bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of actuarial and conventional MCI criteria in a community‐based prospective cohort study: The Adult Changes in Thought (ACT) study
Authors: Eppig Joel S , Madan Raghav , Arrota Kayela , McCurry Susan M , Bowen James D , McCormick Wayne , Cholerton Brenna , Craft Suzanne , Crane Paul K. , Larson Eric B. , Trittschuh Emily H
Published: December 2021

Background

Operationalizations of mild cognitive impairment (MCI) are inconsistent. Actuarial criteria have been proposed to improve accuracy. We investigated dementia and Alzheimer’s disease (AD) conversion for conventional versus actuarial MCI criteria in a community‐based prospective cohort study.

Method

1413 non‐demented participants were administered measures from memory, language, and attention/executive function domains. We used published norms to generate demographically‐adjusted z‐scores. Conventional MCI criteria were met for scores >1.5sd below the mean on any measure. Actuarial MCI criteria were met for 2 scores >1.0sd below the mean in one domain or a score >1.0sd below the mean in all three domains. Participants were followed biennially to capture dementia incidence. A consensus conference used DSM‐IV dementia criteria and NINDS‐ADRDA AD criteria for diagnosis. We focused on 6‐year outcomes following MCI categorization.

Result

At baseline, n=875 (62%) met neither conventional nor actuarial MCI criteria, n=16 (1%) met only actuarial MCI criteria, n=383 (27%) met only conventional MCI criteria, and n=139 (10%) met both. Demographic characteristics are in Table 1. Education differed across criteria (p<0.0001); more people with lower education met only conventional MCI criteria. During follow up (7090 person‐years, mean=5 years), there were 175 incident dementia cases, of whom 110 (63%) met conventional and 53 (30%) met actuarial MCI criteria at their baseline neuropsychological evaluation. In a Cox model adjusting for age, sex, education, and race/ethnicity, the conventional MCI dementia hazard ratio (HR) was 2.93 (95% CI 2.15, 4.01, p<0.001), and the actuarial MCI HR was 3.62 (95% CI 2.60, 5.03; p<0.001). There were 154 incident AD cases; 101 (66%) met conventional and 49 (32%) met actuarial criteria. The adjusted conventional MCI AD HR was 3.25 (95% CI 2.32, 4.56, p<0.001), and the actuarial MCI AD HR was 3.81 (95% CI 2.69, 5.38, p<0.001).

Conclusion

Both conventional and actuarial MCI criteria identified individuals at higher risk of developing dementia and AD over 6 years of follow‐up. Conventional criteria flag a higher proportion of those who ultimately developed dementia and AD compared to actuarial criteria. However, hazard ratios for progression to dementia and AD were slightly higher for the actuarial criteria.
Regulation of intracellular innate immune amyloid beta (aβ) clearance
Authors: Wettergreen Marianne , Gisladottir Berglind , Kirsebom Bjørn Eivind , Christensen Erik , Sharma Kulbhushan , Fladby Tormod
Published: December 2021

Background

Innate immune Aβ clearance may be involved in Alzheimer’s disease (AD) etiology and treatment response following anti‐amyloid immunotherapy. Regulation of intracellular Aβ clearance is not measured in AD risk‐ or diagnostic assessments, and pathways and mechanisms are insufficiently mapped. We present assays for Aβ catalysis in myeloid cells (THP‐1 cells and human iPSC microglia).

Method

THP‐1 cells were differentiated toward macrophages, and treated with various inhibitors including IDE inhibitor (6bK, Tocris),BACE1 inhibitor (LY2886721, Tocris), Nep inhibitor (Phosphoramidon, Tocris), Bafilomycin A1(Sigma)(1h) and Rapamycin (Sigma) (18h) before adding 100 ng/ml Aβ40 (2h), followed by 4h chase. For AD patient derived microglia, reprogrammed iPSCs were differentiated through a myeloid progenitor stage. Mature microglia were characterized by qPCR, Immunofluorescence and phagocytosis assay. Two immunoassays were developed on the Simoa platform using proprietary sheep monoclonal antibodies (Pre Diagnostics, Norway). Both assays employ an Aβ c‐terminal antibody for capture (AB.4D7). Assay 20‐x employs a specific Aβ20’ cut point antibody (NH2‐20.2B8) and assay x‐40 a linear mid‐domain antibody (AB.2A9) binding full length Aβ as detector.

Result

1) Innate immune cells (THP1, microglia) catabolize Aβ 1‐40 producing 20‐x fragments. 2) Inhibition of Nep and BACE1 reduces the production of 20‐x fragment of Aβ in THP1 cells. 3) Autophagy inhibitor BafA1 increases both 1‐40 and 20‐x fragments indicating the role of the endo‐lysosomal system in the degradation of full length and 20‐x Aβ. 4) Autophagy inducer, Rapamycin reduces both 1‐40 and 20‐x fragments indicating the role of mTOR mediated autophagy and the endo‐lysosomal system in the degradation of full length and 20‐x Aβ.

Conclusion

1) We demonstrate a novel assay for Aβ degradation by Innate immune cells including THP‐1 and iPSC derived microglia. 2) Inhibition of Nep and BACE1 reduces 20‐x peptide generation indicating this as a potential marker for Aβ. 3) Modulation of autophagy affects 20‐x peptide generation indicating the potential of targeting endo‐lysosomal and autophagic pathway against AD.
Utility of combined plasma amyloid beta 40, amyloid beta 42, total tau, and NfL along with a measure of cognitive functioning in detecting cognitive impairment among Hispanic, Mexican Americans compared to non‐Hispanic whites
Authors: Petersen Melissa , Hall James R. , Zhang Fan E. , Mozdbar Sima , Johnson Leigh Ann , Yaffe Kristine , Braskie Meredith N. , King Kevin , Toga Arthur W. , O'Bryant Sid ,   Health and Aging Brain Study (HABS‐HD) Team
Published: December 2021

Background

The AT(N) diagnostic framework for Alzheimer’s Disease (AD) highlights the importance of specific plasma biomarkers associated with neurodegeneration (Amyloid Beta, Tau) and neuronal injury (Neurofilament light chain [Nf‐L]). Despite a wealth of research on such plasma biomarkers of AD pathology, limited work has specifically been conducted among minority populations. Our study sought to examine a combination of AD biomarkers both alone and in combination with a select measure of cognition among Hispanic, Mexican Americans (MA) and Non‐Hispanics Whites (NHW) in detecting cognitive impairment.

Method

Plasma samples were assayed on n=1703 participants (n= 890 MA [n=676 Normal Cognition [NC]; n=214 Cognitively Impaired [CI]]; n= 813 NHW [n=673 NC; n=140 CI]) enrolled in a study of health disparities. Plasma Amyloid Beta 40, Amyloid Beta 42, Total Tau, and Nf‐L were assayed using Simoa. A measure of verbal fluency (FAS) was utilized. The samples were randomly split (70/30) to allow for a training and test set. Random Forest (RF) models were conducted with performance on the test set reported.

Result

Among MA, AD biomarkers alone produced an area under the curve (AUC) of 0.50 with a sensitivity (SN) of 0.77 and specificity (SP) of 0.17. When the AD biomarkers were included along with a measure of verbal fluency (FAS)(biomarker‐cognitive profile), AUC increased to 0.63 with an SN of 0.82 and SP of 0.17. Inclusion of demographics (age, gender, education) to the biomarker‐cognitive profile increased only SP, which reached 0.50. Among NHW, AD biomarkers alone produced an AUC of 0.35 with SN of 0.88 and SP of 0.74. The combined biomarker‐cognitive profile increased AUC to 0.66 with an SN of 0.42 and SP of 0.81. The addition of demographics further increased AUC to 0.72 (SN=0.53; SP=0.88).

Conclusion

Detection accuracy differed by ethnicity with a broader range shown among NHW (AUCs 0.35‐0.72) compared to MA (AUCs 0.50‐0.63). Utility of AD plasma biomarkers improved with the addition of a select cognitive measure. This is consistent with prior work showing the application of a combined model (biomarker‐cognitive profile) to distinguish those with cognitive impairment. The addition of demographic factors improved the detection only for NHW.
A new blood‐based biomarker of Aβ clearance: The monocyte Aβ mid‐domain assay
Authors: Christensen Erik , Wettergreen Marianne , Torsetnes Silje Bøen , Gisladottir Berglind , Fladby Tormod
Published: December 2021

Background

Deficiency in cerebral Amyloid beta (Aβ) clearance is implicated in the pathogenesis of Alzheimer’s disease (AD), and Aβ clearance systems are potential therapeutic targets in AD. Clearance of Aβ is a complex process were phagocytosis and degradation of Aβ are two important components. Innate immune‐linked genetic risk factors contribute to AD, and innate immune cells; microglia in the brain and monocytes/macrophages in the peripheral blood (PB), phagocytose Aβ and contribute to clearance. Our objective was to develop an assay measuring Aβ mid‐domain peptides in relevant biological specimens. The intracellular concentration of peptides containing mid‐domain fragments may reflect phagocytic activity or Aβ degradation efficiency.

Method

An immunoassay on the Quanterix Single Molecule Array (Simoa) platform was developed against an Ab 20‐34 peptide using a proprietary anti‐mid‐domain sheep monoclonal antibody as capture antibody (2A9). The detector reagent consists of an anticomplex antibody using Bio‐Rad HuCAL technology (H3) ensuring the optimal Aβ mid‐domain peptide specificity and assay sensitivity. Monocytes were isolated from 8 ml blood samples using a combination of BD CPT blood sampling tubes and RosetteSep antibodies from StemCell.

Result

The 2A9/H3 immunoassay run on the Simoa platform detected Aβ mid‐domain containing peptides with a lower limit of quantification (LLOQ) of approximately 0,7 pg/ml resulting in measurable levels of the peptides in both CSF and monocyte lysates (figure 1 a).

Conclusion

As shown in figure 1 b, the 2A9/H3 combination has a high specificity for mid‐domain restricted peptides. Here we show that as used in a sensitive Simoa‐assay, this assay detects Aβ mid‐domain containing peptides both in CSF and monocyte lysates, and may serve as a tool for PB measurement of Aβ catabolism in both disease progression studies and intervention studies. The PreADx ™ assay is an accurate and highly sensitive immunoassay for quantification of mid domain Aβ peptides in relevant biological fluids and cells. The assay demonstrates high precision with monocyte lysates and linearity in spiking and dilution experiments (not shown).
The effect of attending schools with higher ability peers on memory and language abilities in later‐life
Authors: Seblova Dominika , Dworkin Jordan J , Peters Kelly , Lapham Susan , Prescott Carol Arlene , Glymour Maria M , Manly Jennifer J
Published: December 2021

Background

Peers influence adolescent behavior, educational, and health outcomes. Evaluating the influence of school‐mates’ cognitive aptitude on later‐life cognition is important for understanding the role of school segregation and tracking in establishing inequality. Yet, few studies have the data to study this. We used a national high‐school based study followed up 58 years later to examine if attending schools with more skilled peers predicts individual later‐life cognition.

Method

In 1960, about 5% of US high schools participated in Project Talent (n=377,000), where students reported demographics and completed aptitude tests. Some of these students were enrolled in 2018/2019 (mean age=74.6) in the Project Talent Aging Study (PTAS). For each PTAS participant, we calculated peer cognitive aptitude as the average of cognitive aptitudes of all other students who were in the same high school. The outcome, later‐life cognition, was operationalized as z‐score composites for language (semantic and phonemic fluency) and memory (CERAD learning list and delayed recall). For each outcome we estimated multilevel linear models to account for school clustering. All models were adjusted for age, sex/gender, parental education; secondary models were also adjusted for the participant’s own adolescent cognitive aptitude. To examine heterogeneity of the association, we evaluated interactions of peer ability with sex/gender, and the participant’s own adolescent cognitive aptitude.

Result

Participants were predominantly non‐Hispanic White (80.4%) and women (52.6%). Attending schools with peers who averaged 1 standard deviation higher on cognitive aptitude predicted better later‐life cognition prior to adjustment for own aptitude (language: β=0.162, 95% CI: 0.120, 0.205; memory: β=0.084, 95% CI: 0.041, 0.126), but not after adjustment. However, for women (β=0.045, 95% CI: ‐0.012, 0.101) and those with below mean adolescent cognitive aptitude (β=0.091; 95% CI: 0.016, 0.166), attending schools with higher ability peers predicted better later‐life language scores even after own ability was considered. There was no moderation of these relationships by race/ethnicity.

Conclusion

People with below average cognitive aptitude in adolescence had better language function 58 years later if they attended high schools with high aptitude peers. Future work will examine the plausible life‐course mechanisms to address why certain groups benefit more from schooling contextual factors.
Aging research in the time of COVID‐19: A telephone screen for subjective cognitive concerns in community‐dwelling ethnically diverse older adults
Authors: Nester Caroline O. , Mogle Jacqueline , Katz Mindy J. , Wang Cuiling , Lipton Richard B. , Derby Carol A. , Rabin Laura
Published: December 2021

Background

There is an urgent need for validation of remotely‐administered cognitive screens to identify older adults at risk for dementia, to monitor disease progression, and to facilitate follow‐up when in‐person visits are not feasible. Restrictions on in‐person cognitive assessments due to COVID‐19 have spurred a growing literature on telephone‐based cognitive screening. However, few studies have evaluated the value of telephone‐administered screens of subjective cognitive concerns (SCC), an important early marker of dementia‐risk.

Method

Einstein Aging Study participants (subsample, n=455; Mage=77.0; Myears education=15.0; 64.1% women; 46.4% White) completed the Telephone Screen for Subjective Cognitive Concerns (T‐SSCC), a 16‐item measure of self‐reported memory, language, executive functioning, visuospatial/navigation, concentration, calculation, and mental clarity concerns, as well as the Telephone Montreal Cognitive Assessment (T‐MoCA). In‐person assessments included the paper‐and‐pencil Cognitive Change Index (CCI) and comprehensive neuropsychological evaluation. Classification as cognitively normal (CN; n=288) or mild cognitive impairment (MCI; n=153) was based on Jak/Bondi criteria. Primary analyses included correlations between the objective and subjective screening instruments, and logistic regression to evaluate the association between the T‐SSCC and MCI status.

Result

Total endorsement of concerns on the T‐SSCC (OR 1.095, CI 1.018‐1.178, p=0.015) was significantly associated with MCI status. In particular, endorsement of “Do any of these problems interfere with your daily life?” was strongly related to MCI (OR 2.296, CI 1.284‐4.108, p=0.005). The T‐SSCC was moderately correlated with the in‐person CCI (r[114]=0.577, p<0.001). A small but significant relationship was observed between the T‐SSCC and T‐MoCA (r[258]=‐0.206, p<0.001).

Conclusion

To our knowledge, this is the first study to validate a telephone SCC screen in response to the crucial need for such remotely administered measures. The T‐SSCC was significantly associated MCI status; furthermore, specific items related to the impact of cognitive problems in daily life were particularly sensitive to MCI. Such SCC measures are brief, accessible, and well‐tolerated and may provide additionally valuable information that enhances remotely‐administered cognitive screens.
The technical reliability and stability of ATN quantification using the Fujirebio Lumipulse G1200 fully‐automated immunoassay instrument in cerebrospinal fluid
Authors: Celia Amanda M. , Ramirez Christopher E. , Trombetta Bianca A. , LaCasse Kathryn , Mattingly Zoe A. , Salloum Lauren , Orusakwe Amanze , Esquivel Rianne N. , Carlyle Becky C. , Kivisäkk Pia , Arnold Steven E.
Published: December 2021

Background

Fujirebio’s Lumipulse G1200 is designed to perform fully‐automated, rapid, random access immunoassays for biomarker quantification in biofluids. The Lumipulse instrument was used for quantification of the core Alzheimer’s Disease (AD) cerebrospinal fluid (CSF) biomarkers for Amyloid, Tau, and neurodegeneration (ATN): amyloid β 1–40 (Aβ40), amyloid β 1–42 (Aβ42), phosphorylated Tau 181 (pTau181), and total Tau (tTau). This study evaluated the reliability of the Lumipulse assays by measuring intra‐ and inter‐batch coefficients of variation (CV), and the correlation between Lumipulse values and the clinically used Athena ADmark Aβ42, pTau181 and tTau assays.

Method

423 CSF samples collected from diagnostic lumbar punctures between 2015 and 2020 were obtained from the MIND biorepository. Aβ40, Aβ42, tTau, and pTau were measured using the Lumipulse G1200 instrument in batches of 50‐60 samples. We tested 60 samples in duplicate to compare the intrabatch stability using the CVs between each pair. Each batch was run with a new set of calibrator controls at the start of each assay to ensure stability for each biomarker run. Finally, we correlated values from the Lumipulse with results from the clinical evaluation using the Athena ADmark test.

Result

We observed low variability in calibrator and control signals between batches with an overall calibrator signal CV of <5% for Aβ40 and tTau, and <10% for Aβ42 and pTau. Control signal CV values for all analytes were <5%. The mean duplicate CV across all batches was similarly stable at <10% for Aβ40, Aβ42, and tTau, and <5% for pTau. Subjects with CV >20% were seen <5% of the time. The correlations between Lumipulse and clinical ADmark results were high for pTau and tTau (R2>0.8 for both analytes), but lower for Aβ42 (R2∼0.5).

Conclusion

Our results demonstrated that the Lumipulse G1200 is a reliable, easy to use platform for ATN quantification with low sample to sample variability, and generally high correlation to established clinical standards. Inconsistent preanalytical sample handling of clinical send‐outs for Athena ADmark Aβ42 likely resulted in a poor correlation with Lumipulse G1200. The performance of the calibrators and controls proved that the standardization in each batch was consistent.
Diagnostic accuracy of the monocyte Aβ mid‐domain assay for CSF determined brain amyloid deposition
Authors: Kirsebom Bjørn Eivind , Wettergreen Marianne , Gisladottir Berglind , Sharma Kulbhushan , Christensen Erik , Fladby Tormod
Published: December 2021

Background

 Cells in the innate immune monocyte‐phagocyte system (MPS), including microglia and monocytes/macrophages are important players in Aβ clearance. MPS‐linked genetic variants are risk factors for Alzheimer’s disease, putatively linked to roles in Aβ clearance. The mid‐domain AβX‐34 peptide has recently been suggested as a marker of amyloid clearance. We hypothesize that the mid‐domain AβX‐34 peptides in peripheral blood‐derived monocytes reflect Aβ clearance efficiency and may serve as a biomarker of innate immune brain amyloid deposition. Here, we assess the diagnostic accuracy of blood monocyte derived AβX‐34 levels against an 18F flutemetamol amyloid PET determined CSF Aβ40/42 ratio cut‐off.

Method

 First, to determine the optimum cut‐off for mesoscale discovery (MSD) CSF Aβ42/40 ratio, n=83 cases and controls from the dementia disease initiation (DDI) cohort with 18F flutemetamol amyloid PET scans were included. Using receiver operating curve (ROC) analysis we determined the optimum cut‐off value for the MSD CSF 42/40 ratio based on visual read of the PET images by a trained radiologist as the standard of truth. Next, AβX‐34 levels were determined using an immunoassay developed on the Quanterix Single Molecule Array (Simoa) platform using a proprietary anti‐mid‐domain sheep monoclonal antibody as capture. The detector is an anticomplex antibody using Bio‐Rad HuCAL technology ensuring optimal Aβ mid‐domain peptide specificity and assay sensitivity (Fladby US patent:9,625,474). Lastly, we included n=33 cases and controls and evaluated the diagnostic accuracy of monocyte derived AβX‐34 levels against the PET determined CSF Aβ40/42 ratio cut‐off using a ROC analysis.

Result

 The MSD Aβ 42/40 ratio obtained an expected high diagnostic accuracy (AUC=.957) against amyloid PET. The monocyte derived AβX‐34 showed a comparatively lower, albeit adequate diagnostic accuracy (AUC=.808) against the Aβ 42/40 ratio cut‐off (see table 1 for details).

Conclusion

 A new immunoassay quantitating Aβ mid‐domain peptides is a new innovative strategy integrating the innate immune system in the diagnostic armamentarium for AD. The monocyte derived mid‐domain AβX‐34 shows promise as a viable blood‐based biomarker of brain amyloid deposition. However, assessment of diagnostic accuracy in larger samples are warranted.
Early‐onset APOE‐ε4 carriers show greater decline in memory, language and executive function than late‐onset carriers
Authors: Logan Paige E. , Lane Kathleen A. , Manchella Mohit K. , Sanjay Apoorva Bharthur , Gao Sujuan , Apostolova Liana G.
Published: December 2021

Background

Apolipoprotein‐ε4 (APOE‐ε4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). However, whether APOE‐ε4 accelerates cognitive decline in AD has not been firmly established. We studied the rate of cognitive decline among early‐ (EOAD) and late‐onset (LOAD) APOE‐ε4 carriers vs non‐carriers on measures of memory, attention, language, and executive function.

Method

EOAD and LOAD (onset‐age < or ≥65) subjects were selected from the National Alzheimer’s Coordinating Center (NACC) database. Mixed‐effects models were run separately for EOAD and LOAD with longitudinal neuropsychological measures as dependent variables. APOE‐ε4 carrier status, follow‐up time, and an APOE*time interaction were included as independent variables adjusting for age, sex, education, and disease severity (CDR‐SB) at baseline. For measures where ε4‐carriers had significantly more decline in both groups, mixed‐effects models in the combined samples were used with a three‐way interaction among APOE status, follow‐up time and onset‐age variables to determine whether APOE‐ε4 associated decline was similar between EOAD and LOAD.

Result

Subject demographics are shown in Table 1. The estimated differences in annual cognitive change between ε4‐carriers and non‐carriers are shown in Table 2. Both EOAD and LOAD APOE‐ε4 carriers showed significant decline in Craft Immediate (p=0.0065 and p=0.0134, respectively), semantic fluency (p=0.0001 and p<0.0001, respectively), and Trail‐Making B scores (p=0.0028 and 0.0206, respectively) than non‐ε4 carriers. Only EOAD APOE‐ε4 carriers showed significantly greater decline in Craft Delayed recall than non‐ε4 carriers (p=0.0189). Only LOAD APOE‐ε4 carriers showed significantly greater decline on MoCA (p<0.0001), MINT (p<0.0001), and Trail‐Making A (p<0.0001) than non‐carriers. The accelerated rate of decline in two of the three cognitive tests that showed faster decline in APOE‐ε4 carriers in both EOAD and LOAD was significantly greater in EOAD, while one was trending (Craft Immediate, p=0.0042; semantic fluency, p<0.0001; Trail‐Making B, p=0.0942).

Conclusion

These results suggest that APOE‐ε4 is associated with accelerated rate of decline in both LOAD and EOAD; however, the magnitude of the rate of decline is more pronounced in EOAD. Investigation in other large research consortia such as LEADS and ADNI can further characterize the genetic influences of APOE‐ε4 and other genetic risk factors on AD.
The association between personality and longitudinal cognitive trajectories is independent of baseline brain variables
Authors: De Leon Fransia S , Mungas Dan M , Gavett Brandon E , Fletcher Evan M , Farias Sarah Tomaszewski
Published: December 2021

Background

Previous work has shown that select personality and other interpersonal characteristics influence late‐life cognitive outcomes. However, it is not well understood whether these associations are dissociable from the effects of late‐life brain integrity. The current study examines whether personality characteristics are associated with cross‐sectional and longitudinal cognitive variables in a diverse cohort of older adults and whether these associations are independent of brain integrity as measured by structural MRI.

Method

157 participants (mean age 73.1±6.3 years) from the UC Davis ADC longitudinal Diversity Cohort were evaluated using the Spanish and English Neuropsychological Assessment Scales (SENAS) to assess verbal episodic memory, semantic memory, executive function, and spatial ability. The Big 5 personality measures were used to assess openness, conscientiousness, agreeableness, neuroticism, and extraversion as well as positive affect, sadness, meaning in life, and self‐efficacy. Baseline brain (MRI) variables including total gray matter volume, hippocampus volume and total white matter hyperintensity volume were also measured (n = 131). A parallel process, multi‐level model of the four longitudinal cognitive outcomes yielded intercept and linear slope random effects for each outcome. Slope random effects were highly correlated and summarized by a global slope second order factor. Global slope and individual intercepts were regressed on personality variables, covariates (age, gender, education, race/ethnicity, and recruitment source), and baseline brain variables.

Result

Positive affect (p=0.004) and openness to new experience (p=0.009) demonstrated positive associations with longitudinal change in cognition that were independent of baseline brain variables and covariates (Table 2). Other personality variables, including conscientiousness, extraversion, neuroticism, agreeableness, sadness, meaning in life, and self‐efficacy did not demonstrate significant associations with cognitive change. Lower neuroticism and higher conscientiousness were associated with higher spatial ability intercepts, and lower sadness was associated with a higher episodic memory intercept, independent of covariates and brain variables.

Conclusion

Positive affect and openness are significantly associated with longitudinal cognitive trajectories, independent of demographics and cross‐sectional brain variables, including total gray matter volume, hippocampal volume, and total white matter hyperintensity volume. Future research will help to delineate how individual differences in personality and behavior relate to late‐life brain and cognitive changes.
Brain activation during episodic scene encoding is associated with amyloid and tau levels in amyloid‐positive older adults
Authors: Risacher Shannon L. , Deardorff Rachael , West John D. , Vosmeier Aaron , Tallman Eileen F. , McDonald Brenna C. , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J.
Published: December 2021

Background

The relationship between amyloid and tau deposition and episodic memory‐related brain activity is understudied. Our goal was to determine the association between brain activation on fMRI during encoding of complex scenes and amyloid and tau deposition on PET.

Methods

91 individuals from the Indiana Memory and Aging Study (36 cognitively normal (CN), 27 subjective cognitive decline (SCD), 28 mild cognitive impairment (MCI)) underwent amyloid ([18F]florbetapir or [18F]florbetaben) and [18F]flortaucipir PET, structural and functional MRI, and clinical and cognitive testing. The fMRI task was a scene encoding paradigm in which the participant is asked to try to remember a set of complex scenes relative to viewing a scrambled control image. Amyloid Centiloid (CL) and tau SUVR images were generated using standard methods. Amyloid positivity was defined as global cortical CL≥21. Areas activated during the task (“main effect” (ME)) across all participants were determined (Figure 1A). Mean BOLD signals from ME regions, the entorhinal cortex (EC), and the inferior parietal lobule (IPL) were extracted. Mean cortical amyloid CL and tau SUVR from the bilateral EC, IPL, and lateral temporal lobe (LTL) were also extracted. Tau and amyloid were non‐normally distributed, so Spearman correlation models were used to evaluate the relationship of scene encoding activation and PET. Age, diagnosis, and sex were evaluated as covariates but did not change the observed pattern of results.

Results

Significant association between tau and scene encoding activation was observed (Figure 1B). When limited to amyloid‐positive individuals only (n=28), the observed associations were considerably stronger between scene encoding activation and both amyloid CL level and tau deposition (Figure 1C‐E). Similar results were observed when limiting to the CN and SCD groups.

Conclusion

Amyloid and tau deposition are associated with reduced brain activity during episodic memory encoding in older adults at risk for AD. These findings suggest that brain function is another important biomarker to consider in both the temporal sequencing of biomarkers (Jack et al. 2013) and the A/T/N framework. Future studies in larger samples are warranted. Reference: Jack et al. (2013) Lancet Neurology.
Further preclinical development of a clinically effective bio‐therapeutic against Porphyromonas gingivalis
Authors: Nara Peter Lloyd
Published: December 2021

Background

The ever increasing list of broad adverse medical conditions associated with Porphyromonas gingivalis (Pg) infection associated with the long term, oral, biofilm‐associated colonization in humans leading to a state of chronic systemic inflammation with multiple organ system diseases (atherosclerosis, cardiovascular, stroke, diabetes type 2/metabolic syndrome, cancer, Alzheimer, etc.), stands in stark contrast to a grossly lacking set of effective treatments and/or prophylactic interventions.

Method

Using multiple technologies in microbiology, protein chemistry, proteomics, molecular biology, nucleic acid and protein sequencing, immunochemistry, scanning electron microscopy, biologics development, mid and large scale up hybridoma monoclonal antibody production and human chimeric antibody development and enzymology, an updated status of a newly developed precision biological will be presented.

Result

KB‐001 a murine IgG1 binds directly to a unique hetero‐multimer antigen involved in the bacterial cargo IX transporter secretion protein complex through a high affinity bi‐valent binding (kD 10‐8‐9). About 40‐60 antibody molecules bind to emerging OMVs per bacterial are observed. In addition isolated OMVs demonstrate binding to the outer and inner membranes. Mechanism of action studies demonstrate that the antibody interferes with the proteolytic processing of the larger parent protein required for subsequent endo‐peptidase activity and assembly. More specifically, the binding of antibody to this complex prevents the maturation of the gingipains/LPS endo‐protease/peptidase system‐needed for its absolute survival and the production of its secreted outer membranes vesicles (OMVs) responsible for the majority of its systemic multi‐systems pathology. In an earlier human clinical trial, following its topical oral administration in advanced Pg infected periodontal patients, long term (12 months) prevention of re‐colonization of P. gingivalis following standard dental therapy was observed. In addition, the paratope binding domain from this murine Mab was successfully grafted onto a human IgG1 framework thus creating a second generation human‐chimeric, bio‐therapeutic antibody.

Conclusion

These data now demonstrate the two precision bio‐therapeutics could be valuable for treating and/or preventing P. gingivalis infection in humans.
Neuroinflammation and flortaucipir PET in non‐fluent/agrammatic variant of primary progressive aphasia and/or apraxia of speech
Authors: Pascual Belen , Funk Quentin , Bradbury Kathleen , Jennings Cassandra , Rockers Elijah , Nakawah Mohammad O , Yu Meixiang , Beers David , Faridar Alireza , Appel Stanley , Fujita Masahiro , Masdeu Joseph C
Published: December 2021

Background

Neuroinflammation, a hallmark of frontotemporal dementia, has been sparsely studied in vivo. However, neuroinflammation is a potentially important therapeutic target and biomarkers of inflammation would be welcome. To determine the anatomical specificity of a putative biomarker for inflammation, translocator protein 18 kDa (TSPO) imaging, we used 11C‐PBR28 PET to measure TSPO levels in patients with the non‐fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and/or apraxia of speech (AOS).

Methods

Sixteen patients with nfvPPP/AOS underwent PET using 11C‐PBR28 and 18F‐flortaucipir. All patients were PET amyloid‐negative except two, with a non‐AD flortaucipir PET. Thirty healthy controls underwent PET imaging using 11C‐PBR28 (13 controls) or 18F‐flortaucipir (17 controls). Patients (9/16 women, mean age 65±5.9 years) did not differ significantly in age from the controls (17/30 women, mean age 66±9.3 years). V
T values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. All images were corrected for partial volume effect. A full factorial analysis was performed on V
T and SUVR values between patients and controls at the voxel‐wise level.

Results

Compared to controls, patients showed increased V
T and SUVR values (p < 0.001 uncorrected) in left inferior, middle and superior frontal gyri, as well as in the left putamen and pallidum. However, peak uptake of 18F‐flortaucipir was localized in Broca’s area, epicenter of the pathology, while the distribution of 11C‐PBR28 V
T was more extensive in the frontal lobe, including precentral gyrus, and other regions outside of the frontal lobe, as the supramarginal gyrus and superior temporal sulcus, as well as a small area in the posterior extent of the right inferior frontal gyrus.

Conclusions

11C‐PBR28 and 18F‐flortaucipir uptake patterns corresponded to anatomical areas known to be related to the specific language functions that are impaired in nfvPPA and apraxia of speech. Thus, 11C‐PBR28 seems to be a suitable radioligand for detecting neuroinflammation in nfvPPA. Furthermore, the more extensive anatomical distribution of abnormal 11C‐PBR28 uptake, as compared to 18F‐flortaucipir uptake, suggests that inflammation is key to the progression of the pathologic process in nfvPPA.
Deep learning–based genome‐wide association analysis in Alzheimer’s disease
Authors: Jo Taeho , Nho Kwangsik , Saykin Andrew J.
Published: December 2021

Background

Genome‐wide association study (GWAS) designs are widely used to identify genetic loci associated with Alzheimer’s disease (AD) by performing a statistical test for each single‐nucleotide polymorphism (SNP). This creates a significant multiple testing challenge. Deep learning has demonstrated remarkable ability to identify non‐linear patterns using large data sets but application to AD genetics has been limited. Here we report preliminary results of a deep learning framework developed to identify AD‐associated genetic variation on a genome‐wide scale.

Method

We used genome‐wide genotyping data (12,448,786 SNPs following imputation) from 916 participants in the Alzheimer’s Disease Neuroimaging Initiative (458 cognitively normal controls and 458 AD patients). A convolutional neural network (CNN) consisting of convolutional, pooling and fully connected Softmax layers was used in a two‐stage approach. Data was divided into training‐testing‐validation sets (60:20:20 ratio). Area under the curve (AUC) was used to assess the model performance.

Result

The first stage of the deep learning approach identified 2,335 candidate genetic regions (93,400 SNPs) as associated with AD. The second stage investigated the association of identified SNPs with AD by calculating p‐values for each SNP based on AD influence z‐scores derived from the deep learning model. This approach identified genetic loci in the APOE region as most highly associated with AD (p‐value < 5X10‐8). Case/control classification using the identified SNPs yielded mean AUCs of 0.74, 0.79, 0.82, 0.90 for the thresholds of p‐value = 1x10‐5 (114 SNPs), 1x10‐4 (243 SNPs), 1x10‐3 (724 SNPs) and 1x10‐2 (2,846 SNPs), respectively (Fig. 1) and mean accuracies were 0.66, 0.69, 0.73, and 0.81, respectively.

Conclusion

Preliminary results indicate that a deep learning approach can be used to identify AD‐associated genetic loci and reduce the computational complexity to detect nonlinear interactions between SNPs, which may yield enhanced prediction accuracy for AD risk using genetic information. Future refinements of the deep learning framework are planned, including methods to reduce computational time and integrate additional omics layers and clinical data, as well as validation with independent replication samples.
Quantitative EEG as a translational measure for the assessment of ATH‐1017 neurophysiological changes in mild‐to‐moderate Alzheimer’s disease
Authors: Hua Xue , Church Kevin , Walker William , L'Hostis Philippe , Ereshefsky Larry , Kawas Leen , Moebius Hans J.
Published: December 2021

Background

Athira Pharma, Inc. is developing a new class of blood‐brain barrier (BBB)‐penetrant small molecule drugs aimed at activating the neurotrophic system HGF/MET to promote multiple neurorestorative processes, with the potential to ultimately improve brain function. ATH‐1017 is the lead clinical candidate for the treatment of Alzheimer’s disease (AD). Electroencephalogram (EEG) plays a growing role in facilitating dose exploration of investigational agents like ATH‐1017 by demonstrating brain penetration and target engagement, helping to accelerate CNS drug development.

Method

The translational measure quantitative electroencephalogram (qEEG) was assessed in preclinical animal models and in human volunteers, including healthy young, healthy elderly, and AD subjects as part of a randomized, double‐blind Phase 1a/b trial assessing the safety and pharmacodynamics of ATH‐1017.

Result

As measured by qEEG, ATH‐1017 induced a fast onset and sustained gamma power induction across a range of active doses in humans and animals based on equivalent PK exposures. Additionally, these exposures directly overlapped with the pharmacodynamic active dose range of behavioral and neuroprotective effects shown in dementia animal models. The translational utility of qEEG across species thus allowed for effective pharmacokinetic/pharmacodynamic (PK/PD) modeling and dose‐optimization across healthy volunteers and AD subjects, defining the dose range for late‐stage randomized, double‐blind studies of ATH‐1017 in AD.

Conclusion

The use of qEEG as a translatable tool for PK/PD modeling and dose‐optimization supported brain penetration and pharmacodynamic activity of ATH‐1017, and is indicative of promoting NMDA receptor activities and synaptogenesis across species. The non‐invasive and replicable nature of qEEG measurements provides a direct, quantitative measure of brain activities in response to pharmacological intervention. qEEG facilitates the evaluation of CNS drug candidate early in the drug development process and increases confidence in translation before cognitive assessments in long‐term treatment trials.
Potential utility of longitudinal 123I‐FP‐CIT SPECT imaging in predicting phenoconversion to overt synucleinopathy in isolated REM sleep behavior disorder
Authors: Miyagawa Toji , Przybelski Scott A. , Maltais Daniela D. , Min Hoon‐Ki , Jordan Lennon , Lesnick Timothy G. , St. Louis Erik K. , Silber Michael H. , Graff‐Radford Jonathan , Jones David T. , Savica Rodolfo , Knopman David S. , Petersen Ronald C. , Kremers Walter K. , Forsberg Leah K. , Fields Julie A. , Ferman Tanis J. , Allen Laura A. , Kantarci Kejal , Lowe Val J. , Boeve Bradley F.
Published: December 2021

Background

Isolated REM Sleep Behavior Disorder (iRBD) patients are known to be at high risk for developing an overt synucleinopathy – particularly Dementia with Lewy Bodies (DLB) and Parkinson’s Disease (PD). Reduced nigrostriatal uptake on 123I‐FP‐CIT SPECT reflects dopamine deficiency, which is common in the overt synucleinopathies. We sought to assess how 123I‐FP‐CIT SPECT imaging in iRBD changes longitudinally and whether an abnormal 123I‐FP‐CIT SPECT scan precedes and predicts future transition to an overt synucleinopathy.

Method

Participants with polysomnography‐confirmed iRBD from the Mayo Clinic Alzheimer’s Disease Research Center database +/‐ North American Prodromal Synucleinopathy (NAPS) Consortium who had two or more longitudinal 123I‐FP‐CIT SPECT scans and been followed prospectively for at least 24 months were included in this analysis. Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with 123I‐FP‐CIT SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake.

Result

Thirty‐five iRBD participants (86% male) were evaluated prospectively (mean 62.5 ± 19.4 months) and underwent two or more 123I‐FP‐CIT SPECT scans at a minimum of 12 months intervals. Thirteen participants (37%) developed an overt synucleinopathy (11 DLB and 2 PD; phenoconverters) and 22 participants (63%) remained as iRBD (stable iRBD). Phenoconverters were older (mean 70.8 ± 7.0 vs 63.4 ± 6.0 years old) and had more negative DaTQUANT putamen z‐scores (mean ‐1.68 ± 1.42 vs ‐0.33 ± 1.52) than stable iRBD participants at baseline. Among phenoconverters, nine participants (69%) had one or more 123I‐FP‐CIT SPECT scans with DaTQUANT putamen z‐score of <‐2.0 prior to phenoconversion, and mean time from initial DaTQUANT putamen z‐score of <‐2.0 to phenoconversion was 36.8 ± 28.7 months. In stable RBD participants, eight participants (36%) showed a decline in DaTQUANT putamen z‐score of >1 between the most recent and the baseline scan, and four participants (18%) presented DaTQUANT putamen z‐score of <‐2.0 at the most recent scan.

Conclusion

These findings suggest that a decline in putamen uptake on 123I‐FP‐CIT SPECT in iRBD serves as a predictor and a surrogate biomarker for progression of iRBD to an overt synucleinopathy.
COVID‐19 pandemic: Quantifying the effects of the first lockdown on behavioral and cognitive measures using TASIC
Authors: Stevenson Jenna , Lussier Firoza Z , Servaes Stijn , Chamoun Mira , Rahmouni Nesrine , Tissot Cécile , Poltronetti Nina Margherita , Pascoal Tharick A. , Benedet Andréa Lessa , Bezgin Gleb , King Suzanne , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2021

Background

Following the rapid spread of the COVID‐19 virus throughout Quebec, the TRIAD cohort, a longitudinal observational study, evaluated the effects of COVID‐19 on it’s aging and vulnerable population and their caregivers. This study aims at investigating the behavioural and psychological effects of COVID‐19 and social isolation on the aging population. The TRIAD Assessment of Social Isolation and Cognition (TASIC) was developed to assess these effects on participants of observational trials.

Method

Pre‐pandemic data including, demographical information, Clinical Dementia Rating (CDR), Mini‐Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Montreal Cognitive Assessment (MoCA) and a Social Support Questionnaire, were collected during in‐person visits and take‐home questionnaires. Following the onset of COVID‐19, TASIC was created to include additional COVID‐19 specific scales developed by Dr. Rosa‐Neto and Dr. King that include Knowledge of COVID‐19 scale, the Montreal Assessment of Stress related to COVID‐19 (MASC), as well as the Impact of Events Scale (IESR), the Peritraumatic Distress Inventory (PDI), the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) for COVID‐19. Assessments were conducted via telephone interviews with TRIAD participants (n=292) and their informants (n=243) by eight trained research assistants from April through June 2020. All participants enrolled in previous TRIAD studies, deemed eligible through detailed screening criteria were contacted.

Result

As a result of this study, and previous work done by the cohort, a culmination of information is available, with 90% of TRIAD participants having completed the COVID‐19 study also having plasma collected. 80% of participants from the COVID‐19 study have PET imaging using [18F]AZD4694 and [18F]MK6240 and MRI sequencing.

Conclusion

The COVID‐19 study conducted by TRIAD provides a unique opportunity to understand the effects of a global pandemic on our aging population as well as caregiver burden. This data, in conjunction with other measures available in the cohort, can make important strides in finding ways to help, and better understand those most impacted by the crisis.
Candesartan is associated with lower amyloid accumulation in non‐hypertensive prodromal Alzheimer’s disease
Authors: Okafor Maureen , Wan Limeng , Saleh Sabria , Moore Renee' H , Shaw Les M , Goldstein Felicia C , Hajjar Ihab
Published: December 2021

Background

We have previously reported that candesartan improves executive function and memory in hypertensives with MCI. It is unclear if this drug has an effect on AD mechanisms or biomarkers.

Method

This randomized double‐blind clinical trial enrolled 77 non‐hypertensive participants (mean age: 68.1 years; n=48, 62% women; n=15, 20% African American) with prodromal AD. Individuals were screened and underwent cognitive and physical assessments, lumbar puncture, and blood collection at baseline, 6 months and 12 months. All participants were randomized to escalating doses of candesartan (up to 32 mg daily) or matching placebo. We investigated the target engagement of 1‐year treatment of candesartan vs placebo in MCI patients neither clinically diagnosed nor taking medication for hypertension, who have evidence of AD pathology. We assessed the effect of candesartan vs placebo on CSF AD biomarkers (amyloid‐β (Aβ)42, Aβ40, total tau, and phospho‐tau181 (p‐tau181)) analyzed on the Fujirebio Lumipulse platform using Fujirebio immunoassay reagents. Outcome analyses were conducted following an intent‐to‐treat approach with linear mixed models adjusted for group*time and cholinesterase inhibitors or memantine use.

Result

Participants randomized to candesartan developed fewer symptoms of hypotension compared to placebo (18% vs 26%) and there was no discontinuation from the trial due to adverse event from candesartan compared to placebo (0% vs 2.6%). After 1 year, the candesartan group had significantly higher CSF Aβ40 (‐1211.95, p‐value=0.009) and Aβ42 (‐49.51, p‐value=0.046) levels (Figure) vs placebo, reflecting lower brain amyloid accumulation. CSF Aβ42/Aβ40 showed a trend with an increased ratio in candesartan vs a decreased ratio in placebo, but did not reach statistical significance. Participants randomized to candesartan also showed a trend for decreases in CSF total tau and p‐tau181 and increases in Aβ42/total tau and Aβ42/p‐tau181 levels. Although the within groups were significant, the between groups did not reach significance for the tau‐based biomarkers.

Conclusion

In this first human study in non‐hypertensive prodromal AD, candesartan treatment demonstrates target engagement and a reduction in brain amyloid accumulation compared to placebo. These findings may be useful in the prevention of AD or the slowing of disease progression. A larger trial is urgently needed for candesartan in AD.