychological Assessment Scales (SENAS). The ECog is a self‐rated questionnaire about abilities to perform cognitively relevant functional tasks across multiple domains (on a 4‐point scale from ‘no change’ to ‘much worse’). For analysis, we averaged items within each domain (memory‐2, language‐2, visuospatial abilities‐5, and executive function‐7). The SENAS assesses episodic memory, semantic memory, and executive function domains. We estimated the cross‐sectional associations between self‐rated cognition (ECog) and objectively measured cognition (SENAS) measured at baseline. Using linear regression, we determined in the full cohort which ECog items had the strongest association with each SENAS domain and compared those associations across racial/ethnic groups.

Result

At baseline, participants were on average 92.6 years of age, 62% were women, 45% had a college education, and 68% were racial/ethnic minorities (Table 1). Table 2 shows the associations between ECog items and SENAS domains. ‘Concerned about memory’ was the ECog item most strongly associated with SENAS Verbal Memory, and that association was strongest among Whites and Blacks. The visuospatial ECog items had the strongest association with SENAS Semantic Memory, and that association was present among Whites and Latinos. The executive function ECog items had the strongest association with SENAS Executive Function, and the association was present among Whites and Latinos. No associations between ECog items and SENAS domains were observed among Asians or the multiracial group.

Conclusion

In this oldest‐old cohort, we found differences in how racial ethnic/groups report their everyday cognitive function in relation to their measured cognitive abilities. These differences need to be considered when assessing subjective cognitive function in diverse populations.
Piloting a novel screening tool for reducing heterogeneity in clinical trials in Alzheimer’s disease
Authors: Oxtoby Neil P. ,   UCL Centre for Medical Image Computing
Published: December 2020

Background

Screening for clinical trials in Alzheimer’s disease (AD) ideally selects the right people at the right time to efficiently test a putative therapy. Traditional screening instruments have been clinical/cognitive tests scores, including cognitive composites. Moves towards secondary prevention trials necessitated refinement of the screening process using biomarkers. This hasn’t helped, with the number of negative trials continuing to grow. This work takes screening to the next level by proposing and piloting a novel computational tool capable of improving the precision of cognitive‐ and biomarker‐based screening.

Method

An event‐based model of AD progression is a computational model capable of fusing cognitive and/or biomarker data into a fine‐grained staging tool. The tool assigns individuals a numerical severity score that best fits their data. Here the tool was trained on baseline data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and tested, post hoc, on data from AD Cooperative Study’s MCI trial (clinicaltrials.gov: NCT00000173), which recruited individuals with Mild Cognitive Impairment (MCI) and included three arms: Donepezil, Vitamin E, Placebo. Group differences were analysed at follow‐ups using a t‐test, stratified by severity score.

Result

Figure 1 shows the event‐based model built on N=803 (of 2040) ADNI participants (229 CN, 182 AD, 392 MCI) having complete data (see Methods). The model estimates a probabilistic, ordered sequence (upper‐left to lower‐right) of cognitive decline from Clinical Dementia Rating, through general cognition/memory, to verbal fluency. Model‐based staging assigned a fine‐grained severity score (SS) to each participant in both the training data and the N=473 (of 769) MCI trial participants having complete data for the trial duration. Histograms of SS in Figure 2 show substantial heterogeneity in both ADNI (left) and, in particular, ADCS‐MCI (right) which shows three clusters: SS<5, SS>10, and 5≤SS<10. Table 1 shows significantly lower mean ADAS‐Cog 13 score under Donepezil treatment in the SS>10 cluster, detectable only with the novel tool.

Conclusion

This pilot study proposed a novel screening tool to reduce cohort heterogeneity in clinical trials in Alzheimer’s disease, offering hope for improving efficiency of future trials.
Latinx brain health disparities in cognitive aging: The role of acculturation on brain integrity and cognition among older HIV+ adults
Authors: Mindt Monica Rivera , Savin Micah J. , Morris Emily P. , Summers Angela , Aghvinian Maral N. , Crook Cara L. , Byrd Desiree , Clark Uraina S. , Guzman Vanessa A. , Stiver Jordan , Fidaleo Kaleigh L. , Breen Elizabeth L. , Slaughter Alex L. , Robinson‐Papp Jessica
Published: December 2020

Background

The US Latinx population is the largest ethnoracial minority group and the fastest growing sector of the aging population (Escarce et al., 2006; US Census Bureau, 2008). Compared to non‐Latinx whites (NLW), the Latinx population bears a disproportionate dementia burden secondary to multiple etiologies (e.g., Alzheimer’s, HIV‐infection; Babulal et al., 2018; Rivera Mindt et al., 2014). Yet, little is understood regarding the sociocultural factors underlying these significant brain health disparities. This aim of cross‐sectional study was to investigate indices of brain integrity, cognition, and acculturation in older HIV+ Latinx and NLW adults.

Method

Participants included 75 older HIV+ adults (Age: M=60 yrs [SD=6.9]; Education: M=13.6 yrs [SD=3.1]; 47% Latinx [primarily Caribbean heritage] & 53% NLW; and 71% male) who completed multimodal neuroimaging (structural MRI and resting state fMRI [rs‐fMRI]), cognitive (seven domains; e.g., leaning, memory, executive function), neuromedical (HIV clinical indices [HIV viral load]), and sociocultural (e.g., acculturation [Abbreviated Multidimensional Acculturation Scale, AMAS]) evaluations. Global and domain‐specific Average T‐scores were computed on individual tests based on demographically‐adjusted norms.

Result

Compared to the NLW group, the Latinx group had greater white matter lesion volumes ([mL], FLAIR; Cohen’s d=1.13, p<.01) and lower hippocampal and posterior cingulate intrinsic activity (rs‐fMRI fALFF values; d’s =.61 ‐ .67), and worse global cognition, learning, memory, and processing speed (ds=.53 ‐ .83, ps< .05), with the largest effects in learning and memory. Lower acculturation to US majority culture (i.e., AMAS US Total Score) was related to reduced intrinsic activity of the right hippocampus and posterior cingulate cortex at the trend level (rs‐fMRI fALFF values; rs=.61 ‐ .63, ps<.10) and worse global cognition, learning, memory, and processing speed (rs = .39 ‐ .51, ps<.05).

Conclusion

These findings highlight marked disparities in brain integrity and cognition in older HIV+ Latinx adults. Acculturation may be an important factor for understanding these disparities. Future longitudinal research is needed with HIV‐ controls, larger sample sizes, and the inclusion of other Latinx subpopulations (i.e., Mexican‐American, South American) to extend the current findings and inform culturally‐targeted interventions to promote Latinx brain health. Acknowledgements: The authors thank the Alzheimer’s Association for their support of this study (AARGD‐16‐446038).
Anterolateral entorhinal cortical thinning as a biomarker for Alzheimer’s disease in Down syndrome
Authors: Sathishkumar Mithra , Janecek John , Smith Anna , Phelan Michael , Tustison Nick , Keator David , Doran Eric , Hom Christy , Nguyen Dana , Petersen Melissa , Rosas H. Diana , Lai Florence , Brickman Adam M. , Schupf Nicole , Silverman Wayne , Lott Ira T. , O’Bryant Sid , Yassa Michael A.
Published: December 2020

Background

Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) associated neuropathology by the age of 40 and the majority of them develop dementia by age 60. Atrophy of the anterolateral entorhinal cortex (aLEC) has been previously associated with cognitive decline. Here, we sought to determine whether aLEC thinning is associated with clinical impairment in older adults with DS as well as whether it is associated with blood neurofilament light chain (NfL), another biomarker of neurodegeneration in AD.

Method

103 older adults with DS enrolled in the Alzheimer’s Disease in Down Syndrome (ADDS) study were included in this analysis. Scans were classified into 3 groups based on consensus diagnosis: 14 (6F) possible/definite dementia (DEM), 19 (5F) mild cognitive impairment (MCI‐DS) and 70 (28F) cognitively stable (CS). Images were processed through the joint label fusion (JLF) pipeline in ANTs to obtain medial temporal lobe subregional volumes and thickness. Cortical reconstruction was performed using Freesurfer 6.0 to obtain total intracranial volume(ICV). We used a multiple linear regression model to fit left aLEC thickness using diagnostic group as the independent variable, correcting for age, gender, ICV and scan site differences. For a subset of these data (N=89), plasma NfL was quantified using a Simoa platform and we and tested whether left aLEC thickness was associated with NfL.

Result

Cortical thickness in left aLEC was a significant predictor of clinical status. Thickness values were highest in the CS group, followed by MCI‐DS, followed by DEM. Groupwise differences were significant in DEM vs. CS and DEM vs. MCI‐DS comparisons. We also found a significant correlation between NfL and left aLEC thickness specifically in the DEM group. Finally, random forest classification showed that both NfL and left aLEC thickness were important features in predicting clinical diagnosis DEM vs MCI‐DS. Their estimates provided a diagnosis ROC curve with sensitivity of 0.79 and specificity of 0.92.

Conclusion

In older adults with DS, left aLEC cortical thickness atrophy may be a primary feature of structural neurodegeneration that is associated with MCI‐DS and a blood‐based measurement of NfL may be informative as to this structural degeneration.
Functional fitness assessments predict cognitive outcomes
Authors: Gills Joshua L , Gray Michelle , Glenn Jordan M , Madero Erica N , Fuseya Nami , Hall Aidan , Bott Nicholas T
Published: December 2020

Background

The rate of Alzheimer’s disease (AD) is anticipated to triple by 2050, affecting 131 million people globally. To combat this dramatic increase, it is imperative to detect early cognitive decline in order to provide timely interventions. As a result, the ability to predict cognitive status through ubiquitous functional fitness assessment would provide a cost‐effective method for identifying cognitively at‐risk older adults. This study sought to determine whether functional fitness measures could accurately predict cognitive outcomes.

Method

85 older adults (age: 80.93 ± 5.4) participated in the current study. Each participant completed demographic questionnaires; completed three cognitive tasks: Montreal Cognitive Assessment (MoCA), digit coding symbol test (DCS), and visual paired comparison target foil accuracy (VPCTFA) assessment; and completed six functional fitness assessments : 10‐meter maximal speed walk, dual‐task maximal speed (DTMS), dual‐task habitual speed (DTHS), sit‐to‐stand power, timed up‐and‐go (TUG), and the short physical performance battery (SPPB). Results were analyzed through three multiple linear regressions with MoCA, DCS and VPCTFA test each as the dependent variables, and age, sex, education, DTMS, DTHS, sit‐to‐stand power, TUG, and SPPB as predictor variables.

Result

The first model explained 55% of the variance of the MoCA (p < .001) with DTMS (45%; p < .001) representing the only significant predictor. The second model explained 13% of the variance of the DCS (p = .13) with age (28%; p = .01) and DTMS (23%; p = .04), representing significant predictors. The last model explained 18% of the variance of the VPCTFA (p = .007) with DTMS (21%; p = .05), TUG (21%; p = .05), 10‐meter maximal walking speed (21%; p = .05) and 4‐meter walk (SPPB variable; 22%; p = .04) representing significant predictors.

Conclusion

These results suggest functional fitness assessments may predict cognitive outcomes. Functional fitness assessments accounted for more variance of MOCA scores than DCS and VPCTFA outcomes. This suggests functional fitness assessments may be better predictors of global cognition performance than performance on assessments of processing speed or working memory. Future research will investigate whether functional fitness parameters may be cost‐effective evaluation tools for predicting global cognitive performance over time.
Functional molecular network models for the genetic risk factors of Alzheimer’s disease
Authors: Ming Chen , Marcora Edoardo , Wang Minghui , Renton Alan E. , Wang Erming , Goate Alison , Zhang Bin
Published: December 2020

Background

Genome‐wide association studies (GWAS) have pinpointed a limited number of risk loci in Alzheimer’s disease (AD). However, the biological functions of these AD risk loci remain mostly elusive. Network analysis of functional genomic data provides an excellent opportunity to understand AD systematically. In this study, we leverage a cohort of large‐scale transcriptomic data in AD to develop functional network models for AD risk genes.

Method

We integrated all sumstats of AD risk loci from four previous AD GWAS studies and generated putative AD‐risk genes(PADRG) using MAGMA. We determined the +/‐ 1 Mb cis‐regulome interval for the promoter of each protein‐coding gene, and applied MAGMA in top SNP mode to all AD GWAS summary statistics using cis‐regulome intervals as the unit of aggregation, then retained genes whose interval achieved both p < 5e‐8 in any GWAS and p < 1 in all four GWAS. Based on the Mount Sinai Brain Bank AD cohort comprised of multi‐Omics data from multiple brain regions, we performed the multiscale embedded gene coexpression network (MEGEN) analysis to delineate gene coexpression relationships. Subnetworks centering around each PADRG were then extracted and evaluated for relevance with AD‐related clinical and pathological traits.

Result

The 751 PADRGs are enriched in the immune response‐related modules in the MEGENs from four brain regions, consistent with the known prominent role of immune response in AD. The subnetwork analysis further identifies the functional contexts of PADRGs. All the top thirty‐nine PADRG‐centered subnetworks are from the parahippocampal gyrus region and have a variety of biological functions such as synaptic signaling, protein‐complex subunit organization, and RAS protein signal transduction. The top two subnetworks are centered around FAM81A and RCAN2 and are involved in γ‐aminobutyric acid (GABA) signaling. Three well‐known AD risk genes CLU, MAPKAPK2 and STX3, are predicted to function in the cellular response to organic substance, inflammatory response, synaptic signaling pathways, respectively.

Conclusion

Our multiscale network analysis systematically identifies the functional contexts of the PADRGs. The subnetworks around the PADRGs and the comprehensive characterization of those subnetworks lay down a solid foundation for not only prioritizing AD‐associated genes but also investigating their biological functions.
Associations between lifestyle risk, β‐amyloid, tau, and cognition in late mid‐life
Authors: Cody Karly Alex , Koscik Rebecca L. , Erickson Claire M , Birdsill Alex C , Berman Sara E , Chin Nathaniel A. , Clark Lindsay R , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C
Published: December 2020

Background

Modifiable lifestyle risk (LR) factors are increasingly viewed as preventive strategies for AD and dementia; however, the impact of LR factors on AD biomarkers or AD biomarker‐related cognitive decline remains unknown. We utilized the Lifestyle for BRAin health (LIBRA) index 1)to investigate whether baseline LR predicts incident cognitive impairment and/or β‐amyloid onset; 2)to examine the effect of longitudinal LR on cognitive decline in the presence of β‐amyloid; 3)to preliminarily examine the cross‐sectional relationship between late‐midlife LR and β‐amyloid and tau biomarker groups.

Method

Participants (n=1244, Table 1) from the Wisconsin Registry for Alzheimer’s Prevention completed serial health and neuropsychological assessments with a subset undergoing PiB PET imaging (n=238) and MK‐6240 (n=186) PET imaging. Cox regressions assessed the predictive utility of baseline LIBRA for incident cognitive impairment (1.5 SD below covariate adjusted 3‐test Preclinical Alzheimer’s Cognitive Composite, PACC‐3) and β‐amyloid duration (i.e. age at assessment – estimated age PiB(+)). Linear mixed models examined the main effects and age interactions of LIBRA and β‐amyloid duration on longitudinal cognitive performance. Group differences in LIBRA were assessed across biomarker groups, where amyloid (A+) and tau (T+) positivity were defined as a global PiB DVR>1.19 and entorhinal cortex MK‐6240 SUVR>1.27, respectively.

Result

In the survival analysis, baseline LIBRA predicted risk for incident cognitive impairment of subjects unimpaired at baseline (HR=1.18; Figure 1). In the amyloid imaging subset, baseline LIBRA did not predict β‐amyloid onset (HR=0.85; Figure 1). Linear mixed effects models indicated a significant main effect of LIBRA (higher LIBRA risk = worse PACC‐3) and a significant interaction of β‐amyloid duration×age on PACC‐3 (longer β‐amyloid duration = faster PACC‐3 decline; Figure 2). In the combined imaging subset (n=186), there were no differences in LIBRA across biomarker groups (Kruskal‐Wallis H: 5.08, p=.166; Figure 3).

Conclusion

These findings suggest that a healthy lifestyle is associated with overall cognitive performance but not the rate of cognitive decline or biomarker status. In this sample, LR did not influence the onset of β‐amyloid or hasten AD‐related cognitive decline. Replication of this finding and future work is necessary to better understand the relationships between LR factors, cognitive decline and AD.
CD33, MEF2C, and SORL1 are associated with variability in macroscale functional brain architecture in AD
Authors: Ramanan Vijay K , Botha Hugo , Radford Jonathan Graff , Wiste Heather J. , Senjem Matthew L. , Gunter Jeffrey L. , Boeve Bradley F. , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Lowe Val J. , Jones David T.
Published: December 2020

Background

Alzheimer’s disease (AD) is marked by selective disruptions to anatomically‐distinct brain regions and their connectivity which collectively support cognition. Based on a variation of pattern‐recognition analysis of FDG‐PET images, we previously developed a framework, the global functional state space (GFSS), which captures this macroscale architecture by assigning each individual a series of weightings on 10 independent patterns (eigenbrains=EBs). In this study, we applied the GFSS as a quantitative endophenotype to test whether known AD genetic risk factors were associated with variability in large‐scale neurodynamics represented by the GFSS.

Method

The study sample included 410 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with evidence of cognitive impairment (CDR‐global>0) and amyloidosis (positive amyloid‐PET). The GFSS was estimated for each individual using the set of 10 EBs to describe global patterns of variation in glucose metabolism. AD genetic risk variants identified in prior large consortium case‐control studies were included for analysis if the variant (or a proxy by linkage disequilibrium r
2>0.7) was assayed on both genotyping platforms used in the sample and if the minor allele frequency exceeded 1%. Genetic associations with the collective set of EBs were tested using multivariate linear regression under a dominant genetic model.

Result

Significant multivariate associations were identified for CD33 (p=7.04x10‐4), MEF2C (p=0.001), and SORL1 (p=0.02). These findings remained significant after covarying for age and sex. The strongest component loadings for CD33 (p=9.09x10‐4; std. β=‐0.16) and MEF2C (p=1.59x10‐4; std. β=‐0.18) were for EB1, with the minor allele in each case associated with a negative axis deviation in the direction of the GFSS area representing episodic memory dysfunction. SORL1 displayed its strongest loading onto EB4 (p=0.03, std. β=‐0.11). The association of APOE ɛ4 with the GFSS was marginally nonsignificant (p=0.09).

Conclusion

We identified associations of risk variants in CD33, MEF2C, and SORL1 with differences in patterns of FDG hypometabolism in persons with symptomatic AD. These findings establish the GFSS as a useful endophenotype for genetic analyses, particularly as an avenue toward a mechanistic understanding of how heritable factors may influence inter‐individual variability and syndromic diversity in AD. Further investigation in larger and independent cohorts is warranted.
Neurocognitive mechanisms of spatial pattern separation in older adults with and without subclinical memory impairment
Authors: Márquez Freddie , Larson Myra S , Smith Anna , Miranda Blake A , McMillan Liv , Sathishkumar Mithra , Yassa Michael A
Published: December 2020

Background

Decline in episodic memory is a hallmark feature of Alzheimer’s disease (AD). Episodic memories can be operationalized as detailed conjunctions of items and their spatiotemporal context. Our past work has uncovered deficits in pattern separation of similar object memories in nondemented older adults. However, separation of similar spatial locations was only slightly impaired in this population. We hypothesized that these deficits may be more readily observable in individuals with subclinical memory impairment (assessed by verbal list recall). We also sought to determine the neural mechanisms by which spatial pattern separation deficits may manifest in older adults, focusing on the posterior parietal network which is involved in spatial processing and implicated in AD.

Methods

Two cohorts were included in this analysis. The first is a group of older adults with subclinical memory impairment (aged impaired – AI, age range: 61‐91; mean MMSE: 28.3 ± 1.50; mean RAVLT delayed recall: 9.66 ± 4.05). The second is a group of non‐demented older adults without memory impairment (aged unimpaired – AU; age range: 61‐86; mean MMSE: 28.1 ± 1.59; RAVLT delayed recall: 11.4 ± 3.01). Participants underwent whole brain high‐resolution resting state functional magnetic resonance imaging (1.5 x 1.5 x 2 mm resolution). They were also administered a battery of neuropsychological tests including tests of object and spatial pattern separation. We used performance on the RAVLT as the outcome predicted by performance on the discrimination tests. Specifically, we used delayed recall (DR), retroactive interference (RI), and percent forgetting (PF).

Results

Behaviorally, spatial, but not item, pattern separation performance predicted RAVLT DR, RI and PF scores in the AI group, but not the AU group. Functional connectivity analyses revealed that the connectivity of regions involved in spatial processing was significantly related to spatial pattern separation performance in the AI group, but not the AU group.

Conclusion

These results validate the neurobiological basis of spatial pattern separation and suggest that such tasks can be used to detect early stages of AD, which has important implications for future diagnostics and treatment approaches.
Medial temporal neuroinflammation unleashes tau spreading over the neocortex
Authors: Pascoal Tharick A. , Kang Min Su , Therriault Joseph , Benedet Andréa Lessa , Chamoun Mira , Lussier Firoza Z. , Tissot Cécile , Mathotaarachchi Sulantha , Stevenson Jenna , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

Transentorhinal tau neurofibrillary tangles deposition is a typical finding in cognitively unimpaired (CU) elderly. Thus, how tau tangle spreads over the neocortex, leading to disease progression, is a pressing issue in Alzheimer's disease (AD). Although amyloid is postulated to trigger this spread, the fact that amyloid deposition is present in low concentrations in temporal structures challenges this framework. Here, we tested the hypothesis that brain amyloid burden interacts with medial temporal neuroinflammation unleashing tau spread over the neocortex. To assess neuroinflammation, we used [11C]PBR28 PET, a ligand that binds to the 18‐kDa translocator protein(TSPO), considerate a proxy of inflammation.

Methods

TSPO polymorphism (rs6971) was genotyped in 678 participants from the Montreal catchment area (48% presented rs6971 polymorphism of high TSPO binders). Following inclusion/exclusion criteria, we studied 131 high TSPO binders (22 CU young, 63 CU elderly, 28 MCI, 18 AD). All individuals had PET; amyloid [18F]NAV4694, tau [18F]MK6240, and [11C]PBR28,as well as MRI, cognitive and genetic assessments. Structural equation modeling (SEM) tested associations between markers.

Results

[11C]PBR28 uptake was progressively higher from CU to AD(Fig.1). [18F]NAV4694,[18F]MK6240, and [11C]PBR28 were correlated (Fig.2); however, analysis of variance suggested that an interaction between [18F]NAV4694and[11C]PBR28 on [18F]MK6240 best explain the association between these markers(P<0.0001). Voxel‐wise analysis, taking into consideration global and local tracer effects, suggests an interaction between global [18F]NAV4694 and medial temporal [11C]PBR28 on medial temporal [18F]MK6240(Fig.3). Stratified analysis revealed that individuals with abnormal amyloid, tau, and neuroinflammation (A+/T+/NI+) had elevated cognitive impairment and hippocampus atrophy(Fig.4). SEM suggests that global amyloid interacts with transentorhinal inflammation leading to tau spread over Braak II‐III(Fig.5). Subsequently, tau hierarchically spread from Braak III to VI. Models inverting the variables mentioned above or the order of Braak regions did not fit the data. Accumulation of tau only in Braak IV‐VI was associated with cognitive symptoms (Fig.6).

Conclusion

Our results suggest that an interaction between global amyloid and medial temporal neuroinflammation triggers tau spread over the neocortex. Global amyloid may represent distant amyloid load or amyloid oligomers. Our results suggest individuals with tau deposition confined to transentorhinal cortex as targets for the use of anti‐inflammatory drugs in AD.
How often are patients with Alzheimer disease given that diagnosis?
Authors: Pippenger Mark A
Published: December 2020

Background

Alzheimer Disease (AD) is the most common cause for dementia, but outside the research setting the majority of people who meet diagnostic criteria for AD do not receive the diagnosis of AD, or in some cases do not even receive a diagnosis of dementia. Much of the data on this subject come from research studies, however, and relatively less is drawn from community practice. The author began a Memory Clinic within a large health system in the city of Charlotte, NC, in February 2019. All referrals for cognitive complaints within that system, came to the author's clinic. This affords a "real world" environment to assess the diagnoses assigned by clinicians, to patients who meet diagnostic criteria for AD.

Method

All new patient evaluations for a one‐year period were examined. For those patients determined to meet diagnostic criteria for "probable" AD, the specialty of the referring clinician, and the diagnosis assigned by the referring clinician, was assessed. Severity of dementia was estimated using the Mini‐Mental State Exam (MMSE), as Mild (≥20), Moderate (10‐19), or Severe (≤9).

Result

Of the patients diagnosed with "probable" AD during the first year of clinic, 9% had previously received no cognitive diagnosis, 48% had been given a diagnosis simply of "memory loss," 12% had been given a nonspecific diagnosis of "dementia," a few some other diagnosis, and 25% had been given the diagnosis of AD. These percentages didn't vary a lot between levels of severity, except to note there were few "severe" patients, and interestingly, the majority of patients who carried no cognitive diagnosis at all, had "moderate" dementia.

Conclusion

These data provide further evidence that most people who meet diagnostic criteria for Alzheimer Disease, do not receive a specific etiologic diagnosis for their dementia.
Aerobic exercise effects on the peripheral plasma lipidome in mild cognitive impairment: The influence of prediabetes
Authors: Gross Thomas J. , Cheema Amrita K. , Espeland Mark A. , O'Bryant Sid , Cotman Carl W. , Baker Laura D. , Mapstone Mark
Published: December 2020

Background

Subclinical glucose intolerance (pre‐Type 2 diabetes; pre‐T2D) likely influences cognitive decline in older adults. Disordered glucose metabolism may itself be a feature of early Alzheimer’s disease or mild cognitive impairment (MCI). While aerobic exercise may benefit episodic memory, the plasma lipidomic alterations associated with aerobic exercise in older, at‐risk or cognitively impaired adults remains unclear.

Method

We performed a retrospective analysis of 95 participants randomly assigned to Aerobic Exercise (n = 54) or Stretching (n = 41) arms in the Piedmont Aging, Cognition, and Exercise (PACE) studies. Analysis of blood lipids was conducted using the QTRAP® 5500 LC‐MS/MS (Sciex) targeted mass spectrometry platform. Co‐expressed lipid modules were identified and submitted to differential expression (DE) analysis.

Results

Factorial analysis of co‐expressed lipids revealed a pattern of complex expression heterogeneity. We found a significant metabolic status (pre‐T2D/ MCI/ comorbid) by treatment arm (Aerobic Exercise/ Stretching) by time point (pre/post intervention) interaction (p = 0.02). Specifically, we see a significant reduction of long chain/ very long chain triacylglycerides (TAGs) in the comorbid (pre‐T2D + MCI) group following aerobic exercise (p=0.03).

Conclusion

These findings suggest a complex interrelationship between aerobic exercise and peripheral dyslipidemia associated with pre‐T2D in the context of MCI. Specifically, we see reductions in TAGs following exercise only when the two risk factors are comorbid, but not when they occur alone. These findings may be of value as biomarkers of exercise‐intervention response and suggest specific populations that may benefit from aerobic exercise. Future study of these interrelated risk factors modifying exercise benefit is warranted to understand which MCI patients will benefit from aerobic exercise.
Heart rate variability changes during task shifting testing in pre‐symptomatic Alzheimer’s disease
Authors: Arechavala Rebecca Johnson , Kloner Robert , Hung Shao‐Min , Harrington Michael G. , Arakaki Xianghong , Kleinman Michael T.
Published: December 2020

Background

Early detection of Alzheimer’s disease (AD) is vital to begin and monitor treatments. However, as AD pathology begins long before the onset of symptoms, early detection is difficult. Previous studies have suggested differences in the cardiac and autonomic nervous systems (ANS) in AD patients, providing a possible non‐invasive marker of disease onset. The goal of this study is to compare heart rate variability (HRV) measures, representative of cardiac and ANS function, at rest as well as during cognitive testing to assess the use of HRV as a possible marker of pre‐symptomatic AD.

Method

All participants are cognitively healthy (CH) separated into two subgroups based on ratios of amyloid/tau proteins in cerebrospinal fluid (CSF): normal (CH‐NAT, n=22) and pathological (CH‐PAT, n=36), which represents pre‐symptomatic AD. Heart rate variability (HRV) was assessed during 5‐minute intervals at rest and during Task Shifting testing. Participants were required to name the color or word of a colored word for each stimulus by pressing a button, with two sequential stimuli per trial. The trial could be switching (color‐word or word‐color) or repeat (color‐color or word‐word). ECG traces from subgroups of CH‐NATs (n=8) and CH‐PATs (n=13) were initially screened to remove ectopic beats, followed by identification of normal RR‐intervals (NN). HRV was analyzed as standard deviation of NN (SDNN), root mean squared of successive differences (RMSSD) in the time domain as well as high (HF) and low frequency (LF) in the frequency domain to assess changes to autonomic, and particularly parasympathetic, input to the heart.

Result

Comparing HRV changes assessed during rest and the task shifting testing in each individual, differences became apparent between CH‐NAT and CH‐PAT groups. In the CH‐NAT group, little to no change in SDNN and RMSSD occurred during cognitive testing from rest. The CH‐PAT group however showed a 20 percent drop in both SDNN and RMSSD during testing, indicating an imbalance of the ANS.

Conclusion

This study provides a new approach and technique using HRV to non‐invasively differentiate between normal and pre‐symptomatic AD in cognitively healthy people.
Steroidal inhibitor of Na/K‐ATPase marinobufagenin in a mouse model of Alzheimer’s disease
Authors: Fedorova Olga V , Zahariadis Eleni , McDevitt Ross , Grigorova Yulia N , Wei Wen , Zernetkina Valentina I , Juhasz Ondrej , Zheng Lucy , Petrashevskaya Natalia , Camandola Simonetta , Mattson Mark P , Lakatta Edward G
Published: December 2020

Background

Cardiotonic steroids (CTS), Na/K‐ATPase (NKA) ligands, have potential neuroprotective effects. Despite the importance of the NKA and CTS in the brain physiology, their roles in Alzheimer’s disease (AD) pathology are not fully elucidated. Bufadienolide CTS, marinobufagenin (MBG), was lower in 15‐month old double‐mutant Alzheimer’s mice (APPswe/PS1dE9; AD) compared to age‐matched wild type (WT) controls. The present study examined whether the treatment with MBG affects behavioral and other parameters in the mouse AD model.

Methods

Fifteen‐month old male AD and WT mice were administered MBG (100 µg/day/kg body weight; AD‐MBG, n=8; WT‐MBG, n=4) or vehicle (control: AD‐C, n=8; WT‐C, n=4) using subcutaneous ALZET osmotic minipumps for 3‐month. Systolic blood pressure (SBP; by tail cuff plethysmography), open field test (OFT), home cage activity (HCA), plasma and brain cortex were collected in 18‐mo old mice. SBP was assessed because MBG may increase blood pressure. Statistical analysis: 2‐way ANOVA, t‐test; data presented as mean±SEM.

Results

SBP and heart rate did not differ between WT‐C and AD‐C. MBG administration did not affect SBP, and increase heart rate in WT‐MBG vs. WT‐C. Plasma MBG was lower in AD‐C vs. WT‐C and increased in both WT‐MBG and AD‐MBG (Table). No differences were found in HCA, and in OFT for total distance traveled, nor for time spent in the center between AD‐C and WT‐C, and between AD‐C and AD‐MBG. MBG caused a greater reduction in distance traveled in the center for WT mice than it did for AD mice (Table). AD‐C mice had 1.6‐fold higher expression of inflammatory marker interleukin‐6 (IL6) mRNA in cortex vs. WT‐C; MBG treatment reversed this expression in AD‐MBG (Table).

Conclusion

AD mice had lower endogenous plasma MBG and higher brain pro‐inflammatory mRNA marker IL6 vs. WT mice. Treatment with MBG significantly reduced levels of this inflammatory marker. WT mice exhibited more exploratory behavior than AD mice in the OFT; MBG decreased exploratory behavior. The additional behavioral tests may be needed to assess the MBG effects on different cognitive components. The association of the brain inflammatory response, cognitive functions and MBG will be further explored in this AD mouse model. Supported by the NIH/NIA Intramural Research Program.
Increased neuroanatomic risk for Alzheimer’s disease at preclinical stage: Exploring the interaction of fine particle exposure and psychosocial stress
Authors: Younan Diana , Wang Xinhui , Petkus Andrew J , Gruenewald Tara L , Casanova Ramon , Serre Marc , Vizuete William , Beavers Daniel P , Braskie Meredith N , He Ka , Woods Nancy , Garcia Lorena , Wallace Robert B , Resnick Susan M , Manson JoAnn E , Gatz Margaret , Chui Helena C , Espeland Mark A , Chen Jiu‐Chiuan
Published: December 2020

Background

Ambient air pollution, especially fine particulate matter (aerodynamic diameter <2.5 μm; PM2.5), is a novel neurotoxin. Psychosocial stress has been linked to Alzheimer’s disease (AD) and other dementias (ADRD). We test the hypothesis that PM2.5 and psychosocial stress may interact to accelerate brain aging, by investigating their potential joint effects on neuroanatomic risk for AD.

Method

Community‐dwelling older women (aged 71‐89) from the Women’s Health Initiative (WHI) Memory Study of MRI completed two structural brain MRI scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11). To focus on the preclinical stage, we excluded women who developed MCI or dementia over follow‐up. The AD pattern similarity (AD‐PS) score, developed by supervised machine learning and validated with the AD Neuroimaging Initiative data, was used to determine the degree of high‐dimensional gray matter atrophy in brain areas vulnerable to AD. Residential three‐year average PM2.5 exposure preceding MRI‐1 were aggregated from daily estimates, based on nationwide spatiotemporal modeling. A structured questionnaire was administered to gather information on the frequency of stressful life events (SLEs) and self‐reported sleep duration. Sleep disturbance was measured using the WHI Insomnia Rating Scale, with higher numbers indicating greater insomnia. We examined whether the source (frequency of SLEs) or behavioral manifestation (sleep disturbance; sleep duration) of psychosocial stress modified the association between PM2.5 and AD‐PS scores (5‐year standardized difference) using generalized linear models.

Result

Among 542 women, PM2.5 (per 2.87 µg/m3 increase) was significantly associated with increased AD‐PS scores (β=0.020; p=0.028), adjusting for geographic region, age, socioeconomic status, lifestyle, clinical characteristics, hormone therapy use, and intracranial volume. This negative association with PM2.5, equivalent to a 7% increase in the relative risk for ADRD, was greater among women reporting high (β=0.041; p=0.004) vs. low (β=0.008; p=0.460) frequencies of SLEs (pinteraction=0.06) and among women reporting high (β=0.040; p=0.003) vs. low (β=0.005; p=0.702) sleep disturbance (pinteraction=0.04). There was no evidence of effect modification by sleep duration.

Conclusion

Our novel findings suggest psychosocial stress may increase susceptibility to PM2.5 neurotoxicity based on neuroanatomic AD risk at the preclinical stage. Psychosocial stress may lower the brain’s threshold to neurotoxicity, further accelerating the PM2.5‐induced neurodegeneration.
Do benefits of own education for cognition differ by parental education? Influence of intergenerational educational trajectories and cognitive performance in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort
Authors: Eng Chloe W. , Gilsanz Paola , Glymour M. Maria , Mayeda Elizabeth Rose , Mungas Dan M. , DeCarli Charles , Whitmer Rachel A.
Published: December 2020

Background

Little is known about the influence of parental education on late life cognition or whether parental education modifies the association between own education and cognitive outcomes. Parental education influences own educational access/attainment as well as early cognitive environments and resources (social, financial capital) known to affect health. We investigated whether benefits of own education differed by parental education using intergenerational education trajectories.

Methods

The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort is a diverse sample (approximately equal White, African‐American, Asian, and Latinx) of long‐term members of a managed care organization; cognitive domains of verbal episodic memory, semantic memory, and executive functioning were obtained using the Spanish and English Neuropsychological Assessment Scales (SENAS). Parental education (low defined as either parent with <9 years of schooling) and own education (low defined <college degree; includes some college) were reported by 1,633 participants. Intergenerational education was categorized as stable low (reference), low‐high, high‐low, and stable high. Cognitive domains were analyzed as a z‐score composite and as independent domains using linear mixed models adjusting for age, gender, race, and nativity; potential effect heterogeneity was evaluated as interactions between educational trajectories and (1) SENAS domains, (2) race/ethnicity, (3) gender.

Results

All participants with high own education had higher average cognitive scores than those with low own education; those with low‐high trajectories had higher average cognitive scores (B̂=0.33; 95% CI: 0.23, 0.42) than those with stable high trajectories (B̂=0.19; 95% CI: 0.09, 0.29). Those with high‐low trajectories had lower average cognitive scores (B̂=‐0.16; 95% CI: ‐0.25, ‐0.07) than those with stable low trajectories. Effect sizes but not overall patterns differed by cognitive domain (p<.0001) and gender (p=0.0097); there was no evidence of effect heterogeneity by race (interaction P‐value=0.6691).

Conclusion

Own education was associated with late‐life cognition across all levels of parental education. Effect estimates were largest for an upward trajectory of intergenerational education with similar patterns across cognitive domains. Education may open cognitively beneficial opportunities for individuals with low parental education indicating the importance of supporting college entry/completion, though this may reflect the selection process of individuals who complete college despite low parental education.