bluuebunny/crossref_metadata_2025 huggingface dataset:
Tau antibody 77G7 targeting microtubule binding domain suppresses oligomeric tau to seed tau aggregation
Authors: Liu Fei , Li Longfei , Miao Jin , Chu Dandan , Jin Nana , Tung Yunn Chyn , Dai Chunling , Hu Wen , Gong Cheng‐Xin , Iqbal Khalid
Published: December 2022

Background

Neurofibrillary tangle (NFT) of hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD) and related tauopathies. Tau lesion starts in the trans‐entorhinal cortex, from where it spreads to limbic regions, followed by neocortical areas. The regional distribution of NFTs associates with the progression of AD. Accumulating evidence suggests that proteopathic tau can seed tau aggregation in a prion‐like fashion in vitro and in vivo. Inhibition of the seeding activity of proteopathic tau could provide a potential therapeutic opportunity to block the propagation of tau pathology. In the present study, we investigated the role of 77G7, a monoclonal tau antibody to the microtubule‐binding repeats, in the seeding activity of proteopathic tau.

Method

Affinity of 77G7 to various tau strains, including oligomeric tau (AD O‐tau), sarkosyl insoluble tau (SI‐tau), and heat stable normal tau (HS‐tau) isolated from frozen autopsied AD brains by sedimentation, was analyzed by immuno‐dot‐blots. Seeding activity of AD O‐tau was accessed by the level of aggregated tau in vitro and in cultured cells and by overlay capture assay. Tau pathology in human tau transgenic mice was induced by hippocampal injection of AD O‐tau. 77G7 was mixed with AD O‐tau or was intravenously administrated weekly for 6 weeks started one week prior to AD O‐tau injection. Tau phosphorylation and tau pathology were analyzed by immunohistochemical staining and Western blots 8‐10 weeks after AD O‐tau injection.

Result

We found that 77G7 had a higher affinity toward aggregated tau strains than un‐aggregated tau derived from AD brain. 77G7 inhibited the internalization of tau aggregates by cells, blocked AD O‐tau to capture normal tau and to seed tau aggregation in vitro and in cultured cells. AD O‐tau induced tau pathology in hippocampus of 3xTg‐AD mice was reduced by mixing 77G7 with AD O‐tau. Intravenous administration of 77G7 ameliorated site‐specific hyperphosphorylation of tau induced by AD O‐tau in the hippocampi of Tg/hTau mice.

Conclusion

These findings indicate that 77G7 can effectively suppress the seeding activity of AD O‐tau and thus, could be developed as a potential immunotherapeutic drug to inhibit the propagation of tau pathology in AD and related tauopathies.
Diagnostic value of serum versus plasma phospho‐tau for Alzheimer’s disease
Authors: Kac Przemyslaw Radoslaw , González‐Ortiz Fernándo , Simrén Joel , Vanmechelen Eugeen , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J. , Karikari Thomas K
Published: December 2022

Background

Blood phosphorylated tau (p‐tau) forms are promising Alzheimer’s disease (AD) biomarkers, but validation in matrices other than ethylenediaminetetraacetic acid (EDTA) plasma is limited. Firstly, we assessed the diagnostic potential of p‐tau231 and p‐tau181 in paired plasma and serum. Secondly, we compared serum and cerebrospinal fluid (CSF) samples from biomarker‐positive AD and biomarker‐negative control participants.

Method

We studied three independent cohorts (n=120 total): cohorts 1 and 2 included individuals with paired plasma and serum, while cohort‐3 included paired serum and CSF. Blood‐based p‐tau231 and p‐tau181 were measured using in‐house or commercial Single molecule array (Simoa) methods.

Result

Serum and plasma p‐tau231 and p‐tau181 were two‐fold increased in biomarker‐positive AD versus biomarker‐negative controls (P≤0.0008). Serum p‐tau231 distinguished between diagnostic groups with area under the curve (AUC) of 82.2%‐88.2% compared with 90.2% for plasma. Similarly, p‐tau181 showed AUC of 89.6%‐89.8% in serum versus 85.4% in plasma. P‐tau231 and p‐tau181 correlated slightly better in serum (rho=0.92‐0.93) than in plasma (rho=0.88). Within‐individual p‐tau231 concentrations were twice higher in plasma versus serum, but p‐tau181 levels were not statistically different despite a trend of higher concentrations in plasma. Bland‐Altman plots revealed that the relative difference between serum/plasma was larger in the lower range. P‐tau levels in paired plasma and serum correlated strongly with each other (rho=0.75‐0.93) as well as with CSF Aβ42 (rho= ‐0.56 – ‐0.59), p‐tau and total‐tau (rho=0.53–0.73).

Conclusion

Comparable diagnostic performances and strong correlations between serum versus plasma pairs suggest that p‐tau analyses can be expanded to research cohorts and hospital systems that prefer serum to other blood matrices. However, absolute biomarker concentrations may not be interchangeable, indicating that plasma and serum samples should be used independently. These results should be validated in independent cohorts.
Depressive Symptoms Associated with an Earlier Age at Onset Differ as a Function of Race‐Ethnicity: An Exploratory Analysis
Authors: Zaman Andrew , Mena Pedro Ramon , Adams Larry D. , Contreras Maricarmen , Lacroix Faina C , Tejada Sergio , Starks Takiyah D. , Feliciano‐Astacio Briseida E. , Silva Concepcion , Caban‐Holt Allison M , Byrd Goldie S. , Martinez Izri , Ayodele Temitope , Baez Penelope , Blackshire Gabrielle , Kennedy Sara , Reitz Christiane , Haines Jonathan L. , Vance Jeffery M. , Vance Margaret A. , Cuccaro Michael L.
Published: December 2022

Background

Depression (DEP) is a known risk factor for . However, DEP symptoms vary by race‐ethnicity (e.g. greater somatization among African Americans). The relationship between DEP and AD progression in underrepresented groups is not well‐understood. We hypothesize that certain DEP symptoms will be associated with earlier AAO, and that this relationship is moderated by race‐ethnicity

Method

Self‐declared Non‐Hispanic White (NWH), African American (AA), and Hispanic (HI) participants with AD and CDR data were identified from a larger genetic study. Our dataset consisted of 549 persons with a self‐completed GDS (mean CDR = 0.6; 15% NWH, 43% AA, 42% HI), 334 persons with informant completed CSDD (CDR = 1.7; 41% NWH, 20% AA, 39% HI), and 266 persons with self‐reported DEP and anxiety in a medical history exam (CDR = 0.7; 26% NWH, 23% AA, 51% HI). All measures were completed after the onset of AD. Univariate linear regressions examined the relationship between AAO and DEP (total scores and individual items), and race‐ethnicity x DEP interactions after controlling for sex, race‐ethnicity, disease duration, and APOE‐e4.

Result

Self‐reported (p = 0.04), informant‐reported anxiety (CSDD) (p = 0.02), and self‐reports of feeling empty (GDS) (p = 0.02) were associated with an earlier AAO across all groups. Informant‐reports of poor self‐esteem (CSDD) was associated with an earlier AAO overall (p < 0.01), but an interaction showed that this was not significant in HI (p = 0.). Unique items associated with an earlier AAO in NHW included higher GDS total scores (p = 0.01), feeling bored (GDS) (p < 0.01), and perceived problems with memory (GDS) (p < 0.01). In AA self‐reported DEP was associated with an earlier AAO (p = 0.02). No items were uniquely associated with AAO in HI.

Conclusion

Self‐ and informant‐reported anxiety and self‐reported feelings of emptiness were associated with an earlier AAO in all groups. However, several DEP symptoms associated with earlier AAO differed as a function of race‐ethnicity. We believe our findings suggest that the occurrence of DEP may be culturally or ancestrally influenced, which in turn has a differential impact on AAO in underrepresented groups.
Sphingosine 1‐phosphate receptor signaling is dysregulated in a mouse model of Alzheimer's disease
Authors: Jung Younghun , Lopez‐Benitez Jonathan G , Tognoni Christina M , Carreras Isabel , Dedeoglu Alpaslan
Published: December 2022

Background

Sphingosine 1‐phosphate (S1P) through the activation of five G‐protein‐coupled S1P receptors 1‐5 (S1PR1‐5) plays crucial roles in cellular events. Aberrant sphingolipid metabolism has been identified in the brains of Alzheimer’s disease (AD) patients which implies the significance of S1P/S1PR signaling system. Activation of S1PRs with Fingolimod, an analog of S1P that binds to 4 of the 5 S1PRs, provides neuroprotection in animal models of AD i.e., reduces of Aβ neurotoxicity, inhibits the activation of microglia and astrocytes, and increases the production of brain derived neurotrophic factor (BDNF). The pathways by which dysfunctional S1P/S1PR signaling may promote the development of AD pathology remain unknown. Here we examine the changes occurring in the S1P/S1PR signaling system in 5xFAD mice.

Method

The gene and protein expression of S1P receptors and S1PR1 signaling pathways were examined in the cortex of male wild‐type mice (WT, n=5) and 5xFAD mice (n=5) at 3, 8, and 14 months of age using quantitative real‐time polymerase chain reaction (real‐time PCR) and Western blots. Statistical analyses of the data were performed using one‐ or two‐way ANOVAs with Sidak's multiple‐comparisons test.

Result

S1PR1 gene expression is the most abundant S1PRs in the cortex of both WT and 5xFAD mice. The protein level of S1PR1 is significantly increased in 5xFAD mice compared to WT mice at 3, 8, and 14 months of age. The level of SphK2 that is involved in the activation of S1P as a signaling molecule is also increased in 5xFAD mice at the ages studied. Together with increased level of the truncated form of TrkB, the specific receptor of BDNF, we detected increased levels of the phosphorylated forms of Akt and mTor in 5xFAD mice.

Conclusion

Our previous findings on the neuroprotective effects of Fingolimod in 5xFAD mice directly support the new findings that increased expression of S1PR1 is associated with the development of AD‐like pathology in 5xFAD mice. Our results presage that S1PR1 regulates the activation of downstream signaling pathways Akt and mTor known to contribute to AD‐related pathogenesis and behavior. Together, these studies suggest that S1PR modulators may potentially have therapeutic benefits in AD.
Social epigenetics of racial disparities in aging
Authors: Yannatos Isabel , Xie Sharon X , Brown Rebecca , McMillan Corey T
Published: December 2022

Background

Racial disparities in many aging‐related health outcomes are persistent and pervasive among older Americans. There are well‐documented inequities in the social determinants of health for older adults, including the social and physical environment, due to structural and environmental racism, but there is little understanding of the biological intermediates by which social determinants affect disparate health outcomes. Biological aging measured by DNA methylation (DNAm) is robustly associated with worse age‐related outcomes and higher social adversity. We hypothesize that individual social determinants, the social environment, and air pollution exposures interact to contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm).

Method

We performed retrospective cross‐sectional analyses among 3250 non‐Hispanic participants (80.3% white, 19.7% Black) in the Health and Retirement Study whose 2016 epigenetic age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing epigenetic age on chronological age. Measures of the neighborhood social environment include the Social Deprivation Index and perceived social stress. Air pollution exposures include particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone. Individual‐level determinants include socioeconomic status, healthcare access, health status, and health behaviors. We implemented multivariable linear regression models to identify significant associations, interactions, and mediators in the relationship between each DNAm aging measure and the social and environmental determinants.

Result

We found on average Black individuals have significantly accelerated DNAm aging compared to white individuals (599% and 498%) according to GrimAge and DPoAm, respectively. Individual‐level factors evaluated account for approximately 43% of the disparity in GrimAge and 34% in DPoAm. Further results suggest that associations between neighborhood social environment and DNAm aging are significant and mediated by individual‐level factors. PM2.5 may be associated with DPoAm acceleration in certain sub‐populations. NO2 and ozone are not significantly associated with DNAm aging. We are investigating individual‐level factors that mediate social environmental exposures and increase vulnerability to PM2.5.

Conclusion

DNAm aging may play a role in social determinants “getting under the skin” and contributing to age‐related health disparities between Black and white Americans. Work is ongoing to determine the environmental and individual factors that contribute to these disparities.
Association of Cognition with Alcohol Consumption in Cognitively Unimpaired Older Adults: Results from the A4 study
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Lipton Richard B. , Grober Ellen , Ezzati Ali
Published: December 2022

Background

Excessive alcohol intake and no alcohol intake are associated with an increased risk of dementia relative to low to moderate alcohol consumption. We aimed to investigate the cross‐sectional association between different levels of alcohol consumption and cognition in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4 Study). We examined whether this association would differ between sexes or based on individuals’ β‐amyloid (Aβ) status (Aβ+ vs Aβ‐; Aβ+: PET Composite SUVR > 1.15, Aβ‐: Others).

Method

A total of 4387 cognitively unimpaired older adults who had both objective and subjective cognitive assessments and amyloid Positron Emission Tomography (PET) imaging. Participants were classified into 4 categories based on their average daily alcohol use: none, one, two, and three or more drinks/day. Multivariable linear regression was used to test the main effects as well as interactions with sex and Aβ levels.

Result

Participants were on average 71.28 (SD = 4.67) years old and 59% female. In the whole population, individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those who reported consuming one (β[SE] = 0.19[0.08], p = 0.017) or two (β[SE] = 0.22[0.11], p = 0.05) drinks/day (Table 1, Figure 1). In sex‐stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC (β[SE] = 0.32[0.16], p = 0.043) and Cognitive Function Index (CFI; β[SE] = ‐0.27[0.12], p = 0.026) compared to those who reported no alcohol consumption (Figure 2). In an Aβ status‐stratified sample, the association between alcohol consumption and cognition was present only in the Aβ‐ subgroup. Among Aβ‐ individuals, those who consumed one drink/day had better performance on PACC (β[SE] = 0.28[0.09], p = 0.003) and CFI (β[SE] = ‐0.18[0.07], p = 0.009) compared to those who reported no alcohol consumption (Figure 3). The interaction between Aβ status and alcohol consumption on cognition was not significant.

Conclusion

Low or moderate consumption of alcohol is associated with better cognitive performance in cognitively unimpaired individuals. The association is more prominent in Aβ‐ individuals, which might indicate that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of AD‐pathology. The interaction with Aβ status requires further investigation with larger samples consuming 3 or more drinks/day.
Multifactor mid‐life risk for Alzheimer’s disease associated with alterations in navigation but not episodic memory: the PREVENT‐Dementia study
Authors: Newton Coco , Pope Marianna , Dounavi Maria‐Eleni , Carter Stephen F , Muniz‐Terrera Graciela , Henson Richard N , Ritchie Karen , Ritchie Craig W. , O'Brien John T , Su Li , Chan Dennis
Published: December 2022

Background

The entorhinal cortex (EC) is the first cortical brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). Given that the EC contains unique grid cells underpinning path integration, tests probing this aspect of navigation may have added value in detecting AD in its earliest preclinical stages. Building on our past work showing that a VR path integration task was highly sensitive and specific for prodromal AD (Howett et al., 2019 Brain), we tested the hypothesis that path integration may be affected in asymptomatic middle‐aged individuals at increased risk of AD.

Method

100 cognitively healthy adults (aged 43–66) from the PREVENT Dementia cohort performed an immersive VR path integration task in a simulated environment with distal boundary cues to generate allocentric spatial representations. We manipulated EC‐dependence by pseudo‐randomly removing supportive spatial cues from the virtual environment (Figure 1). Participants additionally performed a battery of cognitive tasks including the ACE‐R and COGNITO episodic memory. Linear mixed effects models and Tukey‐corrected post‐hoc contrasts were used to explore the contributions to task performance of parental family history, APOE‐e4 status, global amyloid PET uptake value (N = 46) and CAIDE lifestyle dementia risk score, adjusted for age, sex and education.

Result

Individuals with a positive family history, APOE‐e4 allele or higher CAIDE dementia risk score showed a selective impairment in path integration only when supportive boundary cues were removed. Significant sex interactions indicated that the family history effect (t = 2.31, pTukey = 0.022, Figure 2) and APOE‐e4 effect (t = 3.18, pTukey = 0.023) was specific to males. The effect of CAIDE risk score was specific to individuals with a family history (t = 2.45, pTukey = 0.038) (Figure 3). Conversely, these AD risk factors showed no effect on performance for the other cognitive tasks. Global amyloid PET uptake values showed no association to any task performance.

Conclusion

These results suggest that navigation tests based on EC grid cell function may identify the earliest cognitive changes in individuals at greater risk of AD. The additional moderation by sex indicates a future need to consider male/female differences when using family history or APOE status to inform detection of initial stages of AD.
Two progression patterns in Alzheimer's disease identified from structural MRI in a memory clinic‐based cohort
Authors: Baumeister Hannah , Ziegler Gabriel , Wolfsgruber Steffen , Ramirez Alfredo , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Fliessbach Klaus , Bürger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Wagner Michael , Duzel Emrah , Jessen Frank , Berron David
Published: December 2022

Background

Alzheimer’s disease (AD) is known to be heterogeneous in pathobiology and clinical manifestation. Most previous studies demarcating AD subtypes rely on data‐driven clustering methods that are likely confounded by interindividual differences in disease progression within samples. Addressing this problem, we aim to identify and characterize distinct AD atrophy progression patterns in a memory clinic‐based cohort.

Method

N = 914 subjects (296 cognitively unimpaired, 366 with subjective cognitive impairment, 153 with mild cognitive impairment, and 99 with AD dementia) from the multicenter observational DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were included. The Subtype and Stage Inference algorithm (Young et al., 2018, Nat. Commun.) was applied to ROI‐based cortical thickness and gray matter volume data obtained from T1w and T2w 3T‐MRI using FreeSurfer. Subtypes were characterized in demographics, ApoE genotype, various fluid biomarkers, and cognition.

Result

Two atrophy subtypes were identified. A limbic‐predominant subtype exhibited initial volume loss in the amygdala and hippocampus, followed by cortical thinning in the medial temporal, temporal, frontal, parietal, and occipital lobes. Contrary, in a hippocampal‐sparing subtype, cortical thinning first occured in the frontal, parietal, and occipital lobes before the temporal and medial temporal lobes, hippocampus, and amygdala were affected. Compared to the hippocampal‐sparing subtype, the limbic‐predominant subtype included subjects who were older, reported fewer years of education, and tended to have more ApoE e4 alleles, higher risk of vascular pathology, and higher plasma neurofilament light levels. The subtypes differed in their CSF biomarker profiles indicating higher β‐amyloid and tau burden in the limbic‐predominant subtype. In the limbic‐predominant subtype, cognitive impairment was accentuated in the learning and memory as well as language domains. Belonging to the hippocampal‐sparing subtype was associated with an impairment in executive functions and processing speed, visuospatial functions, and working memory.

Conclusion

We provide evidence on atrophy heterogeneity that is largely in line with previous theoretical and empirical contributions while overcoming key limitations that are commonly faced in earlier studies. Heterogeneity may have substantial impact even in cohort studies designed to primarily include “typical” amnestic AD which highlights the need for optimized and subtype‐specific measures of early detection and disease progression.
APOE genotype modifies microglial immunometabolism
Authors: Devanney Nicholas A. , Lee Sangderk , Williams Holden C. , Allenger Elizabeth J. , Smith Cathryn T , Segovia Gabriella Morillo , Walsh Adeline E. , Friday Cassi , Morganti Josh M. , Johnson Lance A
Published: December 2022

Background

Metabolic dysfunction and neuroinflammation characterize Alzheimer’s disease (AD), but it is unclear if these two facets of the disease are linked. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset AD and is associated with increased neuroinflammation. Recent data from our lab and others show that E4 is also associated with increased aerobic glycolysis. These two findings may be intrinsically linked through the concept of ‘immunometabolism’ ‐ an emerging paradigm that implicates increased glycolysis as a core requirement during pro‐inflammatory activation, whereas increased oxidative phosphorylation is required for anti‐inflammatory responses.

Method

Primary microglia were isolated from targeted replacement mice expressing human APOE isoforms and stimulated with pro‐inflammatory (lipopolysaccharide (LPS); IFNγ + TNFα) or anti‐inflammatory (IL‐10; IL‐4 + IL‐13) cytokines. Metabolic responses were measured using the Agilent Seahorse platform and targeted metabolomics. We also performed single‐cell RNA sequencing on brains from APOE targeted replacement mice at 3‐, 10‐, and 18 months of age +/‐ LPS.

Result

Seahorse revealed increased glycolysis and decreased mitochondrial respiration in E4 microglia. Targeted metabolomics revealed increased lactate and succinate in E4 microglia, metabolites known to accumulate in pro‐inflammatory macrophages. Aged E4 brains were uniquely found to harbor a metabolically distinct subcluster of microglia that expressed a signature similar to the established ‘disease associated microglia’ phenotype, even in the absence of neuropathology. SCENIC regulon analysis linked this cluster to the transcription network of HIF1a, and increased expression of HIF1a was validated in E4 microglia. In LPS‐treated animals, two distinct microglia subclusters emerged in E4 brains that were defined by altered expression of genes relating to oxidative phosphorylation and mitochondrial function.

Conclusion

Our findings reveal that age and LPS treatment induce a distinct metabolic response in E4 microglia. The accumulation of lactate and succinate and increased glycolysis in E4 microglia indicate altered metabolic preference conducive to pro‐inflammatory activation, whereas the decreased mitochondrial respiration may preclude effective anti‐inflammatory responses. We propose that this altered metabolism skews E4 microglia towards a phenotype that favors chronic neuroinflammation and neurodegeneration. Thus, reprogramming metabolism in E4 microglia may provide a novel therapeutic avenue for the treatment of AD.
An Unsupervised Data‐Driven Approach to Profiling Distinct Tau Progression Patterns
Authors: Tosun Duygu , Rajaram Ramya , Spottiswoode Bruce , Fahmi Rachid
Published: December 2022

Background

Given the central role that accumulation of tau pathology plays in the clinical progression of Alzheimer’s disease, the ability to quantify and predict the spread of tau is of great interest. Due to observed heterogeneity in patterns of tau deposition, though, stratification of individuals into homogenous phenotypes is critical to better understanding the natural course of this pathology progression, and ultimately the clinical disease progression. We propose an unsupervised data‐driven whole‐brain pattern analysis approach leveraging the spatially rich information provided by longitudinal tau‐PET, first to identify distinct tau accumulation profiles from longitudinal observation data and then to build baseline models predictive of tau accumulation type.

Method

Longitudinal ADNI flortaucipir‐PET images (N=530) were normalized to cerebellar‐uptake and corrected for partial‐volume‐effects to estimate flortaucipir‐burden for Braak regions I, III, IV, V, and VI. Braak II region was excluded due to spill‐in from choroid‐plexus. A mixture of multivariate generalized linear mixed models was used as an unsupervised data‐driven longitudinal clustering approach to identify distinct flortaucipir‐progression profiles with random‐intercept to analyze flortaucipir‐burden from all Braak regions and all time‐points simultaneously (i.e., multivariate longitudinal feature‐space) while accounting for inter‐regional dependence and irregular time sampling. Multiclass random‐forest classification (MRFC) was employed to predict the identified flortaucipir‐progression profiles using baseline variables.

Result

Three distinct flortaucipir‐progression profiles were identified: 1) “stable” with minimal flortaucipir‐accumulation across all Braak regions; 2) “moderate‐accumulator” with slow (1.01‐2.35 %SUVR/year) flortaucipir‐accumulation rates within Braak I, III, IV, and V; and 3) “fast‐accumulator” with accelerated (1.07‐4.03 %SUVR/year) flortaucipir‐accumulation rates in Braak IV, V, and VI. Prevalence of moderate to fast flortaucipir‐progression profiles increased with Aβ‐positivity, cognitive impairment, age and APOE‐ϵ4. Majority of Aβ‐negative cognitively unimpaired individuals fell within the "stable” category while Aβ‐positive individuals with dementia presented with moderate to fast flortaucipir‐progression profiles. MRFC trained on baseline demographic/clinical characteristics and baseline Braak flortaucipir burdens (60%/40% train/test) differentiated the three flortaucipir‐progression groups with a balanced accuracy of 93% (sensitivity=92%; specificity=95%).

Conclusion

We derived data‐driven distinct longitudinal tau‐PET patterns that characterize the flortaucipir‐progression differences in ADNI. The ability to detect flortaucipir‐progression with baseline imaging and non‐imaging markers could have potential to screen high‐risk individuals for accelerated pathology progression.
Assessing Risk of Incident Cognitive Impairment Using Stages of Objective Memory Impairment (SOMI) and Cerebrospinal Fluid
Authors: Petersen Kellen K. , Grober Ellen , Lipton Richard B. , Nallapu Bhargav Teja , Ezzati Ali
Published: December 2022

Background

The asymptomatic period for persons with preclinical Alzheimer’s disease (AD) lasts for several years despite the presence of AD biomarkers. These biomarkers are critical for disease detection and monitoring, but collection is burdensome and costly. Sensitive cognitive measures such as Stages of Objective Memory Impairment (SOMI) may be a low‐cost alternative or adjunctive marker of disease‐progression risk. Here, we used longitudinal data from the Knight Alzheimer’s Disease Research Center to investigate the odds of disease progression associated with baseline SOMI stage and cerebrospinal fluid (CSF) biomarkers of Aβ42/Aβ40 ratio, p‐tau181, and t‐tau.

Methods

We used data from 617 cognitively unimpaired participants with baseline Clinical Dementia Rating (CDR) of 0, CSF measures, and longitudinal Free and Cued Selective Reminding Test (FCSRT) scores used to classify participants into different SOMI stages (Table 1). We examined the association between SOMI stage, CSF biomarkers, and incident cognitive impairment based on time to conversion from CDR of 0 to CDR>0 (incident cognitive impairment) using Cox Models.

Results

Participants, at enrollment (Table 2), were on average 67.2 (SD = 9.4) years old, 56.6% were female, and had average 7.5 years of follow‐up (range 1‐18). At baseline, 325 (52.7%) were SOMI‐0, 206 (33.4%) were SOMI‐1, 64 (10.4%) were SOMI‐2, and 22 (3.6%) were SOMI‐3 or ‐4 (merged groups). A total of 127 (20.6%) individuals converted to CDR>0. The Cox proportional hazards regression models indicated that in comparison with individuals in SOMI‐0 stage, those in SOMI‐3/4 stage were more than twice as likely to show disease progression (HR=2.43 (95% CI, 1.21‐4.89, p=0.013)) (Table 3). Adding individual CSF biomarkers to the models did not affect the association of SOMI‐3/4 with incident cognitive impairment (p<0.05 for all). In models that included SOMI stages and all CSF biomarkers, SOMI‐3/4 (HR=2.13, 95% CI 1.07‐4.12, p=0.033) Aβ42/Aβ40 (HR=9.76e‐6, 95% CI=2.70e‐10 ‐ 0.35, p=0.031) and t‐tau (HR=1.001, 95% CI=1.000‐1.002, p=0.018), but not p‐tau (p=0.645), showed significant association with incident cognitive impairment.

Conclusions

SOMI‐3/4 predicts incident cognitive impairment (change in CDR) independently from CSF AD biomarkers. These results support the utility of SOMI stage as an early marker of incident cognitive impairment.
Is Poor Sleep Quality Associated with Lower Levels of and Faster Declines in Cognitive Function? Results from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: Chen Ruijia , Calmasini Camilla , George Kristen M. , Gilsanz Paola , Whitmer Rachel A. , Glymour M. Maria
Published: December 2022

Background

Poor sleep quality has been linked to worse cognitive function, but most research has been conducted in predominantly White samples. We investigated whether poorer sleep quality is associated with lower levels of and faster declines in cognition and whether these associations differ by race/ethnicity.

Method

We used data from KHANDLE (N = 1,438; mean age: 75.7 years), a multi‐ethnic cohort of Kaiser Permanente Northern California members. We created a global sleep score by summing scores on six sleep components assessed by a modified Pittsburgh Sleep Quality Index: subjective sleep quality, latency, duration, disturbances, sleep medication use, and daytime dysfunction. Executive function (EF) and verbal memory (VM) were assessed by the Spanish and English Neuropsychological Assessment Scale (3 waves each separated by 18 months). Linear regression models assessed the associations between sleep quality and baseline cognition. To understand associations with cognitive decline, we fit linear mixed‐effect models with random intercepts accounting for practice effects and interview mode. Covariates included baseline age, gender, income, education, depression, physical activity, and central adiposity. We included interactions between time (years since baseline) and sleep and time and covariates to determine associations between sleep and cognitive decline. To assess racial/ethnic differences, we included interactions (race*sleep in linear regression models and time*sleep*race in mixed‐effect models for each racial/ethnic category) and performed likelihood ratio tests to determine the presence of interactions.

Result

After adjusting for covariates, sleep quality was not associated with baseline EF or VM and the associations did not differ by race/ethnicity (Figure 1). Overall, poorer sleep quality was associated with faster declines in EF (β
time*sleep = ‐0.02, 95% CI ‐0.03, ‐0.004: Figure 2). The associations between sleep and declines in EF were modified by race/ethnicity (β
time*sleep*Black = ‐0.06, 95% CI ‐0.09, ‐0.03), such that poorer sleep quality was associated with faster declines in EF among Black adults only (β
time*sleep = ‐0.06, 95% CI ‐0.08, ‐0.04; Figure 3).

Conclusion

Poorer sleep quality was associated with faster cognitive decline, and the association was particularly strong among Black older adults. Further research is needed to elucidate the mechanisms through which sleep influences cognitive decline among Black populations.
Differences in Alzheimer’s disease and cerebrovascular disease neuropathology between latent class groups of cardiovascular risk factors
Authors: Ruthirakuhan Myuri , Cogo‐Moreira Hugo , Swardfager Walter , Herrmann Nathan , Lanctôt Krista L. , Keith Julia , Black Sandra E.
Published: December 2022

Background

Individual cardiovascular risk factors (CVRFs) have been associated with neurodegeneration. However, CVRFs are often comorbid with one another, and little is known regarding how groups of co‐occurring CVRFs are associated with Alzheimer’s disease (AD)‐ and cerebrovascular disease (CVD)‐related neuropathologies. We identify distinct groups of CVRFs in cognitively normal (CN) individuals with post‐mortem data.

Method

Individuals from the National Alzheimer’s Coordinating Center dataset who were CN one year prior to death were analyzed. To identify CVRF classes, a latent class analysis (LCA) was conducted with seven CVRFs (hypertension, hypercholesterolemia, heart condition, stroke, and smoking history, diabetes, and obesity). Differences in the presence of 1) mixed AD neuropathology (ADNP) and CVD neuropathology (CVNP), and 2) CVNP only, were compared between CVRF groups. Age, sex, years of education, Mini‐Mental State Examination (MMSE) score, and presence of APOE E4 allele were included as covariates. The presence of pure ADNP was not investigated as this was only present in two individuals.

Result

This study included 415 CN individuals (age of death: 86.2+/‐9.6, MMSE: 28.3+/‐1.8, education: 15.8+/‐2.8 years, male = 53%, APOE E4 allele: 21%). The LCA identified three groups of CVRFs (Figure 1). One group had low probabilities of CVRFs (N = 89). The second group had higher probabilities of hypertension and hypercholesterolemia (N = 255) (vascular‐dominant group). The third group had higher probabilities of hypertension, hypercholesterolemia, smoking history, diabetes, and obesity (vascular‐metabolic group) (N = 71). The vascular‐dominant group had significantly more individuals with mixed ADNP/CVNP than the vascular‐metabolic group (24% vs. 9%, p = .014). However, the vascular‐metabolic group had significantly more individuals with CVNP only compared to the vascular‐dominant group (61% vs. 37%, p = .002).

Conclusion

These findings suggest that those in the vascular‐dominant group have an increased odds of having mixed ADNP/CVNP, while those in the vascular‐metabolic group have an increased odds of having increased CVNP only. Future studies targeting ADNP/CVNP in the vascular‐dominant group, and CVNP in the vascular‐metabolic group should be investigated to determine their modifying effects on cognitive‐related outcomes.
GM‐CSF reduces amylin amyloid and prevents pancreatic cell death in the hIAPP mouse model of Type 2 diabetes mellitus, a known risk factor for Alzheimer’s disease
Authors: Wang Athena Ching‐Jung , Boyd Timothy D. , Markham Neil , Adame Vanesa , Potter Huntington
Published: December 2022

Background

People with Type II diabetes mellitus (T2D) are at higher risk for developing Alzheimer’s disease (AD). T2D is characterized histopathologically by the accumulation of fibrillary amyloid deposits in the pancreas, which are comprised primarily of human islet amyloid polypeptide (hIAPP), also known as amylin. Amylin, which self‐aggregates in a manner similar to amyloid beta, has been implicated as a source of pathogenesis in both T2D and AD. In T2D patients, pancreatic amyloid deposition occurs before and induces islet β‐cell apoptosis.

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has demonstrated anti‐apoptotic, neuroprotective, neurotrophic, immunomodulatory, and regenerative effects in several neuronal injury models. We discovered that GM‐CSF treatment rapidly reduced cerebral amyloidosis and reversed cognitive impairment in transgenic AD models (Boyd et al, 2010), which led to the initiation and successful completion of a Phase 2 clinical trial (NCT01409915) using sargramostim (rhuGM‐CSF) in mild‐to‐moderate AD participants (Potter et al., 2021). Thus, we hypothesized the GM‐CSF might also reduce amyloid and prevent cell death in the pancreas of the hIAPP mouse model of T2D.

Method

We investigated GM‐CSF treatment effects in 12‐week‐old male hemizygous hIAPP mice (Jackson strain Tg(Ins2‐IAPP)RHFSoel), which accumulate amylin amyloid in pancreatic islets. Mice received daily subcutaneous injections (5 days/week for 23 total injections) of either recombinant murine GM‐CSF (5 µg/day or ∼167 µg/kg; n=9) or sterile saline (n=7), and the animals were then euthanized, perfused according to CU Anschutz OLAR regulations, and pancreatic tissues were obtained and processed for histopathology. Whole blood samples were obtained before perfusion, and blood chemistry analyses were performed for T2D biomarker levels (BUN, amylase, LDH, glucose, ALT). Unpaired t‐tests were used to determine significant differences (p<0.05) between treatment groups.

Result

Thioflavin‐S staining revealed significantly less pancreatic amyloid (p=0.00114, saline n=3, GM‐CSF n=7) and Caspase‐3 immunohistochemistry showed significantly less apoptosis (p=0.0057, Saline n=7, GM‐CSF n=9) in pancreatic tissue from the GM‐CSF‐treated group. There were no significant differences observed for the blood chemistry biomarkers, but trends were observed for lower levels of BUN and higher levels of amylase in the GM‐CSF‐treated group.

Conclusion

These preliminary data suggest a therapeutic potential for GM‐CSF to prevent or treat T2D, and thereby reduce AD risk.
Leveraging longitudinal, multi‐site diffusion MRI data in conjunction with free‐water analysis to characterize patterns of white matter neurodegeneration in aging
Authors: Archer Derek B , Shashikumar Niranjana , Jasodanand Varuna , Moore Elizabeth E. , Pechman Kimberly R. , Bilgel Murat , Beason‐Held Lori L , An Yang , Shafer Andrea T , Risacher Shannon L. , Landman Bennett A. , Jefferson Angela L. , Saykin Andrew J. , Resnick Susan M. , Hohman Timothy J. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

Background

Several prior studies have used diffusion MRI to investigate the relationship between white matter microstructure and aging; however, many of these studies used conventional diffusion MRI measures and single site data. The goal of the study is to leverage multi‐site harmonized diffusion MRI data in conjunction with a novel post‐processing technique [i.e., free‐water (FW) correction] to quantify the aging related tract‐specific changes in white matter microstructure.

Method

The dataset used in this study was collated using several well‐established longitudinal cohorts of aging [Alzheimer’s Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)]. In total, this dataset included 1,909 participants (mean age at baseline: 72±9 years, 59% female) and 4,844 imaging sessions (mean number of visits: 4 ± 2 years, interval range: 1–12 years). Data was processed using standard approaches and uncorrected fractional anisotropy (FAU) was quantified with seven white matter tractography atlases (see Figure 1A). Data was then post‐processed using the FW correction technique and FW and FW‐corrected FA (FAT) values were quantified. Data were then harmonized using the ComBat technique and linear mixed‐effects regression was conducted on each microstructural measure, covarying for age at baseline, sex, cognitive status, education, APOE‐ε4 carrier status, and APOE‐ε2 carrier status. The effect of aging was modelled using an Age_at_Baseline x Interval interaction term.

Result

Age was associated with lower FAU in all seven tracts (pFDR range: 4.77x10‐10 to ‐0.01). In the FW analysis, age was associated with higher FW in all seven tracts (pFDR range: 7.81x10‐12 to 1.33x10‐6). For FAT, however, age was only associated with lower FAT in the limbic tracts (pFDR=0.024) in addition to the occipital (pFDR=1.19x10‐8), parietal (pFDR=2.32x10‐4), and prefrontal (pFDR=0.024) TC tracts. Figure 1B‐D illustrates our findings.

Conclusion

This study suggests that while there are global associations with FAU and age, these associations are attenuated once correcting for partial volume effects. Leveraging FW analysis, we found a global association with FW and age, whereby age is associated with higher FW. Further, we found that age is associated with reductions in FAT in the limbic and occipital/parietal/prefrontal TC tracts.
Automated method for segmenting enlarged perivascular spaces
Authors: Bown Corey W. , Khan Omair A. , Liu Dandan , Pechman Kimberly R. , Remedios Samuel , Davis L. Taylor , Houston Michelle , Gifford Katherine A. , Hohman Timothy J. , Landman Bennett A. , Jefferson Angela L.
Published: December 2022

Background

Enlarged perivascular spaces (ePVS) on magnetic resonance (MR) imaging are difficult to quantify due to their small size, diffuse distribution, and often, high prevalence. We present a method for automating ePVS volume quantification in the basal ganglia.

Method

Vanderbilt Memory and Aging Project participants (n=327, 73±7, 41% female) underwent MR imaging and serial neuropsychological assessment. Fifty T1‐weighted MR scans were manually coded for basal ganglia ePVS and used to train and test a deep learning U‐net. The model was then used to segment 277 remaining scans. Dice similarity coefficient (DSC), volume Pearson correlation, and mean symmetric surface distance (MSSD) were used to compare ground‐truth segmentations to predicted segmentations. In head‐to‐head regressions using pseudo‐conditional R2, basal ganglia ePVS volume and count were compared to two existing ordinal scores (Patankar et al., 2005; Hansen et al., 2015) to assess which method best predicted longitudinal cognition. Models adjusted for demographic, genetic, and risk factors.

Result

The basal ganglia deep learning model attained a mean DSC of 0.76 on testing images (n=10) with an ePVS volume correlation of 0.95 and MSSD of 1.16 mm. Next, to assess the utility of automated measures derived from the model, ePVS volume and count were compared to commonly used ordinal scores on cognitive trajectory over a mean follow‐up time of 5.2±1.7 years. All automated and ordinal ePVS predictors achieved comparable pseudo‐conditional R2 values (e.g., 0.893 to 0.894 for episodic memory, 0.829 to 0.831 for executive function) on the longitudinal cognitive outcomes. ePVS volume had the highest or identical to the highest pseudo‐conditional R2 value on four of seven outcomes, including episodic memory (0.894), information processing (0.559), executive function (0.831), and visuospatial skills (0.743).

Conclusion

We present a deep learning model that reliably segments ePVS in the basal ganglia of T1‐weighted brain MR scans, creating regional volume measures of ePVS. Automated basal ganglia ePVS volume measures perform comparably to existing validated manual methods when predicting longitudinal cognition. Automated methods are less time‐consuming and produce a continuous measure, providing a more robust way to quantify longitudinal ePVS change.

Funding: F31‐AG066358, IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082
Data‐Driven Methods Highlight Early Signals of Tau in Patients Lacking Global Uptake: Facilitating Enrollment in Clinical Trials
Authors: Rathore Saima , Southekal Sudeepti , Kennedy Ian Andrew , Kotari Vikas , Pontecorvo Michael J.
Published: December 2022

Background

Alzheimer’s Disease (AD) patients showing neocortical Flortaucipir (FTP) tau levels above predetermined cutoffs based on the likelihood of disease progression are enrolled in Lilly trials. However, patients below the cutoffs can also exhibit disease progression, and clinical decline. These patients might be earlier in the course of disease progression and may benefit the most from therapy. The objective of this study is to apply data‐driven methods on regional tau measurements at baseline to identify a relatively homogeneous patient population showing earlier signals of tau.

Method

A standardized uptake value ratio (SUVr) from a weighted composite region (MUBADA;Devous et al,JNM,2017) with respect to cerebral white matter reference signal intensity (Southekal et al,JNM,2018) was calculated using baseline FTP (n=1093) images from AVID FTP development studies (AV1451‐A05:NCT02016560) and Lilly clinical trials (EXPEDITION‐3:NCT01900665, NAVIGATE‐AD:NCT02791191, and AMARANTH:NCT02245737). Using the cutoff of 1.11, we identified a cohort of 431 subjects that were negative by MUBADA. Diagnostic breakdown included 67 cognitively‐normal, 135 mild‐cognitive‐impairment, and 229 AD subjects. Within this cohort, we calculated reference‐region independent, min‐max scaled regional tau measurements in 68 regions from FreeSurfer FsAverage template. An affinity propagation clustering analysis was applied to detect homogeneous subgroups showing patterns of similar tau uptake. Two distinct subgroups—FTPEarly (n=151), and FTPUndetected (n=280), names reflecting their tau uptake levels— emerged in the cohort. The groups were compared on clinical, cognitive, and genetic characteristics using Analysis‐Of‐Covariance.

Result

FTPEarly group demonstrated relatively higher baseline plasma‐tau levels (p‐tau217) and pattern of elevated FTP uptake in inferior‐temporal, fusiform, entorhinal, and para‐hippocampal regions (P<0.01 for all) compared to FTPUndetected group. In FTPEarly group, 98% were MCI or AD, 90% were amyloid+, and 69% were APOE4‐carriers, whereas in FTPUndetected group, the prevalence of MCI or AD, amyloid positivity, and APOE4‐carriers dropped to 76%, 43%, and 37%, respectively. When evaluated on longitudinal sub‐population, FTPEarly patients progressed faster than FTPUndetected patients on FTP SUVr (P<0.01) and cognitive measures (ADAS; P<0.01).

Conclusion

Data‐driven methods identify visually difficult to recognize FTPEarly group characterized by distinct neuroimaging patterns and paralleled by relatively homogeneous clinical, genetic, and cognitive profile. These methods hold promise for targeting enrollment of FTPEarly patient populations into clinical trials.