bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between the glial marker myo‐inositol measured by 7T MRS and other AD‐relevant measures
Authors: Göschel Laura , Fillmer Ariane , Dell'Orco Andrea , Melin Jeanette , Aydin Semiha , Kurz Lea , Riemann Layla Tabea , Wang Hui , Ittermann Bernd , Rujescu Dan , Pendrill Leslie , Köbe Theresa , Flöel Agnes
Published: December 2022

Background

Myo‐inositol (MI) is a presumed marker for glial activation which can be quantified by non‐invasive Magnetic Resonance Spectroscopy (MRS) and is suspected to be elevated in early Alzheimer’s disease (AD). In the framework of the NeuroMET2 project, we investigated the relationship between MI and other AD‐relevant measures.

Methods

Absolute concentrations of MI were measured by 7 tesla MRS in the posterior cingulate cortex (PCC)/precuneus of 26 cognitively healthy individuals (HC), 23 patients with subjective cognitive decline (SCD), 23 with mild cognitive impairment (MCI) and 24 with dementia due to suspected AD. Using linear models, MI’s association with memory ability (NeuroMET Memory Metric), volumes of the hippocampus and PCC/precuneus, and seed‐based functional connectivity were investigated. Interaction terms involving the apolipoprotein E (APOE) ε4 allele were analyzed additionally. All models were adjusted to age and education and weighted based on Cramér‐Lao lower bounds.

Results

Absolute MI concentrations were substantially elevated in AD patients (adjusted mean [95% CI]=8.5 mmol/l [7.8; 9.3]). However, there were no relevant differences between SCD (6.7 mmol/l [6.0; 7.3]) or MCI (7.5 mmol/l [6.8; 8.2]) and participants of the HC group (7.2 mmol/l [6.6, 7.9]). Across the whole cohort, higher levels of MI were associated with lower memory ability (ß [95% CI]=‐0.31 [‐0.44; ‐0.17], std. ß=‐0.40, p<0.001), smaller hippocampus volume (ß=‐59.89 [‐131.40; 11.62], std. ß=‐0.16, p=0.100) and lower seed‐based functional connectivity (ß=‐3948.41 [‐6480.69; ‐1416.13], std. ß=‐0.34, p=0.003). There was no relevant effect between MI and PCC/precuneus volume (ß=83.27 [‐117.89; 284.43], std. ß=0.08, p=0.413). Finally, there was no substantial mediation effect of APOE ε4 carriership on the association between MI and neither memory ability (ß=0.09 [‐0.18; 0.36], std. ß=0.37, p=0.519), hippocampus volume (ß=‐55.60 [‐223.48; 112.29], std. ß=‐0.45, p=0.511), PCC/precuneus volume (ß=‐110.68 [‐546.22; 324.86], std. ß=‐0.32, p=0.614) nor seed‐based functional connectivity (ß=2009.46 [‐4207.40; 8226.32], std. ß=0.55, p=0.520).

Conclusions

Across a cohort with participants ranging from healthy to AD, we showed that glial activation, measured by MI concentration, was associated with key AD‐related processes. The potential of MI as a non‐invasive biomarker for increasing memory impairment in pre‐dementia stages remains to be explored in longitudinal studies.
Passive Digital Markers for Alzheimer’s Disease and Related Dementia Predict Mild Cognitive Impairment
Authors: Abbas Mostafa , Morland Thomas , Lichtenstein Maya , Milad Zina Ben , Finney Glen , Boustani Malaz , El‐Manzalawy Yasser
Published: December 2022

Background

Alzheimer’s Disease and Related Dementia (ADRD) typically progresses through three clinical stages: Normal Cognition (NC), Mild Cognitive Impairment (MCI), and ADRD. Early detection of MCI is critical for identifying individuals at high risk for ADRD for proper management and early interventions to prevent progression to ADRD. Recently, Boustani et al. identified a passive signature in unstructured Electronic Medical Records (EMR) data for early detection of ADRD. Our objective is to test whether machine learning models trained using ADRD Passive Digital Markers (PDMs) can accurately predict MCI 3 years in advance.

Methods

Using a dataset of 1379 and 5516 MCI and healthy individuals (respectively), we represented each individual using 209 markers in the form of the counts of specific words or phrases (e.g., infection, respiration disorders, anti‐anxiety agents) extracted from clinical notes. In addition, we also included three demographic variables (age at prediction time, gender, and race). Each patient was assigned an index date, where the index date for MCI patients is the MCI diagnosis date. Each MCI patient has four distinct controls with adjusted age at their MCI index date. The prediction time is set to index date – k, where k equals 1 and 3 years. The PDMs were extracted from the EMR data collected within two years before the prediction date. Four widely used machine learning algorithms were evaluated using 10‐fold cross‐validation procedures for predicting MCI 1‐year and 3‐years prior. The predictive performance was assessed using ROC curves and Area Under ROC Curve (AUC).

Results

Figure 1 shows that machine learning models developed using ensemble 200 decision trees trained using the gradient boosting algorithm outperform the remaining three algorithms evaluated in this study. The best AUC scores are 0.84 and 0.78 for identifying MCI patients 1 year and 3 years in advance (respectively). Table 1 summarizes the top 30 PDMs and their feature importance scores for predicting 1‐year and 3‐year MCI.

Conclusion

Machine learning models trained using PDMs, originally designed for early detection of ADRD, can also predict MCI. Future work will leverage structured EMR data to improve the performance of our models.
Machine learning assisted neuropathological assessment of 126 brains from PSEN1 E280A familial Alzheimer’s disease
Authors: Villalba‐Moreno Nelson David , Littau Tim , Littau Jessica Lisa , Mejia‐Cupajita Juan Pablo , Hartmann Kristin , Cardona‐Madrigal Duvan , Krasemann Susanne , Glatzel Markus , Lopera Francisco , Villegas‐Lanau Andres , Sepulveda‐Falla Diego
Published: December 2022

Background

During the last 25 years we have collected 126 brains from the largest family in the world carrying PSEN1 mutation E280A and suffering from familial Alzheimer’s disease (FAD). Classical neuropathology scales rate all FAD cases as severe, overlooking the degree of heterogeneity observed in these cases. Here we present a new approach involving High Throughput Digital Neuropathology (HTDNp), Machine Learning (ML) classification of pathology, and multidimensional data analysis.

Method

Frontal, Temporal, Parietal, and Occipital cortices, and cerebellum of all 126 brains were processed for H&E staining and immunohistochemistry (IHC) for amyloid beta (Ab) and hyperphosphorylated tau (pTau). Cases were diagnosed, and staged according to CERAD, Braak and Thal systems. All slides were digitally scanned and processed for ML classification. Ab pathology was classified as core and diffuse plaques, and cerebral amyloid angiopathy (CAA), using a previously trained convolutional neural network (CNN). pTau pathology was classified as neurofibrillary tangles, dystrophic neurites, and diffuse pathology, by training a new CNN. ML was used for data dimensionality reduction, using self‐organizing maps (SOM). Clinical profiles were identified in the pathological clusters, analyzing presence and onset of specific symptoms.

Result

PSEN1 E280A cases showed high degree of heterogeneity regarding ages of onset, disease duration, brain weight, and ApoE haplotype. Clinically, memory and language impairment were prevalent, while depression, insomnia, gait disorders and behavioral symptoms presented only in some cases. All cases were classified as CERAD C, Thal 5, and Braak VI. ML‐assisted classification and quantification of Ab and pTau pathology showed a high degree of variability among patients and brain areas. SOM analysis identified four distinct pathological clusters, each one with a characteristic clinical profile, indicating a clinical correlate for FAD pathological presentation in these cases.

Conclusion

Current neuropathological diagnosis of Alzheimer’s disease is not sensitive enough to differentiate among disease subtypes or heterogeneity. This can be detected by using HTDNp and ML tools, allowing the identification of clinically relevant pathological subtypes even in PSEN1 E280A brains, an otherwise uniform sample. This approach can be explored further in other FAD and sporadic Alzheimer’s disease cases, aiming for a more precise diagnosis, and a better understanding of the disease.
Amyloidogenic amylin deposits on red blood cells of stroke patients
Authors: Leibold Noah S , Kotiya Deepak , Despa Florin , Sheikhi Lila , III David L Dornbos , Pahwa Shivani S , Trout Amanda , Frank Jacqueline A , Pennypacker Keith R , Goldstein Larry B , Fraser Justin F
Published: December 2022

Background

Amylin, a 37‐residue amyloidogenic peptide, is co‐secreted with insulin by pancreatic beta‐cells (Verma et al. 2020). Vascular deposition of amylin has been noted in patients with diabetes and neurocognitive disorders (Ly et al., 2017) Emergent large vessel occlusions (ELVOs) result in severe ischemic strokes without appropriate treatment. Growth factors, including erythropoietin (EPO), are involved in post‐stroke recovery as a potential neuroprotectant target, inhibiting apoptosis and decreasing inflammation (Jerndal et al., 2010). Here, amylin accumulation in plasma, red blood cells (RBCs), and ELVOs (where available) and plasma EPO levels were compared between stroke and control patients. Due to amylin’s amyloidogenic propensity, we hypothesized that there would be an association between amylin uptake and stroke incidence.

Method

A prospective registry (Blood and Clot Thrombectomy Registry and Collaboration; BACTRAC) was developed to analyze blood and thrombus directly in patients presenting with an ELVO. Total protein concentration and amylin concentrations of clot lysates, plasma, and RBC lysates were obtained via bicinchoninic acid assay (BCA) and competitive enzyme‐linked immunosorbent assay (ELISA), respectively. Plasma EPO concentrations were obtained via ELISA. An amylin uptake coefficient (the level of amylin in RBC lysates divided by the sum of amylin present in RBC lysates and plasma) was calculated to determine the degree to which circulating amylin is depositing on RBCs.

Result

Due to a significant difference between control and stroke RBCs (p = 0.0012, Figure 1) in total protein concentration, all downstream analyses were normalized to respective protein concentrations. A significant difference in amylin uptake by RBCs between stroke and control patients is shown in Figure 2 (p = 0.0073). An uptake coefficient greater than 0.50 indicates uptake of amylin by RBCs. Finally, a significant difference in plasma EPO concentration was observed between stroke and control (p = 0.0017; Figure 3).

Conclusion

Consistent with our hypotheses, the present data indicates that amylin uptake by RBCs is significantly increased in stroke patients than in control patients. However, both groups show evidence of accumulation, as indicated by uptake coefficients greater than 0.50. Further, levels of erythropoietin are significantly increased in stroke patients. Further investigation into whether amylin may be thrombogenic is warranted.
Subcutaneous Dose Selection of Lecanemab for Treatment of Subjects with Early Alzheimer’s Disease (EAD)
Authors: Hayato Seiichi , Rawal Sumit , Takenaka Osamu , Landry Ishani , Boyd Peter , Aluri Jagadeesh , Willis Brian A , Swanson Chad J , Yasuda Sanae , Hussein Ziad , Reyderman Larisa
Published: December 2022

Background

Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. Lecanemab 10 mg/kg IV biweekly dose (10BW) is being evaluated in the Clarity AD Phase 3 study in Early AD. A Phase 1 study was conducted to assess the absolute bioavailability (BA) of subcutaneous (SC) administration relative to IV infusion. Modeling and simulation analysis was conducted to demonstrate equivalence of a fixed weekly SC dose to body weight‐based IV 10BW dose with regard to lecanemab exposure, safety and efficacy.

Method

Based on estimates of BA and absorption rate constant from Phase 1 and the population PK model describing lecanemab PK after IV infusion, estimates of the area under the concentration‐time curve (AUC) and maximum concentration (Cmax) at steady‐state were generated for the proposed fixed SC dose and IV 10BW. Exposure‐response simulations were conducted to compare positron emission tomography (PET) standard uptake ratio (SUVr)as a measure of pharmacodynamic effect, and incidence of amyloid related imaging abnormality‐E (ARIA‐E) as a measure of safety between SC and IV doses. The impact of body weight on the lecanemab exposure, reduction in amyloid PET SUVr and ARIA‐E risk when administered as a fixed SC dose and body weight‐based IV dose were explored.

Result

Phase 1 data support a proposed fixed lecanemab SC dose of 720 mg administered weekly (720W). PK simulations demonstrate that the AUC of SC 720W were similar to IV 10BW. Exposure‐response simulations demonstrate comparable reduction in amyloid PET SUVr following SC 720W and IV 10BW, and lower incidence of ARIA‐E in SC 720W due to lower Cmax following SC administration. Lecanemab exposure differences between a fixed SC dose and body weight‐based IV dose were observed at the extremes of body weight; however, this did not have a meaningful effect on the reduction in PET SUVr and ARIA‐E risk.

Conclusion

This analysis demonstrates that the proposed SC 720W results in equivalent AUC predicted to attain a comparable reduction in amyloid PET SUVr and a lower Cmax predicted to produce a lower incidence of ARIA‐E compared to IV 10BW.
Multi‐omics integration via similarity network fusion to detect subtypes of aging
Authors: Yang Mu , Matan‐Lithwick Stuart A , Wang Yanling , De Jager Philip L , Bennett David A , Felsky Daniel
Published: December 2022

Background

Molecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer’s disease (AD). However, existing subtyping studies have mostly focused on single data modalities, such as RNA sequencing (RNAseq), which provide incomplete neurobiological information on pathological processes. To remedy this, we applied similarity Network Fusion (SNF), a method capable of integrating multiple high‐dimensional multi‐‘omics data modalities simultaneously.

Method

We analyzed human frontal cortex brain tissue samples characterized by five ‘omic modalities bulk RNAseq (18,629 genes), DNA methylation (53,932 cpg sites), histone H3K9 acetylation (26,384 peaks), tandem mass tag proteomics (7,737 proteins), and metabolomics (654 metabolites). SNF followed by spectral clustering was used for subtype detection, with subtype numbers determined by eigen‐gaps and dip‐test statistics. Normalized Mutual Information (NMI) was calculated to determine the contribution of each modality and feature to the fused network. Resulting subtypes were characterized by associations with 12 age‐related neuropathologies and cognitive performance.

Result

Fusion of all five data modalities (overlapping n = 111) yielded four molecular subtypes (nS1 = 32, nS2 = 26, nS3 = 31, nS4 = 22); S1 exhibited lower episodic memory performance than other subtypes proximal to death (t = 4.7, p = 1.5×10‐4). Histone acetylation (NMI = 0.32) and RNAseq (NMI = 0.16) contributed most strongly to this fused network; the top individual features were an acetylation peak in the promoter of CD200 and RNA abundance of PARP4. Secondary analysis fusing only RNAseq and histone acetylation (n = 520) yielded five subtypes which were correlated with the fully integrated subtypes (Fisher’s p = 5.0×10‐4) and strongly associated with AD neuropathology and episodic and semantic memory. Sensitivity analyses of all modality combinations and sample subsets found substantial influences of sample size and subtype number, but reinforced the importance of histone acetylation, RNAseq, and DNA methylation.

Conclusion

We identified highly integrative molecular subtypes of aging derived from up to five multi‐‘omics data modalities simultaneously. These subtypes recapitulate some features of previous subtyping work in AD using single modalities, but also provide new molecular targets and shed light on the benefits and challenges of multi‐omic integration and individual subtyping in this field.
Functional Connectivity in Hippocampal Sub‐Regions as a Function of Age, Sex, and ApoE e4 Status
Authors: Frank Conner , Albertazzi Abigail , Cruz Alan De La , Robinson Elizabeth , Lewis Jenna , Chavarin Dalia , Murphy Claire
Published: December 2022

Background

Olfactory disturbances, thought to be related to preclinical neuropathology and functional decline of the medial temporal lobe, are a reliable predictor of later Alzheimer’s Disease (AD) onset (Murphy, 2019). This study focused on the relationship between hippocampal functional connectivity, olfaction, and risk factors for AD by studying the sub‐regions of the hippocampus independently.

Method

Functional and structural MRIs were obtained at 3T from 29 non‐demented older adults, genotyped for ApoE allele status. Archival functional data collected during correct recognition of verbal labels for odors presented prior to scanning were analyzed. Seed‐to‐voxel FC was calculated for six regions of interest (ROIs), including the dorsal and ventral dentate gyrus (dDG and vDG), subiculum, and CA fields 1‐3. The relationship between FC and age, ApoE, and sex was assessed using multiple linear regression.

Result

In the left vDG, decreased FC with the precuneus was observed in e4 positive older adults, while anterior cingulate gyrus FC increases were associated with the interaction of age, gender, and ApoE e4 status. In the right vDG, the presence of an ApoE e4 allele and increasing age were associated with decreased FC with the right anterior precuneus and increased FC with the right posterior precuneus, whereas there was a negative interaction effect between ApoE e4 and age in the posterior precuneus and a positive interaction effect in the anterior precuneus.

Conclusion

Differential FC with the anterior precuneus, involved in self‐referential processing, and posterior precuneus, normally involved in successful memory retrieval, suggests that early risk factors result in greater reliance on posterior parietal processing, with the interaction effect implying that genetic risk and increasing age may result in FC patterns reflective of precuneus connectivity in preclinical AD (Cavanna & Trimble, 2006; Klaassens et al., 2017). The vDG may be of special importance because it is associated with odor memory processing (Kesner, 2018). Further research should focus on hippocampal sub‐region FC during olfactory processing.

Supported by NIH grant # AG062006‐04 to CM. Special thanks to Aaron Jacobson, Lori Haase, Erin Green, MiRan Wang, and Vincent Rupp for data collection efforts.
Absolute Bioavailability of a Single, Fixed Subcutaneous Dose of Lecanemab in Healthy Subjects
Authors: Rawal Sumit , Duong Anh , Landry Ishani , Aluri Jagadeesh , Boyd Peter , Yagi Takuya , Swanson Chad J , Reyderman Larisa
Published: December 2022

Background

Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. A subcutaneous (SC) formulation is in development as an alternative to intravenous (IV) infusion. The present study evaluated the absolute bioavailability (BA), pharmacokinetics (PK), safety and immunogenicity of lecanemab following a single fixed 700 mg SC dose.

Methods

This was an open‐label, parallel‐group study conducted in healthy subjects that were randomized into IV or SC dose group; 5 Japanese subjects were randomized to the SC dose group. Serum samples for determination of lecanemab PK parameters were collected after single dose of 10 mg/kg IV infused over approximately 1 hour or fixed 700 mg SC injection in the abdomen. The absolute BA was determined by the ratio of dose normalized area under the curve from zero to infinity (AUC(0‐inf)) for SC versus IV dosing.

Results

Thirty subjects received IV infusion and 29 subjects received SC injection. After SC dosing, maximum concentration was observed 72 hours post dose and was 4‐fold lower compared to IV infusion, which reflected the long absorption phase following SC administration compared with IV infusion. The AUC was 2‐fold lower for SC administration compared with IV infusion. Lecanemab half‐life (∼ 7 days) was similar following SC and IV administration. The absolute BA following a single SC 700 mg dose of lecanemab was 49.7% (90% CI: 43.5 – 56.8). PK of lecanemab after SC administration in Japanese subjects was similar to those in non‐Japanese subjects. Mild to moderate injection site reactions were experienced by 6 (20.7%) subjects in the SC dose group. Grade 1 and 2 infusion related reactions were experienced by 10 (33.3%) subjects in the IV dose group. One subject in IV and 2 in SC dose group, had confirmed treatment‐emergent positive anti‐drug antibodies (ADA), with low titers ranging from 16 to 32 with no subject being positive for neutralizing antibodies.

Conclusion

Lecanemab was well tolerated following both SC and IV administrations. The estimate of absolute BA of SC compared to IV dosing will be used to define SC dose and dosing regimen equivalent to IV dosing.
ALLFTD Mobile App Balance and Finger Tapping Tasks: Task Description and Initial Reliability and Validity Findings
Authors: Wise Amy B , Clark Annie L , Taylor Jack C , Heuer Hilary W. , Mester Carly T. , Rao Meghana , Brushaber Danielle , Boeve Bradley F. , Forsberg Leah K. , Kramer Joel H. , Rosen Howard J. , Boxer Adam L , Staffaroni Adam M.
Published: December 2022

Background

Motor disturbances are common in patients with a variety of neurodegenerative and neurological syndromes, such as Parkinson’s disease and Frontotemporal Dementia (FTD). Accurately quantifying motoric changes could enable earlier detection and monitoring of these syndromes, and remote quantification may allow for more frequent assessments and may improve access to research for underrepresented and geographically dispersed participants. With these benefits in mind, investigators from the ALLFTD consortium developed smartphone tests of balance and finger tapping speed. Here we present preliminary test‐retest reliability and associations with gold standard tests.

Method

The tasks were analyzed in two independent samples. The first was an in‐person cohort of healthy older adults (n = 7), mild cognitive impairment (MCI, n = 1) and FTD (n = 3) who completed the smartphone standing/balance and finger tapping tests (FTT) twice in person. The second sample included 31 ALLFTD participants with a range of clinical presentations (healthy older adults [n = 11], FTD [n = 5], MCI [n = 2], unknown [n = 13]) who were asked to complete the balance test three times over two weeks at home. The primary outcomes were total taps for the FTT and root mean squared acceleration for the balance test. Test‐retest reliability was calculated using an intraclass correlation coefficient (ICC); given the small sample size, outliers (n = 6) were removed from the balance test. We tested the association of smartphone FTT with the gold standard mechanical FTT and the balance task with the CDR®+NACC‐FTLD‐SB (disease severity) using Spearman’s correlations. A Wilcoxon‐sign rank test compared participants with motor features on the Progressive Supranuclear Palsy Rating Scale (PSPRS>0) to those without (PSPRS = 0).

Result

The smartphone FTT showed good test‐retest reliability (ICC = 0.78) and a strong correlation (r = 0.8,p<0.05) with mechanical FTT. The test‐retest reliability for the balance task was excellent for the remote sample (ICC = 0.97) and in‐person (ICC = 0.89) samples. In the remote sample, greater acceleration was correlated with higher CDR®+NACC‐FTLD‐SB (r = 0.7,p = 0.003), and participants with motor features on the PSPRS had higher acceleration than those without (W = 11,p = 0.04).

Conclusion

These findings provide preliminary support for the reliability and validity of the ALLFTD Mobile App tests of motor function. Replication in a larger sample is required.
Cognitive Correlates of the No Practice Effects (NPE) Battery: Factor Analyses from the Novel Cognitive and Functional Measures for Alzheimer’s Disease Prevention Trials (NoMAD)
Authors: Kim Hyun , Lee Seonjoo , Bell Sophie A. , Levine Alina , Carlson Scott , Gordon Marc L. , Devanand Davangere P. , Rivera Andres M. , Brickman Adam M. , Harvey Philip D. , Schneider Lon S. , Goldberg Terry E.
Published: December 2022

Background

The No Practice Effects (NPE) battery is a novel set of neuropsychological measures designed to assess important cognitive domains and have robust psychometric properties for use in preclinical and early‐stage Alzheimer’s disease clinical trials. The current study used exploratory factor analysis to examine cognitive domains in the NPE battery. We further examined the association between identified cognitive domains with demographic characteristics, brain imaging metrics, and genetic risk markers for Alzheimer’s disease.

Methods

A total of 116 older adults who are cognitively healthy or have early mild cognitive impairment (eMCI) (mean age 70.35 ± 6.53, 62.9% women) and have baseline cognitive assessments were included. The NPE battery contains seven primarily computerized tests of memory and attention. We conducted an exploratory factor analysis using an oblique rotation to identify different cognitive domains within the NPE, then composite scores were calculated for each domain. Simple correlation analyses were conducted to examine the association between these composite scores and demographic characteristics. The multiple regression analyses were performed to examine the association between composite scores and AD risk markers.

Results

The exploratory factor analysis produced three factors within the NPE battery corresponding to 1) Cognitive Control/Executive Functions (including Letter and Category Verbal Fluency, Brown‐Peterson Paradigm, Digit Symbol Substitution Test, Letter‐Number Span, and N‐Back); 2) Response Monitoring (Recognition Memory Test [RMT] learning and correctly rejected recognition items) reflecting encoding process and post‐recollection cognitive monitoring; and 3) Recall/Retention (RMT total recall and hits on recognition items) that may be considered a “memory consolidation” factor. Greater performance on Response Monitoring was associated with younger age (r2 = ‐0.27, P = 0.004), higher education level (r2 = 0.29, P = 0.002), and APOE4 genotype (B = ‐0.27, SE = 0.13, P = 0.04). Recall/Retention was positively associated with the thickness of the entorhinal cortex (B = 0.58, SE = 0.28, P = 0.04), but not hippocampal or parahippocampal volumes. The general composite score encompassing all tests was associated with age (r2 = ‐0.29, P = 0.002), education (0.28, P = 0.003), and APOE4 (B = ‐0.25, SE = 0.10, P = 0.01).

Conclusion

These results provide preliminary evidence that the NPE battery identifies domains characteristic of cognition. These cognitive domains were associated with demographic factors, such as age and education, along with APOE4 genotype, and brain structural measures.
Investigating the role of neuronal hyperactivity in stress susceptibility and brain beta‐amyloid deposition
Authors: Rogers Annika , Sharp Elizabeth , Razlighi Ray , Oh Hwamee
Published: December 2022

Background

Both animal and human literature have suggested a relationship between stress responses and an increased susceptibility to extracellular beta‐amyloid (Aβ) plaque aggregation, one of the pathological features of Alzheimer’s Disease (AD), as well as clinical symptoms of AD. Despite this evidence, a neuro‐mechanistic pathway that underlies the relationship between the psychological stress response and brain Aβ pathology remains poorly understood. We examined the hypothesis that increased stress responses are associated with neuronal hyperactivity and increased brain Aβ deposition along the spectrum of AD.

Method

We included 35 Cognitively Normal (CN) and 21 Significant Memory Concern (SMC) individuals and 81 patients with Mild Cognitive Impairment (MCI), and 29 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Neuropsychiatric Inventory (NPI‐Q) total scores were used to indicate stress responses. The amplitude of low frequency fluctuations (ALFF) was calculated using resting‐state fMRI (rsfMRI) scans as a measure of neuronal activity. AV45‐SUVR measures were downloaded from the ADNI study. In SPM12, general linear models were performed on normalized ALFF maps to examine the associations of stress responses and brain Aβ deposition with neuronal activity, while controlling for age, sex, and APOE4 carrier status.

Result

NPIQ scores were significantly associated with brain Aβ indices across the entire cohort spanning from cognitively normal (CN) older adults to AD patients. The CN group exhibited significant increases in ALFF in the anterior cingulate, caudate, and inferior occipital cortices in relation to increased NPI‐Q scores, while AD participants exhibited decreased ALFF in multiple regions including medial and lateral frontal cortices. Moreover, with higher brain Aβ load, CN participants showed increased ALFF in medial and lateral frontal cortices, while AD participants showed decreased ALFF in medial frontal, temporo‐parietal junction, and inferior parietal cortices.

Conclusion

These results indicate a potential link between heightened stress responses and increased susceptibility to the development of AD pathologies through neuronal hyperactivity, especially in the early stages of AD. These findings provide neural mechanisms underlying the relationship between stress as a risk factor for AD by highlighting the role of neuronal hyperactivity in this association, while validating the use of rsfMRI for these analyses.
Practice makes imperfect: Positive correlation between practice and implicit distraction in asymptomatic individuals with Alzheimer’s disease pathology
Authors: Hung Shao‐Min (Sean) , Wu Daw‐An , Shimojo Shinsuke , Arakaki Xianghong
Published: December 2022

Background

Our recent research showed that cognitively healthy older participants with higher biochemical risk to develop Alzheimer’s disease were more distracted by an incompatible and implicit visual stimulus, which was not observed in low‐risk older participants. This finding shed light on using psychophysical experiments to early identify high‐risk older participants. Here we further examined the role of practice based on our findings in the young healthy participants where implicit distracting information processing was enhanced after practice. We expected the effect of practice on processing the implicit distractor in high‐risk and low‐risk participants would bifurcate.

Methods

Cognitively healthy (CH) participants were recruited from the local community, consisting of two subgroups based on cerebrospinal fluid (CSF) proteins: with normal beta amyloid42/total tau ratio (CH‐NAT, low‐risk, n = 17) or pathological beta amyloid42/total tau ratio (CH‐PAT, high‐risk, n = 19). Their age, gender, education year, and days between the two sessions were all comparable. A task‐switching Stroop task was implemented. Each trial contained two stimuli, and participants had to name the color or word of a colored word for each stimulus with button press. Only correctly responded trials (correct responses to both stimuli in the trial) were analyzed. Below we reported the performance on the second stimulus (target).

Results

In general, participants showed a significant practice effect over the two sessions. Their reaction times (RT) decreased by 6.19 % (3.04 %), and accuracy rates (ACC) increased by 6.09 % (1.04 %). These results showed evident improvement on performance.

Critically, we further investigated the relationship between the practice effect and the subliminal distractor effect. We found a significant positive correlation in high‐risk participants between the practice effect and the strength of subliminal RT interference (p = 0.03). That is, the more RT decrease observed in a high‐risk individual, the stronger interference was found. Such a linkage was not found in low‐risk participants (p > 0.05).

Conclusion

Our results clearly show that high‐risk and low‐risk asymptomatic older participants operate on different cognitive schemes to process implicit distracting sensory information. Intriguingly, better practice effect is correlated with stronger implicit distraction only in high‐risk participants.
Topline Results of EXERT: Can Exercise Slow Cognitive Decline in MCI?
Authors: Baker Laura D. , Cotman Carl W. , Thomas Ronald , Jin Shelia , Shadyab Aladdin H. , Pa Judy , Rissman Robert A. , Brewer James B. , Zhang Jing , Jung Youngkyoo , LaCroix Andrea Z. , Messer Karen , Feldman Howard H.
Published: December 2022

Background

The EXERT trial (NCT02814526) was a Phase 3, multicenter, randomized single‐blind study that examined the effects of regular exercise on cognition and other measures of brain function in a planned sample of 300 older adults with amnestic mild cognitive impairment (MCI).

Method

The Alzheimer’s Disease Cooperative Study (ADCS) coordinated the trial, in partnership with Wake Forest and the YMCA of the USA. Participants were randomized to moderate intensity aerobic training (AX), or to stretching, balance and range of motion (SBR) for 18 months. In the first 12 months, exercise was supervised 2x/week and completed independently 2x/week. All exercise was unsupervised in Months 13‐18. Outcomes assessments were completed at baseline and every 6 months. The primary endpoint was 12‐month change from baseline on the ADAS‐Cog‐Exec, a validated measure of global cognitive function. In addition, 12‐month changes in the ADAS‐Cog‐Exec and CDR‐SB were compared for EXERT intervention groups relative to other cohorts to estimate effects of intervention versus no intervention (i.e., “Usual Care”).

Result

296 participants were enrolled, and over 31,000 exercise sessions were completed during the first 12 months. Attendance remained high (AX: 81%; SBR: 87%), and >60% of participants reported continued exercise through the pandemic. Neither the AX group nor the SBR group showed 12‐month declines on the ADAS‐Cog‐Exec and CDR‐SB. There were no significant treatment differences between AX and SBR on these outcomes. In the Usual Care analysis comparing ADNI‐1 and EXERT participants matched on key variables (demographics, baseline cognitive function, APOE4), ADNI‐1 MCI participants showed the expected 12‐month decline on the ADAS‐Cog‐Exec, but the EXERT AX and SBR groups did not (ADNI‐1 vs. AX: p = 0.012; vs. SBR: p = 0.00049).

Conclusion

Global cognitive function did not change over 12 months of follow‐up for MCI participants in EXERT, suggesting that both the AX and SBR interventions may have stalled cognitive decline. EXERT is the longest exercise trial conducted in MCI to date, and greater ‘volume’ of exercise may have provided more protection, regardless of exercise intensity. Both groups received equal amounts of weekly socialization, which may have contributed to this protection. Our results are noteworthy given that trial was conducted during the COVID‐19 pandemic.
The case for low‐level BACE1 inhibition for the prevention of AD
Authors: Watkins Elyse
Published: December 2022

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease‐modifying therapies targeting amyloid‐β plaques in symptomatic stages of AD have only just been approved in the United States. Small‐molecule inhibitors of β‐site amyloid precursor protein (APP)‐cleaving enzyme 1 (BACE1; also known as β‐secretase 1) reduce the production of amyloid‐β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non‐progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this talk, I discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform ‘go‐no‐go’ decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.
Relationship between beta‐amyloid (Ab) plaque reduction and clinical benefit: the rationale for aducanumab approval
Authors: Wang Yaning
Published: December 2022

Background

Aducanumab was approved in 2021 by the US FDA under the accelerated approval pathway. However, the Office of Clinical Pharmacology at FDA recommended the regular approval based on three key findings.

Method

Exposure‐response analyses were conducted to quantify the relationship between aducanumab longitudinal exposure and responses (standardized uptake values ratios for beta amyloid and various clinical endpoints) in all clinical trials. To explain the difference between aducanumab and other compounds with negative results in the past, publicly available data were combined with the aducanumab data to demonstrate the relationship between amyloid reduction and clinical endpoint improvement across multiple compounds with similar mechanism of action. The probability to observe the overall positive findings in the aducanumab program was quantified under the assumption that aducanumab is ineffective.

Results

Positive exposure‐response (disease progression) relationship for multiple clinical endpoints from all clinical trials was identified. Positive exposure‐amyloid reduction relationship was established. Consistent amyloid reduction‐clinical endpoint improvement relationship across multiple compounds was observed. If aducanumab is assumed to be ineffective, it is extremely impossible to observe the overall positive findings in the aducanumab program. These results provided convincing evidence to support aducanumab’s effectiveness.

Conclusion

FDA made the right decision for millions of Alzheimer patients. The observed clinical benefit from aducanumab treatment is clinically meaningful.
Photocatalytic Generation of Hydrogen Radical (H⋅) with GSH for Photodynamic Therapy
Authors: Peng Jinlei , Du Ke , Sun Jian , Yang Xianli , Wang Xia , Zhang Xiaoran , Song Gang , Feng Fude
Published: December 2022

As a reactive hydrogen species, the hydrogen radical (H⋅) scarcely sees applications in tumor biological therapy due to the very limited bio‐friendly sources of H⋅. In this work, we report that TAF can act as an organic photosensitizer as well as an efficient photocatalytic H⋅ generator with reduced glutathione (GSH) as a fuel. The photoactivation of TAF leads to cell death in two ways including triple amplification of oxidative stress via ferroptosis‐apoptosis under normoxia and apoptosis through biological reductions under hypoxia. TAF presents excellent biosafety with ultrahigh photocytotoxicity index at an order of magnitude of 102–103 on both normoxic and hypoxic cells. The in vitro data suggest that H⋅ therapy is promising to overcome the challenge of tumor hypoxia at low doses of both photocatalyst and light. In addition, the capability of near‐infrared two‐photon excitation would benefit broad biological applications.
Porous Materials for Water Purification
Authors: Song Yanpei , Phipps Joshua , Zhu Changjia , Ma Shengqian
Published: December 2022

Water pollution is a growing threat to humanity due to the pervasiveness of contaminants in water bodies. Significant efforts have been made to separate these hazardous components to purify polluted water through various methods. However, conventional remediation methods suffer from limitations such as low uptake capacity or selectivity, and current water quality standards cannot be met. Recently, advanced porous materials (APMs) have shown promise in improved segregation of contaminants compared to traditional porous materials in uptake capacity and selectivity. These materials feature merits of high surface area and versatile functionality, rendering them ideal platforms for the design of novel adsorbents. This Review summarizes the development and employment of APMs in a variety of water treatments accompanied by assessments of task‐specific adsorption performance. Finally, we discuss our perspectives on future opportunities for APMs in water purification.
Altering Oxygen Binding by Redox‐Inactive Metal Substitution to Control Catalytic Activity: Oxygen Reduction on Manganese Oxide Nanoparticles as a Model System**
Authors: Wu Yi‐Hsuan , Mehta Harshit , Willinger Elena , Yuwono Jodie A. , Kumar Priyank V. , Abdala Paula M. , Wach Anna , Kierzkowska Agnieszka , Donat Felix , Kuznetsov Denis A. , Müller Christoph R.
Published: December 2022

Establishing generic catalyst design principles by identifying structural features of materials that influence their performance will advance the rational engineering of new catalytic materials. In this study, by investigating metal‐substituted manganese oxide (spinel) nanoparticles, Mn3O4:M (M=Sr, Ca, Mg, Zn, Cu), we rationalize the dependence of the activity of Mn3O4:M for the electrocatalytic oxygen reduction reaction (ORR) on the enthalpy of formation of the binary MO oxide, ΔfH°(MO), and the Lewis acidity of the M2+ substituent. Incorporation of elements M with low ΔfH°(MO) enhances the oxygen binding strength in Mn3O4:M, which affects its activity in ORR due to the established correlation between ORR activity and the binding energy of *O/*OH/*OOH species. Our work provides a perspective on the design of new compositions for oxygen electrocatalysis relying on the rational substitution/doping by redox‐inactive elements.
Fluorescence turn‐off and turn‐on sensors of Zn2+ based on π‐conjugated poly(aryleneethynylene)s comprising alloxazine‐6,9‐diyl and 2,7‐diethynylene‐9,9‐dialkylfluorene units
Authors: Yamaguchi Isao , Yoshizawa Soma , Wang Aohan
Published: December 2022

π‐Conjugated poly(aryleneethynylene)s, polymer‐1 comprising alloxazine‐6,9‐diyl and 2,7‐diethynylene‐9,9‐dihexylfluorene units and polymer‐2 comprising alloxazine‐6,9‐diyl and 2,7‐diethynylene‐9,9‐bis(hexaethylene glycol monomethyl ether)fluorene units, were synthesized via Pd‐complex‐catalyzed condensation reactions. The Mn values of polymers 1 and 2 were 5200 and 8100, and Mw values were 24,900 and 69,700, respectively. The onset wavelengths of the polymers were longer wavelength than that of the monomer in the UV–vis spectra, confirming the π‐conjugated system along the polymer chain. The photoluminescence (PL) of the polymers decreased with the addition of Zn2+ until an equimolar amount and then increased upon the addition of an excess amount of Zn2+, which enabled the detection of Zn2+ over a wider concentration range (10−6–10−4 M) than those of the previously reported Zn2+ sensors. The PL intensity upon the addition of excess Zn2+ was greater in polymer‐2 than in polymer‐1 because the Zn2+‐alloxazine complex in polymer‐2 was stabilized by its interaction with the oligoether side chain. The difference in the PL response of the polymers to metal ions such as Cu+, Cu2+, and Zn2+ was analyzed using the Stern–Volmer and Benesi–Hildebrand methods.
Implementation of seed collection programs for the recovery of Argopecten purpuratus populations in the La Rinconada marine reserve (Antofagasta, Chile)
Authors: Avendaño Miguel , Cantillánez Marcela , González Jorge E.
Published: December 2022

‘La Rinconada Marine’ Reserve (MR), Chile was created in 1997 to preserve the genetic stock of the scallop Argopecten purpuratus and eventually to supply seed to areas outside of the reserve and support aquaculture activities. Data from biological and fisheries monitoring of A. purpuratus as well as environmental conditions in the MR are available for the period from 1993 to 2009.

The continuous extraction of A. purpuratus from La Rinconada MR in Chile, without a science‐based exploitation plan, has not only decreased the abundance and population structure of the species but has also significantly affected seed settlement in artificial collectors and population recruitment. Therefore, the goals of the MR have not been achieved.

This review of biological and fishing studies of A. purpuratus in La Rinconada MR provides a basis for the implementation of a sustainable programme for the natural collection of A. purpuratus seed for population recovery.

A. purpuratus recruitment varies substantially between years and is not strongly related to the size of the parental population. Larval collection and recruitment depend on environmental events (El Niño‐Southern Oscillation) and biological substrate availability (Rhodymenia red algae). These factors produce a bentho‐pelagic decoupling between parental abundance, larval production and subsequent recruitment of A. purpuratus that limits stock recovery in the MR.

To address the poor population status of A. purpuratus in the MR, recovery of the adult population is needed. Therefore, an assisted collection and recruitment strategy is proposed to increase the population and enable the generation of surplus seed, fulfilling the initial aims of La Rinconada MR.
Egocentric cocitation networks and scientific papers destinies
Authors: Milard Béatrice , Pitarch Yoann
Published: December 2022

To what extent is the destiny of a scientific paper shaped by the cocitation network in which it is involved? What are the social contexts that can explain these structuring? Using bibliometric data, interviews with researchers, and social network analysis, this article proposes a typology based on egocentric cocitation networks that displays a quadruple structuring (before and after publication): polarization, clusterization, atomization, and attrition. It shows that the academic capital of the authors and the intellectual resources of their research are key factors of these destinies, as are the social relations between the authors concerned. The circumstances of the publishing are also correlated with the structuring of the egocentric cocitation networks, showing how socially embedded they are. Finally, the article discusses the contribution of these original networks to the analyze of scientific production and its dynamics.
Techno‐economic assessment of single‐stream feedstock logistics supply chain for corn stover and grain
Authors: Hemmelgarn Adam B. , Lin Yingquian , Wendt Lynn M. , Hartley Damon S. , Digman Matthew F.
Published: December 2022

The state‐of‐technology for corn stover harvest is a multi‐pass system that collects the stover after grain harvest. An alternative is a single‐stream system where the grain and stover are harvested as a bulk material co‐stored and preserved by anerobic fermentation, and finally, co‐transported to a biorefinery. In the present work, four single‐pass whole‐plant bulk systems were compared with a conventional multi‐pass bale system. The single‐stream systems consisted of the harvest of corn grain and a portion of the stover fraction. Four machine configurations were simulated. This work predicted that a multi‐pass bale system would result in a material cost of 111.80 $2021 Mg–1 stover DM delivered to the biorefinery gate. Alternatively, the lowest cost single‐stream system was the self‐propelled forage harvester (SPFH) configured with the whole‐plant header, which delivered feedstock for 74.76 $2021 Mg stover DM–1. In addition to machine configuration, a sensitivity analysis was performed to understand important drivers of feedstock cost. These analyses revealed that feedstock cost increased with moisture content, fertilizer price, and biorefinery size, and decreased with harvest season length, crop yield, and grower participation. This work demonstrated that single‐stream systems could reduce corn stover feedstock costs in comparison with state‐of‐technology systems. © 2022 The Authors. Biofuels, Bioproducts and Biorefining published by Society of Industrial Chemistry and John Wiley & Sons Ltd.