bluuebunny/crossref_metadata_2025 huggingface dataset:
General Anesthesia and Cerebral Function: Changes in Cognition and Regional Brain Metabolism in Patients following Surgery
Authors: Struble Helen , Liu Stephen , Silverman Daniel H
Published: December 2022

Background

Improved understanding of relationships between general anesthesia and subsequent cognitive decline is critically needed. In this study, previously healthy and mildly impaired subjects were compared pre‐ and post‐surgery, with respect to longitudinal assessments of their neuropsychologic performance and regional brain metabolism.

Method

We screened records of 1,450 Alzheimer’s Disease Neuroimaging Initiative subjects to identify all those undergoing non‐cancer surgeries involving general anesthesia with a minimum of two pre‐surgical and two post‐surgical ADNI visits, yielding neuropsychological data for this analysis acquired during 256 visits by 64 subjects – 32 surgical patients meeting the above criteria, and 32 controls who were demographically matched but with no reported surgeries during enrollment. Cognitive domain scores were correlated with rates of decline in regional cerebral metabolism based on interval changes in pairs of FDG‐PET scans acquired pre‐ and post‐surgery; analogous calculations were performed in the non‐surgical group by setting “surgery” dates according to median elapsed time from first visit to surgery in the surgical group. Imaging data were quantitatively examined by both standardized volume of interest (sVOI) and statistical parametric mapping (spm) methods of analysis.

Result

sVOIs included bilaterally 6 frontal, 5 temporal, 4 parietal, 2 occipital, and sensorimotor cerebral cortical volumes, as well as 7 noncortical volumes. Compared to the non‐surgical group, the surgical group showed greater post‐surgical decline in the two anterior temporal volumes measured (p=0.01), both medially (including the hippocampus and adjacent cortex) and laterally. Within the surgery group, comparing pre‐ versus post‐ timeframes also identified most significant accelerated decline in the two anterior temporal volumes. The spm analyses corroborated significant acceleration of metabolic decline postsurgically in temporal cortex, predominantly in the right hemisphere, with cluster size significant after statistical adjustment for multiple comparisons (P<0.0005, Pcorr = 0.047). Finally, pre‐ and post‐surgical differences in rates of temporal metabolic decline correlated with differences in executive function decline within the surgical group (r=0.785).

Conclusion

Major surgeries involving general anesthesia were associated with significantly accelerated decline in temporal metabolism postsurgically. This in turn was correlated with greater acceleration of decline in cognitive function of surgical patients.
Mining CSF_tau associated genes with deep learning in AD patients
Authors: Wang Qi , Apostolova Liana G.
Published: December 2022

Background

Tau protein abnormalities have been attracting more and more attention in Alzheimer’s disease (AD) pathophysiology. Tau spreads in a hierarchical pattern in the AD brain, likely by trans‐synaptic propagation between neurons. Discovering genetic risk factors associated with tau pathology could be key for improving our ability to predict and treat AD. In this study, we leveraged the non‐linear analytic approach of deep learning to identify genes that are associated with cerebrospinal fluid (CSF) total tau levels.

Method

We selected 384 subjects [118 normal control and 266 mild cognitive impairment (MCI)] from ADNI cohort. We designed a deep neuron network model that predicted CSF total tau levels using peripheral blood transcriptomic data. More specifically, we developed an occlusion map approach to rank 2,364 transcripts, which were initially selected from 49,386 transcripts by dimension reduction. The occlusion map aimed to rank the transcripts and identified the critical ones.

Result

Our deep neural network successfully predicted CSF total tau levels with an accuracy of 67% and the occlusion map identified the critical genes for the prediction. The list included genes like TTL5, AKIRIN2, CPEB1, PTPN7, CIRBP and RPS23, which have been previously reported to be related to AD. For example, TTL5 relates to missorting of tau protein. AKIRIN2 is essential for the formation of the cerebral cortex. CPEB is found to be an interacting factor of amyloid‐precursor protein (APP). PTPN7 belongs to protein tyrosine phosphatases family, among which PTPN1& PTPN5 has been reported to tau pathology and amyloid pathology. CIRBP is reported to exert protective effects against neuronal amyloid toxicity. RPS23 regulates amyloid level and tau phosphorylation.

Conclusion

Uncovering the genes that have critical association with tau protein abnormalities is critically important for improving our understanding of the drivers of neurodegeneration in prodromal AD. Our deep learning algorithm has shown promising results in identifying the critical genes for tau pathology. This study has demonstrated the effectiveness of deep learning in genetic analysis for AD research.

1. Bahureksa, L., et al. (2017)

2. Wilcockson, T.D.W., et al. (2019)

3. Tomoeda, C. K. (2001)

4. Feldman, H. H., et al. (2008)

5. Winblad, B., et al. (2016)

6. Thomann, A. E., et al. (2018)
Capturing DNA methylation heterogeneity and examining its relationship to somatic mutations in Alzheimer’s disease
Authors: Markov Yaroslav , Thrush Kyra , Higgins‐Chen Albert , Morgan Levine
Published: December 2022

Background

One of the barriers to the identification of molecular targets in Alzheimer’s disease (AD) is its biological heterogeneity. However, computational approaches used to quantify heterogeneity in cohorts can be improved to produce more nuanced output. We develop novel and refine existing statistical methods to capture molecular heterogeneity and examine it on multiple ‐omic levels in the context of AD.

Method

As AD is associated with aging, we consider key age‐associated molecular changes: somatic mutations and a novel DNAme biomarker of aging, Stochastic Epigenetic Mutations (SEM). SEM are outliers in DNAme values at genomic sites when compared with the rest of cohort and can quantitatively capture DNAme heterogeneity. However, it was unclear whether the existing SEM detection methods were optimal for capturing biologically meaningful signals. We test statistical approaches to optimize these methods using the strength of association between SEM burden and chronological age as our metric of choice in brain and whole blood. Furthermore, we test the reliability of these methods in technical replicates. Hypothesizing that SEM coming from different types of DNAme probes (e.g., normally unmethylated or methylated) may contain information on distinct processes, we develop machine learning methods to subcategorize SEM and test their associations with AD pathology. Finally, we assess the relationship between somatic mutations, SEM, and AD pathology in multi‐region brain datasets generated by our lab from the ROSMAP cohorts.

Result

We refined the existing approaches for SEM detection using the skewness adjusted Interquartile Range to correct for the non‐symmetrical DNAme distributions. Additionally, we subcategorized SEM and found that only certain SEM types are linked with the hallmarks of AD; we also observe similar associations between AD pathology and somatic mutations burden. Finally, we saw that these associations are present only in certain brain regions that are known to be affected by AD.

Conclusion

We show that DNAme contains important heterogeneous signals associated with AD and somatic mutations. We will perform mediation and enrichment analyses to elucidate the crosstalk of the two age‐associated molecular changes in the context of AD and hope that this will bring us one step closer to identifying novel therapeutic targets for this debilitating disease.
Modulating T cell inflammation in a mouse model of Alzheimer’s disease
Authors: Dressman Dallin , Elyaman Wassim
Published: December 2022

Background

Recent single cell transcriptomic studies using peripheral blood and post‐mortem brain samples from Alzheimer’s disease (AD) patients have suggested a significant role for T cells in modulating AD‐related neuroinflammation. Previous findings from our group and others show that T cells in AD patients and aged individuals are clonally expanded and upregulate genes related to inflammation, cytotoxicity, and senescence. We have found that TSC22D3, a putative anti‐inflammatory transcription factor, is upregulated in brain‐infiltrating CD8+ T cells and found in gene co‐expression modules in peripheral blood from AD patients.

Method

We are pursuing the mechanism of TSC22D3 function and its effect on T cell biology and AD neuropathology. We have generated mice that lack TSC22D3 in CD8 T cells on the 5XFAD background, a mouse model of AD. We used flow cytometry to measure populations of various immune cell subtypes, and sort T cell subtypes for downstream sequencing. We are also using immunocytochemistry to quantify markers of amyloid and tau pathology, microglial interaction with amyloid plaque, and neuronal and synaptic loss in the hippocampus. Finally, we are examining the induction of immune reactions to amyloid and tau protein in TSC22D3 conditional knockout mice without AD transgenes.

Result

In human tissue, TSC22D3 is highly expressed in brain‐infiltrating CD8+ T cells along with genes associated with a senescent, late‐differentiation phenotype. Flow cytometry analysis showed that late‐stage AD mouse splenocytes bore significantly higher percentages of dendritic cells and various cytokines in CD4+ T cells than non‐AD or younger AD mice. Most of these differences were independent of TSC22D3 conditional knockout status. Ongoing bulk sequencing may reveal TSC22D3‐dependent changes in T cell gene expression, with effects on key markers of AD progression in the hippocampus.

Conclusion

TSC22D3 is known to directly suppress NFkB and other pro‐inflammatory mediators. Its co‐expression with more pro‐inflammatory and cytotoxic genes in brain‐infiltrating CD8+ T cells may represent a compensatory mechanism in the face of neuroinflammation related to aging and AD. We expect that knockout of TSC22D3 in CD8+ T cells will increase expression of pro‐inflammatory genes in T cell subsets, and will manifest in advanced AD pathology in older adult mice.
Effect of Cognitive Decline on Facial Appearance Revealed by Artificial Intelligence
Authors: Kameyama Masashi , Kameyama Yumi Umeda , Iizuka Tomomichi , Ogawa Sumito , Iijima Katsuya , Akishita Masahiro , Toba Kenji
Published: December 2022

Background

We have demonstrated that Cognitive function has a stronger correlation with perceived age than with chronological age (Umeda‐Kameyama et al. 2020). Based on this study, we hypothesized that cognitive decline appears in one's face, and have demonstrated the possibility of artificial intelligence to detect cognitive decline using a facial photography (Umeda‐Kameyama et al. 2021). Perceived age can be a useful biomarker in the geriatric field, however it requires many specialists' judgement. We aimed to determine if artificial intelligence can produce reliable perceived age easily.

Method

AI perceived age was acquired with Microsoft azure face API.

Result

AI perceived age showed significant correlation with chronological age and perceived age judged by human. AI perceived age and chronological age showed significant correlation with MMSE in female and total, however,the difference was not significant. A logistic multiple regression analysis showed larger standardized partial correlation coefficient with chronological age than AI perceived age.

Conclusion

The failure to show the superiority of AI perceived age over perceived age by human may be attributable to the weakness of azure system in old people and Asian ethnicity.
Naturally Derived Rho‐kinase 2 Inhibitors Acting as Mitophagy Inducer: A Novel Therapeutic Approach for Alzheimer’s Disease
Authors: Mani Shalini
Published: December 2022

Background

The aged and damaged mitochondria are removed through a selective mode of autophagy called mitophagy. The mitophagy may be triggered mainly via Parkin‐dependent and Parkin‐independent pathways. However, in different pathological conditions, this process is impaired in neuronal cells and lead to a variety of neurodegenerative disease (NDD) including Alzheimer Disease (AD). In case of AD, the pathological conditions such as accumulation of amyloid beta plaques and neurofibrillary tangles are also reported to inhibit the clearance of damaged mitochondria via the process of mitophagy. Hence triggering the mitophagy may be a promising therapeutic approach for the management of such conditions. In light of the significant role of impaired mitophagy in AD, further studies have also investigated the regulatory pathways/ protein involved in triggering mitophagy. Consequently, in the recent past Rho‐kinase 2 (ROCK) in suggested to negatively regulate the Parkin‐dependent mitophagy pathway in neuronal cells. Thus, inhibition of ROCK protein may trigger mitophagy in the treated cells and may alleviate the pathological conditions. Several synthetic compounds are studied for their ROCK2 inhibiting ability, but due to their side effects; immense attention is being diverted towards the use of natural compounds. We explored the ROCK2‐targeting ability of phytocompounds from the 7 medicinal plants (Allium sativum, Camellia sinensis, Centella asiatica, Nelumbo nucifera, Punica granatun, Rosmarinus officinalis and Triticum aestivum) used as neuro‐tonic.

Material & Methods

Selected 350 phytocompounds and y‐27632 dihydrochloride (control) were docked against ROCK2 using GLIDE (Schrödinger). Drug‐likeness and ADMET properties were predicted using Molinspiration and ADMETlab, respectively. Selected phytocompounds were also checked for their toxicity using ProTox‐II. Following these results, Molecular dynamics and simulation (MDS) using GROMACS, were performed for the selected phytocompounds.

Results

Based upon the free energy, toxicity analysis, and drug likeliness predictions, 11 phytocompounds were selected. MDS (100ns) showed mean RMSD for ROCK2‐Isoscutellarein (1.12nm) and ROCK2‐Epicatechin (2.42nm), indicating these may tightly bind with ROCK2 in a stable conformation. Isoscutellarein and Epicatechin also showed a toxicity score of 6 and 5, respectively, indicating their safe usage.

Conclusion

Isoscutellarein and Epicatechin, may behave as a potential inhibitor of ROCK2 and hence may trigger mitophagy in neuronal cells.
Poorer dexterity is associated with underlying Alzheimer’s disease brain pathology
Authors: Gupta Lily Eliza , Kohli Akshay , Oh Jennifer M. , Yang Kao Lee , Betthauser Tobey J , Chin Nathaniel A. , Nair Veena A. , Prabhakaran Vivek , Okonkwo Ozioma C. , Li Shi‐Jiang , Bendlin Barbara B.
Published: December 2022

Background

There has been increasing recognition for the decline of motor function in Alzheimer’s disease (AD) progression and its substantial role in disease morbidity. However, less is known about regional pathology burden—including amyloid‐β and tau protein deposition and cortical trophy—and its relationship to motor performance. Here investigate this relationship using standardized motor function assessment tools.

Method

Participants along a control‐to‐impaired continuum were enrolled in the Alzheimer’s Disease Connectome Project and underwent T1‐weighted MRI (N=206), with a subset undergoing [C‐11]PiB (N=61) and [F‐18 ]Flortaucipir PET (N=58) (Table 1) imaging for amyloid and tau pathology, respectively. T1‐weighted scans were processed using Freesurfer to estimate regional cortical thickness. [C‐11]PiB distribution volume ratios (DVR; cerebellar GM reference region) and [F‐18] Flortaucipir standardized uptake value ratios (SUVr; inferior cerebellar GM reference region) were assessed. Regions of interest (ROI) for analysis included the parahippocampal, entorhinal, motor, and frontal regions. Motor function was assessed utilizing NIH toolbox tests including the 2‐minute walking, 9‐hole pegboard dexterity, and dynamometer grip strength assessments. Motor performance was analyzed using participants uncorrected standardized scores. Scores were collected from participant‐reported dominant hand assessments. Multiple linear regression models tested relationships between AD biomarker burden and motor performance while controlling for age and sex of participants.

Result

Increased amyloid‐β (β‐0.42, p‐value: <0.05) and tau (β: ‐0.53, p‐value: <0.05) burden in primary motor cortices were associated with worse dexterity scores independent of age and sex. Grip strength did not show a significant correlation to cortical amyloid‐β (β: ‐0.14, p‐value 0.33) or tau burden (β: 0.23, p‐value: 0.36). Higher cortical thickness in primary motor regions were associated with higher dexterity (β: 0.21, p‐value <0.0001) and 2‐minute walking scores (β: 0.24, p‐value <0.001). When controlling for age and sex, grip strength predicted decreasing cortical thickness (β: 0.01, p‐value: <0.001) (Table 2).

Conclusion

Lower dexterity performance may be driven by elevated AD pathological burden and cortical thinning in cortical motor regions. Further research into motor performance and clinical disease manifestation is needed to determine the diagnostic utility of fine motor assessment as a predictor of motor decline in individuals with Alzheimer’s disease pathology.
Multi‐modal inadvertent signals enabling the capture of the learning process in real‐time. A new opportunity for preclinical intervention?
Authors: Penney Dana L , Sarkar Sarbari , Davis Randall
Published: December 2022

Background

Gold standard episodic memory tests used to detect AD‐related cognitive decline are insensitive to subjective cognitive decline evident in preclinical AD. We believe a breakdown in the healthy learning process may be a cornerstone in preclinical AD cognitive impairment. We demonstrate the ability to capture the learning process in real‐time using strategic test design, inadvertent eye‐movements and digital ink behavior. We show early evidence of previously unseen learning strategies using data from three participants.

Method

We used the Digital Symbol Digit Learning Test (dSDLT) that we designed to explore learning. One condition presents a key that pairs elementary geometric symbols with numbers and a section of symbols alone, and is administered twice. The participant writes the appropriate digit beneath each symbol using a digitizing pen (providing time‐stamped digital ink coordinates) while wearing a lightweight PupilLabs eye‐tracker (permitting unconstrained head movement, reporting gaze position 240 times/sec to ±2 mm). Time‐synchronized signals measure gaze time in the key. Heat maps show fixation points in the key and response boxes.

Result

Figure 1 shows gaze time in the key for each administration (by item, in sequence for one subject), revealing no time in key for some items and less total time in the key for the second administration. We interpret no time in key as paired‐learning. Fixation heat maps showed an expected gaze pattern of looking from the stimulus symbol up to and scanning the key. Unexpected gaze patterns also emerged: Targeted gazes from the stimulus symbol directly to the corresponding symbol in the key, Figure 2, (suggesting spatial placement learning); Within‐key symbol comparisons, indicated by looking back‐and‐forth between items, suggesting figure discrimination learning (Figure3); and Referring back to a recently completed response box containing the same symbol, suggesting working memory (Figure 4).

Conclusion

Multimodal behavior capture combining inadvertent eye‐tracking signals with digital ink enables the capture of real‐time learning and provides insights into what participants are thinking in addition to what they are doing. The identification of unexpectedly rich, previously unseen learning behaviors provides a glimpse of the complex healthy learning process, provides opportunity to identify strategies heralding preclinical AD and potential preclinical intervention targets.
PCBrainAge: A Brain‐Specific AD‐Associated DNA Methylation Clock
Authors: Thrush Kyra , Markov Yaroslav , Higgins‐Chen Albert , Morgan Levine
Published: December 2022

Background

Our group previously developed PCBrainAge, a novel predictor of brain tissue measured DNA methylation (DNAm) aging. We find that this predictor is correlated with a variety of components of Alzheimer’s disease (AD), including neuropathological criterion, clinical diagnoses, and APOE ε4 carrier status.

Method

We collected publicly available paired blood and brain tissue DNAm from cohorts annotated with AD diagnostic criterion. This includes the gene expression omnibus (GEO) dataset GSE59685 (n = 48). Where possible, we elected to compare blood measures to cortical measures due to the training parameters of PCBrainAge. PCBrainAge scores were calculated: In brief, PCBrainAge uses our method of principal component projection as defined by the original training datasets, followed by pretrained weighted regression to provide a single valued age prediction for the sample of interest. PCBrainAge was calculated and its acceleration, as an age residual, was determined separately for blood and brain samples.

Result

While PCBrainAge Acceleration retains our previously discussed significant difference between AD and control samples in brain, it does not demonstrate any such distinction in blood tissue. We find that the principal components selected for regression in the PCBrainAge model training most highly weight CpGs that tend to be associated with brain specific pathways and development.

Conclusion

Therefore, despite recent evidence supporting systemic changes or even pathogenesis of AD, PCBrainAge capture of neuropathological changes and elevated AD risk associated with APOE ε4 carrier status appears reliant upon brain‐specific DNAm. This indicates that PCBrainAge has the most potential to be used as an investigative tool to track stages of AD development and interrogate underlying molecular changes. However, more work must be done to generate a harmonized brain and blood clock that captures neuropathology and disease to PCBrainAge’s current extent.
A randomized, placebo‐controlled, double‐blind, Phase 1b study to evaluate the safety, tolerability and pharmacodynamics of PRI‐002 in early AD
Authors: Peters Oliver , Cosma Nicoleta Carmen , Kutzsche Janine , Willbold Dieter
Published: December 2022

Background

PRI‐002 is an all‐D‐enantiomeric peptide developed to disassemble Abeta oligomers, which has shown to improve cognition in animal models and which has demonstrated its safety profile in healthy young volunteers (Kutzsche et al. 2020).

Method

20 AD patients in early disease stages fulfilling the ATN‐criteria were recruited to participate in a single center, randomized, placebo –controlled, double‐blind study. Patients received once daily oral doses of 300 mg PRI‐002 or placebo for 28 days. Safety and efficacy assessments were executed at baseline, day 14, day 28 and day 56 (follow up). Blood sampling was carried out at each time point, EEG and CSF measurements before and at the end of treatment. Imaging (MRI) and functional tests (CERAD, CDR) were performed in parallel to EEG/CSF and additionally at follow up.

Result

10 patients (age 76.9±3.4, MMSE 28±1.6) received placebo and 9 patients PRI‐002 (72.4±6.9, 27.2±2.9). One patient withdraw informed consent before treatment was started. 13 patients reported in total 27 adverse events while no serious adverse event was noted. There was no statistical difference regarding adverse events between treatment and placebo. EEG and MRI revealed no changes after treatment. While no significant changes were detected in p‐TAU, Abeta1‐42 and Abeta oligomers in CSF before and after treatment, patients receiving PRI‐002 significantly performed better than those receiving placebo in the CERAD word list at follow up (p≤0.05).

Conclusion

PRI‐002 showed an excellent safety profile in AD patients. While no biomarker changes were detected after 4 weeks of treatment interestingly, an improvement of memory function was noted at follow up. A phase 2 study is scheduled.

Kutzsche J, Jürgens D, Willuweit A, Adermann K, Fuchs C, Simons S, Windisch M, Hümpel M, Rossberg W, Wolzt M, Willbold D. Safety and pharmacokinetics of the orally available antiprionic compound PRI‐002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020 Mar 20;6(1):e12001. https://doi.org/10.1002/trc2.12001.
Reduced density of cholinergic fibers in App knock‐in mouse models of Aβ amyloidosis
Authors: Hirota Yu , Sakakibara Yasufumi , Ibaraki Kyoko , Takei Kimi , Nishijima Risa , Iijima Koichi M. , Sekiya Michiko
Published: December 2022

Background

Cholinergic system is critical for learning, memory, attention, and other cognitive functions. Nucleus basalis of Meynert (NBM) is a nucleus containing the cell bodies of cholinergic neurons in the brain and is severely affected by Alzheimer’s disease (AD). Significant loss of forebrain cholinergic projections is evident at prodromal stage of AD, and, along with locus coeruleus (LC), NBM neurons are among the first to display neurofibrillary tangle, suggesting that abnormality in cholinergic system is involved in the early stage of AD pathogenesis. Acetylcholinesterase inhibitors have been used for symptomatic treatment to improve cognitive function, however, mechanisms underlying neurodegeneration in cholinergic system remain elusive. We have previously reported that AppNL‐G‐F
mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited cognitive deficits, severe neuroinflammation and significant loss of LC noradrenergic fibers accompanied by massive amyloid‐β (Aβ) pathology. In this study, we asked whether and how cholinergic system is altered in AppNL‐G‐F
mice.

Method

To ask whether AppNL‐G‐F
mice exhibit cholinergic degeneration, we compared the density of vesicular acetylcholine transporter (VAChT)‐positive fibers in the cortex and hippocampus as well as the number of choline acetyltransferase (ChAT)‐positive neurons in the NBM between AppNL‐G‐F
and wild‐type (WT) C57BL/6J mice at 24 months of age. We also examined whether tau pathology occurs in the cholinergic system in these mice.

Result

Histochemical analyses revealed that 24‐month‐old AppNL‐G‐F
mice exhibited significant decreases in the density of VAChT‐positive fibers in the cortex and the hippocampal CA1, the regions associated with learning and memory, compared to WT mice.

Conclusion

This study demonstrates that Aβ pathology is sufficient to reduce the density of cholinergic fibers. Quantitative analyses of cell loss and tau accumulation in ChAT‐positive neurons in the NBM are currently underway, and we will present these results at the meeting.
Interactions between apolipoprotein E, sex, and amyloid‐beta on cerebrospinal fluid p‐tau levels in the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS)
Authors: Saunders Tyler S , Jenkins Natalie D , Blennow Kaj , Ritchie Craig W. , Muniz Terrera Graciela , Muniz Graciela
Published: December 2022

Background

Alzheimer’s Disease, the leading cause of dementia, is over‐represented in females. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late‐onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid‐β (Aβ). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed.

Method

We aimed to examine the association between sex, APOE ε4 status, CSF Aβ on t‐tau and p‐tau in 1776 mid‐to‐late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer’s Dementia (EPAD) longitudinal cohort study.

Result

We found a significant interaction between APOE status, sex, and CSF Aβ on CSF p‐tau levels. Specifically, the association between CSF Aβ and CSF p‐tau was stronger in male ε4 carriers relative to female ε4 carriers. Further, in females with high Aβ levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p‐tau levels relative to non‐carriers. However, there were no significant differences in p‐tau between male ε4 carriers and non‐carriers with high Aβ.

Conclusion

An interaction between sex and cerebrospinal fluid Aβ may mediate the relationship between APOE status and CSF p‐tau. These data suggest tau accumulation may be independent of Aβ in females, but not males. Future work would benefit from replication in separate cohorts, longitudinal examination, and the consideration of the role of sex hormones on CSF markers.
Loneliness and subjective cognitive impairment in preclinical Alzheimer’s disease and healthy aging
Authors: Harrington Karra D , Roque Nelson A , Strenger Jennifer , Correia Stephen , Salloway Stephen P. , Sliwinski Martin J. , Thompson Louisa I
Published: December 2022

Background

Loneliness is associated with increased dementia risk, and greater amyloid‐β (Aβ) and tau accumulation in cognitively normal older adults. However, the potential for loneliness to influence cognitive dysfunction during the preclinical disease stage has not yet been examined. Subjective cognitive complaints are an early indicator of cognitive dysfunction in Alzheimer’s disease, and may provide a sensitive endpoint to evaluate the influence of loneliness during the preclinical disease stage. This study evaluated the relationships between loneliness, subjective cognition, and Aβ status in cognitively unimpaired older adults.

Method

Participants were 112 older adults aged 60–81 years (68% female, 89% White) recruited from the Butler Hospital Alzheimer’s Prevention Registry (BAPR). A cut off score of ≥34 on a modified Telephone Interview for Cognitive Status (TICSm) was used to establish unimpaired cognition. All participants completed the 3‐item version of the UCLA Loneliness Scale and the Cognitive Function Index (CFI) to assess loneliness and subjective cognition respectively. At the time of this analysis, a subsample (n = 63) had also undergone PET neuroimaging for classification of Aß status, of which 40% were classified as Aß+.

Result

Of the total sample, 28% reported mild‐moderate levels of loneliness, and another 8% reported severe loneliness. Subjective cognitive function was significantly associated with loneliness group, H(2) = 6.66, p = .036, with post hoc analyses indicating a significant trend for subjective cognitive complaints to increase with loneliness severity. Among the PET subsample, there was no significant difference observed between Aß groups in level of loneliness (p = .754) or subjective cognition (p = .852). However, there was a significant association between Aß status and loneliness group (p = .023), with Aß+ individuals being more likely to a be severely lonely (12%, n = 3) relative to the Aß‐ group (0%, n = 0).

Conclusion

The results of this study highlight the potential for loneliness to be involved in the preclinical stages of AD by demonstrating associations with both subjective cognitive function and Aß status. Prospective investigations are needed to further disentangle whether loneliness may be an indicator of, or a risk factor for, emerging disease.
Bacteroides genus is associated with lower executive function in cognitively unimpaired participants
Authors: Forst Allison A , Heston Margo B. , González Antonio , Chin Nathaniel A. , Przybelski Robert J , Johnson Sterling C. , Asthana Sanjay , Knight Rob , Kaddurah‐Daouk Rima , Rey Federico E. , Bendlin Barbara B.
Published: December 2022

Background

Vitamin B1, B6, and B12 deficiencies are associated with increased prevalence of dementia due to Alzheimer’s disease (AD). Clinical trials suggest that vitamin supplementation may improve cognitive function, however the mechanisms that link these factors remain unknown. A site of vitamin metabolism and synthesis is the gut microbiome, which is compositionally altered in AD. The gut microbiota’s role in perpetuating vitamin deficiencies and subsequent cognitive decline is unclear, so here we tested the hypothesis that lower abundances of vitamin B‐modulating microbes are linked to lower cognitive testing scores.

Method

211 cognitively unimpaired participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention (Table 1). Stool samples were collected at home and returned chilled, and 16S rRNA sequencing was performed to characterize gut microbiome composition. QIIME2 was used to denoise (deblur) and classify features, and phyloseq (R) was used to filter rare taxa, compute relative abundances, and agglomerate at genus rank. Literature review was used to select 10 microbial genera which synthesize/metabolize B vitamins (Table 2). The Rey Auditory Verbal Learning Test (RAVLT) long‐delay recall score and Trail Making Test (TMT) B (number‐letter switching) examined verbal memory and executive function, respectively. Multiple linear regression was conducted on each cognitive outcome to test microbial associations.

Result

Higher relative abundance of the B vitamin‐synthesizing genus Bacteroides was associated with greater time to complete the TMT B. This remained significant after controlling for covariates of participant age, sex, and years of education (Table 3). No other genera were significantly associated with either the TMT B or RAVLT scores.

Conclusion

In a cognitively unimpaired participant group, Bacteroides was correlated with lower performance on an executive function task. This genus was previously identified as elevated in people with AD and mild cognitive impairment; this study, therefore, indicates a relationship between Bacteroides and executive function even before cognitive decline. Bacteroides species are also linked to inflammation, which may explain the results of the current study. Future work should examine how Bacteroides relates to both biomarkers of neuroinflammation and cognitive function in unimpaired participants.
Simultaneous Mass Spectrometric quantification of multiple p‐tau species in plasma – findings along the Alzheimer´s disease continuum
Authors: Montoliu‐Gaya Laia , Benedet Andréa Lessa , Brum Wagner Scheeren , Vrillon Agathe , Ashton Nicholas J. , Rodriguez Juan Lantero , Brinkmalm Gunnar , Nilsson Johanna , Karikari Thomas K , Kern Silke , Zetterberg Henrik , Paquet Claire , Rosa‐Neto Pedro , Gobom Johan , Blennow Kaj
Published: December 2022

Background

Blood phosphorylated tau (p‐tau) species at positions 181, 217 and 231 have been demonstrated accurate biomarkers of Alzheimer´s disease pathology. Comparisons to assess the performance of each phosphorylation along the Alzheimer´s disease (AD) continuum rely on the use of different immunoassays. In the current study, we simultaneously quantified the plasma concentration of six different phosphorylated (p‐tau 181, 199, 202, 205, 217 and 231), and two non‐phosphorylated, tau peptides using a targeted Mass Spectrometric (MS) method.

Method

We analysed a total of 224 samples from two centres, the TRIAD cohort (Canada) and the BioCogBank Paris Lariboisière cohort (France). Tau enrichment prior to MS analysis was performed by immunoprecipitation, using a combination of several non‐phospho‐tau antibodies, followed by tryptic digestion. A parallel reaction monitoring method with Orbitrap MS was used to measure the levels of targeted peptides. Group‐level comparisons were carried with non‐parametric tests. Cross‐sectional associations between plasma tau biomarkers and Aβ and tau PET were investigated using the locally estimated scatterplot smoothing (LOESS) method for local polynomial regression. Voxel‐wise correlations were performed between plasma and PET biomarkers using Rminc.

Result

P‐tau231 levels were significantly increased in amyloid positive and tau negative (A+T‐) individuals compared to A‐T‐ (stratified by CSF biomarkers). Increases in p‐tau217 and p‐tau205 emerged later in the AD continuum, only when tau pathology was present (A+T+). Plasma p‐tau217, p‐tau231 and p‐tau205 were the site‐specific phosphorylations that showed higher correlations with Tau PET (Braak I‐VI) (R=0.7 p<0.0001; R=0.53 p<0.0001; and R=0.53 p<0.0001; respectively) and with Aβ PET (R=0.66 p<0.0001; R=0.56 p<0.0001; R=0.45 p<0.0001, respectively). LOESS analysis revealed that plasma p‐tau231 increases earlier in the disease progression, followed by p‐tau217 and p‐tau205, which showed a progressive increase along Braak stages and amyloid centiloid. Voxel‐wise analysis for tau PET were highest with p‐tau205 with associations in in the inferior, medial, and lateral temporal regions. For Aβ PET, p‐tau217 and p‐tau205 showed the highest associations with frontal, precuneus, posterior cingulate and temporal cortices.

Conclusion

Our results indicate that plasma p‐tau217, p‐tau231 and p‐tau205 are the site‐specific phosphorylations that better reflect amyloid and tau pathologies, although with different emergence along the AD continuum.
Tau protein profiling across brain of different tauopathies using high‐resolution mass spectrometry: quantification of isoforms and phosphorylations
Authors: Camporesi Elena , Rodriguez Juan Lantero , Montoliu‐Gaya Laia , Fox Nick C , Lashley Tammaryn , Zetterberg Henrik , Blennow Kaj , Brinkmalm Gunnar
Published: December 2022

Background

The abnormal accumulation of the microtubule‐associated protein tau in the brain is the main contributing factor of a group of diseases called tauopathies, including Alzheimer’s disease (AD). Due to similarities, it is currently problematic to chemically characterize the tau pathology in these diseases. Our aim was to develop a multiplex assay to detect and quantify isoform‐specific peptides and phospho‐tau species in brain of different tauopathies, possibly holding disease‐specificity.

Method

Frontal cortices from AD (n = 10), progressive supranuclear palsy (PSP, n = 11), Pick’s disease (PiD, n = 10), corticobasal degeneration (CBD, n = 10) and controls (n = 10) were processed to obtain a soluble (tris‐buffered saline, TBS) and a sarkosyl‐insoluble (SI) fraction. Fractions were immunoprecipitated using antibodies targeting all four tau regions. Tryptic peptides corresponding to isoforms and peptides carrying one, two or three phosphorylations were monitored by liquid chromatography/high‐resolution mass spectrometry, using isotope‐labelled protein and phospho‐peptide standards for quantification.

Result

In all samples, the 0N and 1N tau isoforms were most abundant. In the AD group we observed an increase of the 0N isoform in the SI fraction. The SI fraction also showed the 3R/4R isoform predominance characteristic of the different tauopathies, with the 3R being more abundant in PiD, 4R in PSP and CBD, while in AD and controls they had similar abundance. Further, in the SI fraction, peptides from the microtubule‐binding region (MTBR) were markedly more abundant in AD, indicating aggregation of these species (Fig.1). Compared to the TBS fractions, the SI fraction was enriched in double and triple‐phospho peptides (example in Fig.2), which were markedly increased in the AD group as compared to the other non‐AD tauopathies or the control.

Conclusion

The novel assay here developed can identify isoform differences across tauopathies. The parallel investigation of TBS and SI fractions showed higher abundancy of phosphorylations and MTBR region in the SI fraction, possibly reflecting this fraction to contain an interphase between small aggregates and immunohistochemical inclusions. While the measurement of multiply phosphorylated peptides could clearly differentiate AD from the other tauopathies, none of them could discriminate between the non‐AD tauopathies. This further indicate that multiply phosphorylated peptides are highly disease relevant species for AD.
Alzheimer’s Disease risk gene SORL1 affects synaptic function in hiPSC‐derived cortical neurons
Authors: Williams Charles A , Knupp Allison , Mishra Swati , Young Jessica E.
Published: December 2022

Background

The cellular endo‐lysosomal network (ELN) is implicated in Alzheimer’s Disease pathology and Sortilin‐related receptor 1 (SORL1) is important for normal function of the neuronal ELN. Loss of SORL1 in human induced pluripotent stem cell (hiPSC) derived neurons replicates early AD cytopathology, such as enlarged early endosomes. Work in our laboratory has shown that SORL1 deficiency results in decreased cell‐surface expression of glutamate receptor subunit GLUR1 and neurotrophic receptor TRKB. RNAseq of SORL1 deficient neurons revealed alterations in synaptic‐associated gene ontology transcripts. Together, these data implicate a potential functional consequence for SORL1 deletion. Here we investigate the impact of SORL1 on hiPSC‐derived neuronal synaptic function.

Method

Neuronal cultures were differentiated using dual SMAD inhibition of previously generated wild‐type and SORL1 deficient hiPSCs. Following differentiation, neuronal cultures were either purified using cell surface markers CD44, CD184, and CD271 or passaged as mixed cultures for immunocytochemical (ICC) or electrophysiological experiments, respectively. For ICC, neurons were then fixed with paraformaldehyde and stained with experiment‐appropriate antibodies before imaging on a confocal scanning microscope. Mixed cultures were plated onto Axion Biosystems multiple electrode array (MEA) culture plates for electrophysiological analysis. MEA cultures were recorded twice a week for up to ten weeks post‐plating. Recordings and analysis were performed using Axion Biosystems Maestro Pro system.

Result

Using ICC, we find alterations in alterations in synaptic protein and glutamate receptor co‐localization in SORL1 deficient neuronal cultures. When cultured on MEA plates, wild‐type and SORL1 deficient neuronal cultures are active and robust. Neuronal cultures develop glutamate signaling dependent patterns of activity, or network bursting. Neural firing rates are increased in SORL1 deficient neurons. Network bursting properties in SORL1 deficient are altered in comparison to wild‐type cultures, consistent with increased neural excitability.

Conclusion

Loss of SORL1 alters hiPSC‐derived neuronal activity and synapse‐dependent activity. Further investigation is warranted into the alterations in neuronal physiology and will help us understand the role AD‐related ELN disruption plays in synaptic pathologies.
Brain‐targeted N‐Acetyl Cysteine‐loaded nanoparticle for AD treatment
Authors: Xu Peisheng , Wang Mingming
Published: December 2022

Background

The microglia activation‐induced neuroinflammation is one potential cause of Alzheimer’s disease (AD). N‐Acetyl cysteine (NAC), which has anti‐oxidant and anti‐inflammatory effects, has been extensively explored for the treatment of of AD. However, its therapeutic efficacy for AD is limited due to the existence of the blood‐brain barrier (BBB).

Method

To facilitate NAC cross the BBB, a brain‐targeted NAC‐loaded nanoparticle (BTN‐NAC) has been developed. The brain‐targeting efficacy and therapeutic efficacy of BTN‐NAC were evaluated in a 5xFAD transgenic mouse model through nest construction assay and Morris water maze test.

Result

In vivo study revealed that BTN‐NAC could effectively cross the BBB of AD mice. Nest construction assay found that BTN‐NAC treated AD mice exhibited better nesting score than free NAC and control treated mice. In addition, BTN‐NAC treatment significantly improved the learning and cognitive skills of AD mice. Immunohistochemical staining confirmed that BTN‐NAC effectively inhibited the activation of microglia in the brain and attenuated the deposition of Aβ plaques in the hippocampus.

Conclusion

BTN‐NAC can effectively cross the BBB, prevent the activation of microglia, and attenuate Aβ burden in the brain of AD mice. Consequently, BTN‐NAC slows down the progress of AD. Therefore, BTN‐NAC could be safe and effective tool for the treatment of AD.
Modifiable Risk Factors and Explainable Machine Learning Model for Predicting Hospitalization Outcomes in Geriatric Patients with Dementia
Authors: Wang Xin
Published: December 2022

Background

Geriatric patients with dementia incur higher healthcare costs and longer hospital stays than other geriatric patients. There is an urgent need to identify modifiable risk factors and develop predictive models for hospitalization outcomes in order to mitigate risks early on during hospitalization, thus improving outcomes and the quality of life in these patients.

Method

Over 150 clinical and demographic factors of 15,678 elderly patient encounters and 8,407 distinct elderly patients with dementia (January 2010 – December 2019) were retrieved from our hospital clinical data warehouse. We categorized demented geriatric patients into four categories: Alzheimer’s disease dementia, with 4,993 patients encounters; vascular dementia, with 3,735 encounters; Parkinson’s disease with dementia, with 4,173 encounters; and other unspecified dementias, with 2,777 encounters. We narrowed the risk factors down to twenty using analysis of variance (ANOVA) and Glmnet regressive selection. We developed a stacking ensemble tree model using the twenty engineered features to predict hospitalization outcomes defined by hospital stays and discharge dispositions, followed by implementing SHAP (Shapley Additive Explanations) explainable artificial intelligence algorithm to increase the model transparency by ranking the importance of the risk factors.

Result

Our stacking ensemble learning model achieved a cross‐validated performance AUC of 0.757 (95% CI, 0.752‐0.762) on patients with Alzheimer’s disease, 0.658 (95% CI, 0.656‐0.660) on vascular dementia, and 0.664 (95% CI, 0.660‐0.668) on Parkinson’s disease with dementia. The model outperforms the prevalent baseline models, including logistic regression and multilayer perceptron neural networks in identifying hospitalization outcomes of demented geriatric patients across the patient cohorts with Alzheimer’s disease, vascular dementia, Parkinson’s disease with dementia, and other unspecified dementias.

Conclusion

In this study, our explainable machine learning model achieved good accuracy across the four types of dementia patients with well‐defined risk factors. This predictive model will be invaluable in allocating scarce hospital resource for timely interventions on high‐risk demented geriatric patients. Our ongoing study is investigating lateral associations between the risk factors across the four types of dementia, focusing on the modifiable risk factors that can be implemented upon admission and designing a prospective randomized study for hospitalized geriatric patients with cognitive decline.